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GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy

From the Departments of Child Neurology (M.B., I.M., G.U.), Molecular Neurogenetics (E.L., M.Z.), Neuroradiology (A.B.), and Developmental Neurology (M.R.B.), National Neurological Institute "C. Besta," Milano, Italy; and Departments of Paediatric Neurology (S.A.S.) and Neuroradiology (E.B.), Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia.

Address correspondence and reprint requests to Dr. M. Zeviani, Department of Molecular Neurogenetics, National Neurological Institute "C. Besta," via Libero Temolo 4, 20126 Milano, Italy; e-mail: zeviani{at}istituto-besta.it

Background: Pelizaeus-Merzbacher-like disease (PMLD) is an inherited hypomyelinating leukoencephalopathy with onset in early infancy. Like Pelizaeus-Merzbacher disease (PMD), PMLD is characterized clinically by nystagmus, cerebellar ataxia, and spasticity, due to a permanent lack of myelin deposition in the brain. Mutations in the GJA12 gene, encoding connexin 47 (Cx47), were recently reported in five children with autosomal recessive PMLD.

Objectives: To evaluate the impact of mutations in the GJA12 gene in, and define the clinical and neuroimaging features of, autosomal recessive PMLD.

Results: The authors screened for GJA12 mutations in 10 additional PMLD families originating from Italy, Pakistan, and Saudi Arabia. Three novel homozygous GJA12 mutations were identified in 12 mutant cases distributed in 3 of 10 families. The mutations segregated with the disease according to an autosomal recessive trait and included one missense (G236S) and two nonsense (L281fs285X and P131fs144X) changes.

Conclusions: The identification of homozygous mutations predicting the synthesis of aberrant and truncated polypeptides, and their tight segregation with the disease in very large families, clearly demonstrate that the loss of Cx47 function is the cause of the disease. The phenotype of GJA12-related Pelizaeus-Merzbacher-like disease is fairly homogeneous and similar to that of Pelizaeus-Merzbacher disease. However, slower progression of symptoms, greater preservation of cognitive functions, and partial myelination of corticospinal tracts at MRI were distinctive features, which could help in the differential diagnosis.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents to find the July 25 issue to find the title link for this article.

This article was previously published in electronic format as an Expedited E-Pub on May 17, 2006, at www.neurology.org.

Supported by the Pierfranco and Luisa Mariani Foundation.

Disclosure: The authors report no conflicts of interest.

Received January 10, 2006. Accepted in final form March 20, 2006.

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