1Department of Pediatrics, Shaare Zedek Medical Center 2Neuropediatrics Unit, Shaare Zedek Medical Center 3Medical Genetics Institute, Shaare Zedek Medical Center
OBJECTIVE: To identify the genetic basis of a childhood-onset syndrome of variable severity characterized by progressive spinocerebellar ataxia, mental retardation, psychotic episodes and cerebellar atrophy.
METHODS: Identification of the underlying mutations by whole exome and whole genome sequencing. Consequences were examined in patients’ cells and in yeast.
RESULTS: Two brothers from a consanguineous Palestinian family presented with progressive spinocerebellar ataxia, mental retardation and psychotic episodes. Serial brain imaging showed severe progressive cerebellar atrophy. Whole exome sequencing revealed a novel mutation: PITRM1 c.2795C>T, p.T931M, homozygous in the affected children and resulting in 95% reduction in PITRM1 protein. Whole genome sequencing revealed a chromosome X structural rearrangement that also segregated with the disease. Independently, two siblings from a second Palestinian family presented with similar, somewhat milder symptoms and the same PITRM1 mutation on a shared haplotype. PITRM1T931M carrier frequency was 0.027 (3/110) in the village of the first family evaluated, and 0/300 among Palestinians from other locales. Pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme that degrades 10-65 amino acid oligopeptides, including the mitochondrial fraction of amyloid-beta peptide (Ab). Analysis of peptide cleavage activity by the PITRM1T931M protein revealed a significant decrease in the degradation capacity specifically of peptides ≥40 amino acids.
CONCLUSION: PITRM1T931M results in childhood-onset recessive cerebellar pathology. Severity of PITRM1-related disease may be affected by the degree of impairment in cleavage of mitochondrial long peptides. Disruption and deletion of X-linked regulatory segments may also contribute to severity.
