Metachromatic Leukodystrophy Research Articles

Artificially Induced Pluripotent Stem Cell-Derived Whole-Brain Organoid for Modelling the Pathophysiology of Metachromatic Leukodystrophy and Drug Repurposing.

Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disease that results from a deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Worldwide, there are between one in 40,000 and one in 160,000 people living with the disease. While there are currently no effective treatments for MLD, induced pluripotent stem cell-derived brain organoids have the potential to provide a better understanding of MLD pathogenesis. However, developing brain organoid models is expensive, time consuming and may not accurately reflect disease progression. Using accurate and inexpensive computer simulations of human brain organoids could overcome the current limitations. Artificially induced whole-brain organoids (aiWBO) have the potential to greatly expand our ability to model MLD and guide future wet lab research. In this study, we have upgraded and validated our artificially induced whole-brain organoid platform (NEUBOrg) using our previously validated machine learning platform, DeepNEU (v6.2). Using this upgraded NEUBorg, we have generated aiWBO simulations of MLD and provided a novel approach to evaluate factors associated with MLD pathogenesis, disease progression and new potential therapeutic options.

Methods and feasibility study for exome sequencing as a universal second-tier test in newborn screening

Newborn screening disorders increasingly require genetic variant analysis as part of second-tier or confirmatory testing. Sanger sequencing and gene-specific next-generation sequencing (NGS)-based tests, the current methods of choice, are costly and lack scalability when expanding to new conditions. We describe a scalable, exome sequencing-based NGS pipeline with a priori analysis restriction that can be universally applied to any NBS disorder. De-identified abnormal newborn screening specimens representing severe combined immune deficiency (SCID), cystic fibrosis (CF), VLCAD deficiency, metachromatic leukodystrophy (MLD), and in silico sequence read data sets were used to validate the pipeline. To support interpretation and clinical decision-making within the bioinformatics pipeline, variants from multiple databases were curated and validated. CFTR variant panel analysis correctly identified all variants. Concordance compared with diagnostic testing results for targeted gene analysis was between 78.6% and 100%. Validation of the bioinformatics pipeline with in silico data sets revealed a 100% detection rate. Varying degrees of overlap were observed between ClinVar and other databases ranging from 3% to 65%. Data normalization revealed that 11% of variants across the databases required manual curation. This pipeline allows for restriction of analysis to variants within a single gene or multiple genes, and can be readily expanded to full exome analysis if clinically indicated and parental consent is granted.

EP015 - A normal MRI leading to a delayed diagnosis of metachromatic leukodystrophy

eP015 - A normal MRI leading to a delayed diagnosis of metachromatic leukodystrophy

Toward newborn screening of metachromatic leukodystrophy: results from analysis of over 27,000 newborn dried blood spots

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ARSA), which results in the accumulation of sulfatides. Newborn screening for MLD may be considered in the future as innovative treatments are advancing. We carried out a research study to assess the feasibility of screening MLD using dried blood spots (DBS) from de-identified newborns. To minimize the false-positive rate, a two-tier screening algorithm was designed. The primary test was to quantify C16:0-sulfatide in DBS by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The screening cutoff was established based on the results from 15 MLD newborns to achieve 100% sensitivity. The secondary test was to measure the ARSA activity in DBS from newborns with abnormal C16:0-sulfatide levels. Only newborns that displayed both abnormal C16:0-sulfatide abundance and ARSA activity were considered screen positives. A total of 27,335 newborns were screened using this two-tieralgorithm, and 2 high-risk cases were identified. ARSA gene sequencing identified these two high-risk subjects to be a MLD-affected patient and a heterozygote. Our study demonstrates that newborn screening for MLD is highly feasible in a real-world scenario with near 100% assay specificity.

Early Signs and Symptoms of Leukodystrophies: A Case-Based Guide.

1. Maura R.Z. Ruzhnikov, MD*,† 2. Elise Brimble, MS, MSc* 3. Rachel E. Hickey, MS‡ 4. on behalf of the Leukodystrophy Care Network 1. *Department of Neurology and Neurological Sciences and 2. †Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA. 3. ‡Department of Medical Genetics, Ann & Robert H. Lurie Children's Hospital, Chicago, IL. * Abbreviations: CNS: : central nervous system HSCT: : hematopoietic stem cell transplant MLD: : metachromatic leukodystrophy MRI: : magnetic resonance imaging PMD: : Pelizaeus-Merzbacher disease X-ALD: : X-linked adrenoleukodystrophy 1. Clinicians should be familiar with leukodystrophies as a distinct disease group and with symptoms suggestive of a leukodystrophy requiring prompt evaluation and referral. 2. Clinicians should recognize the urgency of diagnosis for leukodystrophies that have time-sensitive therapies. 3. Clinicians should be knowledgeable about the initial evaluation, recommended referrals, and resources for patients and families with a suspected leukodystrophy. After completing this article, readers should be able to: 1. Recognize symptoms of the more common leukodystrophies, including X-linked adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe disease, and Pelizaeus-Merzbacher disease. 2. Describe the importance and limitations of brain magnetic resonance imaging for recognition and diagnosis of a leukodystrophy. 3. Be aware of the commonly used biochemical and genetic tests when considering a leukodystrophy diagnosis. 4. Formulate a plan for prompt evaluation and referral to appropriate specialists for children with a suspected leukodystrophy. 5. Support families with a diagnosis of a leukodystrophy by providing disease-specific resources. Leukodystrophies are inherited white matter disorders of the central nervous system (CNS) that are often characterized by progressive neurologic decline and early mortality. Early presenting features can be nonspecific and masquerade as common pediatric complaints, including inattention, irritability, or motor delays before progressing to frank developmental regression or neurodegeneration. Without familiarity with these disorders, their early manifestations may seem unrelated before the subsequent decline. The insidious nature of these disorders often leads to a prolonged …

Elevated Dipeptidyl Peptidase IV (DPP-IV) Activity in Plasma from Patients with Various Lysosomal Diseases.

Increased activity of dipeptidyl peptidase IV (DPP-IV) was reported earlier in patients with different types of mucopolysaccharidoses. DPP-IV (also known as CD26 lymphocyte T surface antigen) is a transmembrane protein showing protease activity. This enzyme displays various functions in the organism and plays an important role in multiple processes like glucose metabolism, nociception, cell-adhesion, psychoneuroendocrine regulation, immune response and cardiovascular adaptation. In order to evaluate DPP-IV in lysosomal storage diseases (LSD), we examined its activity in plasma samples from 307 patients affected with 24 different LSDs and in 75 control persons. Our results revealed elevated DPP-IV activity especially in individuals affected with mucolipidosis II/III, alpha-mannosidosis, and mucopolysaccharidoses types III, II, and I (p < 0.05). In other LSDs the DPP-IV activity was still significantly increased, but to a lesser extent. In patients with Gaucher disease, ceroid lipofuscinosis type 1 (CLN1), Niemann–Pick disease type C and A, Krabbe and Pompe diseases, gangliosidosis GM2 and metachromatic leukodystrophy discreet or no changes in DPP-IV activity were observed. DPP-IV may serve as a first-tier diagnostic procedure or additional biochemical analysis in recognizing patients with some LSDs. DPP-IV may become an object of basic research for a better understanding of LSDs.

Genetic testing of leukodystrophies unraveling extensive heterogeneity in a large cohort and report of five common diseases and 38 novel variants

This study evaluates the genetic spectrum of leukodystrophies and leukoencephalopathies in Iran. 152 children, aged from 1 day to 15 years, were genetically tested for leukodystrophies and leukoencephalopathies based on clinical and neuroradiological findings from 2016 to 2019. Patients with a suggestive specific leukodystrophy, e. g. metachromatic leukodystrophy, Canavan disease, Tay-Sachs disease were tested for mutations in single genes (108; 71%) while patients with less suggestive findings were evaluated by NGS. 108 of 152(71%) had MRI patterns and clinical findings suggestive of a known leukodystrophy. In total, 114(75%) affected individuals had (likely) pathogenic variants which included 38 novel variants. 35 different types of leukodystrophies and genetic leukoencephalopathies were identified. The more common identified disorders included metachromatic leukodystrophy (19 of 152; 13%), Canavan disease (12; 8%), Tay-Sachs disease (11; 7%), megalencephalic leukodystrophy with subcortical cysts (7; 5%), X-linked adrenoleukodystrophy (8; 5%), Pelizaeus–Merzbacher-like disease type 1 (8; 5%), Sandhoff disease (6; 4%), Krabbe disease (5; 3%), and vanishing white matter disease (4; 3%). Whole exome sequencing (WES) revealed 90% leukodystrophies and genetic leukoencephalopathies. The total diagnosis rate was 75%. This unique study presents a national genetic data of leukodystrophies; it may provide clues to the genetic pool of neighboring countries. Patients with clinical and neuroradiological evidence of a genetic leukoencephalopathy should undergo a genetic analysis to reach a definitive diagnosis. This will allow a diagnosis at earlier stages of the disease, reduce the burden of uncertainty and costs, and will provide the basis for genetic counseling and family planning.

