Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay is an autosomal recessive neurodevelopmental disorder characterized by infantile onset of...
Cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay is an autosomal recessive neurodevelopmental disorder characterized by infantile onset of hypotonia and developmental delay with subsequent impaired intellectual development and severe speech delay. In childhood, affected individuals show delayed walking and develop epilepsy that is usually controlled by medication. Brain imaging shows cerebellar hypoplasia/atrophy (summary by Wang et al., 2019).
▼ Clinical Features
Wang et al. (2019) reported 5 patients from 3 unrelated families with CHEGDD. One patient was 20 years of age, whereas the others ranged from 12 to 15 years; 1 had died at 11 years due to chronic lung disease associated with recurrent aspiration pneumonia. The patients presented in early childhood with hypotonia, global developmental delay, delayed walking at about age 3 years, and severely impaired intellectual development with profound speech delay or even absent language. All also developed epilepsy between 7 and 10 years of age, but the seizures were controlled by medication in most. Subtle nonspecific dysmorphic features seen in some patients included poor overall growth, large forehead, tall face, mild hypertelorism, joint hyperlaxity, and long fingers and toes. Brain imaging in all 5 patients showed cerebellar atrophy and dysplasia. Families 2 and 3 were consanguineous; family history revealed 4 miscarriages in family 3. Additional cerebellar features, such as tremor, ataxia, and nystagmus, were not noted in these patients.
The transmission pattern of CHEGDD in the families reported by Wang et al. (2019) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
In 5 patients from 3 unrelated families with CHEGDD, Wang et al. (2019) identified homozygous or compound heterozygous loss-of-function mutations in the OXR1 gene (605609.0001-605609.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. None of the variants were found in the gnomAD database. Patient-derived fibroblasts from families 2 and 3 showed undetectable OXR1 protein levels. Corroborating studies in Drosophila (see ANIMAL MODEL), Wang et al. (2019) found that patient fibroblasts showed aberrant accumulation of abnormal lysosomal structures, suggesting defects in autophagy. In addition, although OXR1 had been implicated in oxidative stress, patient fibroblasts did not show significantly increased susceptibility to oxidative stress compared to controls. Wang et al. (2019) concluded that lysosomal dysfunction, not oxidative stress, is the driver of the phenotype. The authors postulated a role for OXR1 in lysosomal acidification.
▼ Animal Model
Oliver et al. (2011) found that mutant 'Bella' (bel) mice, which have poor weight gain and progressive ataxia associated with cerebellar neurodegeneration and apoptotic cells in the granule cell layer (GCL), resulted from a deletion on chromosome 15, including the Oxr1 and Abra (609747) genes. Wildtype mice showed expression of Oxr1 in the cerebellar GCL and in major regions of the postnatal brain and spinal cord; Abra was expressed only in skeletal muscle. Bel mice had no Oxr1 protein expression in the brain, and the bel phenotype could be rescued by an Oxr1 transgene, suggesting that loss of Oxr1 is responsible for the neurodegenerative phenotype. Cells from bel mutants showed significantly higher susceptibility to peroxide-induced apoptosis compared to controls, and overexpression of Oxr1 in wildtype cells resulted in protection of neurons against exogenous stress. The cerebellar cells appeared to have unique sensitivity that was not observed in other cell types, including cortical neurons. The studies also showed the importance of the conserved TLDc domain, which may play a specific role in antioxidation.
In normal Drosophila, Wang et al. (2019) found dynamic expression of the OXR1 ortholog 'mustard' (mtd) during neurologic development: it was expressed in the optic lobe, photoreceptor cells, mushroom bodies, olfactory lobes, a few other neurons, axonal and dendritic projections, and synapses. Knockdown of mtd was pupal lethal, impaired eclosion, and/or resulted in death within a week. Expression of human OXR1 containing only the TLDc domain was able to fully rescue this phenotype, as was expression of NCOA7 (609752), which also contains a TLDc domain. Mutant mtd flies that survived showed neurologic coordination abnormalities, including wing defects, increased sensitivity to bang and vortex shaking, and impaired climbing abilities compared to controls. Electron microscopic analysis of photoreceptors from mutant flies showed accumulation of abnormal lysosomal structures, such as autophagosomes, lysosomes, and endolysosomes. Although OXR1 had been implicated in oxidative stress, mutant flies with RNAi knockdown of mtd did not show significantly increased sensitivity to oxidative substances compared to control flies, suggesting that this stress is not the driver of the phenotype.
Crouzon (1929) and Sarrouy et al. (1957) reported 2 pairs of sibs with congenital cerebellar hypoplasia. Norman and Urich (1958) noted parental consanguinity in an isolated case. Wichman et al. (1985) reported 3 pairs of affected sibs in unrelated families. All 6 presented within the first 6 months of life with delayed motor and language development. Mathews et al. (1989) also described autosomal recessive cerebellar hypoplasia. Dooley et al. (1992) reported 2 sisters with cerebellar hypoplasia who also had nonprogressive retinal pigmentary disease. They pointed out that 1 of the 2 sibs reported by Mathews et al. (1989) had bilateral retinal pigmentary changes.