Navigating Pompe Disease Assessment: A Comprehensive Scoping Review

Navigating Pompe Disease Assessment: A Comprehensive Scoping Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Navigating Pompe Disease Assessment: A Comprehensive Scoping Review Israel Davila Rivera, Letícia Nunes Campos, Daiana M. Ibañez Alegre, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3909349/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Pompe Disease (PD) is a rare progressive autosomal recessive disorder resulting from deficient acid alpha-glucosidase (GAA) enzyme activity, necessitating timely identification and management. This scoping review aimed to synthesize the evidence regarding assessment methods for screening, diagnosing, and following up PD. Methods and Results We searched citations in English and Spanish published from 2017 until February 8, 2022, across 11 databases. We included primary studies, reviews, and guidelines that described at least one assessment method for patients with confirmed clinical, genetic, or biochemical PD. Screening and data extraction adhered to PRISMA-ScR. Data was summarized narratively and with descriptive statistics. After screening 2,139 citations, 96 met the eligibility criteria. Cross-sectional studies were the most prevalent design (28%), while guidelines were the least frequent (1%). Newborn screening availability varied among countries, despite its potential to improve PD prevalence estimations. Overall, 81 articles assessed clinical manifestations, with 47 focusing on late-onset PD. We identified considerable heterogeneity in reporting PD phenotypes. The use of dried blood spots for GAA enzyme deficiency detection was described in 18 articles, but reporting lacked standardization. Next-generation sequencing emerged as the gold standard for identifying mutated alleles. Monitoring strategies for pediatric and adult PD lacked consensus, and only one article assessed quality of life. Conclusion This scoping review summarized the evidence to comprehensively evaluate PD patients, emphasizing current practices and existing challenges that must be tackled to optimize screening, diagnosis, and follow-up of PD. Medical Genetics General Practice Glycogen Storage Disease Type II Cardiomyopathy Hypertrophic Lysosomal Storage Diseases Muscle Weakness Rare Diseases Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Pompe disease (PD), also known as glycogen storage disease type II (GSDII; ORPHA:365; ORPHA:308552; MONDO:0009290; MIM #232300 and MIM#606800) is a monogenic, autosomal recessive and progressive metabolic disorder caused by mutations in the acid alpha-glucosidase (GAA) gene located at 17q25.2–q25.3. 1,2 These mutations cause a deficient production of the GAA protein, leading to the lysosomal accumulation of glycogen in several tissues, particularly in skeletal and cardiac muscles as well as the nervous system. This process culminates in cellular dysfunction and muscle damage. 1,2 Until now, more than 600 mutations associated with the GAA gene have been identified. 3,4 Some mutations prevail among specific ethnic groups and geographic regions, such as c.-32-13T > G splice mutation in patients of Caucasian origin. 5 PD is generally divided into two groups depending on age onset, progression rate, severity, and organ involvement. The first is the infantile-onset PD (IOPD; ORPHA:308552), constituting the most severe phenotype with rapidly progressive hypertrophic cardiomyopathy and generalized muscle weakness at birth. Patients born with this phenotype commonly die within the first two years of life. 6 The second group is the late-onset PD (LOPD; ORPHA:420429), which includes childhood, juvenile, and adult-onset disease. Patients with LOPD have a GAA enzyme activity that ranges from 2–40% of the expected functionality compared to healthy individuals. LOPD presents with variable muscle involvement, progressive proximal muscle weakness, and respiratory insufficiency, whose onset varies from infancy to the sixth decade of life. 6,7 Although LOPD has a slower progression than IOPD, it eventually affects the diaphragm and accessory respiratory muscles. Therefore, patients with LOPD can present respiratory failure, the most prevalent cause of mortality in this phenotype. 8 Given the severity of this rare disease, its considerable impact on patient’s quality of life (QOL), and the availability of approved disease-modifying treatments, prompt diagnosis and management of PD are imperative. 9 However, identifying PD presents several challenges due to the wide range of phenotypes, limited awareness, and phenotype overlap with other neuromuscular disorders, such as limb-girdle muscular dystrophies. 9,10 We aimed to map and synthesize the available evidence concerning assessment methods to screen, diagnose, and follow up on patients with PD. Methods Study Design We registered our protocol at Open Science Framework and reported this study following the Preferred Reporting Items for Systematic reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR). 11,12 Our primary aim was to identify the existing methods to assess patients with PD worldwide. We interpreted “assessment” as learning about a patient’s condition. 13 This review considered methods to screen, diagnose, and follow up PD patients. Screening methods consisted of tests, exams, and procedures to identify diseases in a targeted population that is usually asymptomatic. 14 Diagnosing methods encompassed those to determine the nature of a condition or distinguish one from another. 15 Follow-up methods referred to those that assess long-term outcomes of PD. 16 Assessment methods included but were not limited to clinical manifestations, scales, questionnaires, indices as well as genetic, imaging, biochemical, and electrophysiological studies. Eligibility Criteria We considered articles that included patients who fulfilled clinical, genetic, or biochemical PD diagnostic criteria as previously described. 17,18 Table 1 describes the features that raise clinical suspicion of PD. We included human-based research articles that used qualitative or quantitative methods and examined methods to assess PD patients. No geographical restrictions were applied. Eligible articles were primary studies (i.e., case reports, case series, cross-sectional studies, case controls, cohorts, clinical trials, qualitative studies), reviews (i.e., narrative, scoping, and systematic reviews), and guidelines. We excluded editorials, commentaries, personal anecdotes, conference abstracts, books, studies targeting pharmacological and non-pharmacological interventions, animal studies, and in vitro studies. Table 1 Clinical features of Pompe Disease phenotypes Phenotype Infantile Onset Pompe Disease Late Onset Pompe Disease 1. Cardiovascular System: ● Cardiomegaly or hypertrophic cardiomyopathy 2. Musculoskeletal System: ● Rapidly progressive muscle weakness ● Hypotonia ● Delayed or not achieved rolling over, sitting up, and standing 3. Craniofacial Manifestations ● Large, protruding tongue 4. Nutritional and Gastrointestinal System ● Moderate enlargement of the liver ● Feeding and swallowing problems 5. Respiratory System: ● Respiratory dysfunction (combined or not with respiratory tract infections) 6.Nervous System: ● Hearing loss 1. Neuromuscular System: ● Progressive muscle weakness (limb-girdle, upper arms, upper legs) ● Muscle wasting ● Waist dystrophy ● Gait disorders ● Chewing and swallowing difficulties ● Drooping of the upper eyelids (ptosis) 2. Respiratory System: ● Dysfunction of the diaphragm and intercostal muscles ● Restrictive respiratory insufficiency/varying degrees of respiratory weakness 3. Cardiovascular System: ● Blood vessel abnormalities 4. Digestive System: ● Manifestations of digestive system 5. Urinary System: ● Manifestations of urinary system 6. Metabolic and Endocrine System: ● Idiopathic hyperkalemia 7. Connective Tissue and Joints: ● Idiopathic scoliosis 8. Rheumatological Manifestations ● Nonspecific chronic low back pain Information Sources, Search Strategy, and Citation Management A librarian (FFZ) conducted the search strategy at 11 databases: Cochrane Database of Systematic Reviews (John Wiley & Sons, Inc), Directory of Open Access Journals (DOAJ), Epistemonikos (Epistemonikos Foundation), Ingenta Connect (Ingenta), Medline/PubMed (National Library of Medicine, NCBI), SAGE (Sage Publications), SciELO Citation Index (Web of Science, Clarivate), ScienceDirect (Elsevier B.V.), Springer Link (Springer Nature Switzerland AG), Virtual Health Library (Latin American and Caribbean Center on Health Sciences Information, World Health Organization), and Wiley Online Library (John Wiley & Sons, Inc). The search strategy included articles published between 2017 and the search date on February 8, 2022. We included articles published in English and Spanish due to the research team’s language proficiency skills. Supplementary Table 1 provides the strategy per database. References were imported into the EndNote bibliography manager, and duplicated references were automatically purged by searching for simultaneous matches in the author, title, and year fields. 19 FFZ conducted an additional manual search to identify further duplicates. Results from the search strategy were exported as a Google Sheets spreadsheet. 20 Study Selection We screened eligible studies using a standardized Google Form to register reviewers’ decisions. 21 Before the screening, our team performed a calibration exercise with reviewers (IDR, DMIA, FNDPG, MGSJ). Reviewers independently screened a random sample of 20 citations from the search. The screening only commenced when reviewers reached an agreement percentage equal to or greater than 90%. After calibrating, the reviewers independently screened the articles’ titles and abstracts following the eligibility criteria. Next, reviewers screened the remaining studies based on full text. CFA and LNC solved discrepancies between reviewers. Charting and Extraction We developed a chart on Google Sheets to extract data for included articles. Two independent reviewers collected data from each citation. CFA solved any disagreements. We extracted the following data points: title, abstract, authors’ names, digital object identification (DOI), year of publication, language used for publication, study design, number of study participants, patients’ age estimate, sex distribution, and country; described assessment methods, category of assessment methods (e.g., clinical, imaging, genetic), study’s findings for each mentioned assessment method. We did not conduct any risk of bias assessment, which is a consistent approach with the scoping review methodology. 22,23 Synthesis of results We used frequencies and percentages to summarize the characteristics of the included studies. Quantitative and qualitative data from the studies were utilized as primary sources to describe the reported assessment methods for PD. A narrative summary of the findings was provided, along with tables and figures prepared using Microsoft Excel 365 (Microsoft Corporation, Redmond, WA). Results Literature search The literature search yielded 2,494 citations. After removing 355 duplicates, 2,139 articles underwent title and abstract screening. Among these, 470 articles underwent full-text screening. Overall, 96 articles met the eligibility criteria (Fig. 1 and Supplementary Table 2 ). Characteristics of Selected Articles Among the 96 selected articles, 83 (86%) citations were published between 2017 and 2019 (Fig. 2 ). Only three articles were published in Spanish. Most studies were conducted in the United States (13%, n = 14), Italy (10%, n = 11), Germany (9%, n = 10), and The Netherlands (6%, n = 7). Four studies examined patients from multiple countries: one assessed patients from Latin America and three from Europe ( Supplementary Table 2 ). In terms of regional representation, studies from South America, Oceania, and Central America accounted for only 7% (n = 8), 2% (n = 2), and 1% (n = 1) of selected articles, respectively (Figs. 3 and 4 ). Cross-sectional studies (31%, n = 30) were the most prevalent study design. In comparison, guidelines were the least frequent (1%, n = 1) (Fig. 5 ). Characteristics of the studied population Fifty-five percent of selected citations focused only on LOPD (n = 48) and 22% (n = 21) on IOPD. Articles reported the infantile phenotype using various terms, including IODP (n = 18), prenatal PD (n = 1), classic infantile PD (n = 2), and infantile PD (n = 1). Thirty-one percent (n = 27) of the studies focused on both IOPD and LOPD. Supplementary Table 2 provides additional details regarding inclusion criteria, number of patients, sex distribution, and estimated age per included article. Assessment methods Screening Of 96 selected articles, 11% (n = 11) described newborn screening (NBS). Among these, three studies were conducted in North America, three in Europe, and two in Asia. Only one study was conducted in a South American country, specifically Mexico. Four studies noted NBS programs as a mechanism to promote early diagnosis and treatment, especially for IOPD. Six articles cited NBS programs that detected various lysosomal diseases, including PD. One article provided guidance on determining appropriate patient management, monitoring, and the frequency and type of follow-up assessments for all patients identified through NBS ( Supplementary Table 2 ). 