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 tRNA(Phe) gene. This familial case of late-onset predominant axial myopathy and encephalopathy may represent a new clinical phenotype of a mitochondrial disease.

Fig. 1

Pedigree of the family. The arrow indicates the proband. The affected individuals are represented by the solid black symbols; open symbols represent healthy individuals. Gray symbols indicate individuals with elevated CK levels

Fig. 2

a The full-length figure indicates the posture of patient 1 showing her pushed-out waist. b The dorsal view shows the marked atrophy of the paraspinal muscles in patient 1. CT of T10 of c patient 1 (age 71), e patient 2 (age 82), and g a healthy female (age 74) reveals the profound atrophy of the paraspinal muscles in c patient 1 and e patient 2, but not in g the healthy female. Brain MRI studies revealed several differences between the patients 1 and 2. d Axial FLAIR images of patient 1 show moderate cerebellar atrophy and some cerebral cortical atrophy. f The same images of patient 2 revealing hyperintense lesions around the white matter

Fig. 3

Histochemical analysis of the right biceps brachii muscle. a Gomori trichrome staining reveals typical ragged-red fibers. Histochemical analysis of serial sections of samples stained with b SDH or c COX shows a number of ragged-blue fibers with COX deficiency. a−c Bar 100 μm

Fig. 4

Electron micrograph of abnormal mitochondria in the right biceps brachii muscle. Abnormal mitochondria with paracrystalline inclusions that are suggestive of mitochondrial myopathy are shown. a bar 1 μm, b bar 500 nm

Fig. 5

a Sequence chromatogram of the mitochondrial DNA region that encompasses the m.602C>T alteration (asterisk) that was obtained from the skeletal muscle of patient 1 (reverse complement). b Schematic diagram of the mitochondrial tRNA^Phe cloverleaf structure showing previously reported mutations and the m.602C>T alteration in the D-stem. c Comparison of mitochondrial tRNA^Phe from different species. Base pairs, including the 602 nucleotides, are shown in boxes