Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations.

TitleAutosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations.
Publication TypeJournal Article
Year of Publication2005
AuthorsWinterthun, S, Ferrari, G, He, L, Taylor, RW, Zeviani, M, Turnbull, DM, Engelsen, BA, Moen, G, Bindoff, LA
JournalNeurology
Volume64
Issue7
Pagination1204-8
Date Published2005 Apr 12
ISSN1526-632X
KeywordsAdolescent, Adult, Ataxia, Brain, Brain Diseases, Metabolic, Inborn, Disease Progression, DNA Mutational Analysis, DNA, Mitochondrial, DNA-Directed DNA Polymerase, Epilepsy, Female, Genes, Recessive, Genetic Predisposition to Disease, Genetic Testing, Heredodegenerative Disorders, Nervous System, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Migraine Disorders, Mitochondrial Diseases, Muscle, Skeletal, Mutation
Abstract

OBJECTIVE: To investigate three families and one sporadic case with a recessively inherited ataxic syndrome.

METHODS: Clinical and genetic studies were performed in six individuals. Southern blotting and real time PCR were used to detect deletions of mtDNA and mutations in the POLG gene were identified using a combination of DHPLC and direct DNA sequencing.

RESULTS: The patients have a distinctive, progressive disorder that starts with episodic symptoms such as migraine-like headache or epilepsy. Ataxia, which is a combination of central and peripheral disease, develops later as does ophthalmoplegia. The commonest form of epilepsy was focal and involved the occipital lobes. Myoclonus was common and patients have a high risk of status epilepticus. MRI typically shows signal changes in the central cerebellum, olivary nuclei, occipital cortex, and thalami. COX negative muscle fibers were found in four of six; in one patient these were rare and in another absent. Multiple mtDNA deletions were identified in all patients, although in two these were not apparent on Southern blotting and real time PCR was required to demonstrate the defect. Two families were homozygous for a previously described POLG mutation, G1399A (A467T). One family and the sporadic case had the same two new mutations, a G to C at position 1491 (Q497H) and a G to C at 2243 (W748S).

CONCLUSIONS: Mutations in POLG cause a recessively inherited syndrome with episodic features and progressive ataxia. Characteristic changes on MRI are seen and although skeletal muscle may appear morphologically normal, multiple mtDNA deletions can be detected using real-time PCR.

DOI10.1212/01.WNL.0000156516.77696.5A
Alternate JournalNeurology
Citation Key10.1212/01.WNL.0000156516.77696.5A
PubMed ID15824347
Grant List074454 / / Wellcome Trust / United Kingdom
GGP030039 / / Telethon / Italy