24 While implementing NBS was argued to improve the accuracy of PD’s prevalence, 25 other studies emphasized the need to closely monitor asymptomatic patients with abnormal NBS results for diagnosis. 26–30 Clinical presentation Overall, 84% (n = 81) assessed patients’ clinical status comprehensively. Most articles primarily focused on describing clinical manifestations of LOPD (n = 47), as individuals with this phenotype tend to have higher survival rates than IOPD. Furthermore, 16 articles reported manifestations of IOPD, and 18 citations discussed the clinical presentations of both PD subtypes. One article targeted genetic variants and used standardized terms and identification numbers from the Human Phenotype Ontology (HPO) to describe PD phenotypes. Table 2 shows the reported clinical manifestations per article. Table 2 Reported clinical manifestations for Infantile-onset Pompe Disease (IOPD) and Late-onset Pompe Disease (LOPD) PD phenotype Reported clinical manifestation # of articles Infantile-Onset Pompe Disease (IOPD) Growth Low body weight 2 Delay in development 1 Head & Neck Macroglossia 2 Weakness of and inability to control neck muscles 2 Dysarthria with nasal speech 1 Enlarged lips 1 Feeble cry 1 Swelling of gingiva 1 Eyes Imparied vision 1 Multi-directional nystagmus 1 Ptosis 1 Ears Hearing impairment 1 Cardiovascular System Hypertrophic cardiomyopathy / Severe infantile hypertrophic cardiomyopathy 7 Cardiomegaly 2 Cardiomyopathy 2 Arrhythmias (e.g., no sustained and sustained supraventricular tachycardia, atrial or ventricular premature beats, and ventricular tachycardia or fibrillation) 1 Cardiac failure 1 Cardiac murmur 1 Dilated cardiomyopathy (e.g., right atrial enlargement and biventricular hypertrophy) 1 Left ventricular thrombus based at the mitral valve 1 Mild ventricular dysfunction 1 Outflow tract obstruction 1 Reduced ejection fraction 1 Small ventricular lumen 1 Systolic bruit 1 Respiratory System Respiratory distress 4 Dyspnea 2 Recurrent airway infections / Recurring respiratory infections 2 Respiratory failure 2 Tachypnea 2 Inspiratory and expiratory muscle weakness 1 Obstructive sleep apnoea 1 Severe pneumonia 1 Digestive System Feeding difficulties in infancy, including breast feeding 3 Gastric reflux 1 Genitourinary System Urinary tract infection 1 Muscles & Limbs Hypotonia (including generalized, axial, and proximal) 7 Muscular weakness (including generalized and distal) 4 Motor retardation and paucity of movements 2 Hypo- or areflexia (e.g., decreased, or absent deep tendon reflex) 1 Nervous System Extra-axial cerebrospinal fluid accumulation 1 Gross and fine motor delay 1 Delays in speech and social skills 1 Ventricular enlargement 1 Unsteady gait 1 White matter abnormalities (e.g., supratentorial, infratentorial) 1 Miscellaneous Profound sweating 1 Late-Onset Pompe Disease (LOPD) Head & Neck Mild to severe neck flexion weakness 3 Chronic headache 1 Dysphonia 1 Severe mild facial weakness 1 Eyes Subnormal visuospatial functioning 1 Cardiovascular System Systemic hypertension 3 Episode of syncope 1 Respiratory System Dyspnea (including at rest, during and after exercise and other physical efforts) 11 Respiratory failure/insufficiency 5 Orthopnoea 4 Apneas (including sleep apnea hypopnea syndrome) 2 Impaired lung function 1 Nightime hypoventilation 1 Restrictive ventilatory deficiency 1 Recurrent respiratory tract infection 1 Digestive System Dysphagia (including regurgitation, swelling and feeding difficulties) 7 Diarrhea 3 Nausea and vomiting 3 Belly pain 1 Bowel incontinence 1 Constipation 1 Gas and bloating 1 Gastroesophageal reflux 1 Primary biliary cirrhosis 1 Genitourinary System Renal artery fibromuscular dysplasia 1 Stenosis of the left renal artery 1 Muscles and Limbs Progressive muscle weakness (including axial and proximal, in the upper and lower limbs) 21 Difficulties in rising from a seated and supine 5 Gait disturbances (e.g., subtle waddling gait, Trendelenburg gait, myopathic gait) 5 Myalgia (including fibromyalgia-like, exertional, and lower extremity myalgia) 5 Recurrent falls 5 Scapular winging 5 Difficulties to run 4 Generalized fatigue 4 Progressive difficulty in climbing stairs 4 Residual muscle weakness (e.g., in trunk, ptosis, myopathic facies, lumbar lordosis) 4 Lordosis (including lumbar hyperlordosis) 3 Walking difficulties (e.g., reduced cadence and speed) 3 Hypotrophy and atrophy (e.g., of shoulder girdle, pelvic girdle, and paravertebral muscles) 2 Muscle paralysis (e.g., diaphragmatic and tetraplegia) 2 Respiratory muscles impairment and weakness 2 Rigid spine / Rigid spine syndrome 2 Scoliosis 2 Acute low-back pain 1 Camptocormia of the lumbar muscles 1 Decreased lower limb muscle strength and power 1 Distal and proximal myopathy 1 Early deviations in skeletal muscle posture and movement 1 Global hyporeflexia 1 Increased thoracic and pelvic mobility (e.g., increased thoracic sway, hip adduction angles) 1 Left-sided scapula alata 1 Muscular exertion intolerance 1 Muscle aches and cramps 1 Thoracic hyperkyphosis 1 Vertebrobasilar dolichoectasia 1 Nervous System Delay and regression in gross motor skills 3 Sleep Disorders (including hypersomnia) 2 Acute cerebral stroke 1 Apathy 1 Delayed motor development 1 Biochemical Assays as Diagnostic Methods A total of 25 articles described biochemical, hematological, or biomarker studies ( Table 3 ). Dried blood spot (DBS) was the most commonly cited method (n = 18). This test can detect both partial and total decreases in GAA enzyme activity. 31–34 Other frequently reported tests included the quantification of serum creatinine kinase (sCK; n = 17), alanine aminotransferase (ALT; n = 6), aspartate aminotransferase (AST; n = 5), and urinary glucose tetrasaccharide (Glc4; n = 5) ( Table 3 ). These measurements were elevated levels in PD patients. In particular, CK and AST, primarily muscle-specific enzymes, were associated with muscle tissue damage or dysfunction. One article measured serum platelet-derived growth factor BB (PDGF-BB) and suggested its use to monitor asymptomatic LOPD patients based on findings indicating dysregulation of muscle regeneration as an additional pathological mechanism. 35 Genetic Studies as Confirmatory Diagnostic Test Out of 96 included articles, 21 (22%) had information regarding genetic variants within the GAA gene of PD patients. Most citations mentioned Sanger sequencing as the gold standard technique (n = 8; 38%) for detecting gene sequence variants. Three citations employed a combination of sequencing methods, including next-generation sequencing (NGS) followed by Sanger sequencing. 31,33,36 Only one paper mentioned the use of NGS deep sequencing as a primary technique to ascertain the genetic status of patients. Furthermore, one study discussed the utility of whole exome sequencing. 37 All 21 articles referred to databases to assess variant novelty and classified their pathogenicity: very severe, potentially less severe, less severe, potentially mild, presumably non-pathogenic, non-pathogenic, or of unknown significance. The consulted databases included ClinVar, Erasmus MC University Medical Center, Exome Aggregation Consortium, Genome Aggregation Database, Leiden Open Variation Database, and Human Genome Mutation Database. Supplementary Table 4 provides an overview of the extracted genetic information. Across the 21 articles, several variants were detected, with nonsense mutation being the most prevalent, followed by small deletions, including some in-frame deletions. Other variants included deletions, small insertions, and deletions (indels), and complex rearrangements. The most severe variants affected the catalytic domain of the GAA enzyme (exons 7–15). 38 Imaging Studies In total, 44 (15%) articles addressed imaging studies. Magnetic resonance imaging (MRI) was the most commonly employed (n = 31; 70%) and included assessments of the brain, muscles, heart, thoracic region, kidneys, and other anatomical areas. Ultrasound imaging was utilized in 30% (n = 13) of the articles to assess muscle, cardiac, pulmonary, and other structures. Only 11% (n = 5) and 9% (n = 4) of articles mentioned radiographic studies and computed tomography scans, respectively ( Table 3) . Electrophysiological and Functional Studies A total of 35 articles mentioned electrophysiological and functional studies in the primary clinical evaluation of patients with PD. Functional studies were the most frequently cited (89%, n = 53) among the articles devoted to phenotypic assessment. They were mostly focused on muscular (36%, n = 43) or respiratory (46%, n = 57) studies ( Table 3) . Thirteen (11%) articles exclusively mentioned electrophysiological studies where electromyography (EMG, n = 6) serves as a diagnostic indicator, detecting spontaneous activities such as fibrillations and positive sharp waves, along with the frequent occurrence of small, brief early recruiting potentials (myotonic discharges), especially in the paraspinal muscles. Electrocardiography (ECG) was also mentioned (n = 5), and the electroencephalogram was less frequent (n = 1). Scales and Questionnaires Forty-four studies included scales, with 38 (86%) reporting scales not specific to PD. Employed scales evaluated muscles (n = 25), respiratory system (n = 2), gastrointestinal system (n = 1), cognitive function (n = 3), and neurological disability (n = 2). Only two articles (5%) employed specialized scales, for instance, Pompe Disease Symptom Scale (PDSS) and Pompe Disease Impact Scale (PDIS). Furthermore, four articles cited questionnaires to evaluate neuromuscular, respiratory symptoms, and pain ( Table 3 ). Follow-up of Patients with Pompe Disease Throughout this review, we found that functional assessments (n = 107) are the most commonly utilized diagnostic tools. Functional monitoring encompasses various parameters, including muscle (n = 43), respiratory evaluation involving spirometry, the most mentioned (n = 51) among the selected articles, and other pulmonary function tests (PFT, n = 4), including the monitoring of respiratory distress or disturbance using polysomnography (n = 2). In the case of IOPD and progressive LOPD disease, the assessment of swallow function is imperative and should be conducted through serial evaluations. This approach enables the assessment of oropharyngeal muscle weakness and, when necessary, includes Video-Fluoroscopic Swallow Study (VFSS). 23 For those with LOPD, functional assessments are routinely carried out. 39,40 These assessments involve muscle strength measurements, comprehensive neuromuscular scales, and metabolic monitoring using quantitative muscle MRI (T1 weighted imaging) or the Dixon scale. Qualitative assessments cover posture, movement, musculoskeletal status, and standardized tests like the Alberta Infant Motor Scale (AIMS) and Gross Motor Function Measure (GMFM). Additionally, MRI has been recognized as a valuable tool for detecting muscle structure changes in symptomatic patients and can potentially be integrated into daily clinic follow-up protocols. It is worth noting that only one article referenced the use of INQoL as a patient-reported outcome measure. 41 Discussion This scoping review gathered 96 articles concerning assessment methods to screen, diagnose, and follow up with PD. Our study is the first review to comprehensively map and characterize various assessment methods to improve the quality of care for PD patients. Nonetheless, the current literature underscores ongoing research and practice challenges that must be addressed. Screening NBS programs have been established in numerous countries to facilitate early detection and treatment of PD. 26,28,42–44 However, NBS programs are not universally available. 27 The included studies showed disparities in the implementation of NBS among countries, with some having already launched pilot programs while others are in the early planning phases. 45–49 The availability of screening also depended on the country's healthcare infrastructure and resources. 50–52 The data from screening initiatives will prove instrumental in understanding the prevalence of PD and differentiating it from other musculoskeletal disorders. 29,53 Diagnostic Biochemical and Genetic Methods Biochemical assessments are indispensable for detecting and monitoring PD's progression. 54–57 As demonstrated by our review, biochemical analysis may encompass muscle enzymes such as GAA, CK (CPK); along with other enzymes, including AST, ALT, and Glc4. DBS was reported in 18 articles and emerged as the predominant method among reviewed enzyme assays. DBS can detect partial and total decreases in GAA enzyme activity. However, other pseudodeficiencies of GAA activity that do not result in PD should be considered, as they can complicate the diagnosis. 