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GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease
M Henneke1, P Combes, S Diekmann
1Department of Pediatrics and Pediatric Neurology, Georg August University, Faculty of Medicine, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.
Background:
Pelizaeus-Merzbacher-like disease (PMLD) is a genetically heterogeneous disorder within the group of hypomyelinating leukoencephalopathies. Mutations of the gap junction protein alpha 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.
Insights
Mutations in the GJA12 gene are a rare cause of Pelizaeus-Merzbacher-like disease (PMLD), affecting approximately 8.3% of patients. GJA12-related PMLD presents with milder symptoms than PLP1 disorders, including better cognition.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Pelizaeus-Merzbacher-like disease (PMLD) is a rare hypomyelinating leukoencephalopathy.
- Mutations in the gap junction protein alpha 12 (GJA12) gene are a known cause of autosomal recessive PMLD.
- The frequency and spectrum of GJA12-related PMLD remain unclear.
Purpose of the Study:
- To investigate the frequency and spectrum of GJA12 mutations in a large cohort of PMLD patients.
- To characterize the clinical phenotype associated with GJA12 mutations.
Main Methods:
- Mutation analysis of the GJA12 gene.
- Clinical and radiological evaluation of 193 PMLD patients from 182 families.
Main Results:
- GJA12 mutations were identified in 16 patients (8.3%) from 14 families (7.7%).
- Eleven novel GJA12 alterations were discovered.
- Patients with GJA12 mutations exhibited a phenotype comparable to mild PLP1-related disorders, with better cognition and earlier axonal degeneration signs.
Conclusions:
- GJA12 mutations are an infrequent cause of PMLD.
- GJA12-related PMLD has a distinct clinical profile compared to other hypomyelinating leukoencephalopathies.
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