Pediatric X-Linked Adrenoleukodystrophy: Phenotypes, Variants, and HSCT Outcomes

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Early diagnosis is critical for effective hematopoietic stem cell transplantation (HSCT). This study aims to characterize clinical phenotypes, expand the ABCD1 mutational spectrum, and evaluate HSCT outcomes in a Chinese pediatric cohort. Methods: We retrospectively reviewed 31 male children diagnosed with ALD from 2015 to 2023. Clinical features, adrenal function, brain MRI findings, and ABCD1 mutations were analyzed. Loes scores were determined for cerebral ALD (cALD). Overall survival was compared between early-stage cALD patients who underwent allogeneic HSCT and those who did not. Results: Twenty-four patients had cALD, and seven presented with adrenal-only disease. Neurologic symptoms in cALD included visual/hearing impairment (38%), seizures (29%), and cognitive decline (17%). Adrenal insufficiency occurred in 62.5% of cALD patients. Genetic analysis identified 29 ABCD1 variants, including three novel pathogenic variants (c.77C>G, c.1119_1120insTC, c.1291C>T). While statistical significance was limited by sample size (P = 0.24), early-stage cALD patients receiving HSCT showed a clinically meaningful trend toward improved 5-year OS (78%) compared to non-transplanted patients (29%). A pre-transplant Loes score < 9 was a critical determinant of superior outcomes. Conclusion: We expanded the ABCD1 spectrum with three novel variants. Our findings confirm that early-stage HSCT (Loes < 9) offers a distinct survival advantage. The diagnostic delays observed in our cohort underscore the urgent need for implementing newborn screening to capture patients within the optimal therapeutic window. X-linked adrenoleukodystrophy ABCD1 gene mutation Loes score hematopoietic stem cell transplantation Figures Figure 1 Figure 2 Figure 3 What is known – what is new • What is Known: X-linked adrenoleukodystrophy (ALD) shows marked clinical heterogeneity; cerebral ALD progresses rapidly, and early HSCT offers the best outcomes. • What is Known: The Loes score is a key imaging biomarker guiding transplant timing, with lower scores predicting superior prognosis. • What is New: We report a Chinese pediatric cohort expanding the ABCD1 mutation spectrum with three novel pathogenic variants. • What is New: Survival analyses reinforce that HSCT at Loes < 9 confers a clinically meaningful advantage, highlighting diagnostic delays and the need for newborn screening. Introduction Adrenoleukodystrophy (ALD, OMIM#300100) is the most prevalent peroxisomal disorder, classified as a progressive neurometabolic disease resulting from impaired β-oxidation 1 . It follows an X-linked recessive inheritance pattern and is caused by pathogenic variants in the ABCD1 gene located on Xq28. These mutations compromise the function of adrenoleukodystrophy protein (ALDP), which is essential for the transport of very long-chain fatty acids (VLCFAs) into peroxisomes. The resulting disruption in VLCFA β-oxidation leads to their accumulation in body fluids and tissues, particularly in cerebral white matter, spinal cord, adrenal cortex, and testicular Leydig cells. This pathological buildup contributes to extensive demyelination and/or adrenal insufficiency 2 . ALD demonstrates marked clinical heterogeneity, with symptoms that progressively accumulate over time. Studies have shown that more than half of affected males develop cerebral ALD (cALD), characterized by progressive cerebral demyelination. In addition, nearly all patients eventually exhibit adrenal insufficiency and slowly progressive myeloneuropathy in adulthood. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the most effective treatment for cALD. However, due to its insidious onset and rapid progression, cALD frequently results in death within 5–10 years of diagnosis, highlighting the urgent need for early detection and intervention to improve patient outcomes. In this study, we retrospectively analyzed 31 pediatric ALD patients diagnosed and treated at our institution, focusing on their clinical presentations, auxiliary test findings, therapeutic interventions, and prognoses to enhance clinicians' understanding and management of this disorder. We specifically highlight the identification of three novel ABCD1 variants and discuss the critical importance of early diagnosis, potentially via newborn screening, to improve HSCT outcomes. Methods Patients and Clinical Data Collection We retrospectively reviewed 31 children diagnosed with ALD at Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, between 2015 and 2023. Two patients (17a and 17b) were from the same family. Twenty-four patients had cALD, while seven presented with the pure adrenal form. Clinical data—including age at onset and diagnosis, presenting symptoms, neurological and endocrine evaluations, MRI findings, VLCFA profiles, genetic results, treatment strategies, and follow-up outcomes—were systematically collected. VLCFAs were quantified by isotope-dilution gas chromatography–mass spectrometry. Plasma cortisol and adrenocorticotropic hormone (ACTH) were examined by chemiluminescence. Loes scores were assigned by two experienced neuroradiologists for patients with cerebral involvement 3 , 4 . The study protocol was approved by the Ethics Committee of Shanghai Children’s Medical Center. Written informed consent for clinical data collection and genetic analysis was obtained from all guardians. Diagnostic Criteria ALD diagnosis was based on clinical manifestations, endocrine testing, biochemical markers, neuroimaging, and molecular analysis 5 . Diagnostic criteria included: ①Progressive neurological deficits, such as gait disturbances, cognitive decline, or visual impairment; ② Biochemical or clinical adrenal insufficiency, including hyperpigmentation, reduced cortisol levels, and elevated ACTH; ③ Elevated VLCFAs (C26:0, C24:0, C22:0) and increased C24:0/C22:0, C26:0/C22:0 ratios; ④ MRI evidence of symmetric white matter demyelination; ⑤ Detection of pathogenic ABCD1 variants; ⑥ X-linked recessive inheritance pattern. Childhood cALD was defined by fulfilling criteria ①–⑥. Pure adrenal ALD was defined by meeting ②, ③, ⑤, and ⑥ in the absence of neurological involvement. Genetic analysis All exons and exon–intron boundaries of ABCD1 were amplified by PCR and sequenced by ABI3730. Sequences were aligned to the reference ABCD1 transcript (NM_000033.4). Variant pathogenicity was predicted using PolyPhen-2 and multiple in-silico tools. Multiplex ligation-dependent probe amplification (MLPA), quantitative polymerase chain reaction (qPCR), or microarray analysis was performed for patients with suspected ALD but negative sequencing results to screen for large deletions/duplications. Statistical analysis Statistical analyses were performed using SPSS 24.0. Continuous variables were tested for normality and expressed as mean ± standard deviation (SD) or median (interquartile range). Categorical variables were expressed as frequencies (percentage). Kaplan–Meier survival analysis was used to evaluate HSCT outcomes, with significance defined as P < 0.05. Results Thirty-one children with ALD were included (Table 1 and Fig. 1 ). The median age at onset was 5.4 (3.5–7.2) years, and the median age at diagnosis was 6.5 (5.7–8.8) years, suggesting a median diagnostic delay of 0.6 (0.3–2.1) years. Based on clinical subtype, children were classified into cerebral (n = 24) and pure adrenal forms (n = 7). In the cALD group, the median onset age was 5.4 (4.0–6.9) years, diagnosis age was 6.1 (5.5–7.5) years, and the median delay from onset to diagnosis was 0.5 (0.2–1.2) years. In contrast, children with pure adrenal ALD had a median onset age of 3.0 (2.6–7.3) years, diagnosis age of 9.0 (6.0–11.8) years, and a longer diagnostic interval of 3.0 (2.0–7.0) years. Table 1 Clinical data of 31 patients with X-ALD (phenotype, genotype and treatment outcomes) ID a Onset age Neurological dysfunction Adrenal insufficiency ABCD1 gene mutation HSCT Loes Score b Current status and age 1C 5m Developmental delay / c. 1291C > T No 7 Died at 4y 2C 7y Seizures, cognitive impairment Dark skin c. 1679C > T No 12 Died at 12y 3C 13y Gait disturbances, epilepsy Dark skin c. 293C > T Yes 9.5 Died at 16y 4C 6y9m Learning difficulties, strabismus / c. 1825G > A No 10 13y3m Living 5 9y / Dark skin c. 1119_1120 insTC No 0 15y6m Living 6C 6y Visual impairment Dark skin c. 1430del Yes 9 loss to follow up 7C 9m Seizures, developmental delay / c. 77C > G No 10 Died at 1y 8C 5y3m Visual impairment / c. 1825G > A No 9 Died 9C 1y2m / / c. 1552C > T Yes 2 4y6m Living Positive ALD family history 10C 6y / / c. 421G > A Yes 6.5 9y Living Positive ALD family history 11 9.5y / Dark skin c. 1849C > T No 1 (Progress to encephalopathy) 16y Living 12 10y / Dark skin and short stature c. 454C > T c. 887A > T No 0 18y Living 13 6y / Dark skin c. 1886-10G > A No 2 (Progress to encephalopathy) 9y Living 14C 6.5y Seizures Dark skin c. 901 − 25_901-9del Yes 77 5 11y7m Living 15C 9y4m Seizures Dark skin c. 323C > T Yes 9y9m 6 13y Living 16C 6y1m Gait disturbances, dysarthria Laboratory findings c. 1814T > C Yes 6y3m 5 10y5m Living 17aC 5y5m Dysarthria Dark skin c. 454C > T Yes 7y5m 1 10y1m Living 17b 7y3m / Dark skin c. 454C > T No 1 (Progress to encephalopathy) 10y Living 18C 4y Seizures / c. 900 + 1G > T Yes 4y4m 6 6y Living 19C 4y7m / Fatigue c. 1415_1416del Yes 5y 1.5 7y4m Living 20C 5y8m Gait disturbances Dark skin c. 937delC Yes 6y8m 6 8y4m Living 21 2y10m / Dark skin c. 900G > A No 0 13y1m Living 22C 7y5m Visual or auditory impairment Laboratory findings c. 1785G > A No 12 8y7m Living 23C 6y Epilepsy Laboratory findings c. 161G > A Yes 7y 9 Died at 7y, due to bone marrow suppression and infection during HSCT 24C 6y2m Visual impairment, Strabismus / c. 887A > G Yes 6y4m 9 7y Living 25C 8y4m Visual or auditory impairment / c. 1519G > A Yes 8y9m 6 9y3m Living 26C 5y5m Visual