Progressive External Ophthalmoplegia With Mitochondrial Dna Deletions, Autosomal Recessive 4

A number sign (#) is used with this entry because of evidence that autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-4 (PEOB4) is caused by compound heterozygous mutation in the DGUOK gene (601465) on chromosome 2p13.

Biallelic mutation in the DGUOK gene can also cause the more severe disorder mitochondrial DNA depletion syndrome-3 (MTDPS3; 251880).

Description

Autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-4 (PEOB4) is an autosomal recessive disorder characterized by adult onset of eye muscle weakness and proximal limb muscle weakness associated with deletions of mtDNA on skeletal muscle biopsy, which results from defective mtDNA replication in post-mitotic muscle tissue. Additional features are more variable (summary by Ronchi et al., 2012).

For a discussion of genetic heterogeneity of autosomal recessive PEO, see PEOB1 (258450).

Clinical Features

Ronchi et al. (2012) reported 6 patients, including 2 sibs, with adult-onset mitochondrial myopathy. Three patients and the 2 sibs presented between 40 and 69 years of age with slowly progressive external ophthalmoplegia (in 2 patients) and/or limb muscle weakness. Three patients had proximal muscle weakness primarily affecting the lower limbs. Some patients had dysphagia and/or dysphonia; 1 had cataracts and diabetes. EMG studies showed a myopathic pattern, and serum creatine kinase and lactate were mildly increased. Muscle biopsies showed fiber size variability, ragged-red fibers, and COX-negative fibers. All patients had multiple mtDNA deletions in skeletal muscle, without evidence of mtDNA depletion (mtDNA copy number was normal). There was some phenotypic variability: the sibs had distal muscle weakness and atrophy associated with signs of a distal neuropathy, including fasciculations, decreased nerve conduction velocities, hyporeflexia, and neurogenic signs on EMG. Sural nerve biopsy in 1 sib showed a severe axonal neuropathy and demyelination. The sibs also had sensorineural hearing loss and mild cortical atrophy on brain imaging. Another patient (patient 4) had a more severe disorder with features of MTDPS3. She presented in infancy with liver failure and underwent liver transplant at age 9 months. She was then well until age 20 years, when she experienced 2 episodes of acute mitochondrial myopathy with proximal muscle weakness, increased serum creatine kinase, and rhabdomyolysis possibly triggered by infection. Muscle biopsy showed severe COX deficiency and ragged-red fibers.

Inheritance

The transmission pattern of PEOB4 in the families reported by Ronchi et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 patients, including 2 sibs, with adult-onset PEOB4, Ronchi et al. (2012) identified compound heterozygous mutations in the DGUOK gene (601465.0008; 601465.0010-601465.0015). The mutations, which were found by targeted exome sequencing and confirmed by standard sequencing, included both missense and truncating mutations. Skeletal muscle from patients showed mtDNA deletions as well as decreased protein levels and activity of DGUOK. The findings expanded the phenotype associated with DGUOK mutations. In this study, DGUOK mutations accounted for 5.6% of 90 probands with mtDNA deletions in skeletal muscle.