Clinical and Genetic Landscape of Neuronopathic Gaucher Disease in Ukraine: Hepatosplenomegaly and Diagnostic Delay

Clinical and Genetic Landscape of Neuronopathic Gaucher Disease in Ukraine: Hepatosplenomegaly and Diagnostic Delay | 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 Research Article Clinical and Genetic Landscape of Neuronopathic Gaucher Disease in Ukraine: Hepatosplenomegaly and Diagnostic Delay Nataliia Samonenko, Nataliia Olkhovych, Olena Okhotnikova, Nataliia Gorovenko This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9348927/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background: Neuronopathic Gaucher disease (GD types II and III) represents rare and severe phenotypes of glucocerebrosidase deficiency, characterized by neurological involvement and variable systemic manifestations. Data on clinical presentation and genotype–phenotype patterns in Eastern European populations remain limited. Methods: We conducted a retrospective cohort study of 92 patients with confirmed Gaucher disease followed at the National Children’s Specialized Hospital “Okhmatdyt” (Kyiv, Ukraine) between 2001 and 2024. Among them, 4 patients had type II and 6 had type III GD. Diagnosis was established by measurement of leukocyte β-glucocerebrosidase activity and molecular analysis of the GBA1 gene. Clinical, laboratory, and imaging data were analyzed descriptively. Results: Type II GD presented in early infancy (mean age at onset 0.25 ± 0.19 years) and was diagnosed at 0.58 ± 0.19 years. Initial manifestations included cytopenias, splenomegaly, failure to thrive, and ichthyosiform dermatitis. Hepatomegaly was uncommon at onset, but hepatosplenomegaly was documented in all patients at diagnosis, followed by rapid neurological regression and death before 14 months of age. Type III GD had a mean age at onset of 2.3 ± 1.66 years and a mean age at diagnosis of 13.8 ± 16.87 years, reflecting substantial diagnostic delay. Oculomotor apraxia was the most frequent presenting symptom (83%). At diagnosis, all patients exhibited hepatosplenomegaly, cytopenias, and neurological involvement, while liver function remained preserved. Across both phenotypes, genotype analysis identified R/R, R/O, and O/O GBA1 variant combinations. Severe clinical courses were observed even in patients carrying variants associated with predicted residual enzyme activity, indicating limited genotype–phenotype correlation. Conclusions: In this Ukrainian cohort, neuronopathic GD demonstrated distinct clinical trajectories, with rapidly progressive infantile disease in type II and heterogeneous presentation with marked diagnostic delay in type III. Hepatosplenomegaly emerged as a consistent feature during disease progression and may serve as an important clinical indicator in patients with suspected neuronopathic GD. Gaucher disease Neuronopathic Gaucher disease Hepatosplenomegaly Hepatomegaly Liver Children Diagnostic delay GBA1 Rare diseases Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Gaucher disease (GD; OMIM #230800, #230900, #231000) is a rare inherited metabolic disorder belonging to the group of lysosomal storage diseases. Its prevalence in the general population is estimated at 1 case per 60,000-100,000 live births. The disease is associated with a deficiency of the lysosomal enzyme glucocerebrosidase (EC 3.2.1.45), primarily affecting the cells of the liver, spleen, and bone marrow. Depending on the involvement of different organs, the clinical manifestations of the disease include hepatomegaly, splenomegaly, anemia, thrombocytopenia, and bone pathology [14, 21]. Neuronopathic forms of the disease are considered separately, as their course is associated with involvement of the nervous system [4]. Three clinical phenotypes of GD are recognized: type I (GD1; OMIM #230800), or non-neuronopathic; type II (GD2; OMIM #230900), or acute neuronopathic; and type III (GD3; OMIM #231000), chronic neuronopathic. They are defined according to the presence or absence, severity, and rate of progression of neurodegeneration [2]. Type II GD is the most severe form of the disease, with clinical manifestations including pronounced visceral involvement, ichthyosis, thrombocytopenia, developmental delay, and dysphagia. These children usually die in the neonatal period or before the age of two years. Because of the clinical heterogeneity of type III GD, this form is further divided into subphenotypes. Type IIIa is characterized by myoclonic epilepsy; type IIIb, which is the most common, is characterized by impaired saccadic eye movements in combination with pronounced visceral involvement; and type IIIc presents with aortic calcification, hydrocephalus, and/or corneal clouding [18]. Unlike type I, patients with types II and III GD have limited treatment options. At present, there is no effective treatment for type II GD. Unfortunately, enzyme replacement therapy (ERT) has not demonstrated efficacy in the treatment of this form of the disease and is therefore not currently recommended for such patients. Symptomatic therapy is used to improve quality of life. However, it is not pathogenetic and does not halt disease progression or lead to regression of the disease [18]. Palliative care for these patients includes physical therapy, seizure control, respiratory support, and nutritional support. Type III GD progresses more slowly and is associated with variable neurological manifestations. Therefore, in this form, ERT is the standard of care and is effective in eliminating or reducing somatic manifestations, such as hepatosplenomegaly and hematologic abnormalities, but it does not affect neurological symptoms because of its limited ability to cross the blood-brain barrier [14]. In patients with type III GD, hematopoietic stem cell transplantation may be considered when the disease is diagnosed at the presymptomatic stage or early in the course of clinical manifestations [20]. The aim of this study was to characterize the clinical manifestations and genotype of patients with types II and III GD in Ukraine, and to analyze the presence of hepatosplenomegaly as an early and significant clinical syndrome in neuronopathic forms of the disease. Materials and Methods This retrospective study was conducted based on the analysis of medical records of 92 patients from different regions of Ukraine who were diagnosed with Gaucher disease between 2001 and 2024. The data were obtained from the Center for Orphan Diseases and Gene Therapy of the National Children's Specialized Hospital “Okhmatdyt” of the Ministry of Health of Ukraine. Diagnosis of the disease was established using biochemical and molecular genetic methods. In all patients, the activity of β-glucocerebrosidase in leukocytes (EC 3.2.1.45) and the plasma chitotriosidase (EC 3.2.1.14) level were determined. The reference range for leukocyte β-glucocerebrosidase activity was 5.1-9.5 nmol/h/mg protein, and the reference range for chitotriosidase was 0-159 nmol/h/mL plasma. Molecular genetic confirmation of the diagnosis was performed by analysis of allelic variants of the GBA 1 gene using Sanger sequencing and next-generation sequencing (NGS). Clinical evaluation of the patients included detailed history taking, general physical examination, as well as instrumental and laboratory assessment of liver involvement. Ultrasonography (US) was used to assess liver size and structure, and functional status was evaluated based on serum transaminase levels. Liver and spleen size were considered enlarged if their volume exceeded the expected body weight-adjusted values by 2.5-fold or was more than 1.25-fold above the age-specific norm. Depending on the degree of liver and spleen enlargement, all patients were divided into four groups: “normal size” (within the age-specific norm), “mild enlargement” (up to 1.25-fold above the age-specific norm), “marked enlargement” (more than 1.25-fold but less than 2.0-fold above the age-specific norm), and “severe enlargement” (more than 2.0-fold above the expected age-specific value). Allelic variants were classified according to the functional activity of β-glucocerebrosidase on the basis of residual enzyme activity: R (residual), referring to variants with preserved residual activity, and O (other/null), referring to variants leading to severe enzyme deficiency. Statistical analysis was primarily descriptive due to the small sample size of neuronopathic cases. Continuous variables are presented as means ± standard deviation (SD) and ranges, while categorical variables are reported as absolute numbers and percentages. No inferential statistical comparisons between phenotypes were performed because of the limited number of patients in each subgroup. Data analysis was conducted using Statistica 7.0 (StatSoft Inc., Tulsa, OK, USA), MedCalc (MedCalc Software Ltd., Belgium), and Microsoft Excel. Results We analyzed the primary medical records of 92 patients (55 females and 37 males) who were diagnosed with Gaucher disease at the National Children’s Hospital “Okhmatdyt” between 2001 and 2024. Of these, 82 patients (89%) had type I GD, 4 children (4%) had type II GD, and 6 patients (7%) had type III GD (Fig. 1). In type II GD, the mean age at disease onset was 0.25 ± 0.19 years (range, 2-3 weeks to 6 months), and the mean age at diagnosis was 0.58 ± 0.19 years (range, 4-8 months). Patients with type II GD were diagnosed relatively quickly, with a mean interval of 3 months from disease onset to diagnosis. In all patients, type II GD presented with hematologic abnormalities, splenomegaly, and