ORPHA: 2478; DO: 0080318;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q24.2 | Megalencephalic leukoencephalopathy with subcortical cysts 2A | 613925 | Autosomal recessive | 3 | HEPACAM | 611642 |
A number sign (#) is used with this entry because autosomal recessive megalencephalic leukoencephalopathy with subcortical cysts-2A (MLC2A) is caused by homozygous or compound heterozygous mutation in the HEPACAM gene (611642) on chromosome 11q24.
For a discussion of genetic heterogeneity of megalencephalic leukoencephalopathy with subcortical cysts, see MLC1 (604004).
Megalencephalic leukoencephalopathy with subcortical cysts-2A (MLC2A) is an autosomal recessive neurodegenerative disorder characterized by infantile-onset macrocephaly and later onset of motor deterioration, with ataxia and spasticity, seizures, and cognitive decline of variable severity. Brain MRI shows typical white matter abnormalities, including swelling of the cerebral white matter and subcortical cysts, in all stages of the disease (summary by Lopez-Hernandez et al., 2011).
Heterozygous mutations in the HEPACAM gene can cause a similar, but less severe disorder that shows improvement of MRI changes with age (MLC2B; 613926).
Lopez-Hernandez et al. (2011) reported 10 patients from 8 families with MLC2A. All had onset of macrocephaly in the first year of life, and most showed mildly delayed motor development. Neurologic deterioration occurred between age 1 and 6 years, with slowly progressive ataxia, spasticity, dysarthria, and cognitive decline. Eight patients developed seizures, and 4 became wheelchair-bound in late childhood. Brain MRI showed diffuse cerebral white matter signal abnormalities and white matter swelling. There was involvement of the internal and external capsules and corpus callosum. All had subcortical cysts, primarily in the frontal and temporal regions. Many had cavum septi pellucidi and cavum vergae, and most had brainstem and cerebellar involvement (van der Knaap et al., 2010). At follow-up, all patients had the same brain MRI anomalies with mild progression in some, and all had mental retardation except 1 patient, who had normal intelligence at age 18 years.
The transmission pattern of megalencephalic leukoencephalopathy with subcortical cysts-2A in the families reported by Lopez-Hernandez et al. (2011) was consistent with autosomal recessive inheritance.
In 10 patients from 8 families with megalencephalic leukoencephalopathy with subcortical cysts-2A, Lopez-Hernandez et al. (2011) identified homozygous or compound heterozygous mutations in the HEPACAM gene (see, e.g., 611642.0001-611642.0005).
Lopez-Hernandez, T., Ridder, M. C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G. C., Martinez, A., Estevez, R., van der Knaap, M. S. Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism. Am. J. Hum. Genet. 88: 422-432, 2011. [PubMed: 21419380] [Full Text: https://doi.org/10.1016/j.ajhg.2011.02.009]
van der Knaap, M. S., Lai, V., Kohler, W., Salih, M. A., Fonseca, M.-J., Benke, T. A., Wilson, C., Jayakar, P., Aine, M., Dom, L., Lynch, B., Kalmanchey, R., Pietsch, P., Errami, A., Scheper, G. C. Megalencephalic leukoencephalopathy with cysts without MLC1 defect: two phenotypes. Ann. Neurol. 67: 834-837, 2010. [PubMed: 20517947] [Full Text: https://doi.org/10.1002/ana.21980]