impairment, Strabismus Laboratory findings c. 974T > C Yes 5y11m 8.5 6y8m Living 27C 8y6m Visual impairment, Strabismus Laboratory findings c. 1682A > T Yes 8y9m 11.5 9y3m Living 28 4y7m / Dark skin a 7.7 Mb deletion in the Xq28 region (encompassing ABCD1 ) No 0 8y7m Living 29C 7y6m Visual impairment Laboratory findings c. 493dup p. Arg165ProfsTer30 HLA typing 7 7y9m Living 30C 9y7m Visual or auditory impairment Laboratory findings c. 1658T > C No 10 10y7m Living Note: HLA, Human Leukocyte Antigen; HSCT, Haematopoietic Stem Cell Transplant a ID with C means those patients were classified as cALD; b The Loes score is based on the results of the cranial MRI, where 0 means no central nervous system involvement Among the cALD patients, neurological symptoms were the predominant clinical feature, with the most common initial symptoms being visual/auditory decline (37.5%), seizures (29.2%), strabismus (16.7%), cognitive impairment (16.7%), gait abnormalities (12.5%), and dysarthria (8.3%). Two were asymptomatic and diagnosed through family screening. During follow-up, 62.5% (15/24) developed adrenal insufficiency. Among the seven pure adrenal ALD patients, the primary manifestation was hyperpigmentation. Three later developed early white matter changes on MRI. Biochemical and Hormonal Tests Ten patients underwent VLCFA testing at diagnosis, all showing elevated C26:0, with a markedly increased C26:0/C22:0 ratio. The median C26:0/C22:0 ratio was 0.096 µmol/L, significantly higher than the normal reference value of < 0.013 µmol/L. Adrenal cortical function assessment was completed for all participants, and 4 cases underwent additional ACTH stimulation testing. Twenty-two cases (71.0%) had adrenal insufficiency. Mean morning cortisol was 3.9 ± 1.7 µg/dL (reference range: 6.7–22.6 µg/dL), with markedly elevated ACTH of 645.4 ± 426.7 pg/mL (reference range: 0–46 pg/mL). MRI Findings All 24 children diagnosed with cALD demonstrated white matter involvement on cranial MRI. Imaging revealed hyperintense signals on T2-weighted images (T2WI) in affected regions, with lesions typically appearing symmetrical. The most commonly involved areas included the corpus callosum, supratentorial white matter (frontal, parietal, occipital, and temporal lobes), visual and auditory pathways, projection fibers, and the cerebellum. Among the 7 patients initially diagnosed with the pure adrenal form, 3 subsequently developed cerebral involvement during follow-up, while the remaining 4 showed no abnormal findings on cranial imaging. Loes scoring was performed by neuroradiologists for 27 children with cerebral involvement (including the 3 progressed cases). Sixteen children had Loes scores below 9, while 11 had scores ≥ 9, indicating more advanced white matter damage. Genetic Mutation Spectrum All 31 children with ALD were confirmed to carry pathogenic variants in the ABCD1 gene through whole-exome sequencing (Table 1 and Fig. 2 ). In total, 29 distinct variants were found: 75.9% (22/29) were missense mutations, 20.7% (6/29) were frameshift mutations, and one case (P28) harbored a 7.7 Mb deletion in the Xq28 region encompassing the ABCD1 gene. Most variants were located in exon 1 (37.9%, 11/29), followed by exon 8. Among the identified variants, c.1415_1416delAG (found in patient P19) has been previously reported as a hotspot mutation. Three novel variants (c.77C > G, c.1119_1120insTC, and c.1291C > T) were not previously reported or included in existing mutation databases. Additionally, c.454C > T and c.1825G > A were observed in three and two patients, respectively. Those 31 patients originated from 30 unrelated families. Patients 17a and 17b, who were cousins from the same family, both carried the c.454C > T variant. Despite sharing the same mutation, their clinical presentations diverged significantly: one exhibited cALD with adrenal insufficiency, while the other had the pure adrenal phenotype. Treatment Outcomes and Follow-up Regular follow-up (including routine clinic visits and phone tracking) were conducted for all 31 patients. By January 2024, all 7 patients with the pure adrenal form were receiving hydrocortisone replacement therapy without any adrenal crisis events. Among the cohort, 6 patients (P1–3, P7–8, P23), all with cALD, had died; 1 patient (P6) was lost to follow-up; and 2 developed secondary epilepsy, managed with diazepam and carbamazepine. Of the 24 cALD patients, 8 received supportive care alone, with 4 deaths (50%), and 1 pending HSCT. The remaining 16 underwent HSCT, of whom 14 survived (7 for over 3 years). Two post-HSCT deaths were due to disease progression and post-transplant complications, respectively. MRI follow-up showed that central lesions progressed in patients with pre-HSCT Loes scores ≥ 9, while those with scores < 9 remained stable, suggesting that a lower Loes score (< 9) at the time of transplant is associated with better neurological outcomes (Fig. 3 A). Kaplan–Meier analysis revealed a 5-year overall survival (OS) of 55.0% (95% CI: 42.2–65.7%) among all cALD patients. Subgroup analysis (Fig. 3 B) indicated that early-stage cALD patients receiving HSCT demonstrated a clinically meaningful trend toward improved survival (78% vs. 29%), although this difference did not reach statistical significance ( P = 0.24) likely due to the limited sample size. Importantly, patients with pre-transplant Loes scores < 9 showed stabilized MRI findings post-HSCT, whereas those with scores ≥ 9 experienced disease progression despite transplantation. Discussion ALD is a rare peroxisomal disorder with an estimated prevalence of 1 in 14,000 to 1 in 17,000. To date, comprehensive epidemiological data on the prevalence of ALD in China are still lacking. As an X-linked recessive disorder, ALD predominantly affects males, while female carriers typically remain asymptomatic. Consistent with this inheritance pattern, all participants in this study were male. Clinically, ALD presents with a wide range of symptoms that tend to progress over time. Based on the initial presentation, ALD is typically categorized into cALD, adrenomyeloneuropathy (AMN), pure adrenal form, and female carrier status. Previous studies report that cALD is the most prevalent phenotype, accounting for approximately 35%–45% of cases 4 . It most frequently presents around the age of 7, rarely before age 2, and is extremely uncommon after 15 years. Early symptoms often include cognitive and behavioral disturbances, which may be subtle and easily misdiagnosed. As the disease advances, patients may experience worsening cognitive decline, cortical blindness or visual impairment, central hearing loss, and quadriplegia. In our cohort, 77.4% (24/31) of children were diagnosed with cALD, with a median age of onset of 5.4 (4.0–6.9) years and median diagnosis age of 6.1 (5.5–7.5) years, aligning with existing literature. Notably, the youngest cALD patient in our study was only 9 months old and was identified due to developmental delay; diagnosis was confirmed through cranial MRI and whole-exome sequencing. This represents one of the earliest documented cases in China and underscores the need for vigilance even in infants. Unlike earlier studies that emphasized cognitive and behavioral symptoms, most cALD patients in this cohort initially presented with visual or auditory impairment (9/24) or epilepsy (7/24), while cognitive impairment was noted in only 4 cases. These children were ultimately diagnosed based on cranial MRI findings and whole-exome sequencing. Given the broad spectrum of early symptoms, timely diagnosis remains a clinical challenge. However, the disease course of cALD is often aggressive; if untreated, patients may experience irreversible disability within 6 months to 2 years of onset and die within 5 to 10 years 6 . Notably, neuroimaging abnormalities typically precede clinical symptoms. Functional MRI and perfusion studies may detect early brain changes, emphasizing the importance of early imaging in patients with developmental delays or seizures. Moreover, regular MRI monitoring may facilitate earlier detection of white matter lesions and disease progression 7 . Primary adrenal insufficiency is another major clinical phenotype of ALD, with an estimated lifetime prevalence exceeding 80% 8 . Although the underlying mechanism remains unclear, it is believed to involve chronic accumulation of VLCFAs in the zona fasciculata and zona reticularis of the adrenal cortex, leading to cytotoxicity, apoptosis, and cortical atrophy 9 . In our study, 7 patients (22.6%) were diagnosed with pure adrenal ALD. Comprehensive evaluation of adrenal function in all 31 patients revealed that 22 (71.0%) had evidence of adrenal insufficiency. The risk is partially age-dependent, typically peaking between 3 and 10 years, consistent with findings in our cohort. However, we observed adrenal insufficiency as early as 2 years and 10 months, whereas the youngest reported in literature presented with subclinical glucocorticoid abnormalities at just 5 weeks of age. Given that ALD accounts for 4–35% of idiopathic primary adrenal insufficiency cases without autoimmune markers 10 , it is crucial to screen for ALD in boys with unexplained adrenal insufficiency. For patients with confirmed adrenal involvement, glucocorticoid replacement (e.g., hydrocortisone or cortisone acetate at 8–12 mg/m²/day in 2–3 divided doses) is recommended, with dosage adjustments during physiological stress. Mineralocorticoid replacement is generally unnecessary due to relative preservation of the zona glomerulosa, potentially avoiding VLCFA accumulation. In addition to adrenal dysfunction, testicular impairment may occur in ALD. Studies suggest that over 80% of male patients exhibit primary testicular dysfunction, possibly through mechanisms similar to adrenal insufficiency, though the natural progression remains poorly defined. However, a study on male AMN-type patients found that despite biochemical abnormalities, fertility