Metachromatic Leukodystrophy Research Articles

Identification of a Novel ARSA Gene Mutation Through High-Throughput Molecular Diagnosis Method in Two Girls with Late Infantile Metachromatic Leukodystrophy.

Metachromatic leukodystrophy (MLD) is a rare leukoencephalopathy caused by pathogenic mutations in the ARSA gene. It manifests as severe motor symptoms, mental problems, and sometimes, seizures. We aimed to investigate the phenotypic manifestations and genetic causes of MLD in an Iranian family. We present the case of a 3-year-old girl who presented with hypotonia, muscular atrophy, and seizures. Neurological and neuromuscular examinations were performed to evaluate clinical characteristics. Whole exome sequencing (WES) was used to detect disease-causing variants. In silico analysis was performed to predict the pathogenicity of this variant. GROMACS software was utilized for molecular dynamic simulation (MDS). Neurological studies revealed marked slowing of motor conduction velocities and an increased motor unit action potential duration. Brain MRI scan revealed white matter abnormalities. By applying WES, we identified a novel homozygous missense variant (NM_000487.6, c.938G > C, p.R313P) in ARSA. Direct sequencing identified this homozygous variant in her asymptomatic younger sister, whereas both parents carried a heterozygous variant. This mutation has not been reported in genetic databases or in literature. In silico analysis predicted that any variation in this DNA position would cause disease, as it is highly conserved. The c.938G > C variant was classified as a pathogenic variant according to ACMG/AMP guidelines. MDS analysis indicated that c.938G > C had a significant impact on both the structure and stabilization of ARSA, ultimately resulting in impaired protein function. The identification of this variant expands the spectrum of ARSA gene mutations associated with MLD and highlights the importance of genetic testing for the diagnosis of MLD.

Metachromatic leukodystrophy: To screen or not to screen?

Metachromatic leukodystrophy (MLD) is a neurodegenerative lysosomal storage disorder caused by biallelic pathogenic variants in the gene encoding arylsulfatase A. Disease onset is variable (with late infantile, early and late juvenile, and adult forms) and treatment options depend on age and disease symptoms at onset. In the past, allo-hematopoietic stem cell transplantation (allo-HSCT) has been the best treatment option, following strict selection criteria. The outcome however is variable and morbidity remains high. This paved the way to the development of new treatment options, some of them aiming to be curative. In the light of this changing therapeutic field, newborn screening is becoming a valuable option. This narrative review aims to describe the outcome of allo-HSCT in the different MLD disease forms, and, in addition, reviews new treatment options. Finally, the shift of the field towards newborn screening for MLD is discussed.

Engineered arylsulfatase A with increased activity, stability and brain delivery for therapy of metachromatic leukodystrophy

A deficiency of human arylsulfatase A (hASA) causes metachromatic leukodystrophy (MLD), a lysosomal storage disease characterized by sulfatide accumulation and central nervous system (CNS) demyelination. Efficacy of enzyme replacement therapy (ERT) is increased by genetic engineering of hASA to elevate its activity and transfer across the blood-brain barrier (BBB), respectively. To further improve the enzyme's bioavailability in the CNS, we mutated a cathepsin cleavage hot spot and obtained hASAs with substantially increased half-lives. We then combined the superstabilizing exchange E424A with the activity-promoting triple substitution M202V/T286L/R291N and the ApoEII-tag for BBB transfer in a trimodal modified neoenzyme called SuPerTurbo-ASA. Compared with wild-type hASA, half-life, activity, and M6P-independent uptake were increased more than 7-fold, about 3-fold, and more than 100-fold, respectively. ERT of an MLD-mouse model with immune tolerance to wild-type hASA did not induce antibody formation, indicating absence of novel epitopes. Compared with wild-type hASA, SuPerTurbo-ASA was 8- and 12-fold more efficient in diminishing sulfatide storage of brain and spinal cord. In both tissues, storage was reduced by ∼60%, roughly doubling clearance achieved with a 65-fold higher cumulative dose of wild-type hASA previously. Due to its enhanced therapeutic potential, SuPerTurbo-ASA might be a decisive advancement for ERT and gene therapy of MLD.