failure to thrive. In one child (25%), splenomegaly was accompanied by hepatomegaly. Three of the four children (75%) had dry skin from birth, which was interpreted as ichthyosiform dermatitis. One patient (25%) also had early developmental delay (Fig. 2). At presentation to the National Children’s Specialized Hospital “Okhmatdyt,” all patients were in severe condition, with delayed or regressing motor development, seizures, ichthyosis, failure to thrive, and marked hepatosplenomegaly. These symptoms developed rapidly, within 2-3 months of disease onset. At the time of diagnosis, all children had hepatosplenomegaly of varying severity. Two patients (50%) had mild hepatomegaly, with liver size up to 1.25-fold above the age-specific norm, whereas in the remaining two patients (50%) hepatomegaly was more pronounced, ranging from >1.25-fold to 1.25-fold to <2.0-fold, and in the other two children (50%), by 2.0-fold (Fig. 3). All patients (4/4) had a marked cytolytic syndrome, with transaminase levels elevated 2- to 3-fold. All children also showed substantial reductions in platelet counts and hemoglobin levels. Two patients developed severe portal hypertension and liver failure. All patients exhibited rapid progression of neurological manifestations, with developmental regression, loss of acquired skills, and death occurring between 10 months and 1.2 years of age. All patients underwent comprehensive molecular genetic testing. Pathogenic variants in the GBA1 gene were identified, including c.1288C>G/c.84dup, c.721G>A/c.1268C>A, c.721G>A/c.604C>T, and c.255_257delGCG/c.475C>T (Table 1). According to the classification of GBA1 variants based on their functional effect on residual enzyme activity, c.1288C>G, c.1268C>A, and c.475C>T were classified as R variants (residual-function variants), whereas c.84dup, c.721G>A, c.604C>T, and c.255_257delGCG were classified as O variants (severe/null variants) [8-11]. Accordingly, among patients with type II GD, we identified the following R/O combinations: c.475C>T/c.255_257delGCG, c.1288C>G/c.84dup, and c.1268C>A/c.721G>A, as well as one severe O/O combination: c.721G>A/c.604C>T. In three patients, chitotriosidase activity exceeded the reference values by 40- to 86-fold, with a mean increase of 59.7 ± 23.5-fold. In the same patients, β-glucocerebrosidase activity ranged from 43% to 65% of the lower reference limit, with a mean of 56.8 ± 12.4%. In one patient, lysosomal enzyme activity could not be determined because of extensive prior blood transfusions. In type III GD, the mean age at disease onset was 2.3 ± 1.66 years (range, 0.5-5 years), and the mean age at diagnosis was 13.8 ± 16.87 years (range, 2-47 years) (Fig. 1). Among the six patients with type III GD, the most common initial manifestation was oculomotor apraxia, observed in five patients (83%). Hepatosplenomegaly was present at disease onset in three patients (50%), developmental delay in two patients (33%), and isolated splenomegaly in one child (17%) (Fig. 4). The mean interval from the onset of the first symptoms to diagnosis in patients with type III GD was 11.5 ± 17.5 years (range, 1-46.5 years). At the time of diagnosis, all patients had, in addition to neurological manifestations, thrombocytopenia, anemia, marked splenomegaly, and hepatomegaly without evidence of impaired liver function. Hepatomegaly was present in all patients. One child (17%) had mild hepatomegaly, with liver size up to 1.25-fold above the age-specific norm; in four patients (67%), hepatomegaly was more pronounced, ranging from >1.25-fold to <2.0-fold above the age-specific norm; and in one patient (17%), liver size exceeded the age-specific norm by more than 2.0-fold. Splenomegaly was markedly more severe in all patients: in one patient (17%), spleen size exceeded the age-specific norm by >1.25-fold to <2.0-fold, whereas in the remaining five patients (83%), it exceeded the age-specific norm by more than 2.0-fold (Fig. 5). Transaminase and bilirubin levels in all patients remained within the normal range. According to ultrasound examinations, splenic infarction was detected in five patients, whereas one patient had fibrotic liver changes and calculous cholecystitis. All patients exhibited neurological involvement. Two children had marked regression of cognitive and motor development and developed seizures in early childhood; two patients had intention tremor; and three patients had ataxia. In one patient, who had long been followed for isolated splenomegaly, myelopathy presenting as lower paraparesis developed at the age of 40 years. Three patients with type III GD died due to neurological complications: one at 12 years of age and two at 15 years of age. All patients underwent comprehensive molecular genetic testing. Pathogenic variants in the GBA1 gene were identified, including c.721G>A, c.1448T>C, c.203dupC, c.1246G>A, c.1342G>C, c.1129G>A, c.999G>A, c.680A>G, c.732C>A, and c.1226A>G (Table 2). According to the functional classification of GBA1 variants based on their effect on residual enzyme activity, c.721G>A, c.1448T>C, c.203dupC, and c.732C>A were classified as O variants (severe/null variants). Other variants, including c.1226A>G, c.1246G>A, c.680A>G, c.1342G>C, c.1129G>A, and c.999G>A, were classified as R variants (residual-function variants) [8-11]. Among Ukrainian patients, the following genotypes were identified: O/O -c.721G>A/c.1448T>C; R/O -c.203dupC/c.1246G>A, c.721G>A/c.1342G>C, c.680A>G/c.732C>A, and c.1226A>G/c.1448T>C; and R/R -c.1129G>A/c.999G>A. In the study patients, chitotriosidase activity exceeded the reference range by 30- to 130-fold, with a mean increase of 67.1 ± 32.8-fold. β-Glucocerebrosidase activity ranged from 31% to 82% of the lower reference limit, corresponding to a mean activity of 2.52 ± 0.93 nmol/mg/h, or 52.5 ± 19.4%. Discussion Compared with type I GD, types II and III GD are rarer and less well-studied forms of Gaucher disease. Limited physician awareness of the neuronopathic course of GD often leads to delayed diagnosis. This may reduce the effectiveness of disease-specific therapy when available and may also result in unnecessary diagnostic procedures in affected children. Central nervous system involvement, which characterizes these phenotypes, should be taken into account in the differential diagnosis of patients with suspected lysosomal storage disorders (LSDs). In this national series, comprehensive diagnostic evaluation of GD is currently performed only at the Laboratory of Medical Genetics of the National Children’s Specialized Hospital “Okhmatdyt.” Thus, this center allows analysis of all known diagnosed cases in the present study. According to international GD registries, type II accounts for approximately 1% of all reported GD cases, whereas type III accounts for about 5% [1, 5]. In the Ukrainian cohort, according to our own data, type II GD and type III GD accounted for 4% and 7% of cases, respectively. This difference is most likely related to the small sample size, physicians’ awareness of the clinical features of neuronopathic GD, and the availability of diagnostic testing for this disorder. The course of type II GD in Ukrainian patients generally corresponds to previously published data reported by other authors [2, 4, 6]. The main manifestations at disease onset include splenomegaly, hematologic abnormalities, ichthyosiform dermatitis, failure to thrive, and neurological impairment, with neurological manifestations predominating over somatic features. Among the patients observed in this study, stridor and swallowing disturbances were not noted as presenting symptoms; these manifestations developed later as the disease progressed. Hepatosplenomegaly is a common feature in patients with type II GD. All children included in the study showed enlargement of both the liver and spleen. Hepatomegaly was mild in half of the patients (50%), with liver size up to 1.25-fold above the expected age-specific norm, whereas in the remaining 50% it was more pronounced, ranging from >1.25-fold to 1.25-fold to <2.0-fold and more than 2.0-fold above the age-specific norm. These findings are consistent with published data [4, 14] and may represent a marker of severe disease course and rapid progression. The clinical presentation of type III GD is characterized by substantially greater variability than type II GD, which follows a rapidly progressive acute neuronopathic course, and by slower disease progression. In Ukrainian patients, the presenting features included oculomotor apraxia, hepatosplenomegaly, and developmental delay, which later progressed to marked hepatosplenomegaly and neurological manifestations such as ataxia, myoclonus, and regression of cognitive and motor development. These findings are consistent with previously published data on the natural history of this disease [15, 18]. One patient never developed oculomotor apraxia or ataxia but, in adulthood, developed myelopathy with lower paraparesis, which is not entirely typical of type III GD. The clinical course in this patient may correspond to an atypical form of type III GD in which other neurological manifestations did not occur [19]. Splenomegaly and hepatomegaly are consistent clinical features in patients with type III GD. As in type II GD, all patients exhibited hepatosplenomegaly. Hepatomegaly was mild in only one patient (17%), with liver size up to 1.25-fold above the expected age-specific norm, whereas most patients (67%) had more pronounced enlargement in the range of >1.25-fold to 1.25-fold to <2.0-fold and more than 2.0-fold