Megalencephalic Leukoencephalopathy With Subcortical Cysts 2b, Remitting, With Or Without Mental Retardation

A number sign (#) is used with this entry because remitting megalencephalic leukoencephalopathy with subcortical cysts-2B (MLC2B) is caused by heterozygous mutation in the HEPACAM gene (611642) on chromosome 11q24.

Description

Autosomal dominant remitting MLC2B is characterized by infantile-onset of macrocephaly and mildly delayed motor development associated with white matter abnormalities on brain MRI that improve with age. As children, some patients have mild residual hypotonia or clumsiness, but otherwise have no residual motor abnormalities. About 40% of patients have mental retardation (summary by van der Knaap et al., 2010 and Lopez-Hernandez et al., 2011).

Homozygous or compound heterozygous mutations in the HEPACAM gene can cause a more severe and progressive disorder associated with ataxia, spasticity, and mental retardation (MLC2A; 613925).

For a discussion of genetic heterogeneity of megalencephalic leukoencephalopathy with subcortical cysts, see MLC1 (604004).

Clinical Features

Lopez-Hernandez et al. (2011) reported 18 patients from 16 families with the remitting MLC2B phenotype. All developed macrocephaly within the first year of life; 2 showed subsequent normalization of head circumference. Most patients had delayed early motor and language development, which subsequently normalized in most, although some patients had mild hypotonia or clumsiness later in childhood. Intelligence was more variable: 11 had normal intelligence and 7 had mental retardation, associated with autism (209850) in 3. MRI initially showed diffuse swelling of the cerebral white matter and subcortical cysts in the anterior temporal lobe. There was involvement of the posterior limb of the internal capsule and the external capsule. Other changes included cavum septi pellucidi and cavum vergae, as well as cerebellar and brainstem involvement in some. These initial changes were similar to those seen in MLC2A. On follow-up, however, all patients showed major improvement in the MRI changes, with loss of white matter swelling, disappearance of cysts in some cases, and lack of involvement of other brain regions (van der Knaap et al., 2010).

Inheritance

The transmission pattern of MLC2B in the families reported by Lopez-Hernandez et al. (2011) was consistent with autosomal dominant inheritance with incomplete penetrance.

Molecular Genetics

In 18 patients from 16 families with remitting MLC2B, Lopez-Hernandez et al. (2011) identified a heterozygous mutation in the HEPACAM gene (see, e.g., 611642.0006-611642.0008). All the mutations were located in a putative extracellular interface of the first immunoglobulin domain. Eight of 11 parents with a mutant allele had macrocephaly, 1 had transient macrocephaly as a child, and 2 reportedly never had macrocephaly.