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

Abstract

Mutations in the mitochondrial arginyl tRNA synthetase (RARS2) gene are associated with Pontocerebellar Hypoplasia type 6 (PCH6). Here we report two patients, compound heterozygous for RARS2 mutations, presenting with early onset epileptic encephalopathy and (progressive) atrophy of both supra-and infratentorial structures. Early pontocerebellar hypoplasia was virtually absent and respiratory chain (RC) defects could not be detected in muscle biopsies. Both patients carried a novel missense mutation c.1544A>G (p.(Asp515Gly)) in combination with either a splice site (c.297+2T>G) or a frameshift (c.452_454insC) mutation. The splice site mutation induced skipping of exon 4.These two patients expand the phenotypical spectrum associated with RARS2 mutations beyond the first report of PCH6 by Edvardson and colleagues. We propose to classify RARS2-associated phenotypes as an early onset mitochondrial encephalopathy, since this is more in agreement with both clinical presentation and underlying genetic cause.

Diagnostic value of partial exome sequencing in developmental disorders

“…Patient #31 was compound heterozygous for two novel missense variants in RARS2 , but presented with infantile spasms and severe diffuse supratentorial atrophy without cerebellar hypoplasia ( S1 Clinical Data , S2 Fig ). The variants were re-classified as causative after the observation of the missense change in two other unrelated patients with early onset epileptic encephalopathy [ 39 ] and several reports of patients with RARS2 mutations and intact cerebellum [ 40 , 41 ]. Interestingly, the reclassification of the RARS2 -associated phenotype as an early onset mitochondrial encephalopathy [ 39 ] was further supported by elevated lactate levels in cerebrospinal fluid observed in our patient, as well as a lactate peak on her MR-spectroscopy.…”

What’s new in pontocerebellar hypoplasia? An update on genes and subtypes

“…PCH6 is caused by mutations in the nuclear encoded mitochondrial Arginine tRNA-synthetase ( RARS2) , which is responsible for catalyzing the specific attachment of Arginine to its cognate mitochondrial tRNA [ 40 ]. Currently, 31 patients with RARS2 mutations (OMIM # 611523) have been reported [ 39 – 49 ]. None of them have biallelic null mutations, implicating that complete abolishment of mitochondrial tRNA-arg would be lethal.…”

“…None of them have biallelic null mutations, implicating that complete abolishment of mitochondrial tRNA-arg would be lethal. Splice site, nonsense or missense mutations are identified throughout the RARS2 gene, while no clear genotype-phenotype correlation could be established [ 49 ]. All patients surviving the neonatal period had severe developmental delay, and almost all suffered from refractory epilepsy.…”

“…Some early MRIs were normal or showed mild vermal hypoplasia, with often rapidly progressive atrophy of supra- and infratentorial structures (Fig. 2i-j ) [ 49 ].…”

Pontocerebellar hypoplasia: clinical case and literature review

“…PCH5 ti pui yra bû din ga sme ge në liø hi pop la zi ja, ta èiau sme ge në liø kir mi nas la biau hi pop las tið kas nei sme ge në liø pus ru tu liai [17,18]. PCH6 ti pas ið skir ti nis tuo, kad nau jagi mys të je ste bi ma tik sme ge në liø kir mi no hi pop la zi ja, o vë liau pa si reið kia pro gre suo jan ti sme ge në liø, til to, sme genø þie vës ir bal to sios me dþia gos at ro fi ja [19]. PCH7 ti pui bû din ga til to bei sme ge në liø hi pop la zi ja ir kli nið kai iðreikð tas ge ni ta li jø vys ty mo si su tri ki mas [3].…”