54 By characterizing the widespread use of DBS, our review emphasizes this method's potential feasibility and reliability in diagnosing PD. 27 This strategy should be considered in countries with limited resources since PD has available and under-development therapeutic options. 58–60 Nevertheless, we observed a lack of standardization in reporting DBS results, particularly in specifying quantitative thresholds. For example, we encountered eight articles that characterized GAA deficiency solely through qualitative terms like 'significantly decreased,' 'reduced,' 'decreased,' 'low limit level,' and 'deficient activity,' whereas seven articles omitted such descriptive qualifiers. This variation in reporting GAA activity highlights the need for standardization in conveying these results to foster further research correlations, enhance applicability to clinical practice, and facilitate its implementation. 54 As a monogenic recessive disease, diagnosing PD requires the identification of at least two mutations in the GAA gene. In cases where a single or no mutation is detected, diagnosis relies on reduced GAA activity in at least two tissues, with blood and skeletal muscle being the most frequently examined. 61 This approach follows the recommendations of the European Pompe Consortium. 35 In our review, most selected papers emphasized the need for confirmatory genetic analysis of the GAA gene following biochemical observation of reduced GAA activity. 5,36,62–64 Some articles highlighted the limitations of traditional Sanger sequencing in detecting the two alleles. 2,31,65–67 Notably, seven of 21 citations that applied genetic methods did not specify the sequencing strategy they utilized. However, studies utilizing NGS as a diagnostic tool did not encounter these difficulties. 31,36,66,68 Based on our included articles, NGS should be considered the gold standard assessment tool for accurate patient genotyping. 31 Sanger sequencing should be reserved for mutation confirmation when necessary. While “classic infantile” PD patients have mutations that disrupt all GAA protein forms, the precise relationship between specific genotype and phenotype expressions remains elusive. 2,3,5 In this context, the cross-reactive immunologic material (CRIM) status is relevant to classify IODP into two groups: those with detectable (CRIM+) and undetectable GAA protein (CRIM-), with the latter group demonstrating worse prognosis and response to enzyme replacement therapy. 69 The CRIM status can be determined through genotype predictions or a rapid turnaround blood-based leukocyte assay. 70,71 In our review, only one article reported the CRIM status of each evaluated patient. 68 Further research and comprehensive reporting are warranted to elucidate the interplay between genotype, phenotype, CRIM status, and varying levels of GAA enzyme activity. Moreover, although some articles encountered new gene variants, those variants were unavailable on the PD reference database. 4 This finding highlights the urgent demand for creating a universal database dedicated to variants in PD, which should function as a comprehensive point of reference. 3,4,38 These initiatives are essential to standardize the documentation of genetic mutations following widely accepted molecular nomenclature. Evaluation of clinical manifestations Concerning clinical assessment, a pervasive challenge observed in reviewed articles was the heterogeneous classification of PD’s clinical spectrum. 2,72 In this regard, the classification proposed by Güngör and Rouser seems an alternative to mitigate confusion and could be universally adopted to categorize PD subtypes. 73 This classification delineates three yet overlapping categories within the clinical spectrum: ( 1 ) “classic infantile” PD (CIPD), diagnosed within the first year of life and representing the severe form of PD; ( 2 ) pediatric PD (POPD), which encompasses patients with clinical onset from birth to adolescence (e.g., ≤ 14 years) but without persistent and progressive cardiac hypertrophy; and ( 3 ) adult PD (AOPD) for patients with symptom onset from adolescence (e.g., ≥ 14 years) to late adulthood. Achieving consensus in reporting is crucial, as it aids healthcare professionals in increasing awareness of PD clinical manifestations in infants. Furthermore, while the clinical manifestations described in the selected papers provided characteristic indicators that raise suspicion of PD during the diagnostic process, only one article explicitly referenced using standardized terms and identification numbers proposed by HPO in their study. 38 The existing literature exhibits significant discrepancies in the clinical description of patient phenotypes, highlighting the need for standardization. Follow-up After confirming the diagnosis, individuals with PD require ongoing follow-up and monitoring. This may involve regular visits to healthcare providers, including specialists in neuromuscular diseases, cardiology, and pulmonology. The frequency of follow-up visits may vary according to individual needs and disease progression. In our review, we identified a lack of consensus regarding the best approach to follow up with LOPD cases. Also, existing guidelines were not consistently adhered to. 74 The knowledge of the diagnosis, particularly in individuals without symptoms or functional impairment, may trigger psychological issues that impact their quality of life (QoL), such as anxiety or depression. 75–77 Patients and families may benefit from psychosocial support to cope with the emotional and psychological distress associated with this chronic and progressive condition. 78,79 As observed in this scoping review, there is a limited focus on the QoL of LOPD patients, in which only one paper mentioned the use of INQoL as a patient-reported outcome measure. 41 For instance, establishing a national disease registry would provide a starting point for administering QoL assessments among PD patients and increase the number of related studies. 75,76 Another identified concern was the importance of continuous evaluation and vigilant monitoring for asymptomatic PD patients identified through NBS. Notably, one study mentioned serum platelet-derived-growth-factor-BB (PDGF-BB) as a potential biomarker. 24 As indicated by PDGF-BB levels, the dysregulation of muscle regeneration suggests its potential use in monitoring asymptomatic LOPD patients. This emerging biomarker warrants further investigation to clarify its role in disease management. 24 Limitations Despite the comprehensive scope of this review, some limitations must be acknowledged. We only included citations in English or Spanish, excluding relevant research in other languages. Our review relied on literature available up to its knowledge cut-off date of February 8, 2022, and does not encompass advancements in PD assessment published afterward. Additionally, differences in study design, sample size, and methodology across the included studies could affect the generalizability of findings. Although efforts to ensure international representation in the selected studies were made, the overrepresentation of literature from specific geographic regions may limit the application of our findings to other populations. Lastly, as a scoping review, we did not assess individual study biases. Future research should consider these limitations to enhance our understanding of PD screening, diagnosis, and management. Conclusion In this scoping review, we comprehensively evaluated reported assessment methods for PD, including screening, diagnosis, and follow-up. By estimating the prevalence in which methods are applied and its respective findings, our review synthesized evidence that can guide healthcare providers to expedite diagnosis and treatment, especially in infants carrying common genetic variants. Nonetheless, our review also highlighted the need for a more standardized and streamlined approach to PD assessment, encompassing various assessment categories. As research in PD evolves, these aspects should be considered to ultimately enhance the quality of healthcare provided to patients with PD. Abbreviations ALT : Alanine aminotransferase AST : Aspartate aminotransferase CK : Creatine kinase CRIM : Cross-reactive immunologic material CT : Computed tomography DBS : Dried blood spot DOI : Digital Object Identifier System ECG : Electrocardiography EMG : Electromyography GAA : Acid Alpha-glucosidase GMFM : Gross Motor Function Measure Glc4 : Urinary glucose tetrasaccharide GSDII : Glycogen storage disease type II IOPD : Infantile-onset Pompe Disease LOPD : Late-onset Pompe Disease LSD : Lysosomal Disorders MIM : Mendelian Inheritance in Man MRI : Magnetic Resonance Imaging NBS : Newborn screening ORFHA308552 : Orphanet rare disease nomenclature for IOPD ORFHA420429 : Orphanet rare disease nomenclature for LOPD ORPHA365 : Orphanet rare disease nomenclature for PD PD : Pompe Disease PRISMA - ScR : Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews QMFT : Quick motor-function test VFSS : Video-fluoroscopic swallowing study Declarations Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Availability of data and materials: All data generated or analyzed during this study are included in this published article and its supplementary information files. Competing interests: The authors declare that they have no competing interests. Funding: The Rare Diseases Community received financial support from FONTAR (Fondo Tecnológico Argentino) of the Agencia Nacional de Promoción de la investigación, el Desarrollo y la Innovación (Ministerio de Ciencia, Tecnología e Innovación) under grant number ANR 25000 2022 F2 032/22. FONTAR did not contribute to the design, data collection, analysis, interpretation, manuscript preparation, or decision to submit this manuscript. Authors' contributions: LNC, AG, LFS, MMM, JS, CFA conceptualized the study and developed the methodology. FFZ conducted the search strategy at thirteen databases. LNC, FFZ, and CFA performed data curation. IDR, DMIA, FNDPG, and MGSJ screened and extracted data from identified citations. LNC and CFA solved discrepancies between reviewers. LNC, JS, and CFA provided utilized software. CFA conducted a formal analysis. LNC and CFA prepared tables and figures. IDR, LNC, DB, and CFA interpreted the data. IDR, DMIA, FNDPG, LNC and CFA wrote the first draft of the manuscript. All authors revised the manuscript content. Project administration was done by AG, CFA and JS supervised this study. All authors read and approved the final manuscript. Acknowledgements: Authors express their heartfelt appreciation to Dr. Gaston A. Rodriguez-Granillo for having revised the manuscript and provided invaluable insights which enhanced this manuscript. References Marques JS. The Clinical Management of Pompe Disease: A Pediatric Perspective. Children [Internet]. 2022 Sep 16;9(9). 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Available from: http://dx.doi.org/10.1186/s12883-017-0983-2 Kanters TA, van der Ploeg AT, Brouwer WBF, Hakkaart L. The impact of informal care for patients with Pompe disease: an application of the CarerQol instrument. Mol Genet Metab [Internet]. 2013 Nov;110(3):281–6. Available from: http://dx.doi.org/10.1016/j.ymgme.2013.07.020 Table Table 3 is not available with this version. Table 3. Assessments methods for diagnosis and follow-up of Pompe Disease (PD). Additional Declarations The authors declare no competing interests. Supplementary Files SupplementaryTable1.docx SupplementaryTable2ArticlesincludedintheSR.xlsx Supplementary Table 2: Overview of the 96 articles included in the scoping review organized per year. SupplementaryTable3GneticanalysisinPD.xlsx Supplementary Table 3. Selected articles that focused on genetics analysis in Pompe Disease (PD). 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3909349","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":269935393,"identity":"2a9be88c-137d-4258-8948-2323e89487f8","order_by":0,"name":"Israel Davila Rivera","email":"","orcid":"","institution":"Fundación SPINE \u0026 Rare Diseases Community, Buenos Aires, Argentina","correspondingAuthor":false,"prefix":"","firstName":"Israel","middleName":"Davila","lastName":"Rivera","suffix":""},{"id":269935394,"identity":"22fa85d2-8f58-43b7-a961-340cd9c3d0f5","order_by":1,"name":"Letícia Nunes Campos","email":"","orcid":"","institution":"Fundación SPINE \u0026 Rare Diseases Community, Buenos Aires, Argentina and 2Faculdade de Ciências Médicas, Universidade de Pernambuco, Recife, Brazil.","correspondingAuthor":false,"prefix":"","firstName":"Letícia","middleName":"Nunes","lastName":"Campos","suffix":""},{"id":269935395,"identity":"7c0572b0-5332-462e-b6e6-932b311a170f","order_by":2,"name":"Daiana M. 