Neuropathologic features of pontocerebellar hypoplasia type 6

Pontocerebellar hypoplasia is a group of severe developmental disorders with prenatal onset affecting the growth and function of the brainstem and cerebellum. The rarity and genetic heterogeneity of this group of disorders can make molecular diagnosis challenging. We report 3 siblings who were born to nonconsanguineous parents, were hypotonic at birth, developed seizures, had repeated apneic spells, and died within 2 months of life. Neuroimaging showed that all had profound cerebellar hypoplasia and simplified cortical gyration. Genetic analysis by whole-exome sequencing demonstrated compound heterozygous mutations in the mitochondrial arginyl transfer RNA synthetase gene RARS2, indicating that the children had pontocerebellar hypoplasia type 6. Autopsies on the younger twin siblings revealed small and immature cerebella at an approximate developmental age of less than 18 weeks. The basis pontis showed regressive changes, and the medulla had marked inferior olivary hypoplasia. The brains of both twins were microencephalic and had simplified gyri; cortices were immature, and deep white matter had extensive astrocytosis. The findings suggest a near-normal embryologic period followed by midgestation developmental slowing or cessation and later regression in select anatomic regions. This is the first detailed description of neuropathologic findings associated with pontocerebellar hypoplasia type 6 and demonstrates the profound effects of RARS2 disruption during early neurodevelopment.