Mitochondrial Dna Depletion Syndrome 15 (Hepatocerebral Type)

A number sign (#) is used with this entry because of evidence that mitochondrial DNA depletion syndrome-15 (MTDPS15) is caused by homozygous mutation in the TFAM gene (600438) on chromosome 10q21. One such family has been reported.

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

Clinical Features

Stiles et al. (2016) reported 2 sibs, born of consanguineous parents of Colombian-Basque origin, with onset of severe progressive liver disease soon after birth and resulting in death at ages 2 and 4 months, respectively. At or soon after birth, both were noted to have intrauterine growth retardation, hypoglycemia, conjugated hyperbilirubinemia, elevated transaminases, and jaundice. There was evidence of defective liver synthetic function, with hypoalbuminemia, coagulopathy, jaundice, and ascites. Plasma tyrosine and methionine were increased, and there were abnormal urinary organic acids. Liver biopsy from 1 patient showed cirrhosis, microvesicular steatosis, cholestasis, and mitochondrial pleomorphism. Muscle biopsy showed some sarcoplasmic irregularities and mitochondrial hyperplasia and proliferation with abnormal sarcoplasmic distribution, but no major morphologic abnormalities. Fibroblasts and skeletal muscle biopsy from 1 patient showed variably impaired mitochondrial respiration function. Mitochondrial DNA content was reduced in liver and muscle (11% and 21% of normal controls, respectively). Although neurologic exam and brain MRI were normal in both patients, Stiles et al. (2016) concluded that the clinical presentation was similar to that of other patients with hepatocerebral MTDPS and suggested that the patients may have exhibited neurologic problems if they had survived longer.

Inheritance

The transmission pattern of MTDPS15 in the family reported by Stiles et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of consanguineous parents of Colombian-Basque descent, with MTDPS15, Stiles et al. (2016) identified a homozygous missense mutation in the TFAM gene (P178L; 600438.0001). The mutation, which was found by exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed increased TFAM mRNA but decreased protein levels, consistent with a compensatory mechanism. Patient fibroblasts also had decreased mtDNA copy number, decreased basal respiration, decreased number of nucleoids, and presence of abnormal nucleoid aggregates compared to controls, all indicative of mitochondrial dysfunction.

Animal Model

The regulation of mitochondrial DNA expression is crucial for mitochondrial biogenesis during development and differentiation. Larsson et al. (1998) disrupted the mouse Tfam gene by gene targeting. Heterozygous mice exhibited reduced mtDNA copy number and respiratory chain deficiency in heart. Homozygous knockout embryos exhibited a severe mtDNA depletion with abolished oxidative phosphorylation. Mutant embryos proceeded through implantation and gastrulation, but died before embryonic day (E)10.5. Thus, Tfam is the first mammalian protein demonstrated to regulate mtDNA copy number in vivo and is essential for mitochondrial biogenesis and embryonic development.