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Ibañez","lastName":"Alegre","suffix":""},{"id":269935396,"identity":"82a9d480-e8bc-4c0c-a6af-afad08a9e43c","order_by":3,"name":"Fabiana N. del Puerto González","email":"","orcid":"","institution":"Fundación SPINE \u0026 Rare Diseases Community, Buenos Aires, Argentina.","correspondingAuthor":false,"prefix":"","firstName":"Fabiana","middleName":"N. del Puerto","lastName":"González","suffix":""},{"id":269935397,"identity":"960d0e31-dfd5-4d88-b812-1eac1940f5b7","order_by":4,"name":"Mónica Garrido San Juan1","email":"","orcid":"","institution":"Fundación SPINE \u0026 Rare Diseases Community, Buenos Aires, Argentina","correspondingAuthor":false,"prefix":"","firstName":"Mónica","middleName":"Garrido San","lastName":"Juan1","suffix":""},{"id":269935398,"identity":"f176d2d2-e50c-46b8-8634-34451a6d84b5","order_by":5,"name":"Federico Fernandez Zelcer","email":"","orcid":"","institution":"Facultad de Filosofía y Letras, Universidad de Buenos Aires, Buenos Aires, Argentina.","correspondingAuthor":false,"prefix":"","firstName":"Federico","middleName":"Fernandez","lastName":"Zelcer","suffix":""},{"id":269935399,"identity":"3a582018-1d12-467c-bdcf-5c02f604af21","order_by":6,"name":"Delfina Borgobello","email":"","orcid":"","institution":"Fundación SPINE \u0026 Rare Diseases Community, Buenos Aires, Argentina","correspondingAuthor":false,"prefix":"","firstName":"Delfina","middleName":"","lastName":"Borgobello","suffix":""},{"id":269935400,"identity":"82ea57cd-0234-420d-ae57-c11d6afa4b37","order_by":7,"name":"Ayla Gerk","email":"","orcid":"","institution":"Fundación SPINE \u0026 Rare Diseases Community, Buenos Aires, Argentina","correspondingAuthor":false,"prefix":"","firstName":"Ayla","middleName":"","lastName":"Gerk","suffix":""},{"id":269935401,"identity":"f871a82c-f2b2-424a-b8ef-5b97732bb276","order_by":8,"name":"Laura F. Sosa","email":"","orcid":"","institution":"Fundación SPINE \u0026 Rare Diseases Community, Buenos Aires, Argentina","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"F.","lastName":"Sosa","suffix":""},{"id":269935402,"identity":"b2ce2491-5e52-41ed-b226-f79d137ef920","order_by":9,"name":"Marcos M. Miretti","email":"","orcid":"","institution":"Fundación SPINE \u0026 Rare Diseases Community, Buenos Aires, Argentina and Instituto de Biología Subtropical. Nodo Posadas, Universidad Nacional de Misiones (UNaM) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Misiones, Argentina and Facultad de Ciencias de la Salud, Universidad Católica de las Misiones, Misiones, Argentina.","correspondingAuthor":false,"prefix":"","firstName":"Marcos","middleName":"M.","lastName":"Miretti","suffix":""},{"id":269932691,"identity":"86cc78d1-ab83-4038-b0bf-a3cca7511eae","order_by":10,"name":"Carina F. Argüelles","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABD0lEQVRIiWNgGAWjYBAC9gYQaQDjFliAhZjxaeE5gKLFQAIsRIQWOABpkUggoEX68LMHPwrq5PlnH78m8cFAQk5+5hvDzwUVNgz87d0JWLXwpZkb9hgcNpxxLqdMcoaBhLHB7Rxj6Rln0hgkzpzdgE2LPQ+DmTSDwYEEhjM8adI8BhKJG6RzDKR52w4DHZmLVQsPD/s3oJa6BHmQlj8GEvXzZ54x/o1fCw/IFuYEgzPsx4AMoN9vAEUIaCmTBPll4xkeZsseAwnDDWfSyqx5zqTx4PIL0GHbJH78qZOXO8P+8MaPCht5+fbDm2/zVNjI8bf3YtWCrBsWoRxgBg8B5SDA/gCdMQpGwSgYBaMADAAbmFXUvjBxWQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-2120-4945","institution":"Fundación SPINE \u0026 Rare Diseases Community, Buenos Aires, Argentina and 4Instituto de Biología Subtropical. Nodo Posadas, Universidad Nacional de Misiones (UNaM) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Misiones, Argentina and Universidad Católica de las Misiones","correspondingAuthor":true,"prefix":"","firstName":"Carina","middleName":"F.","lastName":"Argüelles","suffix":""},{"id":269935403,"identity":"b721eac4-6200-4ea6-b644-9cfed2af2896","order_by":11,"name":"Jorgelina Stegmann","email":"","orcid":"","institution":"Fundación SPINE \u0026 Rare Diseases Community, Buenos Aires, Argentina","correspondingAuthor":false,"prefix":"","firstName":"Jorgelina","middleName":"","lastName":"Stegmann","suffix":""}],"badges":[],"createdAt":"2024-01-29 18:46:15","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-3909349/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3909349/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50394418,"identity":"d9adb7ef-611c-4b1c-8634-53b1aa37874b","added_by":"auto","created_at":"2024-01-30 21:04:56","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":140137,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA flowchart summarizing the study selection process:\u003c/strong\u003e The flowchart outlines the flow of information by mapping the number of items identified, included, and excluded per screening stage\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3909349/v1/04ea79e486bfa66469aa33d1.jpg"},{"id":50394417,"identity":"c043f1c7-7414-4c45-a10d-0a385015cdf5","added_by":"auto","created_at":"2024-01-30 21:04:56","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":37428,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNumber of included articles per year: \u003c/strong\u003eThe figure shows the number of selected citations per year considering the eligible period of our scoping review (January 1, 2017 - February 8, 2022)\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3909349/v1/2a430ef607eddff3ec1e0f97.jpg"},{"id":50394415,"identity":"df32caf3-3463-41b0-b6b3-47736f515589","added_by":"auto","created_at":"2024-01-30 21:04:56","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":40657,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNumber of included articles per country: \u003c/strong\u003eThis world map depicts the number of included articles per country among the 96 selected articles\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3909349/v1/f2efb429b1ffbb4597a1e64c.jpg"},{"id":50394419,"identity":"8c36d3fd-f16d-4ee8-a93a-aaa91531bb29","added_by":"auto","created_at":"2024-01-30 21:04:56","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":86920,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNumber of included papers per country and geographic distribution: \u003c/strong\u003eThis figure demonstrates the number of\u003cstrong\u003e \u003c/strong\u003eincluded papers per country among the 96 selected articles meeting our criteria. The different colors highlight the geographic regions where the studies were conducted\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3909349/v1/63f30aae47b9aed269ae2bf7.jpg"},{"id":50394422,"identity":"69bfc54d-1c3c-4cb8-a295-9a5d0514b9ad","added_by":"auto","created_at":"2024-01-30 21:04:57","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":165048,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIncluded types of study design: \u003c/strong\u003eNumber and type of study design included among the 96 selected citations. *Screening studies were also included in this category\u003cem\u003e.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3909349/v1/469872016d6dea6ebd07592b.jpg"},{"id":50394683,"identity":"a8ceeb61-6d8b-431a-9468-a1b9d73ad2f4","added_by":"auto","created_at":"2024-01-30 21:12:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1007717,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3909349/v1/3a3cb153-4cb2-4f48-af38-5efc0ceb39db.pdf"},{"id":50394416,"identity":"39beee1c-f090-448c-8399-d4e6e97bc11b","added_by":"auto","created_at":"2024-01-30 21:04:56","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":46970,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3909349/v1/6de6f70e2ba9eae9a966a966.docx"},{"id":50394420,"identity":"170271fd-b4e0-4b96-935b-9d3afddb9088","added_by":"auto","created_at":"2024-01-30 21:04:56","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":28307,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Table 2:\u003c/strong\u003e Overview of the 96 articles included in the scoping review organized per year.\u003c/p\u003e","description":"","filename":"SupplementaryTable2ArticlesincludedintheSR.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3909349/v1/6963d9093b5db777ce1cbc16.xlsx"},{"id":50394421,"identity":"018c2213-5b5d-4f79-9424-2c1cba710c55","added_by":"auto","created_at":"2024-01-30 21:04:56","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":31401,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Table 3. \u003c/strong\u003eSelected articles that focused on genetics analysis in Pompe Disease (PD).\u003c/p\u003e","description":"","filename":"SupplementaryTable3GneticanalysisinPD.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3909349/v1/9763923a6641dd4e07543ee4.xlsx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eNavigating Pompe Disease Assessment: A Comprehensive Scoping Review\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003ePompe disease (PD), also known as glycogen storage disease type II (GSDII; ORPHA:365; ORPHA:308552; MONDO:0009290; MIM #232300 and MIM#606800) is a monogenic, autosomal recessive and progressive metabolic disorder caused by mutations in the acid alpha-glucosidase (GAA) gene located at 17q25.2\u0026ndash;q25.3.\u003csup\u003e1,2\u003c/sup\u003e These mutations cause a deficient production of the GAA protein, leading to the lysosomal accumulation of glycogen in several tissues, particularly in skeletal and cardiac muscles as well as the nervous system. This process culminates in cellular dysfunction and muscle damage.\u003csup\u003e1,2\u003c/sup\u003e Until now, more than 600 mutations associated with the GAA gene have been identified.\u003csup\u003e3,4\u003c/sup\u003e Some mutations prevail among specific ethnic groups and geographic regions, such as c.-32-13T\u0026thinsp;\u0026gt;\u0026thinsp;G splice mutation in patients of Caucasian origin.\u003csup\u003e5\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePD is generally divided into two groups depending on age onset, progression rate, severity, and organ involvement. The first is the infantile-onset PD (IOPD; ORPHA:308552), constituting the most severe phenotype with rapidly progressive hypertrophic cardiomyopathy and generalized muscle weakness at birth. Patients born with this phenotype commonly die within the first two years of life.\u003csup\u003e6\u003c/sup\u003e The second group is the late-onset PD (LOPD; ORPHA:420429), which includes childhood, juvenile, and adult-onset disease. Patients with LOPD have a GAA enzyme activity that ranges from 2\u0026ndash;40% of the expected functionality compared to healthy individuals. LOPD presents with variable muscle involvement, progressive proximal muscle weakness, and respiratory insufficiency, whose onset varies from infancy to the sixth decade of life.\u003csup\u003e6,7\u003c/sup\u003e Although LOPD has a slower progression than IOPD, it eventually affects the diaphragm and accessory respiratory muscles. Therefore, patients with LOPD can present respiratory failure, the most prevalent cause of mortality in this phenotype.\u003csup\u003e8\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eGiven the severity of this rare disease, its considerable impact on patient\u0026rsquo;s quality of life (QOL), and the availability of approved disease-modifying treatments, prompt diagnosis and management of PD are imperative.\u003csup\u003e9\u003c/sup\u003e However, identifying PD presents several challenges due to the wide range of phenotypes, limited awareness, and phenotype overlap with other neuromuscular disorders, such as limb-girdle muscular dystrophies.\u003csup\u003e9,10\u003c/sup\u003e We aimed to map and synthesize the available evidence concerning assessment methods to screen, diagnose, and follow up on patients with PD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy Design\u003c/h2\u003e\n\u003cp\u003eWe registered our protocol at Open Science Framework and reported this study following the Preferred Reporting Items for Systematic reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR).\u003csup\u003e11,12\u003c/sup\u003e Our primary aim was to identify the existing methods to assess patients with PD worldwide. We interpreted \u0026ldquo;assessment\u0026rdquo; as learning about a patient\u0026rsquo;s condition.\u003csup\u003e13\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThis review considered methods to screen, diagnose, and follow up PD patients. Screening methods consisted of tests, exams, and procedures to identify diseases in a targeted population that is usually asymptomatic.\u003csup\u003e14\u003c/sup\u003e Diagnosing methods encompassed those to determine the nature of a condition or distinguish one from another.\u003csup\u003e15\u003c/sup\u003e Follow-up methods referred to those that assess long-term outcomes of PD.\u003csup\u003e16\u003c/sup\u003e Assessment methods included but were not limited to clinical manifestations, scales, questionnaires, indices as well as genetic, imaging, biochemical, and electrophysiological studies.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eEligibility Criteria\u003c/h2\u003e\n\u003cp\u003eWe considered articles that included patients who fulfilled clinical, genetic, or biochemical PD diagnostic criteria as previously described.