Neuropathologic Features of Pontocerebellar Hypoplasia Type 6

Abstract

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.

RARS2 mutations in a sibship with infantile spasms

“…2, 6, 7, 8, 9, 10, 11, 12 One RARS2 mutation in our sibship is novel, and the other previously reported. Glamuzina et al 8.…”

“…2, 6, 7, 8, 9, 10, 11, 12 Our sibship manifest a number of clinical features common to those reported, including infantile‐onset of disease, pharmacoresistant epileptic encephalopathy, severe neurodevelopmental delay, acquired microcephaly, neonatal hypoglycemia, feeding difficulties, abnormal visual behavior, and early raised serum and/or CSF lactate. Patients with RARS2 mutations manifest multiple different electroclinical phenotypes including generalized tonic–clonic, focal clonic, and myoclonic episodes 2, 6, 7, 8, 9, 10, 11, 12. Our patients presented with infantile spasms, which have not been reported in RARS2 PCH6 previously.…”

Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

“…Many RARS2 mutations have been reported in patients with pontocerebellar hypoplasia type 6 (PCH6) which is characterized by intellectual disability, severe motor impairment, and abnormally small cerebellum and brainstem (Edvardson et al 2007;Rankin et al 2010;Namavar et al 2011a, b;Glamuzina et al 2012;Cassandrini et al 2013;Kastrissiankis et al 2013;Joseph et al 2014;Li et al 2015;Lax et al 2015). The RARS2 gene is one of 19 different nucleus-encoded mitochondrial aminoacyl-tRNA synthetases.…”

Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to NovelRARS2Mutations

“…Each affected child was homozygous for an intronic c.110+5A>G mutation leading to aberrant mRNA splicing and associated with respiratory chain defects in muscle and fibroblasts. An additional 16 patients harboring autosomal recessive RARS2 mutations have since been reported (6–10); detailed postmortem neuropathologic reports are only available for 2 cases (11). These cases demonstrated additional features of PCH subtypes 2 and 4, including severe dystonia, optic atrophy, and thinning of the corpus callosum (9).…”