Difficult Diagnosis in a Patient with Phenylketonuria (PKU) and Metachromatic Leukodystrophy (MLD)

Abstract Introduction Since phenylalanine level was included in the national newborn screening program in Egypt, patients with phenylketonuria (PKU) were early diagnosed and management and have better outcome with nearly normal motor and mental development. Neuro-regression or poor cognition is never recognized in compliant patients. Case presentation Herein we present an Egyptian child who was diagnosed by neonatal screening as PKU who was compliant on dietary treatment and normal development. After the age of 18 months, he started to loose previously acquired developmental milestones. Because of his average phenylalanine levels all through, a second neurodegenerative disease was suspected. Several investigations were done and the diagnosis of metachromatic leukodystrophy was suspected and was later confirmed by molecular testing showing homozygous frame shift mutation in ARSA gene c.583del, p. (Trp 195Glyfs*5) in addition to homozygous Missense mutation in PAH gene c.842C>T, p. (Pro281 Leu). Conclusion The presence of two genetic diseases in the same family should be suspected in consanguineous communities like ours especially if the clinical data of the primary disease does not fit.

Olaparib Attenuates Demyelination and Neuroinflammation in an Organotypic Slice Culture Model of Metachromatic Leukodystrophy.

Metachromatic leukodystrophy (MLD) is a severe demyelinating, autosomal recessive genetic leukodystrophy. The disease is underpinned by mutations in the arylsulfatase A gene (ARSA), resulting in deficient activity of the arylsulfatase A lysosomal enzyme and consequential accumulation of galactosylceramide-3-O-sulfate (sulfatide) in the brain. Using an ex vivo murine-derived organotypic cerebellar slice culture model, we demonstrate that sulfatide induces demyelination in a concentration-dependent manner. Interestingly, our novel data demonstrate that sulfatide-induced demyelination is underpinned by PARP-1 activation, oligodendrocyte loss, pro-inflammatory cytokine expression, astrogliosis, and microgliosis. Moreover, such sulfatide-induced effects can be attenuated by the treatment with the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Olaparib (IC50∼100nM) suggesting that this small molecule may be neuroprotective and limit toxin-induced demyelination. Our data support the idea that sulfatide is a key driver of demyelination and neuroinflammation in MLD and suggest that PARP-1 inhibitors have therapeutic utility in the sphere of rare demyelinating disease.

Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix

BackgroundMetachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by mutations in the arylsulfatase A gene (ARSA) and categorized into three subtypes according to age of onset. The functional effect of most ARSA mutants remains unknown; better understanding of the genotype–phenotype relationship is required to support newborn screening (NBS) and guide treatment.ResultsWe collected a patient data set from the literature that relates disease severity to ARSA genotype in 489 individuals with MLD. Patient-based data were used to develop a phenotype matrix that predicts MLD phenotype given ARSA alleles in a patient’s genotype with 76% accuracy. We then employed a high-throughput enzyme activity assay using mass spectrometry to explore the function of ARSA variants from the curated patient data set and the Genome Aggregation Database (gnomAD). We observed evidence that 36% of variants of unknown significance (VUS) in ARSA may be pathogenic. By classifying functional effects for 251 VUS from gnomAD, we reduced the incidence of genotypes of unknown significance (GUS) by over 98.5% in the overall population.ConclusionsThese results provide an additional tool for clinicians to anticipate the disease course in MLD patients, identifying individuals at high risk of severe disease to support treatment access. Our results suggest that more than 1 in 3 VUS in ARSA may be pathogenic. We show that combining genetic and biochemical information increases diagnostic yield. Our strategy may apply to other recessive diseases, providing a tool to address the challenge of interpreting VUS within genotype–phenotype relationships and NBS.

Evaluating meaningful changes in physical functioning and cognitive declines in metachromatic leukodystrophy: a caregiver interview study

BackgroundMetachromatic leukodystrophy (MLD) is a rare lysosomal storage disease caused by deficient activity of arylsulfatase A (ASA). Treatment options for patients are limited; gene therapy based on haematopoietic stem cell transplantation is the only approved treatment for some subtypes of MLD. Any therapeutic benefit of treatments must be meaningful for patients and their families. We evaluated the clinical meaningfulness of slowing the decline in gross motor function as measured by the Gross Motor Function Classification in MLD (GMFC-MLD) from the caregiver perspective via semi-structured telephone interviews with caregivers of children with late-infantile MLD. We also evaluated the perceived significance of declines in communication abilities measured by the Expressive Language Function Classification in MLD (ELFC-MLD). This work could help to inform the endpoints of a phase 2 clinical trial (NCT03771898) assessing the efficacy of intrathecal recombinant human ASA in MLD.ResultsTwelve caregivers were recruited, reporting on 12 children with MLD. Children had a mean age of 6.1 years; mean age at symptom onset was 17.6 months. Most children (10/12) progressed from walking without support (categories 0–1) to a loss of locomotion (categories 5–6) in ≤ 2 years. Caregivers felt that GMFC-MLD and ELFC-MLD accurately described motor and language declines in their children, respectively. Most caregivers (10/12) reported that the idea of delaying disease progression would be meaningful. Further, a slowing of motor function decline in GMFC-MLD, from category 1 to category 3 or from category 2 to category 4 over 2 years, was seen as meaningful by all caregivers asked; however, only 3/12 caregivers reported that delayed decline would be meaningful if baseline category was ≥ 3. Caregivers also reported that delaying expressive language decline at any level that did not indicate a complete loss of expressive language (indicated by categories 1–3) would be meaningful.ConclusionsCaregivers of children with MLD felt that a delayed decline in gross motor function, as assessed by the GMFC-MLD, would be meaningful, supporting the selection of primary and secondary endpoints for the phase 2 clinical trial. Communication abilities were another area of significance for consideration in future clinical trial design.