\u003csup\u003e17,18\u003c/sup\u003e Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e describes the features that raise clinical suspicion of PD. We included human-based research articles that used qualitative or quantitative methods and examined methods to assess PD patients. No geographical restrictions were applied. Eligible articles were primary studies (i.e., case reports, case series, cross-sectional studies, case controls, cohorts, clinical trials, qualitative studies), reviews (i.e., narrative, scoping, and systematic reviews), and guidelines. We excluded editorials, commentaries, personal anecdotes, conference abstracts, books, studies targeting pharmacological and non-pharmacological interventions, animal studies, and \u003cem\u003ein vitro\u003c/em\u003e studies.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eClinical features of Pompe Disease phenotypes\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ePhenotype\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eInfantile Onset Pompe Disease\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLate Onset Pompe Disease\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1. Cardiovascular System:\u003c/p\u003e\n\u003cp\u003e● Cardiomegaly or hypertrophic cardiomyopathy\u003c/p\u003e\n\u003cp\u003e2. Musculoskeletal System:\u003c/p\u003e\n\u003cp\u003e● Rapidly progressive muscle weakness\u003c/p\u003e\n\u003cp\u003e● Hypotonia\u003c/p\u003e\n\u003cp\u003e● Delayed or not achieved rolling over, sitting up, and standing\u003c/p\u003e\n\u003cp\u003e3. Craniofacial Manifestations\u003c/p\u003e\n\u003cp\u003e● Large, protruding tongue\u003c/p\u003e\n\u003cp\u003e4. Nutritional and Gastrointestinal System\u003c/p\u003e\n\u003cp\u003e● Moderate enlargement of the liver\u003c/p\u003e\n\u003cp\u003e● Feeding and swallowing problems\u003c/p\u003e\n\u003cp\u003e5. Respiratory System:\u003c/p\u003e\n\u003cp\u003e● Respiratory dysfunction (combined or not with respiratory tract infections)\u003c/p\u003e\n\u003cp\u003e6.Nervous System:\u003c/p\u003e\n\u003cp\u003e● Hearing loss\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1. Neuromuscular System:\u003c/p\u003e\n\u003cp\u003e● Progressive muscle weakness (limb-girdle, upper arms, upper legs)\u003c/p\u003e\n\u003cp\u003e● Muscle wasting\u003c/p\u003e\n\u003cp\u003e● Waist dystrophy\u003c/p\u003e\n\u003cp\u003e● Gait disorders\u003c/p\u003e\n\u003cp\u003e● Chewing and swallowing difficulties\u003c/p\u003e\n\u003cp\u003e● Drooping of the upper eyelids (ptosis)\u003c/p\u003e\n\u003cp\u003e2. Respiratory System:\u003c/p\u003e\n\u003cp\u003e● Dysfunction of the diaphragm and intercostal muscles\u003c/p\u003e\n\u003cp\u003e● Restrictive respiratory insufficiency/varying degrees of respiratory weakness\u003c/p\u003e\n\u003cp\u003e3. Cardiovascular System:\u003c/p\u003e\n\u003cp\u003e● Blood vessel abnormalities\u003c/p\u003e\n\u003cp\u003e4. Digestive System:\u003c/p\u003e\n\u003cp\u003e● Manifestations of digestive system\u003c/p\u003e\n\u003cp\u003e5. Urinary System:\u003c/p\u003e\n\u003cp\u003e● Manifestations of urinary system\u003c/p\u003e\n\u003cp\u003e6. Metabolic and Endocrine System:\u003c/p\u003e\n\u003cp\u003e● Idiopathic hyperkalemia\u003c/p\u003e\n\u003cp\u003e7. Connective Tissue and Joints:\u003c/p\u003e\n\u003cp\u003e● Idiopathic scoliosis\u003c/p\u003e\n\u003cp\u003e8. Rheumatological Manifestations\u003c/p\u003e\n\u003cp\u003e● Nonspecific chronic low back pain\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\n\u003ch2\u003eInformation Sources, Search Strategy, and Citation Management\u003c/h2\u003e\n\u003cp\u003eA librarian (FFZ) conducted the search strategy at 11 databases: Cochrane Database of Systematic Reviews (John Wiley \u0026amp; Sons, Inc), Directory of Open Access Journals (DOAJ), Epistemonikos (Epistemonikos Foundation), Ingenta Connect (Ingenta), Medline/PubMed (National Library of Medicine, NCBI), SAGE (Sage Publications), SciELO Citation Index (Web of Science, Clarivate), ScienceDirect (Elsevier B.V.), Springer Link (Springer Nature Switzerland AG), Virtual Health Library (Latin American and Caribbean Center on Health Sciences Information, World Health Organization), and Wiley Online Library (John Wiley \u0026amp; Sons, Inc). The search strategy included articles published between 2017 and the search date on February 8, 2022. We included articles published in English and Spanish due to the research team\u0026rsquo;s language proficiency skills. \u003cstrong\u003eSupplementary Table\u0026nbsp;1\u003c/strong\u003e provides the strategy per database.\u003c/p\u003e\n\u003cp\u003eReferences were imported into the EndNote bibliography manager, and duplicated references were automatically purged by searching for simultaneous matches in the author, title, and year fields.\u003csup\u003e19\u003c/sup\u003e FFZ conducted an additional manual search to identify further duplicates. Results from the search strategy were exported as a Google Sheets spreadsheet.\u003csup\u003e20\u003c/sup\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy Selection\u003c/h2\u003e\n\u003cp\u003eWe screened eligible studies using a standardized Google Form to register reviewers\u0026rsquo; decisions.\u003csup\u003e21\u003c/sup\u003e Before the screening, our team performed a calibration exercise with reviewers (IDR, DMIA, FNDPG, MGSJ). Reviewers independently screened a random sample of 20 citations from the search. The screening only commenced when reviewers reached an agreement percentage equal to or greater than 90%. After calibrating, the reviewers independently screened the articles\u0026rsquo; titles and abstracts following the eligibility criteria. Next, reviewers screened the remaining studies based on full text. CFA and LNC solved discrepancies between reviewers.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eCharting and Extraction\u003c/h2\u003e\n\u003cp\u003eWe developed a chart on Google Sheets to extract data for included articles. Two independent reviewers collected data from each citation. CFA solved any disagreements. We extracted the following data points: title, abstract, authors\u0026rsquo; names, digital object identification (DOI), year of publication, language used for publication, study design, number of study participants, patients\u0026rsquo; age estimate, sex distribution, and country; described assessment methods, category of assessment methods (e.g., clinical, imaging, genetic), study\u0026rsquo;s findings for each mentioned assessment method. We did not conduct any risk of bias assessment, which is a consistent approach with the scoping review methodology.\u003csup\u003e22,23\u003c/sup\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003eSynthesis of results\u003c/h2\u003e\n\u003cp\u003eWe used frequencies and percentages to summarize the characteristics of the included studies. Quantitative and qualitative data from the studies were utilized as primary sources to describe the reported assessment methods for PD. A narrative summary of the findings was provided, along with tables and figures prepared using Microsoft Excel 365 (Microsoft Corporation, Redmond, WA).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eLiterature search\u003c/h2\u003e\n\u003cp\u003eThe literature search yielded 2,494 citations. After removing 355 duplicates, 2,139 articles underwent title and abstract screening. Among these, 470 articles underwent full-text screening. Overall, 96 articles met the eligibility criteria (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cstrong\u003eSupplementary Table\u0026nbsp;2\u003c/strong\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eCharacteristics of Selected Articles\u003c/h2\u003e\n\u003cp\u003eAmong the 96 selected articles, 83 (86%) citations were published between 2017 and 2019 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Only three articles were published in Spanish. Most studies were conducted in the United States (13%, n\u0026thinsp;=\u0026thinsp;14), Italy (10%, n\u0026thinsp;=\u0026thinsp;11), Germany (9%, n\u0026thinsp;=\u0026thinsp;10), and The Netherlands (6%, n\u0026thinsp;=\u0026thinsp;7). Four studies examined patients from multiple countries: one assessed patients from Latin America and three from Europe (\u003cstrong\u003eSupplementary Table\u0026nbsp;2\u003c/strong\u003e). In terms of regional representation, studies from South America, Oceania, and Central America accounted for only 7% (n\u0026thinsp;=\u0026thinsp;8), 2% (n\u0026thinsp;=\u0026thinsp;2), and 1% (n\u0026thinsp;=\u0026thinsp;1) of selected articles, respectively (Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Cross-sectional studies (31%, n\u0026thinsp;=\u0026thinsp;30) were the most prevalent study design. In comparison, guidelines were the least frequent (1%, n\u0026thinsp;=\u0026thinsp;1) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e).\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eCharacteristics of the studied population\u003c/h2\u003e\n\u003cp\u003eFifty-five percent of selected citations focused only on LOPD (n\u0026thinsp;=\u0026thinsp;48) and 22% (n\u0026thinsp;=\u0026thinsp;21) on IOPD. Articles reported the infantile phenotype using various terms, including IODP (n\u0026thinsp;=\u0026thinsp;18), prenatal PD (n\u0026thinsp;=\u0026thinsp;1), classic infantile PD (n\u0026thinsp;=\u0026thinsp;2), and infantile PD (n\u0026thinsp;=\u0026thinsp;1). Thirty-one percent (n\u0026thinsp;=\u0026thinsp;27) of the studies focused on both IOPD and LOPD. \u003cstrong\u003eSupplementary Table\u0026nbsp;2\u003c/strong\u003e provides additional details regarding inclusion criteria, number of patients, sex distribution, and estimated age per included article.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003ch2\u003eAssessment methods\u003c/h2\u003e\n\u003cdiv id=\"Sec15\" class=\"Section3\"\u003e\n\u003ch2\u003eScreening\u003c/h2\u003e\n\u003cp\u003eOf 96 selected articles, 11% (n\u0026thinsp;=\u0026thinsp;11) described newborn screening (NBS). Among these, three studies were conducted in North America, three in Europe, and two in Asia. Only one study was conducted in a South American country, specifically Mexico. Four studies noted NBS programs as a mechanism to promote early diagnosis and treatment, especially for IOPD. Six articles cited NBS programs that detected various lysosomal diseases, including PD. One article provided guidance on determining appropriate patient management, monitoring, and the frequency and type of follow-up assessments for all patients identified through NBS (\u003cstrong\u003eSupplementary Table\u0026nbsp;2\u003c/strong\u003e).\u003csup\u003e24\u003c/sup\u003e While implementing NBS was argued to improve the accuracy of PD\u0026rsquo;s prevalence,\u003csup\u003e25\u003c/sup\u003e other studies emphasized the need to closely monitor asymptomatic patients with abnormal NBS results for diagnosis.\u003csup\u003e26\u0026ndash;30\u003c/sup\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n\u003ch2\u003eClinical presentation\u003c/h2\u003e\n\u003cp\u003eOverall, 84% (n\u0026thinsp;=\u0026thinsp;81) assessed patients\u0026rsquo; clinical status comprehensively. Most articles primarily focused on describing clinical manifestations of LOPD (n\u0026thinsp;=\u0026thinsp;47), as individuals with this phenotype tend to have higher survival rates than IOPD. Furthermore, 16 articles reported manifestations of IOPD, and 18 citations discussed the clinical presentations of both PD subtypes. One article targeted genetic variants and used standardized terms and identification numbers from the Human Phenotype Ontology (HPO) to describe PD phenotypes. Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e shows the reported clinical manifestations per article.