Two families with autosomal dominant progressive external ophthalmoplegia
Open Access
- 1 August 2004
- journal article
- case report
- Published by BMJ in Journal of Neurology, Neurosurgery & Psychiatry
- Vol. 75 (8), 1125-1128
- https://doi.org/10.1136/jnnp.2003.025890
Abstract
Objectives: We report here the clinical and genetic features of two new families with autosomal dominant progressive external ophthalmoplegia (adPEO). Patients and methods: The examination of index patients included a detailed clinical characterisation, histological analysis of muscle biopsy specimens, and genetic testing of mitochondrial and nuclear DNA extracted from muscle and leucocytes. Results: Index patients in both families presented with PEO and developed other clinical disease manifestations, such as myopathy and cardiomyopathy (patient 1) and axonal neuropathy, diabetes mellitus, hearing loss, and myopathy (patient 2), later in the course of illness. Both patients had ragged red fibres on muscle histology. Southern blot of mtDNA from muscle of patient 2 showed multiple deletions. In this case, a novel heterozygous missense mutation F485L was identified in the nuclear encoded putative mitochondrial helicase Twinkle. The mutation co-segregated with the clinical phenotype in the family and was not detected in 150 control chromosomes. In the other index patient, sequencing of ANT1, C10orf2 (encoding for Twinkle), and POLG1 did not reveal pathogenic mutations. Conclusions: Our cases illustrate the clinical variability of adPEO, add a novel pathogenic mutation in Twinkle (F485L) to the growing list of genetic abnormalities in adPEO, and reinforce the relevance of other yet unidentified genes in mtDNA maintenance and pathogenesis of adPEO.This publication has 21 references indexed in Scilit:
- Autosomal dominant external ophthalmoplegia and bipolar affective disorder associated with a mutation in the ANT1 geneNeuromuscular Disorders, 2003
- Mutations of mitochondrial DNA polymerase γA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegiaAnnals of Neurology, 2002
- Diseases caused by nuclear genes affecting mtDNA stabilityAmerican Journal of Medical Genetics, 2001
- Role of Adenine Nucleotide Translocator 1 in mtDNA MaintenanceScience, 2000
- Wolfram (DIDMOAD) Syndrome and Leber Hereditary Optic Neuropathy (LHON) Are Associated with Distinct Mitochondrial DNA HaplotypesGenomics, 1997
- Mitochondrial encephalopathy with multiple mitochondrial DNA deletions: a report of two families and two sporadic cases with unusual clinical and neuropathological featuresJournal of the Neurological Sciences, 1996
- Screening for mitochondrial DNA (mtDNA) point mutations using nonradioactive single strand conformation polymorphism (SSCP) analysisClinical Biochemistry, 1995
- Mitochondrial encephalomyopathy with autosomal dominant inheritance: A clinical and genetic entity of mitochondrial diseasesMuscle & Nerve, 1995
- An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop regionNature, 1989
- A mitochondrial encephalomyopathy: the first case with an established defect at the level of coenzyme QEuropean Journal of Pediatrics, 1986