Teaching NeuroImages: A rare case of metachromatic leukodystrophy with multiple bilateral cranial nerve enhancement

Sonowal, Purabi; Lulla, Dinesh; Weber, Amanda; Altınok, Deniz

doi:10.1212/wnl.0000000000008400

Cited by 2 publications

(1 citation statement)

References 2 publications

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“…In addition, Singh et al ( 2009) described a late-infantile MLD patient who presented with esotropia and amblyopia of the right eye, and showed gadolinium enhancement of the oculomotor, trigeminal, facial, vestibulocochlear and glossopharyngeal nerve in the absence of white matter abnormalities on brain MRI (8) . Other gadolinium enhanced cranial nerves that have been reported in cases of late-infantile MLD include the optic and abducens nerves (17)(18)(19)(20) .…”

Section: Discussionmentioning

confidence: 99%

Acute-onset paralytic strabismus in toddlers is important to consider as a potential early sign of late-infantile Metachromatic Leukodystrophy

Beerepoot¹,

Wolf²,

Wehner³

et al. 2022

European Journal of Paediatric Neurology

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Section: Discussionmentioning

confidence: 99%

Acute-onset paralytic strabismus in toddlers is important to consider as a potential early sign of late-infantile Metachromatic Leukodystrophy

Beerepoot¹,

Wolf²,

Wehner³

et al. 2022

European Journal of Paediatric Neurology

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

et al. 2023

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Background Metachromatic 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. Results We 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. Conclusions These 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.

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Teaching NeuroImages: A rare case of metachromatic leukodystrophy with multiple bilateral cranial nerve enhancement

Cited by 2 publications

References 2 publications

Acute-onset paralytic strabismus in toddlers is important to consider as a potential early sign of late-infantile Metachromatic Leukodystrophy

Acute-onset paralytic strabismus in toddlers is important to consider as a potential early sign of late-infantile Metachromatic Leukodystrophy

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

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