above the age-specific norm. These observations are supported by other clinical data indicating that, in patients with type III GD, splenomegaly may be more pronounced than hepatomegaly [15]. Analysis of chitotriosidase activity, which was markedly elevated above the reference range in patients with both type II and type III GD, indicates pronounced macrophage activation in response to glucocerebroside accumulation [12]. At the same time, residual β-glucocerebrosidase activity was preserved in these patients, although this did not prevent the development of a severe clinical phenotype [10, 11]. Among the pathogenic GBA1 variants analyzed in patients with type II and type III GD, R/R, R/O, and O/O combinations were identified according to the classification based on residual enzyme activity. In patients carrying variants associated with potential residual activity (R), the clinical course was nevertheless severe, with early disease onset and rapid progression, which is characteristic of the acute and chronic neuronopathic forms of GD. This is consistent with published data suggesting that even R/O combinations may lead to severe forms of the disease because of the dominant negative effect of the null variant [15-17]. Other disease-modifying factors should also be considered. These include the accumulation of secondary metabolites, disruption of calcium (Ca²⁺) homeostasis, oxidative stress, chronic inflammation, abnormalities of lipid transport, impaired autophagy, endoplasmic reticulum (ER) stress, and activation of the unfolded protein response [13, 16]. To our knowledge, this study represents the first systematic national analysis of neuronopathic Gaucher disease in Ukraine, encompassing all diagnosed cases managed at the country’s primary referral center over more than two decades. The findings highlight a striking diagnostic delay in type III GD, with a mean interval exceeding a decade between symptom onset and diagnosis, underscoring the need for increased awareness among pediatricians and neurologists. Notably, hepatosplenomegaly emerged as a consistent and progressive feature across both phenotypes, suggesting that careful assessment of liver and spleen size may facilitate earlier recognition of neuronopathic GD in patients with neurological manifestations. Furthermore, the observed clinical severity in patients carrying variants predicted to retain residual enzyme activity reinforces the limited predictive value of genotype–phenotype correlations in this cohort and points toward additional modifying factors influencing disease expression. Limitations This study has several limitations. First, the sample size of patients with neuronopathic Gaucher disease was small, reflecting the rarity of these phenotypes and limiting the ability to perform inferential statistical analyses. Second, the retrospective design may have resulted in incomplete documentation of early clinical manifestations and variability in follow-up data. Third, the study was conducted at a single national referral center, which may introduce referral bias and limit the generalizability of findings to other populations. Finally, although genetic variants were classified according to previously published data on predicted residual enzyme activity, genotype–phenotype correlations remain inherently complex in neuronopathic Gaucher disease and should be interpreted with caution. Conclusions The results of this retrospective study highlight the key clinical characteristics of type II and type III Gaucher disease in Ukrainian patients and represent the first systematic national analysis of neuronopathic GD in Ukraine. Type II GD demonstrated very early onset, failure to thrive, dermatological and neurological manifestations, and rapid progression leading to early mortality. In contrast, type III GD showed a more heterogeneous course, including oculomotor apraxia, ataxia, developmental delay, and slower progression. Hepatosplenomegaly was consistently observed across both phenotypes and may serve as an important early clinical indicator in patients presenting with neurological symptoms. Our findings also emphasize the limited predictive value of genotype–phenotype correlations based solely on residual enzyme activity, underscoring the importance of comprehensive clinical evaluation in neuronopathic GD. These data contribute to improving diagnostic pathways and may support the development of national rare disease registries and targeted awareness strategies. Declarations Author contributions NS: Data curation, collected and analyzed data, investigation, coordinated patient management, wrote the manuscript, validation and submitted it to the journal. NO: Formal analysis, investigation, collected and analyzed clinical data, and performed diagnostic testing to confirm Gaucher disease. OO: initiated the research, supervision, writing – review & editing. NG: Investigation, supervision, writing – review & editing. Name of the corresponding author Nataliia Samonenko A cknowledgments The authors would like to thank all the patients and their families for their contribution to this study. We also acknowledge the valuable support of Nataliia Mytsyk, Svitlana Kormoz, and Iryna Hrehul, staff of the Medical Genetics Laboratory, for their involvement in the diagnostic work-up of patients. We are also grateful to Nataliia Pichkur and Yana Doronina for their long-term commitment and work at the Center of Orphan Diseases and Gene Therapy of the National Children’s Specialized Hospital “Okhmatdyt”, Kyiv, Ukraine. We are deeply grateful to every physician in Ukraine who, despite the difficult times of war, continues their vital work in caring for patients and preserving the hard-earned achievements of our healthcare system. Funding The authors declare that no financial support was received for the research, authorship, and/or publication of this article. Ethics statement The studies involving human participants were reviewed and approved by the Ethics Committee of the National Children’s Specialized Hospital "Okhmatdyt" of the Ministry of Health of Ukraine. Written informed consent for diagnostic procedures, clinical assessments, and use of anonymized data for research and publication was obtained from all participants or their legal guardians prior to inclusion in the institutional database. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Consent All patients and their parents or legal representatives provided signed and dated written informed consent for diagnostic evaluation and for publication of de-identified clinical data, in accordance with the legislation of Ukraine and applicable national data protection requirements. References Charrow J, Andersson HC, Kaplan P, et al. 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Genotypes and major clinical features observed in patients with type II GD No Age at onset (months) Age at diagnosis (months) Age at death (months) Presenting symptoms Hepatosplenomegaly Developmental regression Additional clinical information Chitotriosidase activity (nmol/h/mL plasma) β -Glucocerebrosidase activity (nmol/h/mg protein) GBA1 genotype (cDNA) Functional classification 1 1 9 10 Ichthyosis, anemia, splenomegaly Yes Yes Liver failure ND ND c.475C>T / c.255_257delGCG R/O 2 1 5 14 Ichthyosis, hepatosplenomegaly, failure to thrive Yes Yes Liver failure 6000 2.2 c.1288C>G / c.84dup R/O 3 5 9 13 Anemia, failure to thrive, ichthyosis Yes Yes Severe neurological manifestations 12906 3.2 c.721G>A / c.1268C>A R/O 4 5 5 10 Failure to thrive, hepatosplenomegaly, developmental delay Yes Yes Severe neurological manifestations 7956 3.3 c.721G>A / c.604C>T O/O Abbreviations: GD – Gaucher disease; R – residual-function variant; O – null/severe variant Developmental regression refers to loss of previously acquired motor or cognitive skills. ND - not determined Table 2. Genotypes and major clinical features observed in patients with type III GD No Age at onset (years) Age at diagnosis (years) Age at death (years) Presenting symptoms Hepatosplenomegaly Developmental regression Additional clinical information Chitotriosidase activity (nmol/h/mL plasma) β -Glucocerebrosidase activity (nmol/h/mg protein) GBA1 genotype (cDNA) Functional classification 1 1.5 3 - Hepatosplenomegaly, strabismus, developmental delay Yes Yes Seizures 19448 1.6 c.721G>A / c.1448T>C O/O 2 3 6 12 Ophthalmoparesis, developmental delay Yes Yes Seizures 7293 2.6 c.1246G>A / c.203dupC R/O 3 5 12 - Ophthalmoparesis Yes No Motor dysfunction, ataxia 4552 4.2 c.1342G>С / c.721G>A R/O 4 1 2 15 Hepatosplenomegaly, ophthalmoparesis Yes No Intention tremor, ataxia, muscle hypotonia 11934 2.9 c.1129G>A / c.999G>A R/R 5 3 13 15 Hepatosplenomegaly, ophthalmoparesis Yes No Intention tremor, ataxia, muscle hypotonia 6632 2.2 c.680A>G / c.732C>A R/O 6 0.5 47 - Splenomegaly Yes No Paraparesis, myelopathy 10530 1.6 c.1226A>G / c.1448T>C R/O Abbreviations: GD – Gaucher disease; R – residual-function variant; O – null/severe variant Developmental regression refers to loss of previously acquired motor or cognitive skills. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 20 Apr, 2026 Reviewers agreed at journal 15 Apr, 2026 Reviewers agreed at journal 15 Apr, 2026 Reviewers agreed at journal 13 Apr, 2026 Reviewers invited by journal 09 Apr, 2026 Editor assigned by journal 08 Apr, 2026 Submission checks completed at journal 08 Apr, 2026 First submitted to journal 07 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-9348927","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":623419159,"identity":"9b5e488d-7909-401d-ac25-6cbeec2861de","order_by":0,"name":"Nataliia Samonenko","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYLCCBwZAgr0BSBhYEKOemYEhAaSF5wBIiwSxWkC0BIQkrMGc/fzBDwkFdfK6M59f3fCjQIKBv707Aa8Wy55kZokEg8OG227nlN3sATpM4szZDXi1GBxIBjrJ4AAjUEvaDR6gFgOJXAJazj9m/pFgUGe/7eaZtJt/iNJyI5kNaAtz4rYb7MduE2fLjcdmFkC/JG87k8N2W8ZAgoewX84nPr7x4U+d7bbjx5/dfPPHRo6/vRe/FiTAYwAmiVUOAuwPSFE9CkbBKBgFIwgAAChQSoGfIB8ZAAAAAElFTkSuQmCC","orcid":"","institution":"National Specialise Children Hospital “Okhmatdyt”","correspondingAuthor":true,"prefix":"","firstName":"Nataliia","middleName":"","lastName":"Samonenko","suffix":""},{"id":623419160,"identity":"ac5467ec-3d5b-4861-a2d2-e2feec535577","order_by":1,"name":"Nataliia Olkhovych","email":"","orcid":"","institution":"National Specialise Children Hospital “Okhmatdyt”","correspondingAuthor":false,"prefix":"","firstName":"Nataliia","middleName":"","lastName":"Olkhovych","suffix":""},{"id":623419162,"identity":"874aa24b-bd53-45a5-83fb-920c9a12b6a6","order_by":2,"name":"Olena Okhotnikova","email":"","orcid":"","institution":"Shupyk National Healthcare University of Ukraine","correspondingAuthor":false,"prefix":"","firstName":"Olena","middleName":"","lastName":"Okhotnikova","suffix":""},{"id":623419164,"identity":"1974bb10-cc05-4d2d-a768-f31e4be5017f","order_by":3,"name":"Nataliia Gorovenko","email":"","orcid":"","institution":"Shupyk National Healthcare University of Ukraine","correspondingAuthor":false,"prefix":"","firstName":"Nataliia","middleName":"","lastName":"Gorovenko","suffix":""}],"badges":[],"createdAt":"2026-04-07 19:38:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9348927/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9348927/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107256220,"identity":"932100ee-305a-4df9-ae87-ca8c14b4f766","added_by":"auto","created_at":"2026-04-19 12:15:53","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46409,"visible":true,"origin":"","legend":"\u003cp\u003eAge characteristics of patients with different types of GD\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9348927/v1/ebbe37a098ca6cb3c2076f83.png"},{"id":107484466,"identity":"9ac162a8-79e7-453b-be08-091199d83ba5","added_by":"auto","created_at":"2026-04-22 02:32:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":54128,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of presenting symptoms in patients with type II GD\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9348927/v1/e865a5322bbe3b6f038b57c4.png"},{"id":107483616,"identity":"bac0171c-e279-472b-b7e0-2e8fa18a5fab","added_by":"auto","created_at":"2026-04-22 02:28:28","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":31554,"visible":true,"origin":"","legend":"\u003cp\u003eHepatomegaly and splenomegaly at initial diagnosis in patients with type II GD at the National Children’s Specialized Hospital “Okhmatdyt”\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9348927/v1/506616f491ff43eb1cd56a89.png"},{"id":107256222,"identity":"9b20c1d3-17a9-482d-8172-4501cb1d08e7","added_by":"auto","created_at":"2026-04-19 12:15:53","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":49083,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of symptoms at disease onset in patients with type III GD\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9348927/v1/d6691c2117b45a43702c424c.png"},{"id":107484856,"identity":"7e963ea6-9b80-4ea3-882d-8b35d8f63ff5","added_by":"auto","created_at":"2026-04-22 02:33:10","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":35010,"visible":true,"origin":"","legend":"\u003cp\u003eHepatomegaly and splenomegaly at initial diagnosis in patients with type III GD at the National Children’s Specialized Hospital “Okhmatdyt”\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-9348927/v1/813d43aa03527b6031329411.png"},{"id":107487225,"identity":"055464a3-4ab1-452a-ae98-f7791b011a5e","added_by":"auto","created_at":"2026-04-22 02:40:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":555232,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9348927/v1/2bc8323a-4d49-4955-819f-1ec5a4c08ad6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical and Genetic Landscape of Neuronopathic Gaucher Disease in Ukraine: Hepatosplenomegaly and Diagnostic Delay","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGaucher disease (GD; OMIM #230800, #230900, #231000) is a rare inherited metabolic disorder belonging to the group of lysosomal storage diseases. Its prevalence in the general population is estimated at 1 case per 60,000-100,000 live births. The disease is associated with a deficiency of the lysosomal enzyme glucocerebrosidase (EC 3.2.1.45), primarily affecting the cells of the liver, spleen, and bone marrow. Depending on the involvement of different organs, the clinical manifestations of the disease include hepatomegaly, splenomegaly, anemia, thrombocytopenia, and bone pathology [14, 21]. Neuronopathic forms of the disease are considered separately, as their course is associated with involvement of the nervous system [4].\u003c/p\u003e\n\u003cp\u003eThree clinical phenotypes of GD are recognized: type I (GD1; OMIM #230800), or non-neuronopathic; type II (GD2; OMIM #230900), or acute neuronopathic; and type III (GD3; OMIM #231000), chronic neuronopathic. They are defined according to the presence or absence, severity, and rate of progression of neurodegeneration [2].\u003c/p\u003e\n\u003cp\u003eType II GD is the most severe form of the disease, with clinical manifestations including pronounced visceral involvement, ichthyosis, thrombocytopenia, developmental delay, and dysphagia. These children usually die in the neonatal period or before the age of two years.\u003c/p\u003e\n\u003cp\u003eBecause of the clinical heterogeneity of type III GD, this form is further divided into subphenotypes. Type IIIa is characterized by myoclonic epilepsy; type IIIb, which is the most common, is characterized by impaired saccadic eye movements in combination with pronounced visceral involvement; and type IIIc presents with aortic calcification, hydrocephalus, and/or corneal clouding [18].\u003c/p\u003e\n\u003cp\u003eUnlike type I, patients with types II and III GD have limited treatment options.\u003c/p\u003e\n\u003cp\u003eAt present, there is no effective treatment for type II GD. Unfortunately, enzyme replacement therapy (ERT) has not demonstrated efficacy in the treatment of this form of the disease and is therefore not currently recommended for such patients. Symptomatic therapy is used to improve quality of life. However, it is not pathogenetic and does not halt disease progression or lead to regression of the disease [18]. Palliative care for these patients includes physical therapy, seizure control, respiratory support, and nutritional support.\u003c/p\u003e\n\u003cp\u003eType III GD progresses more slowly and is associated with variable neurological manifestations. Therefore, in this form, ERT is the standard of care and is effective in eliminating or reducing somatic manifestations, such as hepatosplenomegaly and hematologic abnormalities, but it does not affect neurological symptoms because of its limited ability to cross the blood-brain barrier [14].\u003c/p\u003e\n\u003cp\u003eIn patients with type III GD, hematopoietic stem cell transplantation may be considered when the disease is diagnosed at the presymptomatic stage or early in the course of clinical manifestations [20].\u003c/p\u003e\n\u003cp\u003eThe aim of this study was to characterize the clinical manifestations and genotype of patients with types II and III GD in Ukraine, and to analyze the presence of hepatosplenomegaly as an early and significant clinical syndrome in neuronopathic forms of the disease.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThis retrospective study was conducted based on the analysis of medical records of 92 patients from different regions of Ukraine who were diagnosed with Gaucher disease between 2001 and 2024. The data were obtained from the Center for Orphan Diseases and Gene Therapy of the National Children\u0026apos;s Specialized Hospital \u0026ldquo;Okhmatdyt\u0026rdquo; of the Ministry of Health of Ukraine.\u003c/p\u003e\n\u003cp\u003eDiagnosis of the disease was established using biochemical and molecular genetic methods. In all patients, the activity of \u0026beta;-glucocerebrosidase in leukocytes (EC 3.2.1.45) and the plasma chitotriosidase (EC 3.2.1.14) level were determined. The reference range for leukocyte \u0026beta;-glucocerebrosidase activity was 5.1-9.5 nmol/h/mg protein, and the reference range for chitotriosidase was 0-159 nmol/h/mL plasma. Molecular genetic confirmation of the diagnosis was performed by analysis of allelic variants of the \u003cem\u003eGBA\u003c/em\u003e\u003cem\u003e1\u003c/em\u003e gene using Sanger sequencing and next-generation sequencing (NGS).\u003c/p\u003e\n\u003cp\u003eClinical evaluation of the patients included detailed history taking, general physical examination, as well as instrumental and laboratory assessment of liver involvement. Ultrasonography (US) was used to assess liver size and structure, and functional status was evaluated based on serum transaminase levels. Liver and spleen size were considered enlarged if their volume exceeded the expected body weight-adjusted values by 2.5-fold or was more than 1.25-fold above the age-specific norm. Depending on the degree of liver and spleen enlargement, all patients were divided into four groups: \u0026ldquo;normal size\u0026rdquo; (within the age-specific norm), \u0026ldquo;mild enlargement\u0026rdquo; (up to 1.25-fold above the age-specific norm), \u0026ldquo;marked enlargement\u0026rdquo; (more than 1.25-fold but less than 2.0-fold above the age-specific norm), and \u0026ldquo;severe enlargement\u0026rdquo; (more than 2.0-fold above the expected age-specific value).