Progressive External Ophthalmoplegia With Mitochondrial Dna Deletions, Autosomal Dominant 6

A number sign (#) is used with this entry because autosomal dominant progressive external ophthalmoplegia-6 (PEOA6) is caused by heterozygous mutation in the DNA2 gene (601810) on chromosome 10q.

Description

PEOA6 is characterized by muscle weakness, mainly affecting the lower limbs, external ophthalmoplegia, exercise intolerance, and mitochondrial DNA (mtDNA) deletions on muscle biopsy. Symptoms may appear in childhood or adulthood and show slow progression (summary by Ronchi et al., 2013).

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640).

Clinical Features

Ronchi et al. (2013) reported 2 sibs and 2 unrelated patients with PEOA6. One of the sibs reported declining muscle strength since young adulthood. At age 49 years, he was diagnosed with a suspected myopathy. Examination at age 62 showed decreased facial expressions, diffuse muscle atrophy, limb-girdle muscle weakness predominantly affecting the lower limbs, abnormal gait with hyperlordosis, and Gowers sign. He also had exertional dyspnea with obstructive sleep apnea. Laboratory studies showed increased serum creatine kinase. His sister reported exercise intolerance and muscle weakness since childhood. At age 40, she had limb-girdle muscle weakness affecting the upper and lower extremities, myalgia, muscle cramps, external ophthalmoplegia, ptosis, Gowers sign, and difficulty walking on tiptoes. Both had a slender build with decreased muscle bulk. Two additional unrelated women presented with adult-onset mitochondrial disease with ptosis and progressive myopathy. One patient also developed a mild weakness of the upper and lower limb-girdle muscles with occasional exertional dyspnea. Muscle biopsies of all patients showed multiple mtDNA deletions and a few COX-negative fibers.

Inheritance

The transmission pattern of PEOA6 in the families reported by Ronchi et al. (2013) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 2 sibs and 2 unrelated women with autosomal dominant progressive external ophthalmoplegia with DNA deletions-6, Ronchi et al. (2013) identified 3 different heterozygous mutations in the DNA2 gene (601810.0001-601810.0003). The first mutation was identified by exome sequencing of the sibs, and the additional patients were ascertained from a larger cohort of 44 patients with mtDNA deletions. In vitro functional expression assays showed that all mutant proteins had impaired nuclease, helicase, and ATPase activities.