Molecular genetic studies in Indian patients with megalencephalic leukoencephalopathy

Mutations in the MLC1 gene cause megalencephalic leukoencephalopathy with subcortical cysts. We sought to identify mutations in the MLC1 gene, to evaluate the genotype-phenotype correlation, and to develop a strategy for diagnosing Indian patients with megalencephalic leukoencephalopathy. Forty patients were enrolled. We developed a rapid restriction fragment length polymorphism method to screen a common mutation, c.135_136insC. Rare and novel mutations were screened by conformation-sensitive gel electrophoresis, followed by sequencing. Three previously reported and two novel mutations were identified in 37 patients. The presence of the c.135_136insC mutation in 29 patients of the Agarwal community suggests a founder effect. The mutation c.959C>A was evident in four patients, and appears to be the second commonest mutation. Genotype could not predict phenotype. We recommend screening for the commonest mutation (c.135_136insC), followed by the next commonest mutation (c.959C>A), and then other rare mutations, using conformation-sensitive gel electrophoresis analysis or direct sequencing.