\u003c/p\u003e\n\u003cp\u003eAllelic variants were classified according to the functional activity of \u0026beta;-glucocerebrosidase on the basis of residual enzyme activity: R (residual), referring to variants with preserved residual activity, and O (other/null), referring to variants leading to severe enzyme deficiency.\u003c/p\u003e\n\u003cp\u003eStatistical analysis was primarily descriptive due to the small sample size of neuronopathic cases. Continuous variables are presented as means \u0026plusmn; standard deviation (SD) and ranges, while categorical variables are reported as absolute numbers and percentages. No inferential statistical comparisons between phenotypes were performed because of the limited number of patients in each subgroup. Data analysis was conducted using Statistica 7.0 (StatSoft Inc., Tulsa, OK, USA), MedCalc (MedCalc Software Ltd., Belgium), and Microsoft Excel.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe analyzed the primary medical records of 92 patients (55 females and 37 males) who were diagnosed with Gaucher disease at the National Children\u0026rsquo;s Hospital \u0026ldquo;Okhmatdyt\u0026rdquo; between 2001 and 2024. Of these, 82 patients (89%) had type I GD, 4 children (4%) had type II GD, and 6 patients (7%) had type III GD (Fig. 1).\u003c/p\u003e\n\u003cp\u003eIn type II GD, the mean age at disease onset was 0.25 \u0026plusmn; 0.19 years (range, 2-3 weeks to 6 months), and the mean age at diagnosis was 0.58 \u0026plusmn; 0.19 years (range, 4-8 months).\u003c/p\u003e\n\u003cp\u003ePatients with type II GD were diagnosed relatively quickly, with a mean interval of 3 months from disease onset to diagnosis.\u003c/p\u003e\n\u003cp\u003eIn all patients, type II GD presented with hematologic abnormalities, splenomegaly, and failure to thrive. In one child (25%), splenomegaly was accompanied by hepatomegaly. Three of the four children (75%) had dry skin from birth, which was interpreted as ichthyosiform dermatitis. One patient (25%) also had early developmental delay (Fig. 2).\u003c/p\u003e\n\u003cp\u003eAt presentation to the National Children\u0026rsquo;s Specialized Hospital \u0026ldquo;Okhmatdyt,\u0026rdquo; all patients were in severe condition, with delayed or regressing motor development, seizures, ichthyosis, failure to thrive, and marked hepatosplenomegaly. These symptoms developed rapidly, within 2-3 months of disease onset.\u003c/p\u003e\n\u003cp\u003eAt the time of diagnosis, all children had hepatosplenomegaly of varying severity. Two patients (50%) had mild hepatomegaly, with liver size up to 1.25-fold above the age-specific norm, whereas in the remaining two patients (50%) hepatomegaly was more pronounced, ranging from \u0026gt;1.25-fold to \u0026lt;2.0-fold above the age-specific norm. Splenomegaly was more severe: in two children (50%), spleen size exceeded the age-specific norm by \u0026gt;1.25-fold to \u0026lt;2.0-fold, and in the other two children (50%), by 2.0-fold (Fig. 3).\u003c/p\u003e\n\u003cp\u003eAll patients (4/4) had a marked cytolytic syndrome, with transaminase levels elevated 2- to 3-fold. All children also showed substantial reductions in platelet counts and hemoglobin levels. Two patients developed severe portal hypertension and liver failure. All patients exhibited rapid progression of neurological manifestations, with developmental regression, loss of acquired skills, and death occurring between 10 months and 1.2 years of age.\u003c/p\u003e\n\u003cp\u003eAll patients underwent comprehensive molecular genetic testing. Pathogenic variants in the \u003cem\u003eGBA1\u003c/em\u003e gene were identified, including\u0026nbsp;c.1288C\u0026gt;G/c.84dup, c.721G\u0026gt;A/c.1268C\u0026gt;A,\u0026nbsp;c.721G\u0026gt;A/c.604C\u0026gt;T, and\u0026nbsp;c.255_257delGCG/c.475C\u0026gt;T (Table 1).\u003c/p\u003e\n\u003cp\u003eAccording to the classification of \u003cem\u003eGBA1\u003c/em\u003e variants based on their functional effect on residual enzyme activity, c.1288C\u0026gt;G, c.1268C\u0026gt;A, and c.475C\u0026gt;T were classified as R variants (residual-function variants), whereas c.84dup, c.721G\u0026gt;A, c.604C\u0026gt;T, and c.255_257delGCG were classified as O variants (severe/null variants) [8-11]. Accordingly, among patients with type II GD, we identified the following R/O combinations: c.475C\u0026gt;T/c.255_257delGCG, c.1288C\u0026gt;G/c.84dup, and c.1268C\u0026gt;A/c.721G\u0026gt;A, as well as one severe O/O combination: c.721G\u0026gt;A/c.604C\u0026gt;T.\u003c/p\u003e\n\u003cp\u003eIn three patients, chitotriosidase activity exceeded the reference values by 40- to 86-fold, with a mean increase of 59.7 \u0026plusmn; 23.5-fold. In the same patients, \u0026beta;-glucocerebrosidase activity ranged from 43% to 65% of the lower reference limit, with a mean of 56.8 \u0026plusmn; 12.4%.\u003c/p\u003e\n\u003cp\u003eIn one patient, lysosomal enzyme activity could not be determined because of extensive prior blood transfusions.\u003c/p\u003e\n\u003cp\u003eIn type III GD, the mean age at disease onset was 2.3 \u0026plusmn; 1.66 years (range, 0.5-5 years), and the mean age at diagnosis was 13.8 \u0026plusmn; 16.87 years (range, 2-47 years) (Fig. 1).\u003c/p\u003e\n\u003cp\u003eAmong the six patients with type III GD, the most common initial manifestation was oculomotor apraxia, observed in five patients (83%). Hepatosplenomegaly was present at disease onset in three patients (50%), developmental delay in two patients (33%), and isolated splenomegaly in one child (17%) (Fig. 4).\u003c/p\u003e\n\u003cp\u003eThe mean interval from the onset of the first symptoms to diagnosis in patients with type III GD was 11.5 \u0026plusmn; 17.5 years (range, 1-46.5 years).\u003c/p\u003e\n\u003cp\u003eAt the time of diagnosis, all patients had, in addition to neurological manifestations, thrombocytopenia, anemia, marked splenomegaly, and hepatomegaly without evidence of impaired liver function.\u003c/p\u003e\n\u003cp\u003eHepatomegaly was present in all patients. One child (17%) had mild hepatomegaly, with liver size up to 1.25-fold above the age-specific norm; in four\u0026nbsp;patients\u0026nbsp;(67%), hepatomegaly was more pronounced, ranging from \u0026gt;1.25-fold to \u0026lt;2.0-fold above the age-specific norm; and in one\u0026nbsp;patient\u0026nbsp;(17%), liver size exceeded the age-specific norm by more than 2.0-fold. Splenomegaly was markedly more severe in all patients: in one\u0026nbsp;patient\u0026nbsp;(17%), spleen size exceeded the age-specific norm by \u0026gt;1.25-fold to \u0026lt;2.0-fold, whereas in the remaining five\u0026nbsp;patients\u0026nbsp;(83%), it exceeded the age-specific norm by more than 2.0-fold (Fig.\u0026nbsp;5).\u003c/p\u003e\n\u003cp\u003eTransaminase and bilirubin levels in all patients remained within the normal range. According to ultrasound examinations, splenic infarction was detected in five patients, whereas one patient had fibrotic liver changes and calculous cholecystitis.\u003c/p\u003e\n\u003cp\u003eAll patients exhibited neurological involvement. Two children had marked regression of cognitive and motor development and developed seizures in early childhood; two patients had intention tremor; and three patients had ataxia.\u0026nbsp;In one patient, who had long been followed for isolated splenomegaly, myelopathy presenting as lower paraparesis developed at the age of 40 years.\u003c/p\u003e\n\u003cp\u003eThree patients with type III GD died due to neurological complications: one at 12 years of age and two at 15 years of age.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll patients underwent comprehensive molecular genetic testing. Pathogenic variants in the \u003cem\u003eGBA1\u003c/em\u003e gene were identified, including\u0026nbsp;c.721G\u0026gt;A,\u0026nbsp;c.1448T\u0026gt;C,\u0026nbsp;c.203dupC,\u0026nbsp;c.1246G\u0026gt;A,\u0026nbsp;c.1342G\u0026gt;C,\u0026nbsp;c.1129G\u0026gt;A,\u0026nbsp;c.999G\u0026gt;A,\u0026nbsp;c.680A\u0026gt;G,\u0026nbsp;c.732C\u0026gt;A, and\u0026nbsp;c.1226A\u0026gt;G (Table 2).\u003c/p\u003e\n\u003cp\u003eAccording to the functional classification of \u003cem\u003eGBA1\u003c/em\u003e variants based on their effect on residual enzyme activity,\u0026nbsp;c.721G\u0026gt;A,\u0026nbsp;c.1448T\u0026gt;C,\u0026nbsp;c.203dupC, and\u0026nbsp;c.732C\u0026gt;A were classified as O variants (severe/null variants). Other variants, including\u0026nbsp;c.1226A\u0026gt;G,\u0026nbsp;c.1246G\u0026gt;A,\u0026nbsp;c.680A\u0026gt;G,\u0026nbsp;c.1342G\u0026gt;C,\u0026nbsp;c.1129G\u0026gt;A, and\u0026nbsp;c.999G\u0026gt;A, were classified as R variants (residual-function variants) [8-11]. Among Ukrainian patients, the following genotypes were identified: O/O\u0026nbsp;-c.721G\u0026gt;A/c.1448T\u0026gt;C; R/O\u0026nbsp;-c.203dupC/c.1246G\u0026gt;A,\u0026nbsp;c.721G\u0026gt;A/c.1342G\u0026gt;C,\u0026nbsp;c.680A\u0026gt;G/c.732C\u0026gt;A, and\u0026nbsp;c.1226A\u0026gt;G/c.1448T\u0026gt;C; and R/R\u0026nbsp;-c.1129G\u0026gt;A/c.999G\u0026gt;A.\u003c/p\u003e\n\u003cp\u003eIn the study patients, chitotriosidase activity exceeded the reference range by 30- to 130-fold, with a mean increase of 67.1 \u0026plusmn; 32.8-fold. \u0026beta;-Glucocerebrosidase activity ranged from 31% to 82% of the lower reference limit, corresponding to a mean activity of 2.52 \u0026plusmn; 0.93 nmol/mg/h, or 52.5 \u0026plusmn; 19.4%.