Stagger along the Corpus Callosum - A Rare form of Adult Metachromatic Leukodystrophy.

Stagger along the Corpus Callosum - A Rare form of Adult Metachromatic Leukodystrophy.

A retrospective cohort study of Libmeldy (atidarsagene autotemcel) for MLD: What we have accomplished and what opportunities lie ahead.

Metachromatic leukodystrophy (MLD) results from ARSA gene mutations. Affected individuals meet early milestones before neurological deterioration and early death. Atidarsagene autotemcel (arsa-cel), an autologous haematopoietic stem cell gene therapy (HSC-GT) product, has demonstrated sustained clinical benefits in MLD. Arsa-cel was approved for NHS treatment in February 2022 for asymptomatic late infantile or early juvenile disease, or early symptomatic early juvenile MLD. We evaluate the impact of this approval in the largest real-world dataset of MLD HSC-GT. Hospital records were reviewed for all patients referred for NHS treatment following arsa-cel approval. Information was gathered about disease phenotype, presentation, eligibility, and affected siblings. In the year following NHS approval, 17 UK MLD patients were referred for treatment. Four patients met eligibility criteria and have been treated, including 1 infant who weighed 5 kg at leukapheresis. Eleven patients failed screening: 10 symptomatic patients with late infantile disease and 1 with early juvenile disease and cognitive decline. Two further patients with later onset subtypes did not meet the approval criteria. Three out of four treated patients were diagnosed by screening after MLD was diagnosed in a symptomatic older sibling. The success of HSC-GT for MLD has heralded a new era of hope for families affected by this devastating disease, yet currently, most patients are ineligible for treatment at diagnosis. The feasibility of apheresis in infants and the availability of a licenced, effective HSC-GT product highlights the urgent need for newborn screening to ensure that patients can be diagnosed and treated before symptom onset.

Spectrum of Magnetic Resonance Spectroscopy (MRS) in Differentiating Paediatric Leukodystrophies in Pakistani Population

Aim: To determine the frequency of findings of MRS in differentiating paediatric leukodystrophies in Pakistani population. Study design: Cross sectional descriptive study. Place and duration of study: Armed Forces Institute of Radiology and Imaging, Military Hospital Rawalpindi from 25thAugust 2018 to 24th February 2019. Methodology: A total of 110 individuals who were coming in for an MRI test and were either male or female, older than one month of age, and younger than 12 years of age, were chosen. A 3.0T MRI scanner equipped with MRS techniques was used for each scan. Axial T1 and T2 Weighted spin-echo, FLAIR, coronal, and sagittal T2 Weighted spin-echo images were all part of the MRI imaging protocol. During the same session, a single section multivoxel 2D chemical shift spectroscopy sequence was also carried out. In MRS, the metabolites that were detected in each of our patients were choline, creatine, lactate, N-acetyl aspartate, and myo-inositol. Data were examined utilizing SPSS 21. Results: The average age was 5.24±1.89 year. 56 (50.91%) of the 110 patients were male children, compared to 54 (49.09%) female children, for a male to female ratio of 1.1:1. The following paediatric leukodystrophies were more often found with MRS in this study: Krabbes disease in 13 (11.82%), Canavan's disease in 19 (17.27%), Adrenoleukodystrophy in 41 (37.27%), Leigh disease in 25 (22.73%), and Metachromatic leukodystrophy in 12 (10.91%). Practical Implication: The underlying issue has recently been linked to mutations in the DARS2 gene, which codes for mitochondrial aspartyl-tRNA synthetase. Conclusion: MRS, which is more affordable than other existing tests, should be utilized in every patient with clinical leukodystrophies. Keywords: Leukodystrophies, Magnetic resonance spectroscopy, MRS

