Mitochondrial Dna Depletion Syndrome 13 (Encephalomyopathic Type)

A number sign (#) is used with this entry because of evidence that encephalomyopathic mitochondrial DNA depletion syndrome-13 (MTDPS13) is caused by homozygous mutation in the FBXL4 gene (605654) on chromosome 6q16.

Description

Mitochondrial DNA depletion syndrome-13 is an autosomal recessive disorder characterized by early infantile onset of encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. Cells derived from patient tissues show defects in mitochondrial oxidative phosphorylation and decreased mtDNA content (summary by Bonnen et al., 2013 and Gai et al., 2013).

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

Clinical Features

Bonnen et al. (2013) reported 3 unrelated consanguineous Arabian families segregating a severe mitochondrial encephalomyopathy. In the first family, 5 infants presented at birth or in the first months of life with global developmental delay, hypotonia, and persistent lactic acidosis resulting in early death by age 4 years. One infant died at age 3 days. Three had microcephaly, and 1 had craniofacial abnormalities and congenital cataracts. Brain MRI showed generalized cerebral atrophy in 1 patient and cerebellar hypoplasia with dilated ventricles in another. Five patients from a second family had a similar phenotype, with lactic acidosis and hypotonia apparent at birth, followed by global developmental delay and early death. The proband in the second family had craniofacial abnormalities, cataracts, and abnormal brain imaging. The proband's unaffected mother had a history of 3 miscarriages. Skeletal muscle biopsies and fibroblasts from the 2 probands showed a combined defect of mitochondrial respiratory chain enzymes and decreased COX histochemical activity. Fibroblasts showed reduced basal respiration, decreased ATP synthesis, and a loss of mitochondrial membrane potential. Steady-state levels of subunits from respiratory chain complexes containing mtDNA-encoded subunits were also decreased. Severe mtDNA depletion (10-30% of control values) was observed in both muscle cells and fibroblasts, and the dynamic mitochondrial network in patient fibroblasts showed fragmentation and shortening of mitochondria. The proband in the third family had a slightly less severe phenotype. He was alive at age 6 years, but had severe developmental delay, hypotonia, cerebral atrophy, and signal abnormalities on brain MRI.

Gai et al. (2013) reported 9 children from 7 unrelated families with early-onset mitochondrial encephalomyopathy. The patients were ascertained from numerous clinical research centers across the world in a collaborative effort. Most patients presented shortly after birth with lactic acidosis, often with hyperammonemia and signs of renal tubular acidosis. All patients showed severe psychomotor delay with hypotonia, failure to thrive, and swallowing difficulties sometimes associated with gastrointestinal dysmotility. Three children died in infancy from metabolic decompensation during intercurrent infections. Most of those who reached late childhood were nonverbal, unable to sit autonomously, and showed muscle wasting and severe truncal ataxia. More variable features included seizures, choreoathetoid movements, hypospadias, neutropenia, scoliosis, small feet, and dysmorphic facial features. Facial features were inconsistent, but included malformed ears, protruding ears, narrow elongated face, everted lower lip, thick eyebrows, epicanthal folds, saddle nose, and downslanting palpebral fissures. Two patients had hypertrophic cardiomyopathy. Brain MRI showed global brain atrophy, thin corpus callosum, and altered signals in the supratentorial white matter with variable involvement of the basal ganglia, thalami, and infratentorial structures. Patient muscle homogenates or isolated mitochondria showed variably decreased activities of the mitochondrial respiratory chain complexes as well as decreased mtDNA content. Cultured skin fibroblasts had reduced maximal oxygen consumption rate, and increased fragmentation of the mitochondrial network. At least 1 patient cell line studied showed a significant reduction of the mitochondrial membrane potential.

Inheritance

The transmission pattern of MTDPS13 in the families reported by Bonnen et al. (2013) and Gai et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected individuals from 3 consanguineous Arabian families with MTDPS13, Bonnen et al. (2013) identified 3 different homozygous mutations in the FBXL4 gene (see, e.g., 605654.0001 and 605654.0002). The mutations, which were found by whole-exome sequencing in the probands, segregated with the disorder in the families. Two of the mutations were truncating mutations. Expression of wildtype FBXL4 in patient cells rescued the mitochondrial biochemical defects and mtDNA depletion. The findings suggested that FBXL4 plays an important role in the maintenance of mtDNA.

In 9 patients from 7 unrelated families with MTDPS13, Gai et al. (2013) identified biallelic mutations in the FBXL4 gene (see, e.g., 605654.0003-605654.0005). The mutations were found by autozygosity mapping and whole-exome sequencing or by exome sequencing alone. The mitochondrial biochemical defects could be rescued by expression of wildtype FBXL4 in patient cells. The findings indicated that FBXL4 is necessary for the homeostasis of mitochondrial bioenergetics.