\u003c/p\u003e\n\u003ctable border=\"1\" width=\"793\"\u003e\u003ccaption\u003e\n\u003cp\u003eTable 2\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eReported clinical manifestations for Infantile-onset Pompe Disease (IOPD) and Late-onset Pompe Disease (LOPD)\u003c/p\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003ePD phenotype\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003e\u003cstrong\u003eReported clinical manifestation\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e\u003cstrong\u003e# of articles\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"58\" width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003eInfantile-Onset Pompe Disease (IOPD)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eGrowth\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eLow body weight\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDelay in development\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eHead \u0026amp; Neck\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eMacroglossia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eWeakness of and inability to control neck muscles\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDysarthria with nasal speech\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eEnlarged lips\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eFeeble cry\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eSwelling of gingiva\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eEyes\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eImparied vision\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eMulti-directional nystagmus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003ePtosis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eEars\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eHearing impairment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eCardiovascular System\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eHypertrophic cardiomyopathy / Severe infantile hypertrophic cardiomyopathy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eCardiomegaly\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eCardiomyopathy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eArrhythmias (e.g., no sustained and sustained supraventricular tachycardia, atrial or ventricular premature beats, and ventricular tachycardia or fibrillation)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eCardiac failure\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eCardiac murmur\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDilated cardiomyopathy (e.g., right atrial enlargement and biventricular hypertrophy)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eLeft ventricular thrombus based at the mitral valve\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eMild ventricular dysfunction\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eOutflow tract obstruction\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eReduced ejection fraction\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eSmall ventricular lumen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eSystolic bruit\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eRespiratory System\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eRespiratory distress\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDyspnea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eRecurrent airway infections / Recurring respiratory infections\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eRespiratory failure\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eTachypnea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eInspiratory and expiratory muscle weakness\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eObstructive sleep apnoea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eSevere pneumonia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eDigestive System\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eFeeding difficulties in infancy, including breast feeding\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eGastric reflux\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eGenitourinary System\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eUrinary tract infection\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eMuscles \u0026amp; Limbs\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eHypotonia (including generalized, axial, and proximal)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eMuscular weakness (including generalized and distal)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eMotor retardation and paucity of movements\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eHypo- or areflexia (e.g., decreased, or absent deep tendon reflex)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eNervous System \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eExtra-axial cerebrospinal fluid accumulation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eGross and fine motor delay\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDelays in speech and social skills\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eVentricular enlargement\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eUnsteady gait\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eWhite matter abnormalities (e.g., supratentorial, infratentorial)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eMiscellaneous\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eProfound sweating\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"68\" width=\"112\"\u003e\n\u003cp\u003e\u003cstrong\u003eLate-Onset Pompe Disease (LOPD)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eHead \u0026amp; Neck\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eMild to severe neck flexion weakness\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eChronic headache\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDysphonia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eSevere mild facial weakness\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eEyes\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eSubnormal visuospatial functioning\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eCardiovascular System\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eSystemic hypertension\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eEpisode of syncope\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eRespiratory System\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDyspnea (including at rest, during and after exercise and other physical efforts)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eRespiratory failure/insufficiency\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eOrthopnoea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eApneas (including sleep apnea hypopnea syndrome)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eImpaired lung function\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eNightime hypoventilation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eRestrictive ventilatory deficiency\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eRecurrent\u0026nbsp;respiratory tract infection\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eDigestive System\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDysphagia (including regurgitation, swelling and feeding difficulties)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDiarrhea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eNausea and vomiting\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eBelly pain\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eBowel incontinence\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eConstipation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eGas and bloating\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eGastroesophageal reflux\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003ePrimary biliary cirrhosis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eGenitourinary System\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eRenal artery fibromuscular dysplasia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eStenosis of the left renal artery\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eMuscles and Limbs\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eProgressive muscle weakness (including axial and proximal, in the upper and lower limbs)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDifficulties in rising from a seated and supine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eGait disturbances (e.g., subtle waddling gait, Trendelenburg gait, myopathic gait)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eMyalgia (including fibromyalgia-like, exertional, and lower extremity myalgia)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eRecurrent falls\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eScapular winging\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDifficulties to run\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eGeneralized fatigue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eProgressive difficulty in climbing stairs\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eResidual muscle weakness (e.g., in trunk, ptosis, myopathic facies, lumbar lordosis)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eLordosis (including lumbar hyperlordosis)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eWalking difficulties (e.g., reduced cadence and speed)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eHypotrophy and atrophy (e.g., of shoulder girdle, pelvic girdle, and paravertebral muscles)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eMuscle paralysis\u0026nbsp;(e.g., diaphragmatic and tetraplegia)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eRespiratory muscles impairment and weakness\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eRigid spine / Rigid spine syndrome\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eScoliosis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eAcute low-back pain\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eCamptocormia of the lumbar muscles\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDecreased lower limb muscle strength and power\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDistal and proximal myopathy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eEarly deviations in skeletal muscle posture and movement\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eGlobal hyporeflexia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eIncreased thoracic and pelvic mobility (e.g., increased thoracic sway, hip adduction angles)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eLeft-sided scapula alata\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eMuscular exertion intolerance\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eMuscle aches and cramps\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eThoracic hyperkyphosis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eVertebrobasilar dolichoectasia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"680\"\u003e\n\u003cp\u003e\u003cstrong\u003eNervous System\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDelay and regression in gross motor skills\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eSleep Disorders (including hypersomnia)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eAcute cerebral stroke\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eApathy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"586\"\u003e\n\u003cp\u003eDelayed motor development\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"94\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n\u003cdiv id=\"Sec18\" class=\"Section3\"\u003e\n\u003ch2\u003eBiochemical Assays as Diagnostic Methods\u003c/h2\u003e\n\u003cp\u003eA total of 25 articles described biochemical, hematological, or biomarker studies (\u003cstrong\u003eTable\u0026nbsp;3\u003c/strong\u003e). Dried blood spot (DBS) was the most commonly cited method (n\u0026thinsp;=\u0026thinsp;18). This test can detect both partial and total decreases in GAA enzyme activity.\u003csup\u003e31\u0026ndash;34\u003c/sup\u003e Other frequently reported tests included the quantification of serum creatinine kinase (sCK; n\u0026thinsp;=\u0026thinsp;17), alanine aminotransferase (ALT; n\u0026thinsp;=\u0026thinsp;6), aspartate aminotransferase (AST; n\u0026thinsp;=\u0026thinsp;5), and urinary glucose tetrasaccharide (Glc4; n\u0026thinsp;=\u0026thinsp;5) (\u003cstrong\u003eTable\u0026nbsp;3\u003c/strong\u003e). These measurements were elevated levels in PD patients. In particular, CK and AST, primarily muscle-specific enzymes, were associated with muscle tissue damage or dysfunction. One article measured serum platelet-derived growth factor BB (PDGF-BB) and suggested its use to monitor asymptomatic LOPD patients based on findings indicating dysregulation of muscle regeneration as an additional pathological mechanism.\u003csup\u003e35\u003c/sup\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n\u003cdiv id=\"Sec20\" class=\"Section3\"\u003e\n\u003ch2\u003eGenetic Studies as Confirmatory Diagnostic Test\u003c/h2\u003e\n\u003cp\u003eOut of 96 included articles, 21 (22%) had information regarding genetic variants within the GAA gene of PD patients. Most citations mentioned Sanger sequencing as the gold standard technique (n\u0026thinsp;=\u0026thinsp;8; 38%) for detecting gene sequence variants. Three citations employed a combination of sequencing methods, including next-generation sequencing (NGS) followed by Sanger sequencing.\u003csup\u003e31,33,36\u003c/sup\u003e Only one paper mentioned the use of NGS deep sequencing as a primary technique to ascertain the genetic status of patients. Furthermore, one study discussed the utility of whole exome sequencing.\u003csup\u003e37\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAll 21 articles referred to databases to assess variant novelty and classified their pathogenicity: very severe, potentially less severe, less severe, potentially mild, presumably non-pathogenic, non-pathogenic, or of unknown significance. The consulted databases included ClinVar, Erasmus MC University Medical Center, Exome Aggregation Consortium, Genome Aggregation Database, Leiden Open Variation Database, and Human Genome Mutation Database. \u003cstrong\u003eSupplementary Table\u0026nbsp;4\u003c/strong\u003e provides an overview of the extracted genetic information.