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCompared with type I GD, types II and III GD are rarer and less well-studied forms of Gaucher disease. Limited physician awareness of the neuronopathic course of GD often leads to delayed diagnosis. This may reduce the effectiveness of disease-specific therapy when available and may also result in unnecessary diagnostic procedures in affected children. Central nervous system involvement, which characterizes these phenotypes, should be taken into account in the differential diagnosis of patients with suspected lysosomal storage disorders (LSDs).\u003c/p\u003e\n\u003cp\u003eIn this national series, comprehensive diagnostic evaluation of GD is currently performed only at the Laboratory of Medical Genetics of the National Children\u0026rsquo;s Specialized Hospital \u0026ldquo;Okhmatdyt.\u0026rdquo; Thus, this center allows analysis of all known diagnosed cases in\u0026nbsp;the present study.\u003c/p\u003e\n\u003cp\u003eAccording to international GD registries, type II accounts for approximately 1% of all reported GD cases, whereas type III accounts for about 5% [1, 5]. In the Ukrainian cohort, according to our own data, type II GD and type III GD accounted for 4% and 7% of cases, respectively. This difference is most likely related to the small sample size, physicians\u0026rsquo; awareness of the clinical features of neuronopathic GD, and the availability of diagnostic testing for this disorder.\u003c/p\u003e\n\u003cp\u003eThe course of type II GD in Ukrainian patients generally corresponds to previously published data reported by other authors [2, 4, 6]. The main manifestations at disease onset include splenomegaly, hematologic abnormalities, ichthyosiform dermatitis, failure to thrive, and neurological impairment, with neurological manifestations predominating over somatic features. Among the patients observed in this study, stridor and swallowing disturbances were not noted as presenting symptoms; these manifestations developed later as the disease progressed.\u003c/p\u003e\n\u003cp\u003eHepatosplenomegaly is a common feature in patients with type II GD. All children included in the study showed enlargement of both the liver and spleen. Hepatomegaly was mild in half of the patients (50%), with liver size up to 1.25-fold above the expected age-specific norm, whereas in the remaining 50% it was more pronounced, ranging from \u0026gt;1.25-fold to \u0026lt;2.0-fold above the age-specific norm. Splenomegaly was more severe: most children showed spleen enlargement in the ranges of \u0026gt;1.25-fold to \u0026lt;2.0-fold and more than 2.0-fold above the age-specific norm. These findings are consistent with published data [4, 14] and may represent a marker of severe disease course and rapid progression.\u003c/p\u003e\n\u003cp\u003eThe clinical presentation of type III GD is characterized by substantially greater variability than type II GD, which follows a rapidly progressive acute neuronopathic course, and by slower disease progression. In Ukrainian patients, the presenting features included oculomotor apraxia, hepatosplenomegaly, and developmental delay, which later progressed to marked hepatosplenomegaly and neurological manifestations such as ataxia, myoclonus, and regression of cognitive and motor development. These findings are consistent with previously published data on the natural history of this disease [15, 18]. One patient never developed oculomotor apraxia or ataxia but, in adulthood, developed myelopathy with lower paraparesis, which is not entirely typical of type III GD. The clinical course in this patient may correspond to an atypical form of type III GD in which other neurological manifestations did not occur [19].\u003c/p\u003e\n\u003cp\u003eSplenomegaly and hepatomegaly are consistent clinical features in patients with type III GD. As in type II GD, all patients exhibited hepatosplenomegaly. Hepatomegaly was mild in only one patient (17%), with liver size up to 1.25-fold above the expected age-specific norm, whereas most patients (67%) had more pronounced enlargement in the range of \u0026gt;1.25-fold to \u0026lt;2.0-fold, and in one patient (17%) liver size exceeded the age-specific norm by more than 2.0-fold. Splenomegaly was more pronounced: most patients showed spleen enlargement in the ranges of \u0026gt;1.25-fold to \u0026lt;2.0-fold and more than 2.0-fold above the age-specific norm. These observations are supported by other clinical data indicating that, in patients with type III GD, splenomegaly may be more pronounced than hepatomegaly [15].\u003c/p\u003e\n\u003cp\u003eAnalysis of chitotriosidase activity, which was markedly elevated above the reference range in patients with both type II and type III GD, indicates pronounced macrophage activation in response to glucocerebroside accumulation [12]. At the same time, residual \u0026beta;-glucocerebrosidase activity was preserved in these patients, although this did not prevent the development of a severe clinical phenotype [10, 11].\u003c/p\u003e\n\u003cp\u003eAmong the pathogenic \u003cem\u003eGBA1\u003c/em\u003e variants analyzed in patients with type II and type III GD, R/R, R/O, and O/O combinations were identified according to the classification based on residual enzyme activity. In patients carrying variants associated with potential residual activity (R), the clinical course was nevertheless severe, with early disease onset and rapid progression, which is characteristic of the acute and chronic neuronopathic forms of GD. This is consistent with published data suggesting that even R/O combinations may lead to severe forms of the disease because of the dominant negative effect of the null variant [15-17]. Other disease-modifying factors should also be considered. These include the accumulation of secondary metabolites, disruption of calcium (Ca\u0026sup2;⁺) homeostasis, oxidative stress, chronic inflammation, abnormalities of lipid transport, impaired autophagy, endoplasmic reticulum (ER) stress, and activation of the unfolded protein response [13, 16].\u003c/p\u003e\n\u003cp\u003eTo our knowledge, this study represents the first systematic national analysis of neuronopathic Gaucher disease in Ukraine, encompassing all diagnosed cases managed at the country\u0026rsquo;s primary referral center over more than two decades. The findings highlight a striking diagnostic delay in type III GD, with a mean interval exceeding a decade between symptom onset and diagnosis, underscoring the need for increased awareness among pediatricians and neurologists. Notably, hepatosplenomegaly emerged as a consistent and progressive feature across both phenotypes, suggesting that careful assessment of liver and spleen size may facilitate earlier recognition of neuronopathic GD in patients with neurological manifestations. Furthermore, the observed clinical severity in patients carrying variants predicted to retain residual enzyme activity reinforces the limited predictive value of genotype\u0026ndash;phenotype correlations in this cohort and points toward additional modifying factors influencing disease expression.\u003c/p\u003e\n\u003cp\u003eLimitations\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. First, the sample size of patients with neuronopathic Gaucher disease was small, reflecting the rarity of these phenotypes and limiting the ability to perform inferential statistical analyses. Second, the retrospective design may have resulted in incomplete documentation of early clinical manifestations and variability in follow-up data. Third, the study was conducted at a single national referral center, which may introduce referral bias and limit the generalizability of findings to other populations. Finally, although genetic variants were classified according to previously published data on predicted residual enzyme activity, genotype\u0026ndash;phenotype correlations remain inherently complex in neuronopathic Gaucher disease and should be interpreted with caution.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe results of this retrospective study highlight the key clinical characteristics of type II and type III Gaucher disease in Ukrainian patients and represent the first systematic national analysis of neuronopathic GD in Ukraine.\u003c/p\u003e\n\u003cp\u003eType II GD demonstrated very early onset, failure to thrive, dermatological and neurological manifestations, and rapid progression leading to early mortality. In contrast, type III GD showed a more heterogeneous course, including oculomotor apraxia, ataxia, developmental delay, and slower progression. Hepatosplenomegaly was consistently observed across both phenotypes and may serve as an important early clinical indicator in patients presenting with neurological symptoms.\u003c/p\u003e\n\u003cp\u003eOur findings also emphasize the limited predictive value of genotype\u0026ndash;phenotype correlations based solely on residual enzyme activity, underscoring the importance of comprehensive clinical evaluation in neuronopathic GD.\u003c/p\u003e\n\u003cp\u003eThese data contribute to improving diagnostic pathways and may support the development of national rare disease registries and targeted awareness strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNS: Data curation,\u0026nbsp;collected and analyzed data,\u0026nbsp;investigation,\u0026nbsp;coordinated patient management, wrote the manuscript,\u0026nbsp;validation\u0026nbsp;and submitted it to the journal. NO:\u0026nbsp;Formal analysis,\u0026nbsp;investigation,\u0026nbsp;collected and analyzed clinical data,\u0026nbsp;and performed diagnostic testing to confirm Gaucher disease. OO:\u0026nbsp;initiated the research,\u0026nbsp;supervision,\u0026nbsp;writing \u0026ndash; review \u0026amp; editing.