was not significantly affected. In our cohort, all three boys with pure adrenal ALD showed normal pubertal onset and development during follow-up. VLCFAs—comprising C22:0, C24:0, and C26:0—serve as key biochemical markers for ALD diagnosis. Elevated serum VLCFA levels, particularly C26:0 and the C26:0/C22:0 ratio, are reliable diagnostic indicators unaffected by diet or stress 11 . In our study, all 10 tested patients exhibited elevated levels consistent with known disease profiles. However, VLCFA levels do not correlate with disease severity or phenotype 8 , limiting their use in monitoring disease progression. Therefore, genetic testing remains essential for definitive diagnosis in patients with abnormal VLCFA profiles. Pathogenic variants in the ABCD1 gene are the definitive cause of ALD 12 . To date, over 900 ABCD1 variants have been reported, with missense variants being the most prevalent (61.4%), followed by frameshift mutations (17.2%). In our cohort, we identified 29 distinct ABCD1 mutations. Of these, 22 (75.9%) were missense mutations, 6 were frameshift mutations, and 1 involved a large genomic deletion encompassing the ABCD1 locus. Notably, exon 1 harbored the highest frequency of mutations (37.9%), followed by exon 8. Additionally, our study expands the genetic spectrum of ALD by identifying three novel pathogenic variants: c.77C > G, c.1119_1120insTC, and c.1291C > T. These variants were absent from public databases and were classified as pathogenic based on ACMG guidelines, co-segregation with the disease phenotype, and elevated VLCFA levels. The discovery of these variants contributes to the global ALD genetic database and facilitates molecular diagnosis for future patients. Consistent with previous literature, we observed no clear genotype-phenotype correlation; notably, cousins carrying the same c.454C > T variant (P17a and P17b) presented with divergent phenotypes (cALD vs. pure adrenal form), suggesting the influence of epigenetic factors or modifier genes 13 . Allo-HSCT remains a critical intervention for improving outcomes in children with cALD. Several studies, including one by Mahmood et al. 14 , have shown that early HSCT markedly increases the 5-year survival rate (95% vs. 54% in untreated patients). A subsequent multicenter study conducted across Europe and North America reported similarly promising results, with a 5-year OS of 94% and a major functional disability (MFD)-free survival rate of 91% in patients receiving timely transplants 15 . In our study, the overall 5-year survival rate for cALD patients was 55.0% (95% CI : 42.2–65.7%). Among those who underwent HSCT, the 5-year OS was 78.0% (95% CI : 64.0–86.6%), compared to 29.0% (95% CI : 11.7–48.2%) in the non-transplanted group. These results further validate the survival benefit of early HSCT intervention in children with cALD. The Loes score is a widely used MRI-based assessment tool that quantifies the extent of cerebral demyelination and brain atrophy, ranging from 0 to 34. Higher scores indicate more advanced disease. Generally, a Loes score between 0.5 and 9.5 is considered optimal for HSCT candidacy 16 . Our findings reinforce this criterion: patients with pre-transplant Loes scores < 9 had better post-HSCT outcomes, whereas disease progression continued in patients with higher pre-transplant scores despite intervention. It is important to note that HSCT does not reverse established neurological damage and has no therapeutic effect on adrenal insufficiency or adult-onset AMN. Additionally, HSCT carries risks such as graft failure, bone marrow suppression, and Graft-versus-host disease (GVHD), which may negatively impact long-term outcomes. To address these limitations, gene therapy has emerged as a novel therapeutic approach. Skysona, an autologous hematopoietic stem cell gene therapy utilizing a lentiviral vector, was approved by the U.S. FDA in September 2022 for the treatment of early cALD. Clinical studies have shown that its efficacy is comparable to HSCT, with no GVHD or transplant-related rejection reported 17 . However, due to its high cost and limited accessibility, HSCT remains the primary treatment option in many settings, particularly in resource-limited regions. critical finding in our cohort was the significant diagnostic delay (median 0.6 years for cALD, but up to 3 years for adrenal form). Many patients in the non-HSCT group missed the life-saving window (Loes < 9) simply because they were diagnosed after symptoms appeared. Currently, ALD newborn screening measuring C26:0-lysophosphatidylcholine (C26:0-LPC) in dried blood spots is standard in the United States and other regions. While pilot studies in China (e.g., Shanghai, Guangzhou) have demonstrated the feasibility of this method, it is not yet universally implemented. Our data—showing high mortality in late-diagnosed cases—strongly advocates for the integration of ALD into national newborn screening (NBS) programs in China. Early detection via NBS allows for prospective MRI monitoring and timely HSCT intervention before irreversible brain damage occurs. This study has several limitations. First, it is a single-center retrospective study with a relatively small sample size, which limited the statistical power of the survival analysis. Second, long-term neurocognitive quality of life (QoL) data for HSCT survivors was not systematically quantified. Future multi-center studies with larger cohorts and longitudinal functional assessments are needed to validate these findings. In summary, early-stage HSCT significantly improves survival in pediatric cALD, particularly when the Loes score is < 9. The identification of three novel variants enriches the ABCD1 mutation spectrum. Crucially, early diagnosis remains challenging due to the heterogeneous nature of initial symptoms, and the diagnostic delays observed highlight the necessity of promoting newborn screening to enable pre-symptomatic diagnosis and timely intervention. Abbreviations ACTH, adrenocorticotropic hormone ALD, adrenoleukodystrophy ALDP, adrenoleukodystrophy protein Allo-HSCT, allogeneic hematopoietic stem cell transplantation AMN, adrenomyeloneuropathy cALD, cerebral ALD GVHD, Graft-versus-host disease MFD, major functional disability MLPA, multiplex ligation-dependent probe amplification OS, overall survival QoL, quality of life qPCR, quantitative polymerase chain reaction SD, standard deviation T2WI, T2-weighted images VLCFAs, very long-chain fatty acids Declarations Ethical approval and consent to participate The protocol was approved by the Ethics Committee of Shanghai Children’s Medical Center (SCMCIRB- K2020060-1). All methods were performed in accordance with the relevant guidelines and regulations [International Ethical Guidelines for Health-related Research Involving Humans, Fourth Edition. Geneva. Council for International Organizations of Medical Sciences (CIOMS); 2016]. Informed consent to participate was obtained from all subjects and/or their legal guardian(s). Data Availability Statement The data that support the findings of this study are available from the corresponding authors upon reasonable request. Conflict of Interest No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. Funding This work was funded by National Key R&D Program (2022YFC2703102), Shanghai Rare Disease Clinical Research Center (20MC1920400), 2024 Medical Service and Guarantee Capacity Improvement (National Clinical Key Specialty Construction) Project (10000015Z155080000004) and the Key Discipline Group of Pudong New Area Health Commission (PWZxq2022-07) Authors’ contributions J.L and L.Y. were equally responsible for the work described in this paper, and should be considered joint first author. J.C. and X.W contributed to the conception and design, revising the manuscript. G.C., Y.D., J.C., and X.W. contributed to provision of study materials or patients. T.Y. contributed to gene analysis. All authors approved the final manuscript as submitted. Acknowledgements We are grateful to the patients and their families for their participation. 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Cite Share Download PDF Status: Published Journal Publication published 16 Apr, 2026 Read the published version in European Journal of Pediatrics → Version 1 posted Editorial decision: Revision requested 17 Mar, 2026 Reviews received at journal 28 Feb, 2026 Reviewers agreed at journal 23 Feb, 2026 Reviewers agreed at journal 19 Feb, 2026 Reviewers invited by journal 18 Feb, 2026 Editor assigned by journal 18 Feb, 2026 Submission checks completed at journal 18 Feb, 2026 First submitted to journal 14 Feb, 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-8883258","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":594166270,"identity":"bb6ae29e-7321-4a6b-9552-d0439eabc485","order_by":0,"name":"Juan Li","email":"","orcid":"","institution":"Shanghai Children's Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Li","suffix":""},{"id":594166271,"identity":"5e05d706-8d75-4150-882a-864901d86a96","order_by":1,"name":"Lingwen Ying","email":"","orcid":"","institution":"Shanghai Children's Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Lingwen","middleName":"","lastName":"Ying","suffix":""},{"id":594166273,"identity":"6b97daf2-9a22-4c32-8ee0-09e8ef84c79a","order_by":2,"name":"Guoying Chang","email":"","orcid":"","institution":"Shanghai Children's Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Guoying","middleName":"","lastName":"Chang","suffix":""},{"id":594166274,"identity":"c40594c1-87c6-416b-9b16-165969e949ea","order_by":3,"name":"Yu Ding","email":"","orcid":"","institution":"Shanghai Children's Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Ding","suffix":""},{"id":594166275,"identity":"92679ceb-2fb3-42c0-b0d2-0f4bec53a4d4","order_by":4,"name":"Tingting Yu","email":"","orcid":"","institution":"Shanghai