Importance:Leukodystrophies are a heterogeneous group of genetic disorders affecting the white matter of the brain, often presenting with overlapping clinical features but differing in neuroanatomical involvement. There is a critical need for quantitative tools to characterize disease burden and support diagnosis, severity stratification, and clinical trial readiness. Objective:To characterize shared and distinct neuroanatomical patterns across six genetically confirmed leukodystrophies using anatomical MRI-derived phenotypes benchmarked against brain growth charts, and to assess the utility of this methodological approach for identifying imaging biomarkers of disease severity. Design:Cross-sectional neuroimaging study using retrospective clinical MRI data. Setting:Multicenter study incorporating data from the Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) and control data from the Children's Hospital of Philadelphia. Participants:The study included 434 MRI scan sessions from 274 patients with genetically confirmed leukodystrophies (Pelizaeus-Merzbacher disease, Metachromatic leukodystrophy, Alexander disease, Aicardi-Goutières syndrome, TUBB4A-related leukodystrophies, and POLR3-related leukodystrophy). Control MRI data (7628 scans from 7205 subjects) were drawn from the Scans with Limited Imaging Pathology cohort at the Children's Hospital of Philadelphia. Exposures:All MRI scans underwent automated segmentation using deep learning segmentation tools to derive global and regional brain volumes. Normative models of brain development ("brain growth charts") were generated for the control cohort using generalized additive models for location, scale, and shape. Centile scores were then calculated for leukodystrophy subjects to quantify deviations from typical development. Main Outcomes and Measures:Centile scores for global and regional brain volumes were compared across leukodystrophy subtypes to identify disease-specific neuroanatomical patterns and to evaluate their potential utility for severity stratification. Results:Distinct patterns of neuroanatomical deviation were observed across leukodystrophy subtypes. Certain leukodystrophies showed preferential involvement of specific cortical or subcortical regions, while others displayed more diffuse volume loss. Centile scores demonstrated potential for differentiating disease subtypes and stratifying individuals by severity. Preliminary longitudinal data suggest centile scores may also track progression over time. Conclusions and Relevance:This study demonstrates the feasibility and utility of MRI profiling of individuals with leukodystrophy using anatomical MRI-derived phenotypes benchmarked against brain growth charts. The approach enables data-driven, quantitative characterization of structural brain abnormalities, offering a scalable method for phenotyping, diagnosis, and future use in clinical trials.

INTRODUCTION:Type I Alexander Disease (AxD) is a rare leukodystrophy that can be subclassified into subtypes (Ia, Ib, Ic, and Id), in order of decreasing severity. To date, no study has correlated MRI findings with AxD type I clinical evolution. This study aims to identify MRI features that may predict disease progression. METHODS:Patients with genetically confirmed type I AxD were recruited from multiple Leukodystrophy Centers worldwide. Clinical data were collected via RedCap, and patients were retrospectively classified by disease subtype. Leukodystrophy experts analyzed the first available MRI scans using an adapted AxD MRI scoring protocol, and imaging findings were correlated with disease subtypes. RESULTS:47 subjects with type I AxD were enrolled. Subtype distribution included 3 Ia, 12 Ib, 8 Ic, 10 Id, 10 Ic/Id, and 4 undetermined. Risk of belonging to type Ib compared to other subtypes was significantly increased in case of involvement of parietal subcortical WM (OR = 16.1, p = 0.003), occipital deep WM (p = 0.008), temporal deep (p = 0.018), and periventricular WM (p = 0.013), body of corpus callosum (p = 0.018), genu of corpus callosum (p = 0.047) and hilar region of cerebellum (p = 0.008). Involvement of occipital periventricular WM was associated to a higher risk of being type Ic compared to type Id (p = 0.010). CONCLUSIONS:Some distinct MRI patterns on initial MRI scans may predict disease outcomes in type I AxD. These findings may help clinicians in early prognostic stratification, with key brain regions needing careful evaluation. Further studies are required to validate these findings and improve prognostic accuracy in type I AxD.

