A novel POLG gene mutation in 4 children with Alpers-like hepatocerebral syndromes.
OBJECTIVE
To describe a novel POLG missense mutation (c.3218C>T; p.P1073L) that, in association with 2 previously described mutations, caused an Alpers-like hepatocerebral syndrome in 4 children.


METHODS
Genotype-phenotype correlation.


METHODS
Tertiary care universities.


METHODS
Four children, 2 related and 2 unrelated, with the novel p.P1073L mutation (all patients) and either the p.A467T (2 patients), p.G848S (1 patient), or p.W748S (1 patient) mutation presented with psychomotor delay, encephalopathy, and liver failure.


METHODS
Detailed clinical and laboratory examinations including brain magnetic resonance imaging, muscle biopsy, measurement of mitochondrial DNA, and sequencing of the POLG gene.


METHODS
Definition of clinical variability.


RESULTS
All 4 patients had psychomotor delay, seizures, and liver disease. Three patients had severe gastrointestinal dysmotility, which may be associated with the new p.P1073L mutation.


CONCLUSIONS
The heterozygous presence of the novel p.P1073L mutation in trans with another recessive POLG mutation causes a hepatocerebral disorder identical or very similar to Alpers syndrome. This adds to the already striking clinical heterogeneity of POLG mutations. In the Belgian patients, the familial occurrence without consanguinity is related to the high frequency of the recessive p.A467T and p.W748S mutations in northwestern Europe and reveals a pitfall for diagnosis and genetic counseling.
Kurt
Bulent
B
Columbia University College of Physicians and Surgeons, 630 W 168th Street, New York, NY 10032, USA.
Jaeken
Jaak
J
Van Hove
Johan
J
Lagae
Lieven
L
Löfgren
Ann
A
Everman
David B
DB
Jayakar
Parul
P
Naini
Ali
A
Wierenga
Klaas J
KJ
Van Goethem
Gert
G
Copeland
William C
WC
DiMauro
Salvatore
S
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000235:genetics*; D005192:Family Health; D005260:Female; D005767:Gastrointestinal Diseases / Q000209:etiology / Q000235:genetics; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D008099:Liver / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010641:Phenotype
D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human