Children's Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Tingting","middleName":"","lastName":"Yu","suffix":""},{"id":594166276,"identity":"3db910ec-92da-4afd-be98-f42cac44098d","order_by":5,"name":"Jing Chen","email":"","orcid":"","institution":"Shanghai Children's Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Chen","suffix":""},{"id":594166277,"identity":"f50cdaf5-bdf6-4c77-95e2-ce2a66005da7","order_by":6,"name":"Xiumin Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYNACAwYGNgbGhgMJFTY8/OwNRGthbnzw4EyajGTPAaKtYm82fNh22MbghgMB84+fPfyap+BwNJ90Y5tEYtt5HoYbDIwfPubg0XImL81yhsHh3DaZg20SCedu8zDObmCWnLkNtxazAzlmBh9AWoBWSCSU3eZhljnAxsyLT8v5N2YGCXAtbOd42IAkfi03cowfQG1pNkhoO8DDQ0iL/Y03ZowzDNJBWhofJJxJ5pHgOdiM1y+S/TnGn3n+WOfOn5H+4OCPCjt7++PNBz98xKMFCNgk0AQYG/CqBwLmD4RUjIJRMApGwQgHAEtwV7RDLm82AAAAAElFTkSuQmCC","orcid":"","institution":"Shanghai Children's Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Xiumin","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2026-02-15 02:38:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8883258/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8883258/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00431-026-06951-1","type":"published","date":"2026-04-16T15:59:29+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":103305182,"identity":"73cd925d-d4c5-4f69-987e-a9a50c04785a","added_by":"auto","created_at":"2026-02-24 08:58:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":584598,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eClinical classification, disease severity, treatment strategies, and outcomes of 31 pediatric patients with X-linked adrenoleukodystrophy.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 31 enrolled patients, 24 presented with cerebral adrenoleukodystrophy (cALD), of whom 15 subsequently developed adrenal insufficiency; the remaining seven had adrenal-only ALD, including three who later progressed to cerebral involvement. Thirteen cALD patients were classified as early-stage disease (Loes \u0026lt; 9): 11 underwent HSCT and remain alive, while two did not receive HSCT—one has died and one is awaiting transplantation. The remaining 11 patients had late-stage disease (Loes ≥ 9): five received HSCT (one lost to follow-up, two alive, and two deceased), and six did not undergo HSCT (three alive and three deceased). The figure summarizes disease subtype, Loes-based severity, treatment pathway, and clinical outcomes for all subjects.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-8883258/v1/0222e31dc27c671456c7b1f1.png"},{"id":103506754,"identity":"071e00b9-1dc3-49e6-a747-8e6c844bbc16","added_by":"auto","created_at":"2026-02-26 13:39:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1285797,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSpectrum and distribution of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eABCD1\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e variants in 31 children with X-linked adrenoleukodystrophy.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWhole-exome sequencing identified 29 distinct ABCD1 variants among 31 patients, including 22 missense (76%), six frameshift (21%), and one large 7.7-Mb deletion. Variants were most frequently located in exons 1 (38%) and 8. Three pathogenic variants (c.77C\u0026gt;G, c.1119_1120insTC, and c.1291C\u0026gt;T) were novel and not reported in existing population or disease databases. No genotype–phenotype correlation was evident across clinical subtypes of X-linked adrenoleukodystrophy (X-ALD).\u003c/p\u003e\n\u003cp\u003eNote: The star represents the novel variants.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-8883258/v1/b1601b4a9ea3d56cb05b098e.png"},{"id":103305183,"identity":"439e8dd3-29f4-4a90-a1e2-197aa90ed10d","added_by":"auto","created_at":"2026-02-24 08:58:51","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":535027,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A) Distribution of Loes scores at diagnosis in pediatric cerebral X-linked adrenoleukodystrophy and (B) Kaplan–Meier overall survival in patients with or without allogeneic HSCT.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Loes scores at diagnosis for 24 children with cerebral ALD. Most patients presented with moderate disease severity, while only a minority were identified at an early stage (Loes \u0026lt; 9), the threshold associated with optimal outcomes following HSCT. The distribution highlights the difficulty of detecting cerebral involvement before substantial neurological injury occurs. (B) Kaplan–Meier survival curves comparing cerebral ALD patients who underwent allogeneic hematopoietic stem cell transplantation (red line) with those who did not receive HSCT (blue line). The results indicate a trend toward improved survival in transplanted patients.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8883258/v1/415df9ca058e7de665b54162.png"},{"id":107351558,"identity":"0c51ef3c-8458-4f6e-b6f6-d14773c918b8","added_by":"auto","created_at":"2026-04-20 16:11:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3730902,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8883258/v1/1d84ac51-766a-44cb-83e4-646f936d21af.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pediatric X-Linked Adrenoleukodystrophy: Phenotypes, Variants, and HSCT Outcomes","fulltext":[{"header":"What is known – what is new","content":"\u003cp\u003e\u0026bull;\u0026nbsp;\u003cstrong\u003eWhat is Known:\u003c/strong\u003e X-linked adrenoleukodystrophy (ALD) shows marked clinical heterogeneity; cerebral ALD progresses rapidly, and early HSCT offers the best outcomes.\u003cbr\u003e\u0026bull;\u0026nbsp;\u003cstrong\u003eWhat is Known:\u003c/strong\u003e The Loes score is a key imaging biomarker guiding transplant timing, with lower scores predicting superior prognosis.\u003cbr\u003e\u0026bull;\u0026nbsp;\u003cstrong\u003eWhat is New:\u003c/strong\u003e We report a Chinese pediatric cohort expanding the ABCD1 mutation spectrum with three novel pathogenic variants.\u003cbr\u003e\u0026bull; \u003cstrong\u003eWhat is New:\u003c/strong\u003e Survival analyses reinforce that HSCT at Loes \u0026lt; 9 confers a clinically meaningful advantage, highlighting diagnostic delays and the need for newborn screening.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eAdrenoleukodystrophy (ALD, OMIM#300100) is the most prevalent peroxisomal disorder, classified as a progressive neurometabolic disease resulting from impaired β-oxidation\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. It follows an X-linked recessive inheritance pattern and is caused by pathogenic variants in the ABCD1 gene located on Xq28. These mutations compromise the function of adrenoleukodystrophy protein (ALDP), which is essential for the transport of very long-chain fatty acids (VLCFAs) into peroxisomes. The resulting disruption in VLCFA β-oxidation leads to their accumulation in body fluids and tissues, particularly in cerebral white matter, spinal cord, adrenal cortex, and testicular Leydig cells. This pathological buildup contributes to extensive demyelination and/or adrenal insufficiency\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eALD demonstrates marked clinical heterogeneity, with symptoms that progressively accumulate over time. Studies have shown that more than half of affected males develop cerebral ALD (cALD), characterized by progressive cerebral demyelination. In addition, nearly all patients eventually exhibit adrenal insufficiency and slowly progressive myeloneuropathy in adulthood. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the most effective treatment for cALD. However, due to its insidious onset and rapid progression, cALD frequently results in death within 5\u0026ndash;10 years of diagnosis, highlighting the urgent need for early detection and intervention to improve patient outcomes.\u003c/p\u003e \u003cp\u003eIn this study, we retrospectively analyzed 31 pediatric ALD patients diagnosed and treated at our institution, focusing on their clinical presentations, auxiliary test findings, therapeutic interventions, and prognoses to enhance clinicians' understanding and management of this disorder. We specifically highlight the identification of three novel \u003cem\u003eABCD1\u003c/em\u003e variants and discuss the critical importance of early diagnosis, potentially via newborn screening, to improve HSCT outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients and Clinical Data Collection\u003c/h2\u003e \u003cp\u003e We retrospectively reviewed 31 children diagnosed with ALD at Shanghai Children\u0026rsquo;s Medical Center, Shanghai Jiao Tong University School of Medicine, between 2015 and 2023. Two patients (17a and 17b) were from the same family. Twenty-four patients had cALD, while seven presented with the pure adrenal form.\u003c/p\u003e \u003cp\u003eClinical data\u0026mdash;including age at onset and diagnosis, presenting symptoms, neurological and endocrine evaluations, MRI findings, VLCFA profiles, genetic results, treatment strategies, and follow-up outcomes\u0026mdash;were systematically collected. VLCFAs were quantified by isotope-dilution gas chromatography\u0026ndash;mass spectrometry. Plasma cortisol and adrenocorticotropic hormone (ACTH) were examined by chemiluminescence. Loes scores were assigned by two experienced neuroradiologists for patients with cerebral involvement\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e The study protocol was approved by the Ethics Committee of Shanghai Children\u0026rsquo;s Medical Center. Written informed consent for clinical data collection and genetic analysis was obtained from all guardians.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDiagnostic Criteria\u003c/h3\u003e\n\u003cp\u003eALD diagnosis was based on clinical manifestations, endocrine testing, biochemical markers, neuroimaging, and molecular analysis\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Diagnostic criteria included:\u003c/p\u003e \u003cp\u003e①Progressive neurological deficits, such as gait disturbances, cognitive decline, or visual impairment; ② Biochemical or clinical adrenal insufficiency, including hyperpigmentation, reduced cortisol levels, and elevated ACTH; ③ Elevated VLCFAs (C26:0, C24:0, C22:0) and increased C24:0/C22:0, C26:0/C22:0 ratios; ④ MRI evidence of symmetric white matter demyelination; ⑤ Detection of pathogenic \u003cem\u003eABCD1\u003c/em\u003e variants; ⑥ X-linked recessive inheritance pattern.