The unfolding clinical spectrum of POLG mutations.
BACKGROUND
Mutations in the DNA polymerase-gamma (POLG) gene are a major cause of clinically heterogeneous mitochondrial diseases, associated with mtDNA depletion and multiple deletions.


OBJECTIVE
To determine the spectrum of POLG mutations in our Dutch patient cohort, to evaluate the pathogenicity of novel mutations, and to establish genotype-phenotype correlations.


RESULTS
The authors identified 64 predominantly recessive mutations in 37 patients from a total of 232 patients, consisting of 23 different mutations. The substitution p.A467T was most frequently observed (n = 23), but was as frequent in childhood cases as in adult cases. Five new pathogenic recessive mutations, p.Lys925ArgfsX42, p.R275X, p.G426S, p.A804T and p.R869Q were identified. The known dominant chronic progressive external ophthalmoplegia (CPEO) mutation p.R943H was for the first time associated with premature ovarian failure as well. In 19 patients the authors identified only a single recessive mutation, or a sequence variant with unclear clinical significance. The data substantiate earlier observations that in POLG patients a fatal status epilepticus and liver failure can be triggered by sodium valproate. It is therefore important to exclude POLG mutations before administering this treatment.


CONCLUSIONS
The clinical features of the patient are the most important features to select putative POLG mutation carriers and not the presence of mtDNA deletions or OXPHOS (oxidative phosphorylation) activity. The authors conclude that POLG mutations are an important cause of heterogeneous mitochondrial pathology and that more accurate genotype-phenotype correlations allow a more rapid genetic diagnosis and improved prognosis for mutation carriers.
Blok
M J
MJ
Department of Clinical Genetics, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
van den Bosch
B J
BJ
Jongen
E
E
Hendrickx
A
A
de Die-Smulders
C E
CE
Hoogendijk
J E
JE
Brusse
E
E
de Visser
M
M
Poll-The
B T
BT
Bierau
J
J
de Coo
I F
IF
Smeets
H J
HJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D016649:Primary Ovarian Insufficiency / Q000235:genetics; D016415:Sequence Alignment
D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase