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A 60-minute webinar with Prof. Paul Gissen (UCL Institute of Child Health / Great Ormond Street Hospital) and Dr Anna Ardissone on the diagnostic journey in metachromatic leukodystrophy (MLD) — the pathology, the tests to request, and the real cases where diagnostic delay closed off treatment. For paediatricians, community paediatricians and paediatric neurologists.
Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder (birth prevalence about 1 in 40,000) caused by mutations in the ARSA gene, and occasionally by PSAP or SUMF1 mutations; arylsulfatase A deficiency causes sulfatide accumulation and progressive demyelination of the central and peripheral nervous systems. Prof. Paul Gissen sets out the pathophysiology, the diagnostic tools — enzyme assay, sulfatide testing and mutation analysis — and the need to distinguish true ARSA deficiency from pseudodeficiency and multiple sulfatase deficiency, and reviews the subtypes (late-infantile, early and late juvenile, adult) and their MRI features, noting that early scans can be normal. Through their own patient cases, both speakers show how delay narrows or closes off treatment: a late-juvenile boy diagnosed only after a high-achieving decline; two siblings with early-juvenile MLD; and a late-infantile child worked up with a broad neuropathy panel while the treatable window passed. Their shared warning is that non-specific whole-genome or panel testing sent as routine can take six months and lose that window, whereas biochemical testing gives a rapid answer. They set out how to improve diagnosis — attention to family history and to cognitive decline versus delay, excluding treatable leukodystrophies first, using abdominal ultrasound for the pathognomonic gallbladder changes, and referring to a reference centre — and make the case for newborn and sibling screening, while acknowledging that genotype does not yet reliably predict phenotype.
After viewing this webinar, participants will be able to:
By a combination of arylsulfatase A enzyme assay and mutation analysis, supported by sulfatide testing (in urine, blood or blood spots) and brain MRI. Mutation analysis is important to distinguish true ARSA deficiency from pseudodeficiency and from multiple sulfatase deficiency, both of which can give abnormal enzyme results.
When a non-specific whole-genome or leukodystrophy/neuropathy panel is sent as a routine, non-urgent test, the result can take around six months. During that time an early-onset child can deteriorate past the treatable window, so specific biochemical testing — which is far faster — should be prioritised when MLD is possible.
Deep white-matter disease with sparing of the subcortical white matter and no leading edge of enhancement, progressing to a 'tigroid' or 'leopard-skin' appearance. Importantly, early MRI can be normal — particularly in late-infantile disease — so a normal scan does not exclude MLD, and an abdominal ultrasound may reveal pathognomonic gallbladder changes.
Because treatment — gene therapy or, in selected juvenile cases, stem-cell transplantation — is only effective pre-symptomatically or very early, and requires preserved walking and an IQ above 85 in early-juvenile disease. In the cases presented, diagnostic delay left patients ineligible, underlining the value of rapid testing, reference-centre referral and sibling or newborn screening.
This content is intended for healthcare professionals only. The views expressed are those of the presenters and do not necessarily reflect those of Excellence in Pediatrics; their inclusion does not imply endorsement. The content is provided for educational purposes only and does not constitute medical advice or replace independent clinical judgement.