Mitochondrial Dna Depletion Syndrome 14 (Cardioencephalomyopathic Type)

A number sign (#) is used with this entry because of evidence that mitochondrial DNA depletion syndrome-14 (MTDPS14) is caused by homozygous mutation in the OPA1 gene (605290) on chromosome 3q29. One such family has been reported.

Compound heterozygous mutations in the OPA1 gene can also cause Behr syndrome (BEHRS; 210000), which shows less severe, but overlapping features.

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

Clinical Features

Spiegel et al. (2016) reported 2 sisters, born of consanguineous Arab parents, with a severe lethal infantile mitochondrial encephalomyopathy and hypertrophic cardiomyopathy. The patients showed hypotonia and peripheral hypertonia with opisthotonic posturing from birth, as well as feeding difficulties and profound neurodevelopmental delay. One patient had a weak cry and abnormal eye pursuits; optic atrophy was not noted. Serum lactate and alanine were elevated, but cerebrospinal fluid (CSF) lactate was normal. She developed progressive nonobstructive hypertrophic cardiomyopathy and died at age 10 months. The other patient had increased serum and CSF lactate, hypotonia with muscle wasting, sensorineural deafness, optic atrophy, and progressive cardiomyopathy. She died at age 11 months. Skeletal muscle biopsies were apparently morphologically normal, but there was a global decrease in all mitochondrial respiratory chain activities, with complexes I and IV being the most affected. Muscle biopsies from both patients also showed significant mtDNA depletion, with a 78% decrease compared to controls. Electron microscopy of 1 patient showed large mitochondria with incomplete fusion of the inner mitochondrial membrane.

Inheritance

The transmission pattern of MTDPS14 in the family reported by Spiegel et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sisters with MTDPS14, Spiegel et al. (2016) identified a homozygous missense mutation in the OPA1 gene (L534R; 605290.0023). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed a significant reduction of protein expression compared to controls. Each parent was a carrier of the mutation; neither had visual or neurologic abnormalities.