\u0026nbsp;NG:\u0026nbsp;Investigation,\u0026nbsp;supervision,\u0026nbsp;writing \u0026ndash; review \u0026amp; editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eName of the corresponding author\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNataliia Samonenko\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e\u003cstrong\u003ecknowledgments\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;The authors would like to thank all the patients and their families for their contribution to this study. We also acknowledge the valuable support of Nataliia Mytsyk, Svitlana Kormoz, and Iryna Hrehul, staff of the Medical Genetics Laboratory, for their involvement in the diagnostic work-up of patients.\u003c/p\u003e\n\u003cp\u003eWe are also grateful to Nataliia Pichkur and Yana Doronina for their long-term commitment and work at the Center of Orphan Diseases and Gene Therapy of the National Children\u0026rsquo;s Specialized Hospital \u0026ldquo;Okhmatdyt\u0026rdquo;, Kyiv, Ukraine.\u003c/p\u003e\n\u003cp\u003eWe are deeply grateful to every physician in Ukraine who, despite the difficult times of war, continues their vital work in caring for patients and preserving the hard-earned achievements of our healthcare system.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no financial support was received for the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe studies involving human participants were reviewed and approved by the Ethics Committee of the National Children\u0026rsquo;s Specialized Hospital \u0026quot;Okhmatdyt\u0026quot; of the Ministry of Health of Ukraine. Written informed consent for diagnostic procedures, clinical assessments, and use of anonymized data for research and publication was obtained from all participants or their legal guardians prior to inclusion in the institutional database.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients and their parents or legal representatives provided signed and dated written informed consent for diagnostic evaluation and for publication of de-identified clinical data, in accordance with the legislation of Ukraine and applicable national data protection requirements.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eCharrow J, Andersson HC, Kaplan P, et al. The Gaucher Registry: Demographics and Disease Characteristics of 1698 Patients With Gaucher Disease. Arch Intern Med. 2000;160(18):2835\u0026ndash;2843. doi:10.1001/archinte.160.18.2835.\u003c/li\u003e\n \u003cli\u003eDaykin EC, Ryan E, Sidransky E. Diagnosing neuronopathic Gaucher disease: New considerations and challenges in assigning Gaucher phenotypes. Mol Genet Metab. 2021;132(2):49\u0026ndash;58. doi:10.1016/j.ymgme.2021.01.002.\u003c/li\u003e\n \u003cli\u003ePeters SP, Hollak CE, Aerts JM, et al. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab. 2004;82(3):192\u0026ndash;207. doi:10.1016/j.ymgme.2004.04.011.\u003c/li\u003e\n \u003cli\u003eRoshan Lal T, Sidransky E. The spectrum of neurological manifestations associated with Gaucher disease. Diseases. 2017;5(1):10. doi:10.3390/diseases5010010.\u003c/li\u003e\n \u003cli\u003eCastillon G, Chang SC, Moride Y. Global incidence and prevalence of Gaucher disease: A targeted literature review. J Clin Med. 2022;12(1):85. doi:10.3390/jcm12010085.\u003c/li\u003e\n \u003cli\u003eTylki-Szymańska A, Vellodi A, El-Beshlawy A, et al. Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the ICGG neurological outcomes subregistry. J Inherit Metab Dis. 2010;33(4):339\u0026ndash;346. doi:10.1007/s10545-009-9009-6.\u003c/li\u003e\n \u003cli\u003eZhao H, Grabowski GA. Gaucher disease: perspectives on a prototype lysosomal storage disorder. Crit Rev Biochem Mol Biol. 2002;37(3):213\u0026ndash;259. doi:10.1080/10409230290771581.\u003c/li\u003e\n \u003cli\u003eHruska KS, LaMarca ME, Scott CR, Sidransky E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA1). Hum Mutat. 2008;29(5):567\u0026ndash;583. doi:10.1002/humu.20676.\u003c/li\u003e\n \u003cli\u003eMistry PK, Sadan S, Yang R, et al. Consequences of diagnostic delays in type 1 Gaucher disease. Am J Hematol. 2007;82(8):697\u0026ndash;701. doi:10.1002/ajh.20913.\u003c/li\u003e\n \u003cli\u003ePavan E, Peruzzo P, Cattarossi S, et al. Deficiency of glucocerebrosidase activity beyond Gaucher disease: PSAP and LIMP-2 dysfunctions. Int J Mol Sci. 2024;25(12):6615. doi:10.3390/ijms25126615.\u003c/li\u003e\n \u003cli\u003eTorralba MA, Olivera S, Bureo JC, et al. Residual enzymatic activity as a prognostic factor in patients with Gaucher disease type 1. QJM. 2016;109(7):449\u0026ndash;452. doi:10.1093/qjmed/hcw002.\u003c/li\u003e\n \u003cli\u003eTylki-Szymańska A, Szymańska-Rożek P, Hasiński P, et al. Plasma chitotriosidase activity vs. plasma glucosylsphingosine in Gaucher disease phenotypes. Mol Genet Metab. 2018;123(4):495\u0026ndash;500. doi:10.1016/j.ymgme.2018.02.004.\u003c/li\u003e\n \u003cli\u003eBoustany RM. Lysosomal storage diseases--the horizon expands. Nat Rev Neurol. 2013;9(10):583\u0026ndash;598. doi:10.1038/nrneurol.2013.163.\u003c/li\u003e\n \u003cli\u003eHughes DA, Pastores GM. Gaucher Disease. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. \u003cem\u003eGeneReviews\u0026reg; [Internet]\u003c/em\u003e. Seattle (WA): University of Washington, Seattle; 1993\u0026ndash;2024 [updated 2023 Dec 7]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1269/.\u003c/li\u003e\n \u003cli\u003eGoker-Alpan O, Ivanova MM. Neuronopathic Gaucher disease: rare in the West, common in the East. J Inherit Metab Dis. 2024;47(5):917\u0026ndash;934. doi:10.1002/jimd.12749.\u003c/li\u003e\n \u003cli\u003eOlkhovych NV, Nedoboy AM, Pichkur NO, et al. Analysis of mutations in GBA gene in Ukrainian patients with Gaucher disease. Biopolym Cell. 2017;33(1):34\u0026ndash;47. doi:10.7124/bc.000940.\u003c/li\u003e\n \u003cli\u003eOlkhovych N. Molecular and genetic principles of lysosomal pathology formation in Gaucher disease in the Ukrainian population [dissertation]. Kyiv: Shupyk National Healthcare University of Ukraine; 2021.\u003c/li\u003e\n \u003cli\u003eSchwartz IVD, G\u0026ouml;ker-Alpan \u0026Ouml;, Kishnani PS, et al. Characteristics of 26 patients with type 3 Gaucher disease: A descriptive analysis from the Gaucher Outcome Survey. Mol Genet Metab Rep. 2018;14:73\u0026ndash;79. doi:10.1016/j.ymgmr.2017.10.011.\u003c/li\u003e\n \u003cli\u003eAndr\u0026eacute;asson M, Solders G, Bj\u0026ouml;rkvall CK, et al. Polyneuropathy in Gaucher disease type 1 and 3 \u0026ndash; a descriptive case series. Sci Rep. 2019;9:15358. doi:10.1038/s41598-019-51976-2.\u003c/li\u003e\n \u003cli\u003eLee FS, Yen HJ, Niu DM, et al. Allogeneic hematopoietic stem cell transplantation for treating severe lung involvement in Gaucher disease. Mol Genet Metab Rep. 2020;25:100652. doi:10.1016/j.ymgmr.2020.100652.\u003c/li\u003e\n \u003cli\u003ePession A, Di Rocco M, Venturelli F, et al. GAU-PED study for early diagnosis of Gaucher disease in children with splenomegaly and cytopenia. Orphanet J Rare Dis. 2023;18:151. doi:10.1186/s13023-023-02760-z.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Genotypes and major clinical features observed in patients with type II GD\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"1112\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eAge at onset\u003c/p\u003e\n \u003cp\u003e(months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003eAge at diagnosis (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eAge at death\u003c/p\u003e\n \u003cp\u003e(months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePresenting symptoms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eHepatosplenomegaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eDevelopmental regression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eAdditional clinical information\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChitotriosidase activity (nmol/h/mL plasma)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta;\u003c/strong\u003e\u003cstrong\u003e-Glucocerebrosidase activity (nmol/h/mg protein)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGBA1 genotype (cDNA)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFunctional classification\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eIchthyosis, anemia, splenomegaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eLiver failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003ec.475C\u0026gt;T /\u003c/p\u003e\n \u003cp\u003ec.255_257delGCG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003eR/O\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eIchthyosis, hepatosplenomegaly, failure to thrive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eLiver failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e6000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003ec.1288C\u0026gt;G /\u003c/p\u003e\n \u003cp\u003ec.84dup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003eR/O\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eAnemia, failure to thrive, ichthyosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eSevere neurological manifestations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e12906\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003ec.721G\u0026gt;A /\u003c/p\u003e\n \u003cp\u003ec.1268C\u0026gt;A\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003eR/O\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eFailure to thrive, hepatosplenomegaly, developmental delay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003eSevere neurological manifestations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 99px;\"\u003e\n \u003cp\u003e7956\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 125px;\"\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003ec.721G\u0026gt;A /\u003c/p\u003e\n \u003cp\u003ec.604C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003eO/O\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAbbreviations: GD \u0026ndash; Gaucher disease; R \u0026ndash; residual-function variant; O \u0026ndash; null/severe variant\u003c/p\u003e\n\u003cp\u003eDevelopmental regression refers to loss of previously acquired motor or cognitive skills.