Autosomal recessive cerebellar ataxia caused by a homozygous mutation in PMPCA.

Sir, Recently, Jobling et al. (2015) reported the identification of mutations in PMPCA in 17 patients from four families affected with autosomal recessive non-progressive cerebellar ataxia. A homozygous missense mutation in PMPCA (c.1129G>A, p.Ala377Thr) was uncovered in three families of Christian Lebanese Maronite origin, while compound heterozygous mutations (c.287C>T, p.Ser96Leu; c.1543G>A, p.Gly515Arg) were identified in a French patient (Jobling et al. , 2015). PMPCA encodes the alpha subunit of the mitochondrial processing peptidase (MPP), which cleaves the targeting peptide of nuclear-encoded mitochondrial precursor proteins upon their import into mitochondria (Teixeira and Glaser, 2013). Jobling et al. (2015) showed compelling evidence for the causality of PMPCA variants. First, they demonstrated co-segregation of the variants with the disease among the four families, including a large consanguineous family of 32 individuals. Moreover, they observed decreased levels of MPPα in lymphoblasts from two affected members compared to heterozygote carriers and healthy controls. Interestingly, they also showed impaired processing of frataxin (FXN), a mitochondrial protein that is a known substrate of MPP (Cavadini et al. , 2000; Schmucker et al. , 2008). The paper by Jobling et al. (2015) is the first to associate defects in PMPCA with a human disease, which suggests a new mechanism for the pathogenesis of non-progressive cerebellar ataxias. We wish to complement this study with our own identification of two brothers affected by a juvenile-onset recessive cerebellar ataxia caused by a homozygous mutation in PMPCA . These two patients were born of French Canadian parents who are distantly related (Fig. 1A). Considerable clinical variability was present between the two affected cases. Patient II.2 started developing impaired gait, dysarthria, dysmetria and mild distal atrophy during adolescence. He was diagnosed with a slowly progressive spinocerebellar ataxia. He did not have intellectual deficiency but had learning difficulties in school. Patient II.3 …