Mitochondrial Dna Depletion Syndrome 12a (Cardiomyopathic Type), Autosomal Dominant

A number sign (#) is used with this entry because of evidence that autosomal dominant mitochondrial DNA depletion syndrome-12A (MTDPS12A) is caused by heterozygous mutation in the SLC25A4 gene (103220) on chromosome 4q35.

Heterozygous mutation in the SLC25A4 gene can also cause the less severe disorder autosomal dominant progressive external ophthalmoplegia-2 (PEOA2; 609283), and biallelic mutation in the SLC25A4 gene can cause the less severe disorder autosomal recessive MTDPS12B (615418).

Description

MTDPS12A is characterized by severe hypotonia due to mitochondrial dysfunction apparent at birth. Affected infants have respiratory insufficiency requiring mechanical ventilation and have poor or no motor development. Many die in infancy, and those that survive have profound hypotonia with significant muscle weakness and inability to walk independently. Some patients develop hypertrophic cardiomyopathy. Muscle samples show mtDNA depletion and severe combined mitochondrial respiratory chain deficiencies (summary by Thompson et al., 2016).

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

Clinical Features

Thompson et al. (2016) reported 7 children from 6 unrelated families who presented at birth with profound hypotonia, little spontaneous movement, lactic acidosis, and respiratory insufficiency necessitating mechanical ventilation. Two infants were monozygotic twins. Four patients had hypertrophic cardiomyopathy. Five of the patients, including the twins, died in the first days or months of life. The 2 surviving patients, 6 and 4 years of age, required artificial ventilation and tube feeding, had little motor development, and were wheelchair-bound. One of the living patients had early-onset seizures and progressive cerebral white matter atrophy on brain imaging; she was unable to speak but could communicate. The other living patient was noted to have normal cognition. Skeletal muscle samples available from 5 of the patients showed decreased activities of mitochondrial respiratory complexes I, III, and IV associated with severe mtDNA depletion (less than 5% of controls in 2 of the patients, and between 11 and 34% of controls in the 3 other patients). Muscle histology showed loss of mitochondrial oxidative enzymes, lipid accumulation, small rounded muscle fibers with little variation in fiber size, and numerous mitochondria with disorganized cristae.

Molecular Genetics

In 7 children from 6 unrelated families with MTDPS12A, Thompson et al. (2016) identified 1 of 2 recurrent de novo heterozygous missense mutations in the SLC25A4 gene (R80H, 103220.0009 or R235G, 103220.0010). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Western blot analysis of patient muscle samples showed decreased levels of ANT1 and decreased levels of components of several mitochondrial respiratory complexes compared to controls. In vitro functional expression studies showed that the mutant proteins had very low residual transporter activity. Complementation and transport studies in yeast confirmed that the mutant proteins were functionally defective: they were unable to complement an oxidative phosphorylation defect and caused decreased transport activity, but did not act in a dominant-negative manner. Thompson et al. (2016) concluded that the highly reduced capacity for ADP/ATP transport in mitochondria probably affects mitochondrial DNA maintenance and thus respiration, causing severe energy depletion.