Refining the phenotype of the THG1L (p.Val55Ala mutation)-related mitochondrial autosomal recessive congenital cerebellar ataxia

Roughly 40 genes have been linked to autosomal recessive (AR) ataxia syndromes. Of these, at least 10 encode gene products localizing to the mitochondrion. tRNA-histidine guanylyltransferase 1 like (THG1L) localizes to the mitochondrion and catalyzes the 3′–5′ addition of guanine to the 5′-end of tRNA-histidine. Previously, three siblings with early onset cerebellar dysfunction, developmental delay, pyramidal signs, and cerebellar atrophy on brain magnetic resonance imaging (MRI) were reported to carry homozygous V55A mutations in THG1L. Fibroblasts derived from these individuals showed abnormal mitochondrial networks when subjected to obligatory oxidative phosphorylation. A carrier rate of 0.8%, but no THG1L V55A homozygotes, was found in a cohort of 3,232 unrelated Ashkenazi Jewish individuals, and no homozygotes were found in Exac or gnomAD. This variant is reported with an allelic frequency of 0.02% in Exac, and is not listed in gnomAD. A similar phenotype was recently reported for another, homozygous variant p.L294P was reported with a similar, but more severely affected phenotype [Shaheen et al. (2019); Genetics in Medicine 21: 545–552]. Here, we report two additional Ashkenazi Jewish patients, carrying the same homozygous V55A mutation. We present bioinformatic analyses of the V55A mutation demonstrating high conservation in metazoan species. We refine the clinical and radiological phenotype and discuss the uniqueness of the clinical course of this novel mitochondrial AR ataxia in comparison to the diverse molecular etiologies and clinical phenotypes of other known mitochondrial AR ataxias.