A number sign (#) is used with this entry because of evidence that hypomyelinating leukodystrophy-24 (HLD24) is caused by heterozygous mutation in the ATP11A gene (605868) on chromosome 13q34. One such patient has been reported.

Hypomyelinating leukodystrophy-24 (HLD24) is an autosomal dominant disorder characterized by global developmental delay and neurologic deterioration (Segawa et al., 2021).

For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.

Segawa et al. (2021) reported a patient who developed epilepsy at 2 weeks of age, followed by global developmental delay, hypothyroidism, and cataracts. At 2 years of age he was able to laugh and had eye tracking. He was able to walk with a walker until he started elementary school when he lost his developmental milestones. He also had frequent infections, including aspiration pneumonia. By 18 years of age, he required mechanical ventilation and was nonambulatory. He had tongue fasciculations, flexion contractures of the limbs, and lack of deep tendon reflexes. Laboratory testing demonstrated a reduction in CD19+ B lymphocytes. Serial MRIs showed nonprogressive severe cerebral atrophy, ventriculomegaly, hypomyelinating leukodystrophy, and thinning of the corpus callosum. Nerve conduction velocity testing was suggestive of an axonal neuropathy.

The transmission pattern of HLD24 in the patient reported by Segawa et al. (2021) was consistent with autosomal dominant inheritance.

In a patient with hypomyelinating leukodystrophy-24, Segawa et al. (2021) identified a de novo heterozygous mutation in the ATP11A gene (Q84E; 605868.0003). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Segawa et al. (2021) stably transfected ATP11A with the Q84E mutation into W3 cells. Mutant ATP11A was shown to have flippase activity against phosphatidylserine, phosphatidylethanolamine, and phosphatidylcholine, whereas the wildtype ATP11A had flippase activity only against phosphatidylethanolamine and phosphatidylserine. Examination of incorporation of labeled lipids into the cell membrane showed that the mutant ATP11A led to increased sphingomyelin and decreased phosphatidylcholine in the outer leaflet of the cellular plasma membrane.

Segawa et al. (2021) developed a mouse model with a heterozygous knock-in Q84E mutation (605868.0001) in the Atp11a gene. The mutant mice had slower growth compared to wildtype mice and early death that was preceded by neurologic abnormalities. Brain MRIs of 11-week-old mutant mice showed a reduction in brain size and dilated ventricles. Microscopic examination of brain tissue from the mutant embryos and mouse pups demonstrated tissue degeneration. Brains from the mutant mouse embryos had increased sphingomyelin content compared to wildtype.