ABSTRACT Purpose X‐linked adrenoleukodystrophy (ALD) encompasses a wide range of neurological manifestations, classically described as distinct phenotypes including childhood cerebral adrenoleukodystrophy and adult‐onset adrenomyeloneuropathy (AMN). Corticospinal tract (CST) and cerebellar involvement on brain magnetic resonance imaging (MRI) are typically attributed to long‐tract axonopathy in AMN, yet the extent to which these features span the ALD spectrum is unclear. To explore whether CST and infratentorial lesions reflect discrete phenotypes or a continuous disease spectrum, we examined their onset and prevalence across the lifespan. Methods We retrospectively analyzed 1189 brain MRIs from 218 male patients diagnosed with ALD evaluated at Massachusetts General Hospital from 2005 to 2024. Imaging reports were screened for CST and infratentorial lesion presence, and serial scans were reviewed to determine chronological patterns of involvement. In pediatric patients with isolated CST lesions, treatment data and post‐treatment imaging were assessed. Results Isolated CST lesions were identified in 8.7% of pediatric and 11.4% of adult patients. All but one adult with cerebellar lesions also demonstrated CST lesions, which preceded or occurred concurrently with the cerebellar abnormalities. Among pediatric patients with isolated CST lesions, 38.5% underwent lentiviral gene therapy, and 23.1% received hematopoietic stem cell transplantation. Imaging post‐treatment revealed lesion size reduction in 87.5%. Conclusion CST involvement, including isolated lesions and those preceding cerebellar involvement, occurs across age groups and may represent a continuous ALD disease spectrum rather than a strictly phenotype‐specific feature. These findings support the importance of dedicated CST assessment in routine MRI review and highlight its potential role in earlier diagnosis and therapeutic decision‐making.

Objectives:To determine whether boys with VUS detected through Newborn screening (NBS) for Adrenoleukodystrophy (ALD) develop adrenal insufficiency (aiALD) and cerebral ALD (cALD) at rates comparable to those with pathogenic variants, and to evaluate the relationship between C26:0-lysophosphatidylcholine (C26:0-LPC) levels and clinical outcomes. Methods:We conducted a retrospective multicenter cohort study (2013-2025) across six US centers, including 201 males identified through NBS in 19 states. Variants were classified as pathogenic (n=65), likely pathogenic (n=45), or VUS (n=88). Primary outcomes were development of aiALD and cALD; secondary outcomes included C26:0-LPC levels. Statistical analyses included Kaplan-Meier, mixed-effects regression, and Cox models. Results:201 males with ABCD1 variants identified through NBS for ALD. Median age at last follow-up was 4.2 years (IQR 2.5-7.9). Overall, 26% developed aiALD (54% pathogenic, 16% likely pathogenic, 11% VUS), and 8% developed cALD (11%, 9%, and 4.5%, respectively). Pathogenic/likely pathogenic variants were associated with higher odds of aiALD than VUS (OR 5.8; 95% CI 2.16-15.58; p=0.001). At 150 months, 39% of individuals with pathogenic/likely pathogenic variants remained free of aiALD versus 85% with VUS. C26:0-LPC levels were higher in pathogenic variants and correlated with genotype (p=0.0006). Higher levels were associated with increased aiALD risk and earlier onset (HR 1.38 per 0.1 µmol/L; 95% CI 1.20-1.59; p<0.0001). Conclusions:Boys with VUS had lower rates of aiALD and lower C26:0-LPC levels than those with pathogenic variants, although some developed disease. C26:0-LPC correlates with genotype and risk, supporting its role in variant classification and risk-stratified surveillance. What’s Known on This Subject:Newborn screening for X-linked adrenoleukodystrophy has increased identification of variants of uncertain significance, accounting for up to 50% of screen-positive cases in some states. These are often associated with borderline biomarker levels, and their natural history remains poorly understood. What This Study Adds:Screen-positive individuals with VUS had substantially lower rates of disease onset than those with pathogenic variants. Newborn biomarker levels also correlated with variant pathogenicity and disease onset, which may aid future variant classification and risk stratification.

