Genotypic Spectrum and Natural History of Cavitating Leukoencephalopathies in Childhood

We aimed to delineate the pattern of natural course, neuroimaging features, and the genotypic spectrum of cavitating leukoencephalopathies.

Children (age of onset ≤16 years) who met the criteria for cavitating leukoencephalopathies from January 2009 to October 2018 were identified. Whole-exome sequencing and prospective follow-up study of the natural history and brain magnetic resonance imaging (MRI) were performed.

Thirty-seven children were clinically diagnosed with cavitating leukoencephalopathies. Pathogenic or likely pathogenic mutations in eight genes were identified in 31 individuals (83.78%): IBA57 (17/37), NDUFS1 (5/37), NDUFV1 (2/37), NDUFV2 (3/37), NDUFAF5 (1/37), LYRM7 (1/37), NDUFB8 (1/37), and GLRX5 (1/37). All genes were engaged in mitochondrial function. IBA57 was identified in half of children. Mutations in NDUFV2, NDUFAF5, NDUFB8, or GLRX5 were first found to be related to cavitating leukoencephalopathies. Follow-up with a median of 23.5 months (four to 107 months) was available. The median age at disease onset was 11 months. All cases presented acute or subacute onset, and the initial presentation was rapid motor regression in 35 cases. Thirty-five children (35/37) exhibited a stabilized or improved pattern. Cavities and high-intensity diffusion-weighted imaging signals were the common MRI features during the acute stage. Although clinically stable, 21 children had reserved high diffusion-weighted imaging signals for a long time. Patients with different gene mutations show different MRI patterns.

The study expands the number of genes involved in cavitating leukoencephalopathies to 22. IBA57 is the most common candidate gene. Most cases showed a stabilized or improved pattern after an acute or subacute onset, which is different from most other inherited metabolic diseases or leukodystrophies. More cases and a longer follow-up period are needed.