Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl‐tRNA synthetase, RARS2

Abstract

Pontocerebellar hypoplasia type 6 (PCH6) (MIM #611523) is a recently described disorder caused by mutations in RARS2 (MIM *611524), the gene encoding mitochondrial arginyl-transfer RNA (tRNA) synthetase, a protein essential for translation of all mitochondrially synthesised proteins. This case confirms that progressive cerebellar and cerebral atrophy with microcephaly and complex epilepsy are characteristic features of PCH6. Additional features of PCH subtypes 2 and 4, including severe dystonia, optic atrophy and thinning of the corpus callosum, are demonstrated. Congenital lactic acidosis can be present, but respiratory chain dysfunction may be mild or absent, suggesting that disordered mitochondrial messenger RNA (mRNA) translation may not be the only mechanism of impairment or that a secondary mechanism exists to allow some translation. We report two novel mutations and expand the phenotypic spectrum of this likely underdiagnosed PCH variant, where recognition of the characteristic neuroradiological phenotype could potentially expedite genetic diagnosis and limit invasive investigations.

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. report a patient harboring an identical 3 bp deletion (c.472_474del), with the same predicted functional consequences (loss of lysine158).…”

“…It is postulated that supra‐and infratentorial atrophy may be progressive over time, and pontine involvement may not be present in the early stages 6, 8, 9, 10. In both our patients, MRI, undertaken within the first year of life, revealed a small cerebellum and generalized reduced white matter bulk with an abnormal corpus callosum.…”

“…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.…”

RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

“…MRIs made in a very early stage were either normal or showed relatively mild vermal hypoplasia, while follow-up MRIs often displayed rapidly progressive atrophy of both supra-and infratentorial structures (Cassandrini et al 2013;Rankin et al 2010;Kastrissianakis et al 2013;Nishri et al 2016). Remarkably, the basal ganglia often remained spared, a finding also endorsed by the patients we describe (Edvardson et al 2007;Cassandrini et al 2013;Glamuzina et al 2012).…”

“…Including the two patients we report here, 29 patients with RARS2 mutations are described in literature so far (Namavar et al 2011a;Cassandrini et al 2013;Rankin et al 2010;Glamuzina et al 2012;Kastrissianakis et al 2013;Joseph et al 2014;Li et al 2015;Lax et al 2015;Nishri et al 2016;Ngoh et al 2016;Alkhateeb et al 2016). Splice site, nonsense, or missense mutations are identified throughout the RARS2 gene, but no patients with biallelic null mutations were identified, supporting the assumption that complete abolishment of tRNA-arg would be lethal.…”