Newborn screening in metachromatic leukodystrophy - European consensus-based recommendations on clinical management.

INTRODUCTION: Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder resulting from arylsulfatase A enzyme deficiency, leading to toxic sulfatide accumulation. As a result affected individuals exhibit progressive neurodegeneration. Treatments such as hematopoietic stem cell transplantation (HSCT) and gene therapy are effective when administered pre-symptomatically. Newborn screening (NBS) for MLD has recently been shown to be technically feasible and is indicated because of available treatment options. However, there is a lack of guidance on how to monitor and manage identified cases. This study aims to establish consensus among international experts in MLD and patient advocates on clinical management for NBS-identified MLD cases. METHODS: A real-time Delphi procedure using eDELPHI software with 22 experts in MLD was performed. Questions, based on a literature review and workshops, were answered during a seven-week period. Three levels of consensus were defined: A) 100%, B) 75-99%, and C) 50-74% or >75% but >25% neutral votes. Recommendations were categorized by agreement level, from strongly recommended to suggested. Patient advocates participated in discussions and were involved in the final consensus. RESULTS: The study presents 57 statements guiding clinical management of NBS-identified MLD patients. Key recommendations include timely communication by MLD experts with identified families, treating early-onset MLD with gene therapy and late-onset MLD with HSCT, as well as pre-treatment monitoring schemes. Specific knowledge gaps were identified, urging prioritized research for future evidence-based guidelines. DISCUSSION: Consensus-based recommendations for NBS in MLD will enhance harmonized management and facilitate integration in national screening programs. Structured data collection and monitoring of screening programs are crucial for evidence generation and future guideline development. Involving patient representatives in the development of recommendations seems essential for NBS programs.

Inventory of current practices regarding hematopoietic stem cell transplantation in metachromatic leukodystrophy in Europe and neighboring countries.

BACKGROUND: For decades, early allogeneic stem cell transplantation (HSCT) has been used to slow neurological decline in metachromatic leukodystrophy (MLD). There is lack of consensus regarding who may benefit, and guidelines are lacking. Clinical practice relies on limited literature and expert opinions. The European Reference Network for Rare Neurological Diseases (ERN-RND) and the MLD initiative facilitate expert panels for treatment advice, but some countries are underrepresented. This study explores organizational and clinical HSCT practices for MLD in Europe and neighboring countries to enhance optimization and harmonization of cross-border MLD care. METHODS: A web-based EUSurvey was distributed through the ERN-RND and the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Personal invitations were sent to 89 physicians (43 countries) with neurological/metabolic/hematological expertise. The results were analyzed and visualized using Microsoft Excel and IBM SPSS statistics. RESULTS: Of the 30 countries represented by 42 respondents, 23 countries offer HSCT for MLD. The treatment is usually available in 1-3 centers per country (18/23, 78%). Most countries have no or very few MLD patients transplanted during the past 1-5 years. The eligibility criteria regarding MLD subtype, motor function, IQ, and MRI largely differ across countries. CONCLUSION: HSCT for MLD is available in most European countries, but uncertainties exist in Eastern and South-Eastern Europe. Applied eligibility criteria and management vary and may not align with the latest scientific insights, indicating physicians' struggle in providing evidence-based care. Interaction between local physicians and international experts is crucial for adequate treatment decision-making and cross-border care in the rapidly changing MLD field.

Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease.

MRPL39 encodes one of 52 proteins comprising the large subunit of the mitochondrial ribosome (mitoribosome). In conjunction with 30 proteins in the small subunit, the mitoribosome synthesizes the 13 subunits of the mitochondrial oxidative phosphorylation (OXPHOS) system encoded by mitochondrial Deoxyribonucleic acid (DNA). We used multi-omics and gene matching to identify three unrelated individuals with biallelic variants in MRPL39 presenting with multisystem diseases with severity ranging from lethal, infantile-onset (Leigh syndrome spectrum) to milder with survival into adulthood. Clinical exome sequencing of known disease genes failed to diagnose these patients; however quantitative proteomics identified a specific decrease in the abundance of large but not small mitoribosomal subunits in fibroblasts from the two patients with severe phenotype. Re-analysis of exome sequencing led to the identification of candidate single heterozygous variants in mitoribosomal genes MRPL39 (both patients) and MRPL15. Genome sequencing identified a shared deep intronic MRPL39 variant predicted to generate a cryptic exon, with transcriptomics and targeted studies providing further functional evidence for causation. The patient with the milder disease was homozygous for a missense variant identified through trio exome sequencing. Our study highlights the utility of quantitative proteomics in detecting protein signatures and in characterizing gene-disease associations in exome-unsolved patients. We describe Relative Complex Abundance analysis of proteomics data, a sensitive method that can identify defects in OXPHOS disorders to a similar or greater sensitivity to the traditional enzymology. Relative Complex Abundance has potential utility for functional validation or prioritization in many hundreds of inherited rare diseases where protein complex assembly is disrupted.