\u003c/p\u003e\n\u003cp\u003eAcross the 21 articles, several variants were detected, with nonsense mutation being the most prevalent, followed by small deletions, including some in-frame deletions. Other variants included deletions, small insertions, and deletions (indels), and complex rearrangements. The most severe variants affected the catalytic domain of the GAA enzyme (exons 7\u0026ndash;15).\u003csup\u003e38\u003c/sup\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n\u003ch2\u003eImaging Studies\u003c/h2\u003e\n\u003cp\u003eIn total, 44 (15%) articles addressed imaging studies. Magnetic resonance imaging (MRI) was the most commonly employed (n\u0026thinsp;=\u0026thinsp;31; 70%) and included assessments of the brain, muscles, heart, thoracic region, kidneys, and other anatomical areas. Ultrasound imaging was utilized in 30% (n\u0026thinsp;=\u0026thinsp;13) of the articles to assess muscle, cardiac, pulmonary, and other structures. Only 11% (n\u0026thinsp;=\u0026thinsp;5) and 9% (n\u0026thinsp;=\u0026thinsp;4) of articles mentioned radiographic studies and computed tomography scans, respectively (\u003cstrong\u003eTable\u0026nbsp;3)\u003c/strong\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\n\u003ch2\u003eElectrophysiological and Functional Studies\u003c/h2\u003e\n\u003cp\u003eA total of 35 articles mentioned electrophysiological and functional studies in the primary clinical evaluation of patients with PD. Functional studies were the most frequently cited (89%, n\u0026thinsp;=\u0026thinsp;53) among the articles devoted to phenotypic assessment. They were mostly focused on muscular (36%, n\u0026thinsp;=\u0026thinsp;43) or respiratory (46%, n\u0026thinsp;=\u0026thinsp;57) studies (\u003cstrong\u003eTable\u0026nbsp;3)\u003c/strong\u003e. Thirteen (11%) articles exclusively mentioned electrophysiological studies where electromyography (EMG, n\u0026thinsp;=\u0026thinsp;6) serves as a diagnostic indicator, detecting spontaneous activities such as fibrillations and positive sharp waves, along with the frequent occurrence of small, brief early recruiting potentials (myotonic discharges), especially in the paraspinal muscles. Electrocardiography (ECG) was also mentioned (n\u0026thinsp;=\u0026thinsp;5), and the electroencephalogram was less frequent (n\u0026thinsp;=\u0026thinsp;1).\u003c/p\u003e\n\u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\n\u003ch2\u003eScales and Questionnaires\u003c/h2\u003e\n\u003cp\u003eForty-four studies included scales, with 38 (86%) reporting scales not specific to PD. Employed scales evaluated muscles (n\u0026thinsp;=\u0026thinsp;25), respiratory system (n\u0026thinsp;=\u0026thinsp;2), gastrointestinal system (n\u0026thinsp;=\u0026thinsp;1), cognitive function (n\u0026thinsp;=\u0026thinsp;3), and neurological disability (n\u0026thinsp;=\u0026thinsp;2). Only two articles (5%) employed specialized scales, for instance, Pompe Disease Symptom Scale (PDSS) and Pompe Disease Impact Scale (PDIS). Furthermore, four articles cited questionnaires to evaluate neuromuscular, respiratory symptoms, and pain (\u003cstrong\u003eTable\u0026nbsp;3\u003c/strong\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\n\u003ch2\u003eFollow-up of Patients with Pompe Disease\u003c/h2\u003e\n\u003cp\u003eThroughout this review, we found that functional assessments (n\u0026thinsp;=\u0026thinsp;107) are the most commonly utilized diagnostic tools. Functional monitoring encompasses various parameters, including muscle (n\u0026thinsp;=\u0026thinsp;43), respiratory evaluation involving spirometry, the most mentioned (n\u0026thinsp;=\u0026thinsp;51) among the selected articles, and other pulmonary function tests (PFT, n\u0026thinsp;=\u0026thinsp;4), including the monitoring of respiratory distress or disturbance using polysomnography (n\u0026thinsp;=\u0026thinsp;2).\u003c/p\u003e\n\u003cp\u003eIn the case of IOPD and progressive LOPD disease, the assessment of swallow function is imperative and should be conducted through serial evaluations. This approach enables the assessment of oropharyngeal muscle weakness and, when necessary, includes Video-Fluoroscopic Swallow Study (VFSS).\u003csup\u003e23\u003c/sup\u003e For those with LOPD, functional assessments are routinely carried out.\u003csup\u003e39,40\u003c/sup\u003e These assessments involve muscle strength measurements, comprehensive neuromuscular scales, and metabolic monitoring using quantitative muscle MRI (T1 weighted imaging) or the Dixon scale. Qualitative assessments cover posture, movement, musculoskeletal status, and standardized tests like the Alberta Infant Motor Scale (AIMS) and Gross Motor Function Measure (GMFM). Additionally, MRI has been recognized as a valuable tool for detecting muscle structure changes in symptomatic patients and can potentially be integrated into daily clinic follow-up protocols. It is worth noting that only one article referenced the use of INQoL as a patient-reported outcome measure.\u003csup\u003e41\u003c/sup\u003e\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e This scoping review gathered 96 articles concerning assessment methods to screen, diagnose, and follow up with PD. Our study is the first review to comprehensively map and characterize various assessment methods to improve the quality of care for PD patients. Nonetheless, the current literature underscores ongoing research and practice challenges that must be addressed.\u003c/p\u003e \u003cdiv id=\"Sec26\" class=\"Section2\"\u003e \u003ch2\u003eScreening\u003c/h2\u003e \u003cp\u003eNBS programs have been established in numerous countries to facilitate early detection and treatment of PD.\u003csup\u003e26,28,42\u0026ndash;44\u003c/sup\u003e However, NBS programs are not universally available.\u003csup\u003e27\u003c/sup\u003e The included studies showed disparities in the implementation of NBS among countries, with some having already launched pilot programs while others are in the early planning phases.\u003csup\u003e45\u0026ndash;49\u003c/sup\u003e The availability of screening also depended on the country's healthcare infrastructure and resources.\u003csup\u003e50\u0026ndash;52\u003c/sup\u003e The data from screening initiatives will prove instrumental in understanding the prevalence of PD and differentiating it from other musculoskeletal disorders.\u003csup\u003e29,53\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section2\"\u003e \u003ch2\u003eDiagnostic Biochemical and Genetic Methods\u003c/h2\u003e \u003cp\u003eBiochemical assessments are indispensable for detecting and monitoring PD's progression.\u003csup\u003e54\u0026ndash;57\u003c/sup\u003e As demonstrated by our review, biochemical analysis may encompass muscle enzymes such as GAA, CK (CPK); along with other enzymes, including AST, ALT, and Glc4. DBS was reported in 18 articles and emerged as the predominant method among reviewed enzyme assays. DBS can detect partial and total decreases in GAA enzyme activity. However, other pseudodeficiencies of GAA activity that do not result in PD should be considered, as they can complicate the diagnosis.\u003csup\u003e54\u003c/sup\u003e By characterizing the widespread use of DBS, our review emphasizes this method's potential feasibility and reliability in diagnosing PD.\u003csup\u003e27\u003c/sup\u003e This strategy should be considered in countries with limited resources since PD has available and under-development therapeutic options.\u003csup\u003e58\u0026ndash;60\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eNevertheless, we observed a lack of standardization in reporting DBS results, particularly in specifying quantitative thresholds. For example, we encountered eight articles that characterized GAA deficiency solely through qualitative terms like 'significantly decreased,' 'reduced,' 'decreased,' 'low limit level,' and 'deficient activity,' whereas seven articles omitted such descriptive qualifiers. This variation in reporting GAA activity highlights the need for standardization in conveying these results to foster further research correlations, enhance applicability to clinical practice, and facilitate its implementation.\u003csup\u003e54\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAs a monogenic recessive disease, diagnosing PD requires the identification of at least two mutations in the GAA gene. In cases where a single or no mutation is detected, diagnosis relies on reduced GAA activity in at least two tissues, with blood and skeletal muscle being the most frequently examined.\u003csup\u003e61\u003c/sup\u003e This approach follows the recommendations of the European Pompe Consortium.\u003csup\u003e35\u003c/sup\u003e In our review, most selected papers emphasized the need for confirmatory genetic analysis of the GAA gene following biochemical observation of reduced GAA activity.\u003csup\u003e5,36,62\u0026ndash;64\u003c/sup\u003e Some articles highlighted the limitations of traditional Sanger sequencing in detecting the two alleles.\u003csup\u003e2,31,65\u0026ndash;67\u003c/sup\u003e Notably, seven of 21 citations that applied genetic methods did not specify the sequencing strategy they utilized. However, studies utilizing NGS as a diagnostic tool did not encounter these difficulties.\u003csup\u003e31,36,66,68\u003c/sup\u003e Based on our included articles, NGS should be considered the gold standard assessment tool for accurate patient genotyping.\u003csup\u003e31\u003c/sup\u003e Sanger sequencing should be reserved for mutation confirmation when necessary.\u003c/p\u003e \u003cp\u003eWhile \u0026ldquo;classic infantile\u0026rdquo; PD patients have mutations that disrupt all GAA protein forms, the precise relationship between specific genotype and phenotype expressions remains elusive.\u003csup\u003e2,3,5\u003c/sup\u003e In this context, the cross-reactive immunologic material (CRIM) status is relevant to classify IODP into two groups: those with detectable (CRIM+) and undetectable GAA protein (CRIM-), with the latter group demonstrating worse prognosis and response to enzyme replacement therapy.\u003csup\u003e69\u003c/sup\u003e The CRIM status can be determined through genotype predictions or a rapid turnaround blood-based leukocyte assay.\u003csup\u003e70,71\u003c/sup\u003e In our review, only one article reported the CRIM status of each evaluated patient.\u003csup\u003e68\u003c/sup\u003e Further research and comprehensive reporting are warranted to elucidate the interplay between genotype, phenotype, CRIM status, and varying levels of GAA enzyme activity.\u003c/p\u003e \u003cp\u003eMoreover, although some articles encountered new gene variants, those variants were unavailable on the PD reference database.\u003csup\u003e4\u003c/sup\u003e This finding highlights the urgent demand for creating a universal database dedicated to variants in PD, which should function as a comprehensive point of reference.\u003csup\u003e3,4,38\u003c/sup\u003e These initiatives are essential to standardize the documentation of genetic mutations following widely accepted molecular nomenclature.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec28\" class=\"Section2\"\u003e \u003ch2\u003eEvaluation of clinical manifestations\u003c/h2\u003e \u003cp\u003eConcerning clinical assessment, a pervasive challenge observed in reviewed articles was the heterogeneous classification of PD\u0026rsquo;s clinical spectrum.\u003csup\u003e2,72\u003c/sup\u003e In this regard, the classification proposed by G\u0026uuml;ng\u0026ouml;r and Rouser seems an alternative to mitigate confusion and could be universally adopted to categorize PD subtypes.\u003csup\u003e73\u003c/sup\u003e This classification delineates three yet overlapping categories within the clinical spectrum: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) \u0026ldquo;classic infantile\u0026rdquo; PD (CIPD), diagnosed within the first year of life and representing the severe form of PD; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) pediatric PD (POPD), which encompasses patients with clinical onset from birth to adolescence (e.g., \u0026le;\u0026thinsp;14 years) but without persistent and progressive cardiac hypertrophy; and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) adult PD (AOPD) for patients with symptom onset from adolescence (e.g., \u0026ge;\u0026thinsp;14 years) to late adulthood. Achieving consensus in reporting is crucial, as it aids healthcare professionals in increasing awareness of PD clinical manifestations in infants.\u003c/p\u003e \u003cp\u003eFurthermore, while the clinical manifestations described in the selected papers provided characteristic indicators that raise suspicion of PD during the diagnostic process, only one article explicitly referenced using standardized terms and identification numbers proposed by HPO in their study.