\u003c/p\u003e \u003cp\u003eChildhood cALD was defined by fulfilling criteria ①\u0026ndash;⑥. Pure adrenal ALD was defined by meeting ②, ③, ⑤, and ⑥ in the absence of neurological involvement.\u003c/p\u003e\n\u003ch3\u003eGenetic analysis\u003c/h3\u003e\n\u003cp\u003eAll exons and exon\u0026ndash;intron boundaries of \u003cem\u003eABCD1\u003c/em\u003e were amplified by PCR and sequenced by ABI3730. Sequences were aligned to the reference \u003cem\u003eABCD1\u003c/em\u003e transcript (NM_000033.4). Variant pathogenicity was predicted using PolyPhen-2 and multiple in-silico tools. Multiplex ligation-dependent probe amplification (MLPA), quantitative polymerase chain reaction (qPCR), or microarray analysis was performed for patients with suspected ALD but negative sequencing results to screen for large deletions/duplications.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using SPSS 24.0. Continuous variables were tested for normality and expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or median (interquartile range). Categorical variables were expressed as frequencies (percentage). Kaplan\u0026ndash;Meier survival analysis was used to evaluate HSCT outcomes, with significance defined as \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThirty-one children with ALD were included (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median age at onset was 5.4 (3.5\u0026ndash;7.2) years, and the median age at diagnosis was 6.5 (5.7\u0026ndash;8.8) years, suggesting a median diagnostic delay of 0.6 (0.3\u0026ndash;2.1) years. Based on clinical subtype, children were classified into cerebral (n\u0026thinsp;=\u0026thinsp;24) and pure adrenal forms (n\u0026thinsp;=\u0026thinsp;7). In the cALD group, the median onset age was 5.4 (4.0\u0026ndash;6.9) years, diagnosis age was 6.1 (5.5\u0026ndash;7.5) years, and the median delay from onset to diagnosis was 0.5 (0.2\u0026ndash;1.2) years. In contrast, children with pure adrenal ALD had a median onset age of 3.0 (2.6\u0026ndash;7.3) years, diagnosis age of 9.0 (6.0\u0026ndash;11.8) years, and a longer diagnostic interval of 3.0 (2.0\u0026ndash;7.0) years.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical data of 31 patients with X-ALD (phenotype, genotype and treatment outcomes)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eID\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOnset age\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNeurological dysfunction\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdrenal insufficiency\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eABCD1\u003c/em\u003e gene mutation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHSCT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLoes Score\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCurrent status and age\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDevelopmental delay\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 1291C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDied at 4y\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSeizures, cognitive impairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDark skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 1679C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDied at 12y\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGait disturbances, epilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDark skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 293C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDied at 16y\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6y9m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLearning difficulties, strabismus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 1825G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e13y3m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDark skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 1119_1120 insTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e15y6m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVisual impairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDark skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 1430del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eloss to follow up\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSeizures, developmental delay\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 77C\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDied at 1y\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5y3m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVisual impairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 1825G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDied\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e9C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1y2m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ec. 1552C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e4y6m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ePositive ALD family history\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e10C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e6y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ec. 421G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e9y\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ePositive ALD family history\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.5y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDark skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 1849C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e(Progress to encephalopathy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e16y\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDark skin and short stature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 454C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003cp\u003ec. 887A\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e18y\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDark skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 1886-10G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e(Progress to encephalopathy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e9y\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.5y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSeizures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDark skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 901\u0026thinsp;\u0026minus;\u0026thinsp;25_901-9del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11y7m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9y4m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSeizures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDark skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 323C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e9y9m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e13y\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6y1m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGait disturbances, dysarthria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLaboratory findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 1814T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e6y3m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10y5m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17aC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5y5m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDysarthria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDark skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 454C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e7y5m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10y1m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7y3m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDark skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 454C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e(Progress to encephalopathy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10y\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSeizures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 900\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e4y4m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6y\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4y7m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 1415_1416del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e5y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7y4m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5y8m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGait disturbances\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDark skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 937delC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e6y8m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8y4m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2y10m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDark skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 900G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e13y1m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7y5m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVisual or auditory impairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLaboratory findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 1785G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8y7m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEpilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLaboratory findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 