Tumefactive Inflammatory Lesions in Juvenile Metachromatic Leukodystrophy

In the Clinical Scientific Note “Tumefactive inflammatory lesions in juvenile metachromatic leukodystrophy” by Meier et al.,1 a few of the references to …

Demographic and clinical characteristics of patients with metachromatic leukodystrophy in the United Kingdom: Interim results from an observational real-world study

Demographic and clinical characteristics of patients with metachromatic leukodystrophy in the United Kingdom: Interim results from an observational real-world study

Quality of life of patients with metachromatic leukodystrophy and their caregivers in the US, UK, Germany and France

Quality of life of patients with metachromatic leukodystrophy and their caregivers in the US, UK, Germany and France

HMI-202: A gene therapy development candidate for metachromatic leukodystrophy (MLD)

HMI-202: A gene therapy development candidate for metachromatic leukodystrophy (MLD)

An affordable combined method to achieve a confirming diagnosis of metachromatic leukodystrophy

An affordable combined method to achieve a confirming diagnosis of metachromatic leukodystrophy

Lentiviral hematopoietic stem and progenitor cell gene therapy provides durable clinical benefit in early-symptomatic early-juvenile metachromatic leukodystrophy

Lentiviral hematopoietic stem and progenitor cell gene therapy provides durable clinical benefit in early-symptomatic early-juvenile metachromatic leukodystrophy

Giant axonal neuropathy with novel GAN pathogenic variant in a patient of consanguineous origin from Poonch Jammu and Kashmir-India

Giant axonal neuropathy (GAN) is a severe and rare autosomal recessive neurodegenerative disorder of childhood affecting both the peripheral and central nervous systems (CNS). It is caused by mutations in the GAN (gigaxonin) gene linked to chromosome 16q24. Here, we present a 15-year-old male patient with GAN from a consanguineous family of Poonch, Jammu and Kashmir (J&K)-India. Whole-exome sequencing (WES) was employed to unravel the genetic cause of GAN in the proband. Pathogenic variant identified with WES was confirmed in other affected sibling using Sanger sequencing. Magnetic resonance imaging (MRI) and detailed clinical investigation was also carried out on proband. WES revealed a novel homozygous stopgain GAN mutation (NM_022041, c.C1028G, p.S343X) in the patient. MRI of brain displayed bilateral symmetrical confluent areas of deep white matter signal changes affecting periventricular regions (withsparing ofsubcortical U-fibers), posterior limbs of internal capsules, thalami, external capsules, and semioval centers. The patient was initially suspected to be a case of metachromatic leukodystrophy. However, WES analysis revealed a pathogenic variant in GAN gene as causative. No other pathogenic variant relevant to any other type of dystrophy was reported in WES. Our findings extend the geographical distribution of GAN to even a very remote region in India, extend the mutational and imaging spectrum of GAN and substantiate the need for introducing genetic testing and counselling in primary referral centers/district hospitals in India.

Lentiviral haematopoietic stem cell gene therapy for metachromatic leukodystrophy: Results in nine patients treated with a cryopreserved formulation of OTL-200

Lentiviral haematopoietic stem cell gene therapy for metachromatic leukodystrophy: Results in nine patients treated with a cryopreserved formulation of OTL-200

A tractography tool that detects abnormalities in function in early metachromatic leukodystrophy

A tractography tool that detects abnormalities in function in early metachromatic leukodystrophy

Health-related quality of life in metachromatic leukodystrophy based on a societal utility study in the UK

Health-related quality of life in metachromatic leukodystrophy based on a societal utility study in the UK

AAV9-hARSA decreases sulfatide accumulation in the aged ARSA−/−mouse model for metachromatic leukodystrophy

AAV9-hARSA decreases sulfatide accumulation in the aged ARSA−/−mouse model for metachromatic leukodystrophy

RANSIP newborn screening program: Working to bring early diagnostics, inclusion, and therapeutic access to metachromatic leukodystrophy patients

RANSIP newborn screening program: Working to bring early diagnostics, inclusion, and therapeutic access to metachromatic leukodystrophy patients

Initial signs and symptoms of metachromatic leukodystrophy: A caregiver perspective

Initial signs and symptoms of metachromatic leukodystrophy: A caregiver perspective