A number sign (#) is used with this entry because of evidence that megalencephalic leukoencephalopathy with subcortical cysts-3 (MLC3) is caused by heterozygous mutation in the GPRC5B gene (605948) on chromosome 16p12.

Megalencephalic leukoencephalopathy with subcortical cysts-3 (MLC3) is a neurodegenerative disorder characterized by increased head circumference in infancy followed by progressive motor and cognitive decline in early childhood. Affected individuals either do not achieve walking or lose independent ambulation in the first or second decades. Cognitive impairment is variable and accompanied by poor speech and dysarthria. Most patients have early-onset seizures, which may be mild or refractory. Brain imaging shows unremitting megalencephalic leukoencephalopathy with subcortical cysts and swelling of the cerebral white matter (Passchier et al., 2023).

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

Passchier et al. (2023) reported 3 unrelated patients (P1-P3), ranging from 19 to 27 years of age, who presented with increased head circumference between 6 and 9 months of age. P1 and P2 had delayed motor development, with P2 walking at 3 years of age and P1 never achieving walking. P3 had normal early development and walked at 13 months. Slow motor decline was noted in all patients between 4 and 8 years of age, resulting in loss of independent ambulation and full wheelchair dependency by 6 years in P1 and P2 and 12 years in P3. Motor decline was characterized by clumsiness, spasticity of the upper and lower limbs, trunk and limb ataxia, rigidity, and variable dystonia. Cognitive decline was noted at age 4 in P1, and at 14 to 15 years of age in P2 and P3. Dysarthria was present in all 3, and P2 had dysphagia. The seizure phenotype was variable. P1 developed severe refractory epilepsy at age 4, P2 had mild epilepsy beginning at age 14, and P3 had 2 single seizures after a fall as an adult. At age 19, P1 had limited motor function, marked cognitive deficit, and no speech. At 27 years, P2 could handle objects and use a wheelchair, but had mild cognitive and speech deficits. P3 had mild cognitive deficits and mood problems at age 24. Brain imaging in all patients showed classic unremitting megalencephalic leukoencephalopathy with diffusely abnormal and swollen cerebral white matter and subcortical cysts in the anterior temporal and frontal white matter.

The heterozygous mutations in the GPRC5B gene that were identified in patients with MLC3 by Passchier et al. (2023) occurred de novo.

In 3 unrelated patients (P1-P3) with MLC3, Passchier et al. (2023) identified 2 different de novo heterozygous 3-bp in-frame duplications in the GPRC5B gene (605948.0001 and 605948.0002). Both mutations occurred in the fourth transmembrane protein domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. Western blot analysis of patient lymphoblasts showed a strong increase in GPRC5B levels compared to controls. Levels of modulator of VRAC current-1 (MLC1; 605908) were similar to controls, but levels of the cation channel TRPV4 (605427) were strongly decreased. In vitro functional studies showed that regulatory volume decrease (RVD) in patient lymphoblasts was reduced following swelling compared to controls. These findings indicated disturbed volume regulation in patient lymphoblasts, potentially due to increased GPRC5B expression. Overexpression of mutant and wildtype GPRC5B in human astrocytoma cells increased volume-regulated anion channel (VRAC) function to similar degrees. Passchier et al. (2023) suggested that increased GPRC5B expression causes chronic white matter edema by disrupting fine tuning of the essential volume-regulating channels VRAC and TRPV4.