A Novel PSAP Gene Mutation in A Lebanese Patient with A Limited Phenotypic Expression

Metachromatic leukodystrophy is an autosomal recessive neurodegenerative disorder that affects the central and peripheral nervous system and falls under the family of lysosomal storage diseases (LSDs). It is divided into three clinical forms (late infantile, juvenile, and adult) depending on how early the disease manifests and with varying prognosis for each form. Common presentations of the disease include cognitive, behavioral, and motor symptoms. Here, we present a Lebanese patient with a novel variant in the prosaposin gene, confirming the diagnosis of metachromatic leukodystrophy due to saposin B mutation, with a phenotypic expression of the disease limited to an attention deficit disorder, and a clear leukodystrophy.

EE408 Direct Cost Analysis Associated with the Management of Patients with Metachromatic Leukodystrophy (MLD) across Nine European Countries

MLD is an ultra-rare neurodegenerative disease which leads to progressive motor and cognitive decline. The GMFC-MLD is a validated measure of motor dysfunction in MLD, which represents all clinically relevant stages from normal (GMFC-MLD 0) to loss of all gross motor function (GMFC-MLD 6). Each of the seven GMFC-MLD levels are associated with healthcare costs necessary to manage the condition. This study aimed to determine and compare the average cost of care by GMFC-MLD health state across nine countries.

PCR176 Estimating Utility Values for Health States in Metachromatic Leukodystrophy (MLD)

Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disease caused by deficient arylsulfatase A activity, leading to progressive cognitive and motor dysfunction and death. We estimated late-infantile MLD (LI-MLD) patient and caregiver health state utilities to inform cost–utility evaluations of MLD treatments. Utilities range from 1 (full health) to 0 (dead); values <0 reflect states considered worse than dead.

Vanishing white matter disease: a case of combined saposin deficiency

Vanishing white matter disease (VWMD) is an autosomal recessive neurodegenerative disease often present during childhood and is exacerbated by trauma and other stressors. VWMD is caused by EIF2B gene mutation, which encodes eukaryotic initiation factor 2 B (EIF2B), a transcription factor activated by insulin that is a major protein synthesis regulator during the integrated stress response. Autosomal recessive combined saposin deficiency is a metachromatic leukodystrophy, a progressive neurological disorder characterized by motor delay, regression of gained skills, and nerve demyelination. Here, we present the case of an 11-year-old Hispanic male presenting with ataxia, dysphagia, and global developmental delay which was found to have VWMD on imaging. A genetic panel reveals the PSAP gene, a novel presentation in the setting of VWMD.

Safety and Efficacy of Intravenous and Intrathecal Delivery of AAV9-Mediated ARSA in Minipigs.

Metachromatic leukodystrophy (MLD) is a hereditary neurodegenerative disease characterized by demyelination and motor and cognitive impairments due to deficiencies of the lysosomal enzyme arylsulfatase A (ARSA) or the saposin B activator protein (SapB). Current treatments are limited; however, gene therapy using adeno-associated virus (AAV) vectors for ARSA delivery has shown promising results. The main challenges for MLD gene therapy include optimizing the AAV dosage, selecting the most effective serotype, and determining the best route of administration for ARSA delivery into the central nervous system. This study aims to evaluate the safety and efficacy of AAV serotype 9 encoding ARSA (AAV9-ARSA) gene therapy when administered intravenously or intrathecally in minipigs, a large animal model with anatomical and physiological similarities to humans. By comparing these two administration methods, this study contributes to the understanding of how to improve the effectiveness of MLD gene therapy and offers valuable insights for future clinical applications.

Neurodegenerative disease after hematopoietic stem cell transplantation in metachromatic leukodystrophy.

