A novel POLG gene mutation in 4 children with Alpers-like hepatocerebral syndromes

Abstract

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.

Figure 1

Pedigree of the Belgian family showing the compound heterozygous mutations in POLG of patient 3 (III-1) and patient 4 (III-2).

Figure 2

Electrophoretograms (A and D) and amino acid sequences (B and E) of the 2 mutations in patient 1, confirmed by restriction fragment length polymorphism (C and F). A and B, G1399A substitution (arrow) is shown. D and E, C3218T substitution (arrow) is shown. C, Wild-type DNA is cut into fragments by the MwoI restriction enzyme, while mutant DNA is not. In the patient’s sample, an additional 146–base pair (bp) band is seen. F, Wild-type DNA is cut into fragments by the MpsI restriction enzyme, while mutant DNA is not. In the patient’s sample, an additional 186-bp band is seen. G, Alignment of the pol-γ, fragment containing the novel p.P1073L mutation across 9 species shows the high conservation of proline 1073. Sc indicates Saccharomyces cerevisiae; S pombe, Saccharomyces pombe.