Megalencephalic Leukoencephalopathy with Subcortical Cysts via the HEPACAM Gene

Megalencephalic leukoencephalopathy with subcortical cysts (MLC, OMIM 604004), also known as Van der Knaap disease, is a slowly progressive myelinopathy characterized by macrocephaly, delay in walking, early-onset ataxia, seizure, and spasticity. Motor dysfunction, mild mental retardation, and behavioral problems may occur later in life. Additional late-onset symptoms include cerebellar ataxia, hypertonia, dysarthria, and dysphagia. Hallmark magnetic resonance imaging (MRI) findings include subcortical cysts in the tips of the temporal lobes and in frontoparietal subcortical areas and swollen cerebral white matter. Onset of symptoms usually occurs during the first year of life (Van der Knaap et al. Ann Neurol 37:324-334, 1995). MLC is clinically heterogeneous with regards to age of onset, degree of macrocephaly and mental impairment, severity, and disease progression. MLC is a rare disease that affects patients worldwide. Incidence is higher than expected within consanguineous populations (Topcu et al. Brain Dev 20:142-153, 1998).

Defects in two genes, MLC1 and HEPACAM, have been reported in patients with MLC (Leegwater et al. Am J Hum Genet 68:831-838, 2001; López-Hernández et al. Am J Hum Genet 88:422-32, 2011). About 75% of MLC patients have variants in the MLC1 gene. In these patients, the disease is inherited with an autosomal recessive pattern. Variants in the HEPCAM gene have been reported in the majority of patients without MLC1 variants. In about 45% of these patients, the clinical symptoms and MRI findings recover significantly over time, while the macrocephaly is maintained. In this group, patients have only one heterozygous HEPACAM variant, and the parents with the variants have macrocephaly, indicating a dominant mode of inheritance. About 25% of the patients without MLC1 variants have the typical MLC phenotype. This group of patients have two recessive HEPACAM variants, while their asymptomatic parents are heterozygous for the variants, indicating a recessive mode of inheritance. To date, fifteen different pathogenic HEPACAM variants, mostly missense, have been reported. The HEPACAM gene encodes GlialCAM, an IgG-like cell adhesion molecule that binds directly to the MLC1 protein (López-Hernández et al. 2011).

This test detects variants in ~ 75% of individuals with MLC, who do not have MLC1 variants.

This test provides full coverage of all coding exons of the HEPACAM gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.