Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations.
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.
Winterthun
S
S
Department of Neurology, Haukeland University Hospital, University of Bergen, Norway.
Ferrari
G
G
He
L
L
Taylor
R W
RW
Zeviani
M
M
Turnbull
D M
DM
Engelsen
B A
BA
Moen
G
G
Bindoff
L A
LA
D000293:Adolescent; D000328:Adult; D001259:Ataxia / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D001921:Brain / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D020739:Brain Diseases, Metabolic, Inborn / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D018450:Disease Progression; D004827:Epilepsy / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D020271:Heredodegenerative Disorders, Nervous System / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000235:genetics; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics
D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human