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GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease

From the Department of Pediatrics and Pediatric Neurology (M.H., S.D., K.B., J.K., A.O., J.G.), Georg August University, Göttingen, Germany; INSERM, Université d’Auvergne, UMR 384, Faculté de Médecine Clermont-Ferrand, and CHU Clermont-Ferrand, Department of Human Genetics (P.C., O.B.-T.), University Hospital, Clermont-Ferrand, France; Department of Molecular Medicine (E.B.), Ospedale Pediatrico Bambino Gesu, Scientific Institute, IRCCS, Rome, Italy; Department of Neuroscience (A.P.B.), Neurological Clinic, University Hospital, Padua, Italy; Department of General Pediatrics (B.P.), University of Graz, Austria; and INSERM, UMR 546, Université Paris Pitié Salpétrière, and AP-HP, Department of Pediatric Neurology (D.R.), Hopital A. Trousseau, Paris, France.

Address correspondence and reprint requests to Dr. Jutta Gärtner, Department of Pediatrics and Pediatric Neurology, Georg August University, Faculty of Medicine, Robert-Koch-Strasse 40, 37075 Göttingen, Germany gaertnj{at}med.uni-goettingen.de

Background: Pelizaeus-Merzbacher-like disease (PMLD) is a genetically heterogeneous disorder within the group of hypomyelinating leukoencephalopathies. Mutations of the gap junction protein 12 (GJA12) gene are known to cause one autosomal recessive PMLD form. Few patients with GJA12 mutated PMLD have been reported, and to date, the frequency as well as the genotypic and phenotypic spectrum of GJA12 related PMLD is unclear.

Methods: We report mutation analysis of the GJA12 gene in a clinical and radiologic well-characterized multiethnic cohort of 193 patients with PMLD from 182 families.

Results and Conclusions: Only 16 patients (8.3%) from 14 families (7.7%) carry GJA12 mutations including five families where we detected only one mutated allele. Among those, we identified 11 novel alterations. Thus, GJA12 mutations are a rather rare cause for Pelizaeus-Merzbacher-like disease. The clinical phenotype of patients with a GJA12 mutation was evaluated and is overall comparable to the clinical features seen in mild forms of proteolipid protein 1 (PLP1) related disorder but with better cognition and earlier signs of axonal degeneration.

Abbreviations: PMLD = Pelizaeus-Merzbacher-like disease; SPG = spastic paraplegia.

Editorial, page 744

e-Pub ahead of print on December 19, 2007, at www.neurology.org.

*These authors contributed equally to this study.

Supported by the Deutsche Forschungsgemeinschaft, grant number GA 354/6-1 (J.G. and M.H.), the European Leukodystrophy Association (P.C. and O.B.-T.), and the Jean-Pierre and Nancy Boespflug myopathic research foundation (P.C. and O.B.-T.).

Disclosure: The authors report no conflicts of interest.

Received February 17, 2007. Accepted in final form June 13, 2007.