Adult Refsum disease (ARD; OMIM 266510) is a degenerative autosomal recessive condition typically diagnosed in adulthood. It affects visual, auditory and nervous system function. It is characterised by plasma, neuro-ophthalmological and adipose tissue accumulation of the dietary-derived phytanic acid (PA). This guidance reviews the clinical aspects of ARD and discusses interventions to address various co-morbidities of the disease. This GRADE-aligned guidance is based on a review of the literature and a consensus statement reflecting the conclusions of professionals with experience in the diagnosis and management of ARD. This statement reviews clinical aspects of ARD and discusses current and potential interventions to address various symptoms of the disease. It provides an overview of the clinical phenotype, reviews the clinical, biochemical, and genetic findings in ARD, and the neurological and ophthalmological investigations needed at diagnosis and during follow-up. It highlights the importance of dietary management and its role in situations such as acute hospital admissions for inter-current illness. Furthermore, it provides guidance on the acute management of decompensation in ARD and outlines when therapeutic plasma exchange/lipoprotein plasmapheresis should be considered. Greater clinician and patient awareness will lead to early diagnosis and improved outcomes. Implementation of a low PA diet before further end organ involvement offers the best prognosis. Life-long dietary therapy, along with therapeutic plasma exchange/lipoprotein apheresis during acute decompensations, remains the mainstay of management. Patients should have access to a multidisciplinary team to ensure specialist dietary input and supportive management of comorbidities.

INTRODUCTION: Adrenoleukodystrophy (ALD) is a rare, X-linked disease caused by pathogenic ABCD1 gene variants, resulting in heterogeneous and debilitating conditions. We report on an Externally-Led Patient-Focused Drug Development (EL-PFDD) meeting involving patients and caregivers, Food and Drug Administration representatives, and physicians to hear the patient’s voice regarding living with adult manifestations of ALD. METHODS: Adult patients with ALD and/or caregivers were invited to the EL-PFDD to discuss the impact of living with ALD and their desires for future treatment/management. RESULTS: On July 22, 2022, the virtual EL-PFDD meeting took place with 254 individuals, including 153 adult patients with ALD and/or caregivers. Men and women with ALD suffer from many health conditions with top concerns being balance issues (81%), altered gait (67%), and spasticity (67%). Disease impact on daily activities was significant; 69% had issues with walking, playing sports (45%), and sleeping (41%). Overall, 88% of respondents feared their condition worsening, being unable to walk (61%), and developing cerebral ALD (39%). There are no disease-specific treatments for adults; patients used various medications and physical therapies for symptom management, with either ‘very little’ (39% respondents) or ‘somewhat’ (44% respondents) of a response; 10% received no relief with treatments. In the future, patients want to be involved in treatment development and clinical trials. CONCLUSION: ALD is a progressive disease that can be life-limiting. There is an urgent need to develop treatments that will either slow, halt, or cure adult manifestations of ALD, and men and women are eager to be involved in studies.

Childhood-onset movement disorders are clinically and genetically heterogeneous, with over 500 implicated genes. Standard clinical genetic testing, including exome sequencing, has limited sensitivity for certain variants, including repeat expansions, structural variants (SVs), copy number variants (CNVs), and deep intronic changes. We evaluated the diagnostic utility of short-read whole genome sequencing (srWGS) and, in selected cases, long-read genome sequencing (lrWGS) in a real-world cohort of children and young adults with early-onset progressive movement disorders and prior nondiagnostic genetic testing. One hundred individuals (<30 years) with progressive movement disorders with a suspected genetic etiology were recruited from a tertiary pediatric movement disorders program. All had prior nondiagnostic testing. SrWGS (Illumina NovaSeq 6000) assessed single nucleotide variants (SNVs), CNVs, SVs, and repeat expansions; lrWGS (Pacific Biosciences) was applied to select unsolved trios. Variants were reviewed by a multidisciplinary team using standard variant interpretation guidelines and phenotype correlation. A molecular diagnosis was achieved in 27% (27/100) of cases, and candidate variants were identified in an additional 33% (33/100). Among solved cases, 81.5% (22/27) were identified from exome-level data, while 18.5% (5/27) required genome-level analysis to detect variants such as repeat expansions in HTT and FXN, an intragenic duplication in MECP2, an Alu insertion in ATM, and a deletion in FA2H. Genome-level analysis contributed an additional diagnostic yield of 5% (5/100) only. Notably, in 33.3% (9/27) of solved cases, variants had been previously reported but not recognized as diagnostic. LrWGS of 14 unsolved trios did not yield additional diagnoses. SrWGS provided a modest incremental yield over exome sequencing in early-onset movement disorders, with most diagnoses achieved through reanalysis of exome-level data. Findings highlight the importance of iterative variant interpretation and the need for improved analytic pipelines to fully realize the potential of genome sequencing.

