A number sign (#) is used with this entry because of evidence that remitting megalencephalic leukoencephalopathy with subcortical cysts-4 (MLC4) is caused by homozygous mutation in the AQP4 gene (600308) on chromosome 18q11. One such family has been reported.

Remitting megalencephalic leukoencephalopathy with subcortical cysts-4 (MLC4) is an autosomal recessive neurologic disorder characterized by macrocephaly in infancy associated with developmental delay, delayed walking, variable cognitive decline, behavioral abnormalities, and early-onset seizures. The severity of neurologic dysfunction is variable, even within a family, but tends to show improvement with time. Brain imaging shows swelling of the cerebral white matter and subcortical cysts in the anterior temporal region, consistent with MLC. Brain imaging abnormalities also tend to improve with time, indicating a remitting disease course (Passchier et al., 2023).

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

Passchier et al. (2023) reported a brother (P4) and a sister (P5), born of consanguineous parents, who developed macrocephaly in the first 6 months of life; head circumference normalized in the boy and remained just above 2 SD in the girl. Both showed developmental delay and hypotonia, although P4 was more severely affected. He walked at 4-5 years, whereas his sister walked at age 2. Both had seizures from 1 year of age. P4 had frequent status epilepticus, which eventually was controlled, and P5 had epilepsy that was well-controlled. At 16 years of age, P4 had marked cognitive decline with limited language ability. He could walk with difficulty and had limited hand function. Additional features in P4 included truncal and limb ataxia, dystonia, rigidity, and dysarthria. At age 13, P5 had close to normal motor function with mild clumsiness and mild cognitive deficit. Both patients demonstrated behavioral problems in early childhood, including agitation, impulsivity, and hyperactivity, which later improved (P4) or normalized (P5). Brain imaging of P4 at 8 months of age showed diffuse signal abnormalities, mild swelling of the cerebral white matter, and subcortical cysts in the anterior temporal region. Follow-up at age 4 showed normalization of the cerebral white matter, but persistence of small temporal cysts. Brain imaging of P5 showed similar findings, but milder. The brain imaging findings were consistent with remitting MLC.

The transmission pattern of MLC4 in the family reported by Passchier et al. (2023) was consistent with autosomal recessive inheritance.

In 2 sibs (P4 and P5), born of consanguineous parents, with MLC4, Passchier et al. (2023) identified a homozygous missense mutation in the AQP4 gene (A215T; 600308.0001) affecting the second NPA motif that forms part of the channel pore. The mutation, which was found by a combination of homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. Western blot analysis of MDCK cells transfected with the mutation showed no detectable expression of mutant AQP4, suggesting that the mutant protein is unstable and rapidly degraded. Functional studies showed no change in swelling and shrinking rate constants when the cells with the A215T mutation were exposed to hypotonic or hypertonic shock, whereas cells with wildtype AQP4 responded with increased swelling and shrinking under the same conditions. Overexpression of the A215T mutation in HEK293 cells showed detectable, but reduced, AQP4 membrane localization compared to controls. Mutant AQP4 formed large intracellular protein aggregates, and there was a 60% reduction in membrane localization compared to wildtype. Overexpression of mutant AQP4 increased swelling and shrinking in response to shock, but the rates were significantly reduced compared to wildtype. The findings suggested that mutant A215T AQP4 reaching the cell membrane retains some residual water channel function.