Cerebellar Atrophy With Seizures And Variable Developmental Delay

A number sign (#) is used with this entry because of evidence that cerebellar atrophy with seizures and variable developmental delay (CASVDD) is caused by homozygous or compound heterozygous mutation in the CACNA2D2 gene (607082) on chromosome 3p21.

Description

Cerebellar atrophy with seizures and variable developmental delay (CASVDD) is an autosomal recessive neurologic disorder characterized by cerebellar ataxia associated with atrophy of the cerebellar vermis on brain imaging. Most patients also have onset of severe refractory seizures in the first year of life and show global developmental delay, compatible with epileptic encephalopathy (summary by Edvardson et al., 2013). However, at least 1 patient with normal cognitive development and only 1 febrile seizure has been reported (Valence et al., 2019), suggesting significant clinical variability of this disorder.

Clinical Features

Edvardson et al. (2013) reported 3 sibs, born of consanguineous Arab-Palestinian parents, with early infantile epileptic encephalopathy, global developmental delay, and cerebellar atrophy. The patients showed hypotonia at birth and developed refractory seizures in the first months of life. Seizure types included eye rolling and facial twitching, as well as atonic, clonic, and tonic attacks. EEG was consistent with epileptic encephalopathy and later evolved to slow background with multifocal spike and slow-wave discharges. Additional features included brisk reflexes and choreiform movements. The children had poor or absent eye contact, no speech, almost no psychomotor development, and absent purposeful hand movements. Brain imaging showed atrophy of the cerebellar vermis.

Pippucci et al. (2013) reported a 9-year-old boy, born of consanguineous Italian parents, with epileptic encephalopathy and cerebellar atrophy. The patient had a severe phenotype, presenting with seizures in the first months of life, followed by severely delayed psychomotor development, leg hypertonia, brisk reflexes, axial hypotonia, dyskinetic and myoclonic movements, no eye contact, and abnormal eye movements, such as oculomotor apraxia, strabismus, and nystagmus. He had multiple resistant seizure types, including clonic, partial, and absence. EEG showed multifocal spikes and slowed background activity. He also had facial dysmorphism, with epicanthus, arched palate, cupid's bow, and clinodactyly. Brain imaging showed cerebellar atrophy. Pippucci et al. (2013) noted the phenotypic similarities to the 'ducky' mouse (see ANIMAL MODEL).

Butler et al. (2018) reported a 5-year-old boy, born of unrelated parents, who was noted to have hypotonia and abnormal eye movements soon after birth. He developed refractory seizures at age 7 months. A ketogenic diet was partially effective, but various types of seizures recurred. EEG showed multifocal discharges, generalized spike-wave discharges, and later a photoparoxysmal response. He had global developmental delay, could sit with support but not walk, showed ataxic movements, had poor eye contact, and was nonverbal. Brain imaging showed cerebellar atrophy; dysmorphic features were not noted.

Clinical Variability

Valence et al. (2019) reported a 20-year-old man (P12), born of consanguineous Portuguese parents, with cerebellar ataxia. Compared to previously reported patients with CACNA2D2 mutations, he had a mild phenotype. He had myoclonus at age 40 days, only a single febrile seizure at 12 months of age, and mild motor delay with walking achieved at 4 years of age. He had an ataxic gait, dysmetria, dysarthria, and cerebellar atrophy on brain imaging. Cognitive development was apparently normal and he did not have intellectual disability.

Inheritance

The transmission pattern of CASVDD in the family reported by Edvardson et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 sibs, born of consanguineous Arab-Palestinian parents, with CASVDD manifest as early infantile epileptic encephalopathy, Edvardson et al. (2013) identified a homozygous missense mutation in the CACNA2D2 gene (L1040P; 607082.0001). The variant, which was identified by linkage analysis combined with whole-exome sequencing, was not found in 102 controls or in 6,503 control exomes. In vitro expression studies in Xenopus oocytes showed that the variant had detrimental effects on channel function. Exome sequencing in 1 of the 3 affected sibs also identified a homozygous missense variant in the CELSR3 gene (M2630I; 604264.0001). This variant also segregated with the disease state in the family. Edvardson et al. (2013) could not exclude a role for the CELSR3 mutation in the epileptic phenotype in this family.

In a 9-year-old boy, born of consanguineous Italian parents, with CASVDD manifest as epileptic encephalopathy, Pippucci et al. (2013) identified a homozygous frameshift mutation in the CACNA2D2 gene (607082.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient muscle cells showed almost absent CACNA2D2 protein levels (less than 3% of controls). Genetic analysis also identified a homozygous missense variant in the CELSR3 gene (G2136D; 604264.0002) that segregated with the disorder in the family. However, calculation of statistical significance of the CELSR3 variant suggested that it was likely an incidental finding. Pippucci et al. (2013) noted the phenotypic similarities to the 'ducky' mouse (see ANIMAL MODEL).

In a 5-year-old boy, born of unrelated parents, with CASVDD, Butler et al. (2018) identified compound heterozygous missense mutations at highly conserved residues in the CACNA2D2 gene (P261L, 607082.0003 and L1046P, 607082.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed. The patient also carried a heterozygous missense variant in the CELSR3 gene (Q1758R) that is common in the general population and thought not to contribute to the phenotype.

In a 20-year-old Portuguese man (patient P12), born of consanguineous parents, with CASVDD, Valence et al. (2019) identified a homozygous splice site mutation in the CACNA2D2 gene (607082.0005). The authors hypothesized that the relatively mild phenotype in this patient may be due to production of significant amounts of the wildtype protein. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The patient was from a cohort of 20 probands from consanguineous families with cerebellar ataxia who underwent exome sequencing.

Animal Model

Brodbeck et al. (2002) showed that mice with the 'ducky' (du) mutation, a model for absence epilepsy (see 600131), had a mutation in Cacna2d2 gene. The mutation resulted in the introduction of a premature stop codon and the expression of a truncated protein encoded by the first 3 exons of Cacna2d2, followed by 8 novel amino acids. The shortened mRNA and protein were expressed in mutant mouse cerebellum and Purkinje cells. Brodbeck et al. (2002) detected high expression of the normal protein in cerebellar Purkinje cells, but found that ducky mice had abnormalities in their Purkinje cell dendritic trees. Functional analysis indicated that the mutant Cacna2d2 protein failed to increase or even decreased the peak current density of the voltage-gated Ca(V)2.1 (CACNA1A; 601011)/beta-4 (CACNB4; 601949) channel combination, suggesting that it may contribute to the ducky phenotype.

Brill et al. (2004) identified a recessive mouse phenotype, 'entla,' caused by an in-frame duplication of 39 amino acids in the Cacna2d2 gene, resulting in expression of a full-length, membrane-associated protein, but with loss of the disulfide linkage between the 2 derived proteins. Mutant mice developed ataxia by postnatal day 13 to 15 followed by paroxysmal dyskinesia. The mice showed reduced size and weight, increased mortality before weaning, and female infertility. EEG studies suggested absence epilepsy, with 2- and 4-Hz spike-wave discharges in the cortex and hippocampus. Cerebellar Purkinje cells isolated from mutant mice showed about a 50% reduction in current, as well as a reduction of gabapentin binding to the membrane compared to wildtype and to heterozygous mice. Entla (ent) mice showed no neuroanatomical abnormalities.