161G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e7y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eDied at 7y,\u003c/p\u003e \u003cp\u003edue to bone marrow suppression and infection during HSCT\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6y2m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVisual impairment, Strabismus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 887A\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e6y4m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7y\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8y4m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVisual or auditory impairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 1519G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e8y9m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e9y3m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e26C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5y5m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVisual impairment, Strabismus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLaboratory findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 974T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e5y11m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6y8m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e27C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8y6m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVisual impairment, Strabismus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLaboratory findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 1682A\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e8y9m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e9y3m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4y7m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDark skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ea 7.7 Mb deletion in the\u003c/p\u003e \u003cp\u003eXq28 region\u003c/p\u003e \u003cp\u003e(encompassing \u003cem\u003eABCD1\u003c/em\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8y7m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e29C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7y6m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVisual impairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLaboratory findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 493dup\u003c/p\u003e \u003cp\u003ep. Arg165ProfsTer30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHLA typing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7y9m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9y7m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVisual or auditory impairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLaboratory findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec. 1658T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10y7m\u003c/p\u003e \u003cp\u003eLiving\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eNote: HLA, Human Leukocyte Antigen; HSCT, Haematopoietic Stem Cell Transplant\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003csup\u003ea\u003c/sup\u003eID with C means those patients were classified as cALD;\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003csup\u003eb\u003c/sup\u003eThe Loes score is based on the results of the cranial MRI, where 0 means no central nervous system involvement\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAmong the cALD patients, neurological symptoms were the predominant clinical feature, with the most common initial symptoms being visual/auditory decline (37.5%), seizures (29.2%), strabismus (16.7%), cognitive impairment (16.7%), gait abnormalities (12.5%), and dysarthria (8.3%). Two were asymptomatic and diagnosed through family screening. During follow-up, 62.5% (15/24) developed adrenal insufficiency. Among the seven pure adrenal ALD patients, the primary manifestation was hyperpigmentation. Three later developed early white matter changes on MRI.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBiochemical and Hormonal Tests\u003c/h2\u003e \u003cp\u003eTen patients underwent VLCFA testing at diagnosis, all showing elevated C26:0, with a markedly increased C26:0/C22:0 ratio. The median C26:0/C22:0 ratio was 0.096 \u0026micro;mol/L, significantly higher than the normal reference value of \u0026lt;\u0026thinsp;0.013 \u0026micro;mol/L.\u003c/p\u003e \u003cp\u003eAdrenal cortical function assessment was completed for all participants, and 4 cases underwent additional ACTH stimulation testing. Twenty-two cases (71.0%) had adrenal insufficiency. Mean morning cortisol was 3.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 \u0026micro;g/dL (reference range: 6.7\u0026ndash;22.6 \u0026micro;g/dL), with markedly elevated ACTH of 645.4\u0026thinsp;\u0026plusmn;\u0026thinsp;426.7 pg/mL (reference range: 0\u0026ndash;46 pg/mL).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMRI Findings\u003c/h3\u003e\n\u003cp\u003eAll 24 children diagnosed with cALD demonstrated white matter involvement on cranial MRI. Imaging revealed hyperintense signals on T2-weighted images (T2WI) in affected regions, with lesions typically appearing symmetrical. The most commonly involved areas included the corpus callosum, supratentorial white matter (frontal, parietal, occipital, and temporal lobes), visual and auditory pathways, projection fibers, and the cerebellum. Among the 7 patients initially diagnosed with the pure adrenal form, 3 subsequently developed cerebral involvement during follow-up, while the remaining 4 showed no abnormal findings on cranial imaging.\u003c/p\u003e \u003cp\u003eLoes scoring was performed by neuroradiologists for 27 children with cerebral involvement (including the 3 progressed cases). Sixteen children had Loes scores below 9, while 11 had scores\u0026thinsp;\u0026ge;\u0026thinsp;9, indicating more advanced white matter damage.\u003c/p\u003e\n\u003ch3\u003eGenetic Mutation Spectrum\u003c/h3\u003e\n\u003cp\u003eAll 31 children with ALD were confirmed to carry pathogenic variants in the \u003cem\u003eABCD1\u003c/em\u003e gene through whole-exome sequencing (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In total, 29 distinct variants were found: 75.9% (22/29) were missense mutations, 20.7% (6/29) were frameshift mutations, and one case (P28) harbored a 7.7 Mb deletion in the Xq28 region encompassing the \u003cem\u003eABCD1\u003c/em\u003e gene. Most variants were located in exon 1 (37.9%, 11/29), followed by exon 8. Among the identified variants, c.1415_1416delAG (found in patient P19) has been previously reported as a hotspot mutation. Three novel variants (c.77C\u0026thinsp;\u0026gt;\u0026thinsp;G, c.1119_1120insTC, and c.1291C\u0026thinsp;\u0026gt;\u0026thinsp;T) were not previously reported or included in existing mutation databases. Additionally, c.454C\u0026thinsp;\u0026gt;\u0026thinsp;T and c.1825G\u0026thinsp;\u0026gt;\u0026thinsp;A were observed in three and two patients, respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThose 31 patients originated from 30 unrelated families. Patients 17a and 17b, who were cousins from the same family, both carried the c.454C\u0026thinsp;\u0026gt;\u0026thinsp;T variant. Despite sharing the same mutation, their clinical presentations diverged significantly: one exhibited cALD with adrenal insufficiency, while the other had the pure adrenal phenotype.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eTreatment Outcomes and Follow-up\u003c/h2\u003e \u003cp\u003eRegular follow-up (including routine clinic visits and phone tracking) were conducted for all 31 patients. By January 2024, all 7 patients with the pure adrenal form were receiving hydrocortisone replacement therapy without any adrenal crisis events. Among the cohort, 6 patients (P1\u0026ndash;3, P7\u0026ndash;8, P23), all with cALD, had died; 1 patient (P6) was lost to follow-up; and 2 developed secondary epilepsy, managed with diazepam and carbamazepine.\u003c/p\u003e \u003cp\u003eOf the 24 cALD patients, 8 received supportive care alone, with 4 deaths (50%), and 1 pending HSCT. The remaining 16 underwent HSCT, of whom 14 survived (7 for over 3 years). Two post-HSCT deaths were due to disease progression and post-transplant complications, respectively. MRI follow-up showed that central lesions progressed in patients with pre-HSCT Loes scores\u0026thinsp;\u0026ge;\u0026thinsp;9, while those with scores\u0026thinsp;\u0026lt;\u0026thinsp;9 remained stable, suggesting that a lower Loes score (\u0026lt;\u0026thinsp;9) at the time of transplant is associated with better neurological outcomes (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eKaplan\u0026ndash;Meier analysis revealed a 5-year overall survival (OS) of 55.0% (95% CI: 42.2\u0026ndash;65.7%) among all cALD patients. Subgroup analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB) indicated that early-stage cALD patients receiving HSCT demonstrated a clinically meaningful trend toward improved survival (78% vs. 29%), although this difference did not reach statistical significance (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.24) likely due to the limited sample size. Importantly, patients with pre-transplant Loes scores\u0026thinsp;\u0026lt;\u0026thinsp;9 showed stabilized MRI findings post-HSCT, whereas those with scores\u0026thinsp;\u0026ge;\u0026thinsp;9 experienced disease progression despite transplantation.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eALD is a rare peroxisomal disorder with an estimated prevalence of 1 in 14,000 to 1 in 17,000. To date, comprehensive epidemiological data on the prevalence of ALD in China are still lacking. As an X-linked recessive disorder, ALD predominantly affects males, while female carriers typically remain asymptomatic. Consistent with this inheritance pattern, all participants in this study were male.