Mitochondrial Dna Depletion Syndrome 11

A number sign (#) is used with this entry because mitochondrial DNA depletion syndrome-11 (MTDPS11) can be caused by homozygous mutation in the MGME1 gene (615076) on chromosome 20p11.

Description

Mitochondrial DNA depletion syndrome-11 is an autosomal recessive mitochondrial disorder characterized by onset in childhood or adulthood of progressive external ophthalmoplegia (PEO), muscle weakness and atrophy, exercise intolerance, and respiratory insufficiency due to muscle weakness. More variable features include spinal deformity, emaciation, and cardiac abnormalities. Skeletal muscle biopsies show deletion and depletion of mitochondrial DNA (mtDNA) with variable defects in respiratory chain enzyme activities (summary by Kornblum et al., 2013).

For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).

Clinical Features

Kornblum et al. (2013) reported a Lebanese family in which 3 sibs had a severe multisystem mitochondrial disorder starting in the first decade. Initial symptoms included ptosis, progressive external ophthalmoplegia, and diffuse skeletal muscle wasting and weakness. The 2 older sibs developed spinal deformities and respiratory weakness and distress necessitating noninvasive ventilation. From late-childhood, these patients also developed gastrointestinal symptoms, such as nausea, abdominal fullness, and diarrhea, and all were severely emaciated. Facial muscle weakness was also present, with nasal speech, dysphonia, and dysphagia. The 1 female had primary amenorrhea due to hypergonadotropic hypogonadism, and 1 of the males developed renal colic. The youngest had similar features, but also had dilated cardiomyopathy that resulted in cardiac failure and death at age 25 years. All 3 sibs had mental retardation and cerebellar atrophy on brain MRI. A second family contained 2 brothers, born of consanguineous Italian parents, with a similar disorder, but without mental retardation. Both patients presented in their thirties with easy fatigability and dyspnea. Other features included proximal limb weakness, facial weakness with progressive external ophthalmoplegia, respiratory insufficiency, and profound emaciation with muscle wasting. Both developed spinal deformities, and 1 had renal colic. An affected German woman was also identified. At age 35 years, she developed PEO, exercise intolerance, and generalized muscle weakness. The disorder was progressive, especially affecting the respiratory muscles. She also had chronic renal failure, progressive limb-girdle weakness, and cardiac arrhythmias. She died at age 73 years of respiratory failure; she was in a severely emaciated state. Skeletal muscle biopsies from all patients showed scattered COX-negative fibers and ragged-red fibers with variable decreases in mitochondrial respiratory chain activities. Muscle biopsies also showed multiple mtDNA deletions and depletions.

Inheritance

The transmission pattern of MTDPS11 in the families reported by Kornblum et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 affected members from 2 unrelated families with mitochondrial DNA depletion syndrome-11, Kornblum et al. (2013) identified a homozygous truncating mutation in the MGME1 gene (W152X; 615076.0001). The mutation was identified by exome sequencing. A second mutation (615076.0002) was identified in a German woman with a similar disorder. Fibroblast cultures from 1 of the patients with the truncating mutation showed severely perturbed mtDNA replication under specific conditions with evidence of replication stalling and accumulation of replication intermediates. The findings suggested that perturbed mtDNA maintenance is the primary cause of the multisystem disorder in these patients.