SNP Shot: Genomic Insights

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a progressive disorder impacting brain development and function. A key feature is an enlarged brain (megalencephaly), noticeable at or soon after birth, leading to an abnormally large head (macrocephaly). Affected individuals also exhibit leukoencephalopathy, a white matter abnormality. White matter, composed of myelin-covered nerve fibers, facilitates rapid nerve impulse transmission. In MLC, the myelin swells, forming fluid-filled vacuoles. Over time, this swelling diminishes, and the myelin atrophies. Subcortical cysts, located beneath the cerebral cortex, may also develop and increase in size and number.

The brain abnormalities in MLC patients affect motor skills, resulting in movement difficulties. Common symptoms include muscle stiffness (spasticity) and coordination problems (ataxia). Walking ability varies; some individuals require wheelchairs early in life, while others walk independently into adulthood. Even minor head injuries can worsen movement and potentially cause coma. Other possible symptoms include uncontrolled muscle tensing (dystonia), involuntary limb movements (athetosis), difficulty swallowing (dysphagia), and impaired speech (dysarthria). Seizures (epilepsy) occur in over half of affected individuals. Despite significant brain abnormalities, intellectual disability is usually mild to moderate.

MLC is classified into three types based on symptoms, signs, and genetic origins. Types 1 and 2A, while having different genetic causes, present nearly identical symptoms and signs. Types 2A and 2B share the same genetic cause, but type 2B often shows improvement after the first year. Following this improvement, individuals with type 2B typically continue to exhibit macrocephaly and may have intellectual disability.

Inheritance:

Type 1 MLC, caused by mutations in the MLC1 gene, and some cases of type 2A, caused by mutations in the HEPACAM gene, are inherited in an autosomal recessive manner. This means that both copies of the gene in each cell must have mutations for the disorder to manifest. Parents of individuals with autosomal recessive MLC each carry one copy of the mutated gene but usually do not exhibit symptoms of the condition. Type 2B MLC is inherited in an autosomal dominant manner, meaning that only one copy of the altered HEPACAM gene is enough to cause the disorder. Most type 2B cases arise from new (de novo) mutations in the HEPACAM gene during the formation of reproductive cells or early embryonic development. These cases occur in individuals with no family history of the condition.