Molecular diagnosis of Alpers syndrome.

BACKGROUND/AIMS 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.