A new phenotype of mitochondrial disease characterized by familial late-onset predominant axial myopathy and encephalopathy

Abstract

Axial myopathy is a rare neuromuscular disease that is characterized by paraspinal muscle atrophy and abnormal posture, most notably camptocormia (also known as bent spine). The genetic cause of familial axial myopathy is unknown. Described here are the clinical features and cause of late-onset predominant axial myopathy and encephalopathy. A 73-year-old woman presented with a 10-year history of severe paraspinal muscle atrophy and cerebellar ataxia. Her 84-year-old sister also developed late-onset paraspinal muscle atrophy and generalized seizures with encephalopathy. Computed tomography showed severe atrophy and fatty degeneration of their paraspinal muscles. Their mother and maternal aunt also developed bent spines. The existence of many ragged-red fibers and cytochrome c oxidase-negative fibers in the biceps brachii muscle of the proband indicated a mitochondrial abnormality. No significant abnormalities were observed in the respiratory chain enzyme activities; however, the activities of complexes I and IV were relatively low compared with the activities of other complexes. Sequence analysis of the mitochondrial DNA from the muscle revealed a novel heteroplasmic mutation (m.602C>T) in the mitochondrial tRNAPhe gene. This familial case of late-onset predominant axial myopathy and encephalopathy may represent a new clinical phenotype of a mitochondrial disease.

Heteroplasmic m.1624C>T mutation of the mitochondrial tRNAVal gene in a proband and his mother with repeated consciousness disturbances

“…In the present study, we first detected heteroplasmy by mtDNA sequencing, although a low proportion of heteroplasmy can be masked in the background noise. As demonstrated in other studies (Bai and Wong, 2004;Genasetti et al, 2007;Sakiyama et al, 2011), using ARMS, we were able to detect variable proportions of the m.1624C>T mutation. The proportion of heteroplasmic mtDNA is generally one determinant of phenotypic severity (Choi et al, 2010;Laloi-Michelin et al, 2009).…”

A proposed consensus panel of organisms for determining evolutionary conservation of mt-tRNA point mutations

“…m.3243A>G (Goto et al, 1990) and m.4269A>G (Taniike et al, 1992) score 2 points, and m.8344A>G (Shoffner et al, 1990) scores 0 points), many obtain a lower score (e.g. m.602C>T (Sakiyama et al, 2011) decreases by 2 points, whilst m.4285T>C (Silvestri et al, 1996) and m.7510T>C (Hutchin et al, 2000) decrease by 1 point) and a few receive a higher score (e.g. 608A>G (Tzen et al, 2001) gains 2 points).…”

Crystal Structure of Human Mitochondrial PheRS Complexed with tRNAPhe in the Active “Open” State

“…[26][27][28] Most mutations are transitions (pyrimidine into pyrimidine and/or purine into purine), rather than conversions, and are localized throughout the acceptor stem and the anticodon arm of the tRNA body. Kinetic experiments showed a reduced aminoacylation activity of hmPheRS toward the mutated tRNA Phe variants.…”