Metachromatic leukodystrophy is a lysosomal storage disease caused by deficient arylsulfatase A. It is characterized by progressive demyelination and thus mainly affects the white matter. Hematopoietic stem cell transplantation may stabilize and improve white matter damage, yet some patients deteriorate despite successfully treated leukodystrophy. We hypothesized that post-treatment decline in metachromatic leukodystrophy might be caused by gray matter pathology. Three metachromatic leukodystrophy patients treated with hematopoietic stem cell transplantation with a progressive clinical course despite stable white matter pathology were clinically and radiologically analyzed. Longitudinal volumetric MRI was used to quantify atrophy. We also examined histopathology in three other patients deceased after treatment and compared them with six untreated patients. The three clinically progressive patients developed cognitive and motor deterioration after transplantation, despite stable mild white matter abnormalities on MRI. Volumetric MRI identified cerebral and thalamus atrophy in these patients, and cerebellar atrophy in two. Histopathology showed that in brain tissue of transplanted patients, arylsulfatase A expressing macrophages were clearly present in the white matter, but absent in the cortex. Arylsulfatase A expression within patient thalamic neurons was lower than in controls, the same was found in transplanted patients. Neurological deterioration may occur after hematopoietic stem cell transplantation in metachromatic leukodystrophy despite successfully treated leukodystrophy. MRI shows gray matter atrophy, and histological data demonstrate absence of donor cells in gray matter structures. These findings point to a clinically relevant gray matter component of metachromatic leukodystrophy, which does not seem sufficiently affected by transplantation.

An in silico approach to identify early damage biomarker candidates in metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) is a rare, autosomal recessive lysosomal storage disease. Deficient activity of arylsulfatase A causes sulfatides to accumulate in cells of different tissues, including those in the central and peripheral nervous systems, leading to progressive demyelination and neurodegeneration. Although there is some association between specific arylsulfatase A alleles and disease severity, genotype–phenotype correlations are not fully understood. We aimed to identify biomarker candidates of early tissue damage in MLD using a modeling approach based on systems biology. A review of the literature was performed in an initial disease characterization step, allowing identification of pathophysiological processes involved in MLD and proteins relating to these processes. Three mathematical models were generated to simulate different stages of MLD at the molecular level: an early pro-inflammatory stage model (including only processes considered to be active in the early stages of disease), a pre-demyelination stage model (including additional processes that are active after some disease progression), and a demyelination stage model (in which all pathophysiological processes are active). The models evaluated 3457 proteins of interest, individually and by pairs through data mining techniques, applying five filters to prioritize biomarkers that could differentiate between the models. Sixteen potential biomarkers were identified, including effectors relating to mitochondrial dysfunction, remyelination, and neurodegeneration. The findings were corroborated in a gene expression data set from T lymphocytes of patients with MLD; all candidates formed combinations that were able to distinguish patients with MLD from controls, and all but one candidate distinguished late-infantile MLD from juvenile MLD as part of a combinatorial biomarker pair. In particular, pro-neuregulin-1 appeared as differential on all comparisons (patients with MLD vs controls and within clinical subtypes); casein kinase II subunit alpha was detected as a potential individual marker within clinical subtypes. These findings provide a panel of biomarker candidates suitable for experimental validation and highlight the utility of mathematical models to identify biomarker candidates of early tissue damage in MLD with a high degree of accuracy and sensitivity.

Clinical Significance of Diffusion Tensor Imaging in Metachromatic Leukodystrophy.

Metachromatic leukodystrophy (MLD) is a lysosomal enzyme deficiency disorder leading to progressive demyelination and, consecutively, to cognitive and motor decline. Brain magnetic resonance imaging (MRI) can detect affected white matter as T2 hyperintense areas but cannot quantify the gradual microstructural process of demyelination more accurately. Our study aimed to investigate the value of routine MR diffusion tensor imaging in assessing disease progression. MR diffusion parameters (apparent diffusion coefficient [ADC] and fractional anisotropy [FA]) were in the frontal white matter, central region (CR), and posterior limb of the internal capsule in 111 MR datasets from a natural history study of 83 patients (age: 0.5-39.9 years; 35 late-infantile, 45 juvenile, 3 adult, with clinical diffusion sequences of different scanner manufacturers) as well as 120 controls. Results were correlated with clinical parameters reflecting motor and cognitive function. ADC values increase and FA values decrease depending on disease stage/severity. They show region-specific correlations with clinical parameters of motor and cognitive symptoms, respectively. Higher ADC levels in CR at diagnosis predicted a disease course with more rapid motor deterioration in juvenile MLD patients. In highly organized tissues such as the corticospinal tract, in particular, diffusion MR parameters were highly sensitive to MLD-associated changes and did not correlate with the visual quantification of T2 hyperintensities. Our results show that diffusion MRI can deliver valuable, robust, clinically meaningful, and easily obtainable/accessible/available parameters in the assessment of prognosis and progression of MLD. Therefore, it provides additional quantifiable information to established methods such as T2 hyperintensity.

Experiences of patients and their family members with metachromatic leukodystrophy, adrenoleukodystrophy, and Krabbe disease: a qualitative systematic review protocol.

