Molecular diagnosis of Alpers syndrome.
OBJECTIVE
Alpers syndrome is a developmental mitochondrial DNA depletion syndrome leading to fatal brain and liver disease in children and young adults. Mutations in the gene for the mitochondrial DNA polymerase (POLG) have recently been shown to cause this disorder.


METHODS
The POLG locus was sequenced in 15 sequential probands diagnosed with Alpers syndrome. In addition, the POLG mutations found to cause Alpers syndrome in the 20 cases published to date were analyzed.


RESULTS
POLG DNA testing accurately diagnosed 87% (13/15=87%: 95% confidence interval=60-98%) of cases. Five new POLG amino acid substitutions (F749S, R852C, T914P, L966R, and L1173fsX) were found that were associated with Alpers syndrome in five unrelated kindreds, and 14 different allelic combinations of POLG mutations were found to cause Alpers syndrome in the 20 probands published to date. The most common Alpers-causing mutation was the A467T substitution, located in the linker region of the pol gamma protein, which accounted for about 40% of the alleles and was present in 65% of the patients. All patients with POLG mutations had either the A467T or the W748S substitution in the linker region.


CONCLUSIONS
Screening for A467T and W748S substitutions in POLG now constitutes the most rapid and sensitive test available for confirming the clinical diagnosis of Alpers syndrome.
Department of Medicine, University of California, San Diego School of Medicine, 214 Dickinson Street, Bldg. CTF, Rm. C-103, San Diego, CA 92103-8467, USA.
Khue V
KV
Nguyen
Farida S
FS
Sharief
Sherine S L
SS
Chan
William C
WC
Copeland
Robert K
RK
Naviaux
D000328:Adult; D001483:Base Sequence; D001927:Brain Diseases / Q000235:genetics; D002648:Child; D004247:DNA / Q000737:chemistry / Q000235:genetics; D000074002:DNA Polymerase gamma; D017931:DNA Primers; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000235:genetics; D008297:Male; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction
D017931:DNA Primers; D004272:DNA, Mitochondrial; D004247:DNA; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human