Clinical characteristics: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by two phenotypes: classic MLC and improving MLC.

1. Individuals with classic MLC present with macrocephaly, often in association with seizures, gradual onset of ataxia, spasticity, and sometimes extrapyramidal findings, mild gross motor developmental delays, and late-onset cognitive deterioration. Macrocephaly, observed in most affected individuals, may be present at birth but more frequently develops during the first year of life. The degree of macrocephaly is variable, with head circumferences reaching four to six standard deviations greater than the mean. After the first year of life, head growth trajectory typically normalizes and growth follows a line parallel to, although several standard deviations above, the 98th centile. Initial mental and motor development is normal in most individuals. Walking is often unstable, followed by ataxia of the trunk and extremities, pyramidal dysfunction, and brisk deep tendon reflexes. Early-onset seizures are common, and approximately 60% of individuals have epilepsy that is typically well controlled with anti-seizure medication, but status epilepticus occurs relatively frequently. Cognitive deterioration occurs later in the course of the disease and is usually mild in severity. Overall disease severity varies, with some individuals being able to ambulate independently for only a few years from disease onset to other individuals continuing to independently walk in the fifth decade of life.

2. Individuals with improving MLC have a similar initial presentation with delayed cognitive or motor development, followed by an improving clinical course: macrocephaly usually persists, but some children become normocephalic; motor function improves or normalizes; hypotonia and clumsiness may persist in some or neurologic examination may become normal. Some individuals have intellectual disability that is stable, with or without autism spectrum disorder. Epilepsy is much less frequent than in classic MLC.

Diagnosis/testing: The diagnosis of classic MLC is established in individuals with suggestive clinical findings and characteristic abnormalities identified on brain MRI examination, including abnormal and swollen cerebral hemispheric white matter and subcortical cysts in the anterior temporal and often frontoparietal regions; and/or biallelic loss-of-function variants in MLC1 or HEPACAM or a heterozygous pathogenic variant in GPRC5B identified by molecular genetic testing.

The diagnosis of improving MLC is established in individuals with suggestive clinical findings and a heterozygous gain-of-function variant in HEPACAM or biallelic pathogenic variants in AQP4 identified by molecular genetic testing.

Management: Treatment of manifestations: Physical therapy to improve motor function; speech therapy as needed; special education; anti-seizure medication to control seizures.

Agents/circumstances to avoid: Contact sports and other activities associated with a high risk of head trauma should be avoided.

Genetic counseling: MLC is inherited in an autosomal recessive or an autosomal dominant manner.

1. Classic MLC is most commonly caused by biallelic pathogenic variants in MLC1 or HEPACAM and is inherited in an autosomal recessive manner. If both parents of a child with MLC1-related classic MLC or biallelic HEPACAM-related classic MLC are known to be heterozygous for an MLC1 or HEPACAM pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the autosomal recessive MLC-related pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives is possible. Rarely, classic MLC occurs as an autosomal dominant disorder caused by a heterozygous GPRC5B pathogenic variant. All individuals with GPRC5B-related classic MLC reported to date have had the disorder as a result of a de novo pathogenic variant.

2. Improving MLC most commonly occurs as an autosomal dominant disorder caused by an inherited or de novo pathogenic variant in HEPACAM. Approximately 20% of individuals with heterozygous HEPACAM-related improving MLC have the disorder as a result of a de novo pathogenic variant. Each child of an individual with heterozygous HEPACAM-related improving MLC has a 50% chance of inheriting the pathogenic variant. Rarely, improving MLC is due to biallelic pathogenic variants in AQP4 and is inherited in an autosomal recessive manner.

Once the MLC-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for MLC are possible.