Mitochondrial DNA depletion syndrome-12 is an autosomal recessive mitochondrial disorder characterized by childhood onset of slowly progressive hypertrophic cardiomyopathy and generalized skeletal myopathy resulting in exercise intolerance and, in some patients, muscle weakness and atrophy. Skeletal muscle biopsy ... Mitochondrial DNA depletion syndrome-12 is an autosomal recessive mitochondrial disorder characterized by childhood onset of slowly progressive hypertrophic cardiomyopathy and generalized skeletal myopathy resulting in exercise intolerance and, in some patients, muscle weakness and atrophy. Skeletal muscle biopsy shows ragged red fibers, mtDNA depletion, and accumulation of abnormal mitochondria (summary by Echaniz-Laguna et al., 2012). For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (603041).
Palmieri et al. (2005) reported a 25-year-old Slovenian male with hypertrophic cardiomyopathy, mild myopathy with exercise intolerance, and lactic acidosis, but no ophthalmoplegia. Muscle biopsy revealed numerous ragged-red fibers, and Southern blot analysis disclosed multiple deletions of muscle ... Palmieri et al. (2005) reported a 25-year-old Slovenian male with hypertrophic cardiomyopathy, mild myopathy with exercise intolerance, and lactic acidosis, but no ophthalmoplegia. Muscle biopsy revealed numerous ragged-red fibers, and Southern blot analysis disclosed multiple deletions of muscle mitochondrial DNA. Echaniz-Laguna et al. (2012) reported a 21-year-old girl, born of consanguineous Portuguese parents, with hypertrophic cardiomyopathy and exercise intolerance. As a child, she had normal psychomotor development with no delay in main milestones. She also had congenital cataracts. Examination at age 21 years showed slow progression of the disease: she had generalized muscle weakness and atrophy primarily affecting the proximal muscles, a positive Gowers sign, and was unable to climb stairs. She was also obese and had an IQ of 65. Ptosis, ophthalmoplegia, dysphonia, and dysphagia were absent. EMG showed a myopathic pattern and serum lactate was increased. Skeletal muscle biopsy showed ragged red fibers, many of which stained negative for cytochrome c oxidase, as well as accumulation of pleomorphic mitochondria with paracrystalline inclusions. Muscle cells also showed multiple mtDNA deletions. Mitochondrial complex IV activity was 52% of control values.
In a 25-year-old Slovenian male with hypertrophic cardiomyopathy and exercise intolerance, Palmieri et al. (2005) identified homozygosity for a mutation in the SLC25A4 gene (A123D; 103220.0005). The unaffected mother was heterozygous for the mutation, and the father was ... In a 25-year-old Slovenian male with hypertrophic cardiomyopathy and exercise intolerance, Palmieri et al. (2005) identified homozygosity for a mutation in the SLC25A4 gene (A123D; 103220.0005). The unaffected mother was heterozygous for the mutation, and the father was unavailable for testing. The mutation was absent in 500 control individuals. Muscle tissue was unavailable from the patient's mother, so the presence of subclinical amounts of multiple deletions could not be ruled out. The clinical and biochemical features were different from those found in dominant ANT1 mutations, resembling those described in ANT1-knockout mice. No ATP uptake was measured in proteoliposomes reconstituted with protein extracts from the patient's muscle. The equivalent mutation in AAC2, the yeast ortholog of human ANT1, resulted in a complete loss of transport activity and in the inability to rescue the severe oxidative phosphorylation phenotype displayed by WB-12, an AAC1/AAC2-defective yeast strain. In a 21-year-old Portuguese girl with MTDPS12, Echaniz-Laguna et al. (2012) identified a homozygous splice site mutation in the ANT1 gene (103220.0006). The mutant transcript was undetectable in patient cells, consistent with complete loss of protein expression and function. The clinically unaffected mother, who was heterozygous for the mutation, had low levels (less than 2%) of mtDNA rearrangements in skeletal muscle. The deceased father was reportedly unaffected.