The objective of this review is to synthesize the experiences of patients with metachromatic leukodystrophy (MLD), adrenoleukodystrophy (ALD), and Krabbe disease and the experiences of their family members. MLD, ALD, and Krabbe disease are rare disorders that are classified as lysosomal storage or peroxisomal disorders, with similar presentations as leukodystrophy. As these diseases cause cognitive and neurological decline due to the progression of leukodystrophy associated with demyelination, they have significant impact on the lives of patients and their families. It is important to identify the impact and challenges of these diseases on patients' lives and on their families, as well as to synthesize qualitative studies regarding their experiences. We will consider studies including patients with MLD, ALD, or Krabbe disease and their family members. These experiences will include the challenges, dissatisfactions, and frustrations with symptoms and treatments; complications of hematopoietic stem cell transplantation; and the increased caregiver burden with disease progression. This is important since the impacts of disease progression are experienced in a variety of settings beyond the hospital, such as in the community and at home. The search strategy will follow JBI methodology and be conducted in 3 steps: an initial limited search, a comprehensive database search, and a reference search of the included articles. MEDLINE, CINAHL Plus, PsycINFO, and Scopus will be searched with no restriction on language or publication dates. The study selection, critical appraisal, data extraction, and data synthesis will be performed according to JBI guidelines for systematic reviews of qualitative research. Final syntheses will be assessed using the ConQual approach. PROSPERO CRD42022318805.

Prevalence of Peripheral Nervous System Involvement in Adult Leukodystrophies (P2-5.031)

<h3>Objective:</h3> na <h3>Background:</h3> Leukodystrophies are genetic, neurodegenerative white matter diseases of the central nervous system (CNS) caused by mutations in various genes, presenting with heterogeneous clinical features and age of onset. It is well established that some leukodystrophies have peripheral nervous system (PNS) involvement, whether demyelinating, axonal or mixed in pathology. However, the prevalence of peripheral neuropathy in adult leukodystrophies is unknown. Early recognition of PNS involvement in these disorders is imperative to enable appropriate management and care of the symptoms. <h3>Design/Methods:</h3> We performed a retrospective review of all adult subjects followed at our two institutions for white matter disease of genetic origin to select patients with evidence of PNS involvement as documented by nerve conduction studies (NCS) and/or electromyography (EMG)For these subjects we collected and analyzed data on sociodemographic status, family history, clinical characteristics, and disease course, nerve conduction studies (NCS), electromyography (EMG), MRI features and genetic testing results. <h3>Results:</h3> From our combined cohorts of 161 adult subjects followed for genetic white matter diseases, we identified 14 patients (8.7%) with documented PNS involvement. A definite genetic diagnosis was established in 5 subjects (3 with adult polyglucosan body disease, 1 with metachromatic leukodystrophy, 1 with POLR3-related disorder) while 9 subjects remained undiagnosed despite extensive genetic investigations. The demographic, clinical, radiological, and electrophysiological data will be presented. <h3>Conclusions:</h3> This is the first study conducted to assess the prevalence of peripheral neuropathy in adult patients with leukodystrophy. In our two independent cohorts, PNS involvement is rare, however, early recognition of the concurrence of CNS and PNS involvement is essential to plan appropriate management of the patients’ symptomatic care and is key as more treatment options are becoming available. <b>Disclosure:</b> Dr. Alsabah has nothing to disclose. Dr. Hasiloglu has nothing to disclose. Dr. Massie has received personal compensation in the range of $500-$4,999 for serving as a Expert consultant with INESS (Quebec Public Health agency). Dr. Massie has received personal compensation in the range of $500-$4,999 for serving as a Lecturer with Amylyx Pharmaceuticals. Dr. Brais has nothing to disclose. Dr. Orthmann Murphy has received research support from Conrad N. Hilton Foundation. Dr. Orthmann Murphy has received research support from Institute for Translational Medicine and Therapeutics’ (ITMAT) Transdisciplinary Program in Translational Medicine and Therapeutics, University of Pennsylvania. The institution of Dr. Orthmann Murphy has received research support from Vigil Neurosciences. The institution of Dr. Orthmann Murphy has received research support from National MS Society. Dr. Orthmann Murphy has received personal compensation in the range of $500-$4,999 for serving as a Invited Speaker with Temple University . Dr. Orthmann Murphy has received personal compensation in the range of $0-$499 for serving as a Consultant with American Neurological Association. Roberta La Piana has nothing to disclose.