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Megalencephalic Leukoencephalopathy with Subcortical Cysts.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
2003 Aug 11 [updated 2011 Nov 3].



The classic phenotype of megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by early-onset macrocephaly, often in combination with mild gross motor developmental delay and seizures; gradual onset of ataxia, spasticity, and sometimes extrapyramidal findings; and usually late onset of mild mental deterioration. Macrocephaly, observed in all individuals, may be present at birth but more frequently develops during the first year of life. The degree of macrocephaly is variable and can be as great as 4 to 6 SD above the mean in some individuals. After the first year of life, head growth rate normalizes and growth follows a line parallel to the 98th percentile, usually several centimeters above it. Almost all individuals have epilepsy from an early age. Initial mental and motor development is normal in most cases. Walking is often unstable, followed by ataxia of the trunk and extremities, then minor signs of pyramidal dysfunction and brisk deep-tendon stretch reflexes. Mental deterioration is late and mild. Severity ranges from independent walking for a few years only to independent walking in the fifth decade. Some individuals have died in their teens or twenties; others are alive in their forties. An atypical improving phenotype has a similar initial presentation without mental or motor regression, followed by an improving clinical course: motor and cognitive functions improve or normalize; macrocephaly usually persists, but some children become normocephalic; hypotonia and clumsiness may persist in some or neurologic examination may become normal. Some have intellectual disability that is stable with or without autism.


The diagnosis of MLC is established in individuals with typical clinical findings and characteristic abnormalities observed on cranial MRI, including abnormal and swollen cerebral hemispheric white matter and presence of subcortical cysts in the anterior temporal region and often in the frontoparietal region. When associated with biallelic mutation of MLC1, the classic phenotype is known as MLC1; when caused by biallelic mutation of HEPACAM it is known as MLC2A. The improving phenotype associated with heterozygous mutation of HEPACAM is known as MLC2B. Pathogenic variants in MLC1 are observed in approximately 75% of persons with MLC; pathogenic variants in HEPACAM are found in approximately 20%.


Treatment of manifestations: Antiepileptic drugs (AEDs) to control epileptic seizures; physical therapy to improve motor function; special education.


MLC1 and MLC2A are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic alleles have been identified in the family. MLC2B is inherited in an autosomal dominant manner. De novo pathogenic variants are common. Each child of an individual with MLC2B has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing allele has been identified in the family

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