Mitochondrial Myopathy, Infantile, Transient

A number sign (#) is used with this entry because transient infantile mitochondrial myopathy is caused by mutation in the MTTE gene (590025), which is encoded by the mitochondrial genome.

Description

Infantile mitochondrial myopathy due to reversible COX deficiency is a rare mitochondrial disorder characterized by onset in infancy of severe hypotonia and generalized muscle weakness associated with lactic acidosis, but is distinguished from other mitochondrial disorders in that affected individuals recover spontaneously after 1 year of age (summary by Mimaki et al., 2010).

See also transient infantile liver failure (LFIT; 613070), which is a similar disorder.

Clinical Features

Jerusalem et al. (1973) described a girl with profound weakness and hypotonia in all but the ocular muscles in the first months of life. She also had hyporeflexia, hepatomegaly, macroglossia, and slight elevation of muscle enzymes in serum. Muscle biopsy showed mild glycogen and marked lipid and mitochondrial excess. Subsequently, the child had normal intellectual and delayed motor development, and macroglossia disappeared.

DiMauro et al. (1983) reported a 2-week-old boy with profound generalized weakness, hypotonia, hyporeflexia, macroglossia, and severe lactic acidosis. He improved spontaneously; he held his head at 4.5 months, rolled over at 7 months, and walked by 16 months. At 33 months of age, he had mild proximal weakness, waddling gait, lumbar lordosis, pes planus, and areflexia. Cognitive development was normal. Blood lactic acid declined steadily and was normal by 14 months of age. Histochemical and ultrastructural studies of muscle biopsy specimens obtained at 1 and 7 months of age showed excessive mitochondria, lipid, and glycogen; a third biopsy at age 36 months showed only atrophy of scattered fibers. COX staining was positive in less than 5% of muscle fibers at the first biopsy, in approximately 60% of fibers at the second biopsy, and in all fibers at the third biopsy. Biochemical analysis showed an isolated defect of COX activity, at about 8% of control level at the first biopsy, increasing to 47% activity at the second biopsy, and higher than normal activity at the third biopsy. In contrast to the fatal infantile form of COX deficiency (see 220110 and 604377), the enzyme defect in this condition was reversible. DiMauro et al. (1983) noted the similarity to the patient reported by Jerusalem et al. (1973).

Zeviani et al. (1987) reported a 6-week-old boy with reversible COX deficiency who presented with failure to thrive, lactic acidosis, and severe generalized weakness and wasting of the limb, neck, and facial muscles. He required assisted ventilation due to hypotonia and muscle weakness. Laboratory studies showed increased serum lactate, pyruvate, creatine kinase, and triglycerides. At age 6 months, the lactic acidosis resolved, and the patient started to improve; assisted ventilation was discontinued at 15 months. Muscle biopsies at 4 and 11 months showed accumulation of mitochondria, lipid, and glycogen; COX activity was 11% of the lowest control at the first biopsy and 57% at the second. However, the second muscle biopsy showed severe fibrosis. At age 20 months, he had full range of motion, good head control, and improved muscle bulk, but still could not walk.

Salo et al. (1992) reported 2 sibs, born of nonconsanguineous parents, with a similar clinical course of reversible mitochondrial myopathy with COX deficiency. Within the first weeks of life, both presented with sucking and breathing difficulties due to profound hypotonia. Other features included hepatomegaly, increased serum creatine kinase, and lactic acidosis. Both improved gradually and were free of clinical symptoms at age 4 years and 28 months, respectively. Abnormal muscle findings during the acute phase of the disorder included ragged-red fibers, abnormal mitochondria, and reduced COX staining and activity. Salo et al. (1992) emphasized that early diagnosis is crucial to provide intensive treatment until spontaneous clinical improvement appears.

Horvath et al. (2009) reported 17 patients from 12 families with infantile mitochondrial myopathy due to reversible COX deficiency. All were white Caucasians from different ethnic groups. One family had 4 affected sibs. Age at onset ranged from birth to 12 weeks, and the clinical presentation included severe muscle weakness often requiring artificial ventilation and/or tube feeding. Only 1 child died of pneumonia at age 39 days; all other children recovered spontaneously between age 4 and 20 months; however, some had a mild residual myopathy. The study included patients previously reported by DiMauro et al. (1983), Zeviani et al. (1987), and Salo et al. (1992).

Mimaki et al. (2010) reported 8 Japanese patients, including 2 sibs, with infantile mitochondrial myopathy due to reversible COX deficiency. All had profound generalized muscle weakness and hypotonia with onset between birth and 3 months of age. Two had involvement of facial muscles with a high-arched palate. Recovery to a normal state during the 3-year follow-up occurred in all patients except 1, who had a slight delay in gross motor development. All had increased serum creatine kinase in infancy, which subsequently normalized. Two sibs had increased signals in the caudate and putamen on brain MRI, which the authors noted was a previously unreported finding. Muscle biopsies showed marked variation in fiber size and COX-negative ragged-red fibers, as well as decreased RNA levels of mitochondrial tRNA-Glu. However, the aminoacylation ratio of tRNA-Glu was normal. Biochemical studies of cybrids carrying the 14774T-C mutation (590025.0002) showed reduced levels of complexes I, III, and IV, whereas naive myoblasts showed normal respiratory chain enzyme activities and protein levels. The findings were significant in that multiple respiratory enzymes, not just COX, were affected by the mutation. Mimaki et al. (2010) postulated that nuclear factors that become apparent during muscle cell proliferation and/or differentiation may compensate for the mitochondrial defects.

Uusimaa et al. (2011) reported 5 patients from 4 families with transient acute infantile mitochondrial myopathy and lactic acidosis. Age at presentation ranged from birth to 4 months, but all had subtle symptoms of hypotonia and feeding difficulties from birth. Two patients also had transient cardiac impairment, 2 had respiratory impairment, and 2 had eye muscle weakness. Only 1 had hepatomegaly. All recovered over months or years, but all showed delayed walking and had persistent muscle weakness, fatigability, or myalgia. Facial weakness, ptosis, and a myopathic facial appearance became more prominent with age. In 2 families, the mother of the index case had mild to moderate myopathic features without the typical infantile presentation. Two patients and the mother of a patient developed hypothyroidism. Muscle biopsies showed ragged-red fibers, increased glycogen and lipids, decreased COX activity, and deficiency of other mitochondrial respiratory enzymes, which improved with age.

Molecular Genetics

In all 17 patients from 12 families with reversible infantile COX deficiency myopathy, Horvath et al. (2009) identified a homoplasmic 14674T-C transition in the MTTE gene (590025.0002). The mutation was not found in 200 German controls. High-resolution Northern blot analysis of skeletal muscle in some patients showed significantly decreased levels of MTTE, most severe at ages 1 to 3 months (16 to 30% control levels), with improvement at a later date. Some mutation carriers were unaffected, indicating incomplete penetrance. Horvath et al. (2009) suggested that tissue-specific, developmentally timed processes may play a role both in the age-dependent expression and in the reversibility of this disorder.

Mimaki et al. (2010) identified a homoplasmic 14674T-C mutation in 6 Japanese patients with reversible infantile COX deficiency myopathy. Two additional patients with the same disorder had a 14674T-G (590025.0003) substitution affecting the same nucleotide.

Uusimaa et al. (2011) identified a homoplasmic 14674T-C mutation in 5 patients from 4 families with transient infantile mitochondrial myopathy and lactic acidosis.