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Bulent Kurt, MD; Jaak Jaeken, MD, PhD; Johan Van Hove, MD; Lieven Lagae, MD, PhD; Ann Löfgren, MSc; David B. Everman, MD; Parul Jayakar, MD; Ali Naini, PhD; Klaas J. Wierenga, MD, MSc; Gert Van Goethem, MD, PhD; William C. Copeland, PhD; Salvatore DiMauro, MD

Arch Neurol. 2010;67(2):239-244.

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.

Design  Genotype-phenotype correlation.

Setting  Tertiary care universities.

Patients  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.

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

Main Outcome Measures  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.

Author Affiliations: Department of Neurology, Columbia University Medical Center, New York, New York (Drs Kurt, Naini, and DiMauro); Center for Metabolic Disease (Dr Jaeken), and Division of Pediatric Neurology (Dr Lagae), University Hospital Gasthuisberg, Leuven, Belgium; Division of Clinical Genetics and Metabolism, The Children's Hospital, Denver, Colorado (Dr Van Hove); VIB-Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium (Ms Löfgren); Greenwood Genetic Center, Greenwood, South Carolina (Dr Everman); Division of Genetics and Metabolism, Miami Children's Hospital, Miami, Florida (Drs Jayakar and Wierenga); Section of Genetics, Department of Pediatrics, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma (Dr Wierenga); Department of Neurology and Neuromuscular Reference Center, University Hospital of Antwerp, Antwerpen, Belgium (Dr Van Goethem); Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (Dr Copeland).

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