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Hepatic disease as the first manifestation of progressive myoclonus epilepsy of Lafora

From Laboratorio y Servicio de Neurología (P.G.-G., E.G.-D., C.G.-A., J.M.-C., V.E.V., J.M.S.), Fundación Jiménez Díaz, Madrid; Centro de Investigaciones Biológicas (S.R.C.), Consejo Superior de Investigaciones Científicas, Madrid; Departamento de Anatomía Patológica (J.L., M.G.), Hospital Universitario La Paz, Madrid; and Departamento de Neurología (J.B.), Hospital Universitario Marqués de Valdecilla (UC), Santander, SpainV. is currently affiliated with Unidad de Epilepsia, Servicio de Neurología, Hospital La Fe, Valencia, Spain.

Address correspondence and reprint requests to Dr. José M Serratosa, Servicio de Neurología, Fundación Jiménez Díaz, Avda Reyes Católicos, 2, 28040 Madrid, Spain serratosa{at}telefonica.net

Background: Lafora disease (LD; progressive myoclonus epilepsy type 2; EPM2) is an autosomal recessive disorder caused by mutations in the EPM2A and EPM2B genes. LD is characterized by the presence of strongly PAS-positive intracellular inclusions (Lafora bodies) in several tissues. Glycogen storage disease type IV (GSD-IV; Andersen disease) is an autosomal recessive disorder characterized by cirrhosis leading to severe liver failure. GSD-IV has been associated with mutations in the glycogen branching enzyme gene (GBE). Histopathologic changes of the liver in both diseases show an identical appearance, although cirrhosis has never been described in patients with LD. We report a LD family in which the proband presented severe liver failure at onset of the disease.

Methods: Clinical histories, physical and neurologic examination, laboratory tests, EEGs, MRI of the brain, and liver or axillary skin biopsies were performed in the two affected siblings. The diagnosis was confirmed by molecular genetic analysis of the EPM2A, EPM2B, and GBE genes and loci.

Results: During the first decade of life, abnormalities in liver function tests were detected in the two affected siblings. The proband's liver dysfunction was severe enough to require liver transplantation. Subsequently, both sibs developed LD. Mutation analysis of EPM2A revealed a homozygous Arg241stop mutation in both patients.

Conclusions: This is the first description of severe hepatic dysfunction as the initial clinical manifestation of LD. The phenotypic differences between the two affected siblings suggest that modifier genes must condition clinical expression of the disease outside the CNS.

Received August 21, 2006. Accepted in final form December 15, 2006.

Disclosure: The authors report no conflicts of interest.

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