\u003c/p\u003e \u003cp\u003eClinically, ALD presents with a wide range of symptoms that tend to progress over time. Based on the initial presentation, ALD is typically categorized into cALD, adrenomyeloneuropathy (AMN), pure adrenal form, and female carrier status. Previous studies report that cALD is the most prevalent phenotype, accounting for approximately 35%\u0026ndash;45% of cases\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. It most frequently presents around the age of 7, rarely before age 2, and is extremely uncommon after 15 years. Early symptoms often include cognitive and behavioral disturbances, which may be subtle and easily misdiagnosed. As the disease advances, patients may experience worsening cognitive decline, cortical blindness or visual impairment, central hearing loss, and quadriplegia. In our cohort, 77.4% (24/31) of children were diagnosed with cALD, with a median age of onset of 5.4 (4.0\u0026ndash;6.9) years and median diagnosis age of 6.1 (5.5\u0026ndash;7.5) years, aligning with existing literature. Notably, the youngest cALD patient in our study was only 9 months old and was identified due to developmental delay; diagnosis was confirmed through cranial MRI and whole-exome sequencing. This represents one of the earliest documented cases in China and underscores the need for vigilance even in infants.\u003c/p\u003e \u003cp\u003eUnlike earlier studies that emphasized cognitive and behavioral symptoms, most cALD patients in this cohort initially presented with visual or auditory impairment (9/24) or epilepsy (7/24), while cognitive impairment was noted in only 4 cases. These children were ultimately diagnosed based on cranial MRI findings and whole-exome sequencing. Given the broad spectrum of early symptoms, timely diagnosis remains a clinical challenge. However, the disease course of cALD is often aggressive; if untreated, patients may experience irreversible disability within 6 months to 2 years of onset and die within 5 to 10 years\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Notably, neuroimaging abnormalities typically precede clinical symptoms. Functional MRI and perfusion studies may detect early brain changes, emphasizing the importance of early imaging in patients with developmental delays or seizures. Moreover, regular MRI monitoring may facilitate earlier detection of white matter lesions and disease progression\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePrimary adrenal insufficiency is another major clinical phenotype of ALD, with an estimated lifetime prevalence exceeding 80%\u003csup\u003e8\u003c/sup\u003e. Although the underlying mechanism remains unclear, it is believed to involve chronic accumulation of VLCFAs in the zona fasciculata and zona reticularis of the adrenal cortex, leading to cytotoxicity, apoptosis, and cortical atrophy\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. In our study, 7 patients (22.6%) were diagnosed with pure adrenal ALD. Comprehensive evaluation of adrenal function in all 31 patients revealed that 22 (71.0%) had evidence of adrenal insufficiency. The risk is partially age-dependent, typically peaking between 3 and 10 years, consistent with findings in our cohort. However, we observed adrenal insufficiency as early as 2 years and 10 months, whereas the youngest reported in literature presented with subclinical glucocorticoid abnormalities at just 5 weeks of age. Given that ALD accounts for 4\u0026ndash;35% of idiopathic primary adrenal insufficiency cases without autoimmune markers\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, it is crucial to screen for ALD in boys with unexplained adrenal insufficiency. For patients with confirmed adrenal involvement, glucocorticoid replacement (e.g., hydrocortisone or cortisone acetate at 8\u0026ndash;12 mg/m\u0026sup2;/day in 2\u0026ndash;3 divided doses) is recommended, with dosage adjustments during physiological stress. Mineralocorticoid replacement is generally unnecessary due to relative preservation of the zona glomerulosa, potentially avoiding VLCFA accumulation.\u003c/p\u003e \u003cp\u003eIn addition to adrenal dysfunction, testicular impairment may occur in ALD. Studies suggest that over 80% of male patients exhibit primary testicular dysfunction, possibly through mechanisms similar to adrenal insufficiency, though the natural progression remains poorly defined. However, a study on male AMN-type patients found that despite biochemical abnormalities, fertility was not significantly affected. In our cohort, all three boys with pure adrenal ALD showed normal pubertal onset and development during follow-up.\u003c/p\u003e \u003cp\u003eVLCFAs\u0026mdash;comprising C22:0, C24:0, and C26:0\u0026mdash;serve as key biochemical markers for ALD diagnosis. Elevated serum VLCFA levels, particularly C26:0 and the C26:0/C22:0 ratio, are reliable diagnostic indicators unaffected by diet or stress\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. In our study, all 10 tested patients exhibited elevated levels consistent with known disease profiles. However, VLCFA levels do not correlate with disease severity or phenotype\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, limiting their use in monitoring disease progression. Therefore, genetic testing remains essential for definitive diagnosis in patients with abnormal VLCFA profiles.\u003c/p\u003e \u003cp\u003ePathogenic variants in the \u003cem\u003eABCD1\u003c/em\u003e gene are the definitive cause of ALD\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. To date, over 900 \u003cem\u003eABCD1\u003c/em\u003e variants have been reported, with missense variants being the most prevalent (61.4%), followed by frameshift mutations (17.2%). In our cohort, we identified 29 distinct \u003cem\u003eABCD1\u003c/em\u003e mutations. Of these, 22 (75.9%) were missense mutations, 6 were frameshift mutations, and 1 involved a large genomic deletion encompassing the \u003cem\u003eABCD1\u003c/em\u003e locus. Notably, exon 1 harbored the highest frequency of mutations (37.9%), followed by exon 8. Additionally, our study expands the genetic spectrum of ALD by identifying three novel pathogenic variants: c.77C\u0026thinsp;\u0026gt;\u0026thinsp;G, c.1119_1120insTC, and c.1291C\u0026thinsp;\u0026gt;\u0026thinsp;T. These variants were absent from public databases and were classified as pathogenic based on ACMG guidelines, co-segregation with the disease phenotype, and elevated VLCFA levels. The discovery of these variants contributes to the global ALD genetic database and facilitates molecular diagnosis for future patients. Consistent with previous literature, we observed no clear genotype-phenotype correlation; notably, cousins carrying the same c.454C\u0026thinsp;\u0026gt;\u0026thinsp;T variant (P17a and P17b) presented with divergent phenotypes (cALD vs. pure adrenal form), suggesting the influence of epigenetic factors or modifier genes\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAllo-HSCT remains a critical intervention for improving outcomes in children with cALD. Several studies, including one by Mahmood et al.\u003csup\u003e14\u003c/sup\u003e, have shown that early HSCT markedly increases the 5-year survival rate (95% \u003cem\u003evs.\u003c/em\u003e 54% in untreated patients). A subsequent multicenter study conducted across Europe and North America reported similarly promising results, with a 5-year OS of 94% and a major functional disability (MFD)-free survival rate of 91% in patients receiving timely transplants\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. In our study, the overall 5-year survival rate for cALD patients was 55.0% (95% \u003cem\u003eCI\u003c/em\u003e: 42.2\u0026ndash;65.7%). Among those who underwent HSCT, the 5-year OS was 78.0% (95% \u003cem\u003eCI\u003c/em\u003e: 64.0\u0026ndash;86.6%), compared to 29.0% (95% \u003cem\u003eCI\u003c/em\u003e: 11.7\u0026ndash;48.2%) in the non-transplanted group. These results further validate the survival benefit of early HSCT intervention in children with cALD.\u003c/p\u003e \u003cp\u003eThe Loes score is a widely used MRI-based assessment tool that quantifies the extent of cerebral demyelination and brain atrophy, ranging from 0 to 34. Higher scores indicate more advanced disease. Generally, a Loes score between 0.5 and 9.5 is considered optimal for HSCT candidacy\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Our findings reinforce this criterion: patients with pre-transplant Loes scores\u0026thinsp;\u0026lt;\u0026thinsp;9 had better post-HSCT outcomes, whereas disease progression continued in patients with higher pre-transplant scores despite intervention. It is important to note that HSCT does not reverse established neurological damage and has no therapeutic effect on adrenal insufficiency or adult-onset AMN. Additionally, HSCT carries risks such as graft failure, bone marrow suppression, and Graft-versus-host disease (GVHD), which may negatively impact long-term outcomes. To address these limitations, gene therapy has emerged as a novel therapeutic approach. Skysona, an autologous hematopoietic stem cell gene therapy utilizing a lentiviral vector, was approved by the U.S. FDA in September 2022 for the treatment of early cALD. Clinical studies have shown that its efficacy is comparable to HSCT, with no GVHD or transplant-related rejection reported\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. However, due to its high cost and limited accessibility, HSCT remains the primary treatment option in many settings, particularly in resource-limited regions.\u003c/p\u003e \u003cp\u003ecritical finding in our cohort was the significant diagnostic delay (median 0.6 years for cALD, but up to 3 years for adrenal form). Many patients in the non-HSCT group missed the life-saving window (Loes\u0026thinsp;\u0026lt;\u0026thinsp;9) simply because they were diagnosed after symptoms appeared. Currently, ALD newborn screening measuring C26:0-lysophosphatidylcholine (C26:0-LPC) in dried blood spots is standard in the United States and other regions. While pilot studies in China (e.g., Shanghai, Guangzhou) have demonstrated the feasibility of this method, it is not yet universally implemented. Our data\u0026mdash;showing high mortality in late-diagnosed cases\u0026mdash;strongly advocates for the integration of ALD into national newborn screening (NBS) programs in China. Early detection via NBS allows for prospective MRI monitoring and timely HSCT intervention before irreversible brain damage occurs.