Mitochondrial Dna Depletion Syndrome 12b (Cardiomyopathic Type), Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive mitochondrial DNA depletion syndrome-12B (MTDPS12B) is caused by homozygous or compound heterozygous mutation in the SLC25A4 gene (103220), which encodes ANT1, on chromosome 4q35.

Heterozygous mutation in the SLC25A4 gene causes autosomal dominant progressive external ophthalmoplegia-2 (PEOA2; 609283) and autosomal dominant MTDPS12A (617184).

Description

Mitochondrial DNA depletion syndrome-12B 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).

Clinical Features

Bakker et al. (1993) described an 8-year-old boy with adenine nucleotide translocator deficiency in muscle who was first investigated at the age of 3.5 years because of shortness of breath and rapid fatigue. Lactate levels in serum and cerebrospinal fluid were greatly elevated, and histochemical and electron-microscopic examination of skeletal muscle suggested a mitochondrial myopathy. Great clinical improvement was observed with the administration of vitamin E (Bakker et al., 1993). Korver-Keularts et al. (2015) reported follow-up of the patient originally reported by Bakker et al. (1993), who was now 28 years of age. He had a mild mitochondrial myopathy manifest as exercise intolerance and early signs of hypertrophic cardiomyopathy without muscle weakness or external ophthalmoplegia. However, he used a wheelchair for outdoor transportation. Muscle samples were not available for determination of mtDNA deletions.

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.

Inheritance

The transmission pattern of MTDPS12B in the family reported by Echaniz-Laguna et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

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 woman with MTDPS12B, 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.

In the patient with a mitochondrial myopathy reported by Bakker et al. (1993), Korver-Keularts et al. (2015) identified compound heterozygous mutations in the SLC25A4 gene (103220.0007 and 103220.0008): a frameshift mutation demonstrated to result in nonsense-mediated mRNA decay, and a missense mutation (R236P; 103220.0008). functional studies of the missense variant were not performed. The patient's unaffected father and brother were heterozygous for the R236P mutation; DNA from the deceased mother was not available for study.

Animal Model

Graham et al. (1997) found that Ant1-null mice developed cardiac hypertrophy and severe exercise intolerance associated with ragged-red muscle fibers and a dramatic proliferation of mitochondria in muscle. Mitochondria isolated from mutant skeletal muscle exhibited a severe defect in coupled respiration. Ant1-mutant adults also had a resting serum lactate level 4-fold higher than that of controls, indicative of metabolic acidosis.