Recognizing early MRI signs (or their absence) is crucial in diagnosing metachromatic leukodystrophy

Abstract Objectives Metachromatic leukodystrophy (MLD) has characteristic white matter (WM) changes on brain MRI, which often trigger biochemical and genetic confirmation of the diagnosis. In early or pre‐symptomatic disease stages, these typical MRI changes might be absent, hampering early diagnosis. This study aims to describe the characteristics of MRI WM abnormalities at diagnosis, related to clinical presentation. Methods We retrospectively reviewed brain MRIs of MLD patients followed in 2 centers at the time of diagnosis regarding MLD MRI score and presence of tigroid pattern. In addition, MLD subtype, symptom status, CNS/PNS phenotype, motor/cognitive/mixed phenotype, and the presence of CNS symptoms were evaluated. Results We included 104 brain MRIs from patients with late‐infantile (n = 43), early‐juvenile (n = 24), late‐juvenile (n = 20) and adult (n = 17) onset. Involvement of the corpus callosum was a characteristic early MRI sign and was present in 71% of the symptomatic late‐infantile patients, 94% of the symptomatic early‐juvenile patients and 100% of the symptomatic late‐juvenile and adult patients. Symptomatic early‐juvenile, late‐juvenile and adult patients generally had WM abnormalities on MRI suggestive of MLD. By contrast, 47% of the early‐symptomatic late‐infantile patients had no or only mild WM abnormalities on MRI, even in the presence of CNS symptoms including pyramidal signs. Interpretation Patients with late‐infantile MLD may have no or only mild, nonspecific abnormalities at brain MRI, partly suggestive of ‘delayed myelination’, even with clear clinical symptoms. This may lead to significant diagnostic delay. Knowledge of these early MRI signs (or their absence) is important for fast diagnosis

Vanishing white matter: Eukaryotic initiation factor 2B model and the impact of missense mutations

Abstract Background Vanishing white matter (VWM) is a leukodystrophy, caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B)‐subunit genes (EIF2B1–EIF2B5); 80% are missense mutations. Clinical severity is highly variable, with a strong, unexplained genotype–phenotype correlation. Materials and Methods With information from a recent natural history study, we severity‐graded 97 missense mutations. Using in silico modeling, we created a new human eIF2B model structure, onto which we mapped the missense mutations. Mutated residues were assessed for location in subunits, eIF2B complex, and functional domains, and for information on biochemical activity. Results Over 50% of mutations have (ultra‐)severe phenotypic effects. About 60% affect the ε‐subunit, containing the catalytic domain, mostly with (ultra‐)severe effects. About 55% affect subunit cores, with variable clinical severity. About 36% affect subunit interfaces, mostly with severe effects. Very few mutations occur on the external eIf2B surface, perhaps because they have minor functional effects and are tolerated. One external surface mutation affects eIF2B‐substrate interaction and is associated with ultra‐severe phenotype. Conclusion Mutations that lead to (ultra‐)severe disease mostly affect amino acids with pivotal roles in complex formation and function of eIF2B. Therapies for VWM are emerging and reliable mutation‐based phenotype prediction is required for propensity score matching for trials and in the future for individualized therapy decisions