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, it is a single-center retrospective study with a relatively small sample size, which limited the statistical power of the survival analysis. Second, long-term neurocognitive quality of life (QoL) data for HSCT survivors was not systematically quantified. Future multi-center studies with larger cohorts and longitudinal functional assessments are needed to validate these findings.\u003c/p\u003e \u003cp\u003eIn summary, early-stage HSCT significantly improves survival in pediatric cALD, particularly when the Loes score is \u0026lt;\u0026thinsp;9. The identification of three novel variants enriches the \u003cem\u003eABCD1\u003c/em\u003e mutation spectrum. Crucially, early diagnosis remains challenging due to the heterogeneous nature of initial symptoms, and the diagnostic delays observed highlight the necessity of promoting newborn screening to enable pre-symptomatic diagnosis and timely intervention.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACTH, adrenocorticotropic hormone\u003c/p\u003e\n\u003cp\u003eALD, adrenoleukodystrophy\u003c/p\u003e\n\u003cp\u003eALDP, adrenoleukodystrophy protein\u003c/p\u003e\n\u003cp\u003eAllo-HSCT, allogeneic hematopoietic stem cell transplantation\u003c/p\u003e\n\u003cp\u003eAMN, adrenomyeloneuropathy\u003c/p\u003e\n\u003cp\u003ecALD, cerebral ALD\u003c/p\u003e\n\u003cp\u003eGVHD, Graft-versus-host disease\u003c/p\u003e\n\u003cp\u003eMFD, major functional disability\u003c/p\u003e\n\u003cp\u003eMLPA, multiplex ligation-dependent probe amplification\u003c/p\u003e\n\u003cp\u003eOS, overall survival\u003c/p\u003e\n\u003cp\u003eQoL, quality of life\u003c/p\u003e\n\u003cp\u003eqPCR, quantitative polymerase chain reaction\u003c/p\u003e\n\u003cp\u003eSD, standard deviation\u003c/p\u003e\n\u003cp\u003eT2WI, T2-weighted images\u003c/p\u003e\n\u003cp\u003eVLCFAs, very long-chain fatty acids\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe protocol was approved by the Ethics Committee of Shanghai Children’s Medical Center (SCMCIRB- K2020060-1). All methods were performed in accordance with the relevant guidelines and regulations [International Ethical Guidelines for Health-related Research Involving Humans, Fourth Edition. Geneva.\u003c/p\u003e\n\u003cp\u003eCouncil for International Organizations of Medical Sciences (CIOMS); 2016]. Informed consent to participate was obtained from all subjects and/or their legal guardian(s).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding authors upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was funded by National Key R\u0026amp;D Program (2022YFC2703102), Shanghai Rare Disease Clinical Research Center (20MC1920400), 2024 Medical Service and Guarantee Capacity Improvement (National Clinical Key Specialty Construction) Project (10000015Z155080000004) and the Key Discipline Group of Pudong New Area Health Commission (PWZxq2022-07)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.L and L.Y. were equally responsible for the work described in this paper, and should be considered joint first author. J.C. and X.W contributed to the conception and design, revising the manuscript. G.C., Y.D., J.C., and X.W. contributed to provision of study materials or patients. T.Y. contributed to gene analysis. All authors approved the final manuscript as submitted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to the patients and their families for their participation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEngelen M, Kemp S, de Visser M et al (2012) X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis 7:51\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMosser J, Douar AM, Sarde CO et al (1993) Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 361(6414):726\u0026ndash;730\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLoes DJ, Hite S, Moser H et al (1994) Adrenoleukodystrophy: a scoring method for brain MR observations. AJNR Am J Neuroradiol 15(9):1761\u0026ndash;1766\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiberato AP, Mallack EJ, Aziz-Bose R et al (2019) MRI brain lesions in asymptomatic boys with X-linked adrenoleukodystrophy. Neurology 92(15):e1698\u0026ndash;1708\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGujral J, Sethuram S (2023) An update on the diagnosis and treatment of adrenoleukodystrophy. Curr Opin Endocrinol Diabetes Obes 30(1):44\u0026ndash;51\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKemp S, Huffnagel IC, Linthorst GE et al (2016) Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. 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Nature 361(6414):726\u0026ndash;730\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKemp S, Berger J, Aubourg P (2012) X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochim Biophys Acta 1822(9):1465\u0026ndash;1474\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahmood A, Raymond GV, Dubey P et al (2007) Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol 6(8):687\u0026ndash;692\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaymond GV, Aubourg P, Paker A et al (2019) Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transpl 25(3):538\u0026ndash;548\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePage KM, Stenger EO, Connelly JA et al (2019) Hematopoietic Stem Cell Transplantation to Treat Leukodystrophies: Clinical Practice Guidelines from the Hunter's Hope Leukodystrophy Care Network. Biol Blood Marrow Transpl 25(12):e363\u0026ndash;374\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEichler F, Duncan C, Musolino PL et al (2017) Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med 377(17):1630\u0026ndash;1638\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"X-linked adrenoleukodystrophy, ABCD1, gene mutation, Loes score, hematopoietic stem cell transplantation","lastPublishedDoi":"10.21203/rs.3.rs-8883258/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8883258/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePurpose: X-linked adrenoleukodystrophy (ALD) presents variable neurologic and adrenal manifestations. Early diagnosis is critical for effective hematopoietic stem cell transplantation (HSCT). This study aims to characterize clinical phenotypes, expand the ABCD1 mutational spectrum, and evaluate HSCT outcomes in a Chinese pediatric cohort.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethods: We retrospectively reviewed 31 male children diagnosed with ALD from 2015 to 2023. Clinical features, adrenal function, brain MRI findings, and ABCD1 mutations were analyzed. Loes scores were determined for cerebral ALD (cALD). Overall survival was compared between early-stage cALD patients who underwent allogeneic HSCT and those who did not.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: Twenty-four patients had cALD, and seven presented with adrenal-only disease. Neurologic symptoms in cALD included visual/hearing impairment (38%), seizures (29%), and cognitive decline (17%). Adrenal insufficiency occurred in 62.5% of cALD patients. Genetic analysis identified 29 ABCD1 variants, including three novel pathogenic variants (c.77C\u0026gt;G, c.1119_1120insTC, c.1291C\u0026gt;T). While statistical significance was limited by sample size (P = 0.24), early-stage cALD patients receiving HSCT showed a clinically meaningful trend toward improved 5-year OS (78%) compared to non-transplanted patients (29%). A pre-transplant Loes score \u0026lt; 9 was a critical determinant of superior outcomes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusion: We expanded the ABCD1 spectrum with three novel variants. Our findings confirm that early-stage HSCT (Loes \u0026lt; 9) offers a distinct survival advantage. The diagnostic delays observed in our cohort underscore the urgent need for implementing newborn screening to capture patients within the optimal therapeutic window.\u003c/p\u003e","manuscriptTitle":"Pediatric X-Linked Adrenoleukodystrophy: Phenotypes, Variants, and HSCT Outcomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-24 08:58:46","doi":"10.21203/rs.3.rs-8883258/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-17T20:02:31+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-01T04:38:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"197667107096323941766578819086358424677","date":"2026-02-23T19:32:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"175534698873301308873032379341922884842","date":"2026-02-20T00:46:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-18T15:52:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-18T11:24:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-18T11:18:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Pediatrics","date":"2026-02-15T02:24:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"79aefb71-f691-4edc-9325-dadbdcece115","owner":[],"postedDate":"February 24th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-20T16:07:52+00:00","versionOfRecord":{"articleIdentity":"rs-8883258","link":"https://doi.org/10.1007/s00431-026-06951-1","journal":{"identity":"european-journal-of-pediatrics","isVorOnly":false,"title":"European Journal of Pediatrics"},"publishedOn":"2026-04-16 15:59:29","publishedOnDateReadable":"April 16th, 2026"},"versionCreatedAt":"2026-02-24 08:58:46","video":"","vorDoi":"10.1007/s00431-026-06951-1","vorDoiUrl":"https://doi.org/10.1007/s00431-026-06951-1","workflowStages":[]},"version":"v1","identity":"rs-8883258","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8883258","identity":"rs-8883258","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}