Abstract
BackgroundPontocerebellar hypoplasia type 6 (PCH6) is a mitochondrial disease caused by mutations in the RARS2 gene. RARS2 encodes mitochondrial arginyl transfer RNA synthetase, an enzyme involved in mitochondrial protein translation. A total of 27 patients from 14 families have been reported so far. Characteristic clinical features comprise neonatal lactic acidosis, severe encephalopathy, intractable seizures, feeding problems and profound developmental delay. Most patients show typical neuroradiologic abnormalities including cerebellar hypoplasia and progressive pontocerebellar atrophy.MethodsWe describe the clinical, biochemical and molecular features of 2 siblings with a novel homozygous mutation in RARS2. Both patients presented neonatally with lactic acidosis. While the older sibling had severe neurological symptoms with microcephaly, seizures and developmental delay, the younger patient was still neurologically asymptomatic at the age of 2 months.ResultsMRI studies in both children lacked pontocerebellar involvement. The expression of the OXPHOS complex proteins was decreased in both patients, whereas oxygen consumption was increased.ConclusionsCharacteristic neuroradiological abnormalities of PCH6 such as vermis and cerebellar hypoplasia and progressive pontocerebellar atrophy may be missing in patients with RARS2 mutations. RARS2 testing should therefore also be performed in patients without pontocerebellar hypoplasia but otherwise typical clinical symptoms.
Highlights
Pontocerebellar hypoplasia type 6 (PCH6) is a mitochondrial disease caused by mutations in the RARS2 gene
Pontocerebellar hypoplasia type 6 (PCH6) is a mitochondrial disease with autosomal recessive inheritance caused by mutations in the RARS2 gene
Genetic studies Next-generation sequencing based analysis identified a novel homozygous RARS2 missense mutation, c.392T > G; p.Phe131Cys, in both siblings. This variant has not been observed in sequence analysis of normal individuals or other patients with suspected PCH6, nor is it represented in the SDS-PAGE We measured the protein expression levels of the respiratory chain complexes
Summary
Pontocerebellar hypoplasia type 6 (PCH6) is a mitochondrial disease caused by mutations in the RARS2 gene. RARS2 encodes mitochondrial arginyl transfer RNA synthetase, an enzyme involved in mitochondrial protein translation. Most patients show typical neuroradiologic abnormalities including cerebellar hypoplasia and progressive pontocerebellar atrophy. Pontocerebellar hypoplasia type 6 (PCH6) is a mitochondrial disease with autosomal recessive inheritance caused by mutations in the RARS2 gene. RARS2 encodes the mitochondrial arginyl transfer RNA (tRNA) synthetase, an enzyme which belongs to the group of mitochondrial aminoacyl tRNA synthetases. Most patients present characteristic neuroradiological abnormalities including cerebellar hypoplasia and progressive cerebral cortical atrophy together with progressive pontocerebellar atrophy [3]. Our cases demonstrate that pontocerebellar hypoplasia (PCH) is no sine qua non for the diagnosis of RARS2 mutations
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