Novel Homozygous Mitochondrial Arginyl-tRNA Synthetase 2 (RARS2) Gene Mutation without Pontocerebellar Hypoplasia Type 6

Introduction: Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been associated with early onset encephalopathy with signs of oxidative phosphorylation defects classified as pontocerebellar hypoplasia 6 (PCH6). Only 16 patients with mostly compound heterozygous RARS2 mutations have been reported so far. We report two siblings with a novel homozygous RARS2 gene mutation without pontocerebellar hypoplasia, but typical neurological findings.

Case Report: Patient 1 is a Saudi Arabian boy born to healthy consanguineous parents. Postnatally lethargy, a metabolic acidosis and hypoglycemia was noted. Since the age of 3 months he has shown muscular hypotonia, frequent convulsions and delayed motor development. At 40 months diagnosis of PCH6 was made by use of a multi-gene panel for mitochondrial translation defects which revealed a novel homozygous RARS2 gene mutation (c.392T > G; p.(Phe131Cys)), brain MRI, muscle biopsy, electromyography and ophthalmological examination yielded normal results. At 45 months the boy is severely retarded and shows aggravated muscular hypotonia, cerebral visual impairment, microcephaly and symptomatic epilepsy. Under anticonvulsive therapy he is currently seizure-free. His 9 months older sister carrying the same homozygous RARS2 gene mutation presented with severe neonatal lactic acidosis, but also no pontocerebellar hypoplasia.

Conclusion: Our cases demonstrate that pontocerebellar hypoplasia is not a sine qua non for the diagnosis of PCH6 extending the clinical spectrum of RARS2 gene mutations. Disordered mitochondrial mRNA translation not being the only mechanism of impairment, secondary mechanisms leading to partial translation, only partial affection of the mitochondrial respiratory chain or repair mechanisms might explain the phenotype.