Subdural effusions and lack of early pontocerebellar hypoplasia in siblings with RARS2 mutations

Abstract

Mutations in the recently described RARS2 gene encoding for mitochondrial arginyl-transfer RNA synthetase give rise to a disorder characterised by early onset seizures, progressive microcephaly and developmental delay. The disorder was named pontocerebellar hypoplasia type 6 (PCH6) based on the corresponding radiological findings observed in the original cases. We report two siblings with the RARS2 mutation who displayed typical clinical features of PCH6, but who had distinct neuroimaging features. Early scans showed marked supratentorial, rather than infratentorial, atrophy, and the pons remained preserved throughout. One sibling also had bilateral subdural effusions at presentation. The deceleration in head growth pointed to an evolving genetic/metabolic process giving rise to cerebral atrophy and secondary subdural effusions. RARS2 mutations should be considered in infants presenting with seizures, subdural effusions, decelerating head growth and evidence of cerebral atrophy even in the absence of pontocerebellar hypoplasia on imaging.

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.…”

“…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?

“…Severity of cerebellar hypoplasia/atrophy was variable. 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.…”