The ATPase AAA-domain protein 3 (ATAD3) is a ubiquitously expressed mitochondrial protein involved in mitochondrial dynamics, DNA-nucleoid structural organization, cholesterol transport and steroidogenesis. Mutations within the ancestral ATAD3A gene are strongly associated with neurological abnormalities due to alterations in the mitochondrial function and homeostasis. Here, we report the case of a subject diagnosed with developmental delay associated with ataxia and progressive atrophy of both cerebellar hemispheres and cerebellar vermis, despite exhibiting a normal biochemical profile. By whole exome sequencing, we identified two biallelic single nucleotide variants within the coding region of ATAD3A in the affected subject. Both variants were previously reported as monoallelic variants with uncertain clinical significance. Importantly, the variant ATAD3A c.251T>C leads to an amino acid change of a highly conserved residue across species and in silico analysis revealed structural alteration in the ATAD3A protein. Ketogenic diet was administered to the subject as a novel therapeutic approach. Notably, the treatment correlated with a reduction in cerebellum atrophy progression and the gradual enhancement of the subject’s physical skills, vitality and personal interactions. Thus, we report the first subject with a homozygous status for the ATAD3A c.251T>C (p.Thr84Met) variant. We propose that this mutation led to an alteration of the mitochondrial function, causing the neurological symptoms observed in the subject. The symptoms were partially alleviated following ketogenic diet, improving the subject’s quality of life.
- ATAD3A c.251T>C (p.Thr84Met) rs546711654
- Cerebellar atrophy
- Ketogenic diet
- Whole exome sequencing