Most MLC patients have mutations in the gene MLC1. However, about 20-25% of the MLC patients lack mutations in MLC1 and genetic studies show that in these families MLC1 cannot be involved. Because we and other groups have been unable to find another gene for MLC, we thought that there could be several other genes that are involved in MLC. We studied the clinical symptoms and MRIs of MLC patients without MLC1 mutations to see if there could be different sub-groups of patients and we found two distinct groups. The patients in the first group were indistinguishable from patients with MLC1 mutations, for both the clinical symptoms and the changes that are seen on MRI. Patients in the second group started with the typical clinical and MRI phenotype of MLC in the first year of life. After that, the MRI abnormalities decreased over time and the MRI became normal or greatly improved. These patients lacked all signs of a loss of motor skills on prolonged follow-up. Some of the patients were intellectually normal; some were mentally retarded or autistic. These findings were published in the Annals of Neurology (van der Knaap et al., Ann Neurol 2010; 67:834-837).
Mutations in HEPACAM explain the two phenotypes.
We have found that the MLC1 protein binds to another protein called GlialCAM. This 'hepatocyte and glial cell adhesion molecule' is encoded by the gene HEPACAM. Analysis of the gene HEPACAM in MLC patients show that mutations in this gene can cause the classical phenotype with autosomal recessive inheritance, where the children inherit two mutations, one form each parent. Interestingly, the more benign phenotype has an autosomal dominant mode of inheritance. The children inherit only one mutation from one of the parents. In this latter group, the parent with the mutation very often has a large head. This indicates that HEPACAM is a gene that can be involved in benign familial macrocephaly and macrocephaly with retardation and autism Studies on the interaction between MLC1 and GlialCAM show that MLC1 is not localized properly in the membrane of the cells in the presence of mutant GlialCAM.
These findings were recently published in the American Journal of Human Genetics (Lopez-Hernandez et al., Am J Hum Genet 2011; 88:422-432).