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Nuclear-mitochondrial proteins: too much to process?

This scientific commentary refers to ‘ PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia’, by Jobling et al. (doi:10.1093/brain/awv057). 

In the not too distant past, non-progressive focal neurological deficits emerging during child development were all labelled as ‘cerebral palsy’, and assumed to be caused by an insult during pregnancy or in the perinatal period. This view has changed dramatically over the last two decades, in large part as a result of advances in structural brain imaging, which failed to identify the characteristic patterns of hypoxic-ischaemic brain injury or perinatal infection in every case. Metabolic and genetic studies subsequently unravelled a diverse and unexpected range of mechanisms responsible for these ‘static’ neurological deficits, and the pace has accelerated with the application of exome sequencing (Srivastava et al. , 2014). Patients with non-progressive cerebellar ataxia have been particularly difficult to explain. The number of known causes has remained limited, and includes extreme rarities such as congenital disorder of glycosylation type Ia, caused by phosphomannomutase 2 deficiency (Boddaert et al. , 2010). However, the differential diagnosis and mechanisms responsible for this phenotype have now broadened with the findings of Jobling et al. (2015), described in this issue of Brain .

Initially studying a family from the Bekaa valley in north east Lebanon, Jobling et al. looked for regions of shared homozygosity using microsatellite markers in 12 individuals with non-progressive ataxia, spasticity, and intellectual disability (Delague et al. , 2002). All shared a 12.1-cM homozygous region on chromosome 9q34-qter between markers D9S67 and D9S312. Exome sequencing identified homozygous mutations in two genes within the mapped candidate region: PMPCA and CAMSAP1 , neither previously associated with disease. These findings presented a …