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Genetic leukodystrophies (gLD), encompassing inherited disorders affecting cerebral white matter, are a heterogeneous group of diseases.1 While they classically first manifest in childhood, adolescent and adult-onset forms are increasingly recognised.2 3 Different pathological mechanisms produce white matter abnormalities (WMAs) depending on the affected gene.1 Hypomyelinating gLD (H-gLD) share the common histological feature of decreased myelin formation in the brain, in contrast to demyelinating gLD (loss of previously formed myelin), dysmyelinating gLD (deposition of structurally abnormal myelin) and myelinolytic disorders (vacuolisations disrupting myelin integrity).1
MRI characteristics help discriminate hypomyelination from other WMAs. In H-gLD, WMAs are widespread, mildly hyperintense on T2/fluid attenuation inversion recovery and associated with diffuse T1 hyperintense, isointense or mildly hypointense signal relative to the grey matter.4 In other gLD, WMAs can be focal or confluent, often with regional predominance, and prominent T2 hyperintensity with marked T1 hypointensity.2 4 H-gLD typically present in the neonatal period with axial hypotonia, followed by spastic paraparesis and delayed motor development in early childhood.2 4 Nystagmus, cerebellar ataxia, extrapyramidal syndrome and cognitive impairment can later develop.3 4 Depending on the gene defect, extraneurological signs have been described.4 Adolescent/adult-onset H-gLD are exceptionally reported.2 We report findings in three unrelated patients with late-onset neurological symptoms and hypomyelinating features on brain MRI.
Brain MRI of our patients are shown in figure 1, all showing diffuse WMAs suggestive of isolated hypomyelination. Candidate variants detected by next-generation sequencing (NGS), clinical and electrophysiological features are summarised in online supplementary table 1. The genes included in the panels are listed in online supplementary table 2. Genetic methodology, molecular characteristics and bioinformatics prediction tools of …
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