\u003c/p\u003e\n\u003cp\u003eND - not determined\u003c/p\u003e\n\u003cp\u003eTable 2. Genotypes and major clinical features observed in patients with type III GD\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"1096\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eAge at onset\u003c/p\u003e\n \u003cp\u003e(years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eAge at diagnosis\u003c/p\u003e\n \u003cp\u003e(years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003eAge at death\u003c/p\u003e\n \u003cp\u003e(years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePresenting symptoms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHepatosplenomegaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eDevelopmental regression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eAdditional clinical information\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChitotriosidase activity (nmol/h/mL plasma)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta;\u003c/strong\u003e\u003cstrong\u003e-Glucocerebrosidase activity (nmol/h/mg protein)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGBA1 genotype (cDNA)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFunctional classification\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1.5\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eHepatosplenomegaly, strabismus, developmental delay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eSeizures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e19448\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ec.721G\u0026gt;A /\u003c/p\u003e\n \u003cp\u003ec.1448T\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eO/O\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e12\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eOphthalmoparesis, developmental delay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eSeizures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e7293\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ec.1246G\u0026gt;A /\u003c/p\u003e\n \u003cp\u003ec.203dupC\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eR/O\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e5\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e12\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eOphthalmoparesis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eMotor dysfunction, ataxia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e4552\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e4.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ec.1342G\u0026gt;С /\u003c/p\u003e\n \u003cp\u003ec.721G\u0026gt;A\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eR/O\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e15\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHepatosplenomegaly, ophthalmoparesis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eIntention tremor, ataxia, muscle hypotonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e11934\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ec.1129G\u0026gt;A /\u003c/p\u003e\n \u003cp\u003ec.999G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eR/R\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e13\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e15\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eHepatosplenomegaly, ophthalmoparesis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eIntention tremor, ataxia, muscle hypotonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e6632\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ec.680A\u0026gt;G /\u003c/p\u003e\n \u003cp\u003ec.732C\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eR/O\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0.5\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e47\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eSplenomegaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eParaparesis, myelopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e10530\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ec.1226A\u0026gt;G /\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ec.1448T\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eR/O\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: GD \u0026ndash; Gaucher disease; R \u0026ndash; residual-function variant; O \u0026ndash; null/severe variant\u003c/p\u003e\n\u003cp\u003eDevelopmental regression refers to loss of previously acquired motor or cognitive skills.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Gaucher disease, Neuronopathic Gaucher disease, Hepatosplenomegaly, Hepatomegaly, Liver, Children, Diagnostic delay, GBA1, Rare diseases","lastPublishedDoi":"10.21203/rs.3.rs-9348927/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9348927/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003cbr\u003e\nNeuronopathic Gaucher disease (GD types II and III) represents rare and severe phenotypes of glucocerebrosidase deficiency, characterized by neurological involvement and variable systemic manifestations. Data on clinical presentation and genotype–phenotype patterns in Eastern European populations remain limited.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003cbr\u003e\nWe conducted a retrospective cohort study of 92 patients with confirmed Gaucher disease followed at the National Children’s Specialized Hospital “Okhmatdyt” (Kyiv, Ukraine) between 2001 and 2024. Among them, 4 patients had type II and 6 had type III GD. Diagnosis was established by measurement of leukocyte β-glucocerebrosidase activity and molecular analysis of the \u003cem\u003eGBA1\u003c/em\u003e gene. Clinical, laboratory, and imaging data were analyzed descriptively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003cbr\u003e\nType II GD presented in early infancy (mean age at onset 0.25 ± 0.19 years) and was diagnosed at 0.58 ± 0.19 years. Initial manifestations included cytopenias, splenomegaly, failure to thrive, and ichthyosiform dermatitis. Hepatomegaly was uncommon at onset, but hepatosplenomegaly was documented in all patients at diagnosis, followed by rapid neurological regression and death before 14 months of age.\u003c/p\u003e\n\u003cp\u003eType III GD had a mean age at onset of 2.3 ± 1.66 years and a mean age at diagnosis of 13.8 ± 16.87 years, reflecting substantial diagnostic delay. Oculomotor apraxia was the most frequent presenting symptom (83%). At diagnosis, all patients exhibited hepatosplenomegaly, cytopenias, and neurological involvement, while liver function remained preserved.\u003c/p\u003e\n\u003cp\u003eAcross both phenotypes, genotype analysis identified R/R, R/O, and O/O \u003cem\u003eGBA1\u003c/em\u003e variant combinations. Severe clinical courses were observed even in patients carrying variants associated with predicted residual enzyme activity, indicating limited genotype–phenotype correlation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u003cbr\u003e\nIn this Ukrainian cohort, neuronopathic GD demonstrated distinct clinical trajectories, with rapidly progressive infantile disease in type II and heterogeneous presentation with marked diagnostic delay in type III. Hepatosplenomegaly emerged as a consistent feature during disease progression and may serve as an important clinical indicator in patients with suspected neuronopathic GD.\u003c/p\u003e","manuscriptTitle":"Clinical and Genetic Landscape of Neuronopathic Gaucher Disease in Ukraine: Hepatosplenomegaly and Diagnostic Delay","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-19 12:15:45","doi":"10.21203/rs.3.rs-9348927/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-20T10:45:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"146528727042134398422595504381316302119","date":"2026-04-15T07:31:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294449956153924548520048552703282192990","date":"2026-04-15T06:48:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"237752251300758489217825323895315307847","date":"2026-04-13T04:59:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-09T15:52:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-08T13:02:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-08T13:02:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2026-04-07T19:29:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fea84987-31d7-4333-9674-efaa25ae5be6","owner":[],"postedDate":"April 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-19T12:15:46+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-19 12:15:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9348927","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9348927","identity":"rs-9348927","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}