Caregiver-reported outcome measures (CROMs) complement clinical assessments of neurodevelopmental functions (NDF) in pediatric rare disease trials. This scoping review summarizes use of CROMs of NDF across bodily function, activity, and participation domains of the International Classification of Functioning, Disability, and Health (ICF) model in pediatric lysosomal storage disorders (LSDs), characterizes assessed neurodevelopmental domains, and outlines considerations for CROM selection within a comprehensive functional assessment strategy. We applied JBI methodology and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). Primary articles reporting CROM of NDF use in children with LSDs ≤ 12 years old were identified. Study characteristics, design, and CROMs utilized were extracted. CROMs were classified as condition-general or disease-specific. CROM content was mapped to neurodevelopmental domains (activities of daily living [ADL], cognition, communication, physical, social-emotional function). Ninety-eight articles published in the last 10 years reported on 38 distinct CROMs of NDF across > 20 LSDs. Nearly all studies (93%) used ≥ 1 condition-general CROM of NDF, most commonly the Vineland Adaptive Behavioral Scales or the Pediatric Quality of Life Inventory. Eleven disease-specific CROMs were reported, typically alongside condition-general measures. Physical, ADL, and social-emotional domains were indexed most consistently. CROMs were endpoints in 32 LSD clinical trials. Findings illustrate the variety and common trends of CROMs of NDF used in pediatric LSD studies. This review informs selection of complementary caregiver-reported endpoints in LSD trials based on a well-defined, clinically meaningful construct; alignment with other endpoints and expert consensus; and operational practicality.

INTRODUCTION:Myopathy and dysphagia are common manifestations of nephropathic cystinosis, a rare autosomal recessive lysosomal storage disorder. We previously demonstrated that both the oral and pharyngeal phases of swallowing are affected and impact function and quality of life in patients. To better understand and characterize swallowing impairment, we evaluated patients with nephropathic cystinosis experiencing dysphagia and myopathy. METHODS:We prospectively evaluated patients who had participated in a prior clinical trial readiness study of myopathy and dysphagia, using functional outcomes and video fluoroscopic swallowing studies. RESULTS:Eight patients underwent functional and swallowing assessments. Oral and pharyngeal stages of swallowing were affected in all subjects. There was an improvement in oral stage dysphagia (Visit 3 8 [3:9]; Visit 4 5 [1:5]) between Visits 3 and 4 median of 1090 days (IQR [921:1288]) while pharyngeal stage dysphagia Modified Barium Swallow Impairment Profile scores stayed unchanged in the same amount of time. There was also improvement in M. D. Anderson Dysphagia Inventory (MDADI) scores (MDADI-C Visit 3 73 [62:87], Visit 4 96 [76:99]; MDADI-F Visit 3 18 [17:21], Visit 4 25 [23:25]), indicating a higher quality of life pertaining to swallowing. DISCUSSION:Despite the progressive nature of the myopathic changes typically described in patients with nephropathic cystinosis, we demonstrated improvement in some swallowing metrics. This may suggest a possible late-onset effect of respiratory training or cognitive-behavioral impact from repeated swallowing measurements.

The field of leukodystrophies (LDs) has undergone a paradigm shift in recent decades. Several factors underlie this change: newborn screening, advanced genetic and metabolic testing, improved understanding and medical management of disease, and targeted therapies addressing underlying molecular etiologies. Recent trials as well as regulatory approvals are testimony to the transformative effects of gene therapy. However, the risks of these treatments remain incompletely understood and include malignancies/premalignancies, immune-mediated hepatic injury, and thrombotic microangiopathy, among others. The implementation of newborn screening for individual LDs allows for improved monitoring and earlier treatment but also extends the measured lifespan following diagnosis, skewing survival data compared to historical data based on symptomatic diagnosis. Lastly, population screening leads to identification of genetic variants with milder or uncertain pathogenicity. In this article, we review the shifting framework impacting life expectancy and decision-making in the LDs along with the risks and uncertainties that have arisen in the setting of recent advancements.