\u003csup\u003e38\u003c/sup\u003e The existing literature exhibits significant discrepancies in the clinical description of patient phenotypes, highlighting the need for standardization.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up\u003c/h2\u003e \u003cp\u003eAfter confirming the diagnosis, individuals with PD require ongoing follow-up and monitoring. This may involve regular visits to healthcare providers, including specialists in neuromuscular diseases, cardiology, and pulmonology. The frequency of follow-up visits may vary according to individual needs and disease progression. In our review, we identified a lack of consensus regarding the best approach to follow up with LOPD cases. Also, existing guidelines were not consistently adhered to.\u003csup\u003e74\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe knowledge of the diagnosis, particularly in individuals without symptoms or functional impairment, may trigger psychological issues that impact their quality of life (QoL), such as anxiety or depression.\u003csup\u003e75\u0026ndash;77\u003c/sup\u003e Patients and families may benefit from psychosocial support to cope with the emotional and psychological distress associated with this chronic and progressive condition.\u003csup\u003e78,79\u003c/sup\u003e As observed in this scoping review, there is a limited focus on the QoL of LOPD patients, in which only one paper mentioned the use of INQoL as a patient-reported outcome measure.\u003csup\u003e41\u003c/sup\u003e For instance, establishing a national disease registry would provide a starting point for administering QoL assessments among PD patients and increase the number of related studies.\u003csup\u003e75,76\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAnother identified concern was the importance of continuous evaluation and vigilant monitoring for asymptomatic PD patients identified through NBS. Notably, one study mentioned serum platelet-derived-growth-factor-BB (PDGF-BB) as a potential biomarker.\u003csup\u003e24\u003c/sup\u003e As indicated by PDGF-BB levels, the dysregulation of muscle regeneration suggests its potential use in monitoring asymptomatic LOPD patients. This emerging biomarker warrants further investigation to clarify its role in disease management.\u003csup\u003e24\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"Limitations","content":"\u003cp\u003eDespite the comprehensive scope of this review, some limitations must be acknowledged. We only included citations in English or Spanish, excluding relevant research in other languages. Our review relied on literature available up to its knowledge cut-off date of February 8, 2022, and does not encompass advancements in PD assessment published afterward. Additionally, differences in study design, sample size, and methodology across the included studies could affect the generalizability of findings. Although efforts to ensure international representation in the selected studies were made, the overrepresentation of literature from specific geographic regions may limit the application of our findings to other populations. Lastly, as a scoping review, we did not assess individual study biases. Future research should consider these limitations to enhance our understanding of PD screening, diagnosis, and management.\u003c/p\u003e"},{"header":"Conclusion","content":" \u003cp\u003eIn this scoping review, we comprehensively evaluated reported assessment methods for PD, including screening, diagnosis, and follow-up. By estimating the prevalence in which methods are applied and its respective findings, our review synthesized evidence that can guide healthcare providers to expedite diagnosis and treatment, especially in infants carrying common genetic variants. Nonetheless, our review also highlighted the need for a more standardized and streamlined approach to PD assessment, encompassing various assessment categories. As research in PD evolves, these aspects should be considered to ultimately enhance the quality of healthcare provided to patients with PD.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eALT\u003c/strong\u003e: Alanine aminotransferase\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAST\u003c/strong\u003e: Aspartate aminotransferase\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCK\u003c/strong\u003e: Creatine kinase\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRIM\u003c/strong\u003e: Cross-reactive immunologic material\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCT\u003c/strong\u003e: Computed tomography\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDBS\u003c/strong\u003e: Dried blood spot\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDOI\u003c/strong\u003e: Digital Object Identifier System\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eECG\u003c/strong\u003e: Electrocardiography\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEMG\u003c/strong\u003e: Electromyography\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGAA\u003c/strong\u003e: Acid Alpha-glucosidase\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGMFM\u003c/strong\u003e: Gross Motor Function Measure\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGlc4\u003c/strong\u003e: Urinary glucose tetrasaccharide\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGSDII\u003c/strong\u003e: Glycogen storage disease type II\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIOPD\u003c/strong\u003e: Infantile-onset Pompe Disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLOPD\u003c/strong\u003e: Late-onset Pompe Disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLSD\u003c/strong\u003e: Lysosomal Disorders\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMIM\u003c/strong\u003e: Mendelian Inheritance in Man\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMRI\u003c/strong\u003e: Magnetic Resonance Imaging\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNBS\u003c/strong\u003e: Newborn screening\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eORFHA308552\u003c/strong\u003e: Orphanet rare disease nomenclature for IOPD\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eORFHA420429\u003c/strong\u003e: Orphanet rare disease nomenclature for LOPD\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eORPHA365\u003c/strong\u003e: Orphanet rare disease nomenclature for PD\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePD\u003c/strong\u003e: Pompe Disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePRISMA\u003c/strong\u003e-\u003cstrong\u003eScR\u003c/strong\u003e: Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQMFT\u003c/strong\u003e: Quick motor-function test\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVFSS\u003c/strong\u003e: Video-fluoroscopic swallowing study\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eAll data generated or analyzed during this study are included in this published article and its supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThe Rare Diseases Community received financial support from FONTAR (Fondo Tecnol\u0026oacute;gico Argentino) of the Agencia Nacional de Promoci\u0026oacute;n de la investigaci\u0026oacute;n, el Desarrollo y la Innovaci\u0026oacute;n (Ministerio de Ciencia, Tecnolog\u0026iacute;a e Innovaci\u0026oacute;n) under grant number ANR 25000 2022 F2 032/22.\u0026nbsp;FONTAR did not contribute to the design, data collection, analysis, interpretation, manuscript preparation, or decision to submit this manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u0026nbsp;\u003c/strong\u003eLNC, AG, LFS, MMM, JS, CFA conceptualized the study and developed the methodology. FFZ conducted the search strategy at thirteen databases. LNC, FFZ, and CFA performed data curation. IDR, DMIA, FNDPG, and MGSJ screened and extracted data from identified citations. LNC and CFA solved discrepancies between reviewers. LNC, JS, and CFA provided utilized software. CFA conducted a formal analysis. LNC and CFA prepared tables and figures. IDR, LNC, DB, and CFA interpreted the data. IDR, DMIA, FNDPG, LNC and CFA wrote the first draft of the manuscript. All authors revised the manuscript content. Project administration was done by AG, CFA and JS supervised this study. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e Authors express their heartfelt appreciation to Dr. Gaston A. Rodriguez-Granillo for having revised the manuscript and provided invaluable insights which enhanced this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMarques JS. 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Available from: http://dx.doi.org/10.1016/j.nmd.2018.05.007\u003c/li\u003e\n\u003cli\u003eNi\u0026ntilde;o MY, Wijgerde M, de Faria DOS, Hoogeveen-Westerveld M, Bergsma AJ, Broeders M, et al. Enzymatic diagnosis of Pompe disease: lessons from 28 years of experience. Eur J Hum Genet [Internet]. 2021 Mar;29(3):434\u0026ndash;46. Available from: http://dx.doi.org/10.1038/s41431-020-00752-2\u003c/li\u003e\n\u003cli\u003eGoldstein JL, Young SP, Changela M, Dickerson GH, Zhang H, Dai J, et al. Screening for Pompe disease using a rapid dried blood spot method: experience of a clinical diagnostic laboratory. Muscle Nerve [Internet]. 2009 Jul;40(1):32\u0026ndash;6. Available from: http://dx.doi.org/10.1002/mus.21376\u003c/li\u003e\n\u003cli\u003eKishnani PS, Amartino HM, Lindberg C, Miller TM, Wilson A, Keutzer J. Methods of diagnosis of patients with Pompe disease: Data from the Pompe Registry. Mol Genet Metab [Internet]. 2014 Jul 16;113(1-2):84\u0026ndash;91. 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Available from: http://dx.doi.org/10.1016/j.ymgme.2013.07.020\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 3 is not available with this version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Assessments methods for diagnosis and follow-up of Pompe Disease (PD).\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Fundación SPINE \u0026 Rare Diseases Community, Buenos Aires, Argentina","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Glycogen Storage Disease Type II, Cardiomyopathy, Hypertrophic, Lysosomal Storage Diseases, Muscle Weakness, Rare Diseases","lastPublishedDoi":"10.21203/rs.3.rs-3909349/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3909349/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePompe Disease (PD) is a rare progressive autosomal recessive disorder resulting from deficient acid alpha-glucosidase (GAA) enzyme activity, necessitating timely identification and management. This scoping review aimed to synthesize the evidence regarding assessment methods for screening, diagnosing, and following up PD.\u003c/p\u003e\u003ch2\u003eMethods and Results\u003c/h2\u003e \u003cp\u003eWe searched citations in English and Spanish published from 2017 until February 8, 2022, across 11 databases. We included primary studies, reviews, and guidelines that described at least one assessment method for patients with confirmed clinical, genetic, or biochemical PD. Screening and data extraction adhered to PRISMA-ScR. Data was summarized narratively and with descriptive statistics. After screening 2,139 citations, 96 met the eligibility criteria. Cross-sectional studies were the most prevalent design (28%), while guidelines were the least frequent (1%). Newborn screening availability varied among countries, despite its potential to improve PD prevalence estimations. Overall, 81 articles assessed clinical manifestations, with 47 focusing on late-onset PD. We identified considerable heterogeneity in reporting PD phenotypes. The use of dried blood spots for GAA enzyme deficiency detection was described in 18 articles, but reporting lacked standardization. Next-generation sequencing emerged as the gold standard for identifying mutated alleles. Monitoring strategies for pediatric and adult PD lacked consensus, and only one article assessed quality of life.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003e This scoping review summarized the evidence to comprehensively evaluate PD patients, emphasizing current practices and existing challenges that must be tackled to optimize screening, diagnosis, and follow-up of PD.\u003c/p\u003e","manuscriptTitle":"Navigating Pompe Disease Assessment: A Comprehensive Scoping Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-30 21:04:52","doi":"10.21203/rs.3.rs-3909349/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ccf361d7-1379-48e2-8068-28364699fc8d","owner":[],"postedDate":"January 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":28440708,"name":"Medical Genetics"},{"id":28440709,"name":"General Practice"}],"tags":[],"updatedAt":"2024-01-30T21:04:52+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-30 21:04:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3909349","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3909349","identity":"rs-3909349","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}