Mitochondrial Myopathy With Diabetes

A number sign (#) is used with this entry because the phenotype is caused by mutation in the mitochondrially-encoded tRNA-glu gene (MTTE; 590025).

Clinical Features

Worsfold et al. (1973) described a kindred in which persons in 4 generations showed a myopathy with expression ranging from subclinical to moderately severe weakness and wasting clinically resembling facioscapulohumeral dystrophy (158900), but which on ultrastructural grounds had been designated a 'mitochondrial myopathy' (Hudgson et al., 1972; Johnson et al., 1973). In vitro oxidative phosphorylation by mitochondria showed reduced or absent respiratory control. Greatly increased muscle lipid, in the form of triglyceride, was demonstrated.

Mechler et al. (1981) studied further the family reported by Hudgson et al. (1972). By inference, the disorder could be traced through 6 generations. Although the authors considered autosomal dominant inheritance with variable expression and incomplete penetrance likely, mitochondrial inheritance could not be excluded because full-blown disease was transmitted only by females. A male with a fully affected mother showed subclinical myopathy and all 3 of his children (1 male, 2 females) had subclinical myopathy; this was the only instance of male transmission in the kindred. Diabetes mellitus was present in 8 members with myopathy, and 2 of the 8 also had cerebellar ataxia. Mechler et al. (1981) concluded that the myopathy, cerebellar disorder, and diabetes may all be manifestations of a single underlying metabolic defect. Sengers et al. (1984) provided an extensive review of mitochondrial myopathies.

McFarland et al. (2004) provided more information and follow-up of 7 members of the family originally reported by Hudgson et al. (1972). The most severely affected man had onset at age 14 years of insulin-dependent diabetes mellitus, dysarthria, and ataxia. Although he complained of fatigue since adolescence, he did not have muscle weakness or myalgia until his forties. Other features included weakness of the orbicularis oculi muscles and severe peripheral vascular disease with motor and sensory neuropathy. Other affected family members exhibited various combinations of proximal myopathy, ataxia, diabetes mellitus, and weakness of the orbicularis muscles. Muscle biopsy showed histologic features of mitochondrial disease with variation in fiber diameter, interstitial fibrosis, fat accumulation, and subsarcolemmal aggregates of mitochondria. Cultured fibroblasts showed a severe reduction in complex I activity.

Hao et al. (1995) reported a 29-year-old man with progressive muscle weakness, especially of the neck and limbs, and exercise intolerance since the age of 27 years. Gait was normal except for mild difficulty walking on heels. Tendon reflexes were hypoactive in the arms, but brisk in the legs, with bilateral Babinski signs. Muscle biopsy showed many ragged-red fibers, most of which showed cytochrome c oxidase deficiency. Electron microscopy showed an increased number of abnormal mitochondria with disorganized and vacuolated cristae and paracrystalline inclusions. At age 29 years, the patient was also found to have diabetes mellitus. He reported increased strength after insulin injections, and physical examination confirmed his subjective assessment.

Hanna et al. (1995) reported a family with a variety of clinical features including congenital myopathy, mental retardation, cerebellar ataxia, and diabetes mellitus. Both the proband, a 28-year-old man, and his sister had congenital myopathy and mental retardation, and subsequently developed cerebellar ataxia. Their mother was well until age 45 years when she developed diabetes mellitus, limb weakness, and exercise intolerance. Other family members had either adult-onset diabetes mellitus with muscle weakness or diabetes mellitus alone. The authors emphasized the variable phenotype.

Molecular Genetics

In a patient with adult-onset myopathy and diabetes mellitus, Hao et al. (1995) identified a heteroplasmic mutation in the MTTE gene (14709T-C; 590025.0001).

In the family originally reported by Hudgson et al. (1972) with IDDM and myopathy, McFarland et al. (2004) identified the 14709T-C mtDNA mutation. The mutation was homoplasmic in almost all tissues from the most severely affected patient and in the muscle tissue from another affected family member. Other members had high percentages of heteroplasmy (80 to 94% mutant load). One asymptomatic family member was homoplasmic for the mutation in white blood cells.