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SPINOCEREBELLAR ATAXIA 42, EARLY-ONSET, SEVERE, WITH NEURODEVELOPMENTAL DEFICITS; SCA42ND

SPINOCEREBELLAR ATAXIA 42, EARLY-ONSET, SEVERE, WITH NEURODEVELOPMENTAL DEFICITS; SCA42ND

Chemin et al. (2018) reported 4 unrelated girls, ranging in age from 3 to 13 years, with a severe neurodevelopmental disorder associated with cerebellar atrophy ...

Chemin et al. (2018) reported 4 unrelated girls, ranging in age from 3 to 13 years, with a severe neurodevelopmental disorder associated with cerebellar atrophy on brain imaging. The patients presented soon after birth or in early infancy with severe hypotonia, and thereafter showed delayed psychomotor development with severe to profound intellectual disability and absent speech, although some had a few words. They had poor or absent eye contact and poor head control. There was severe axial hypotonia and variable spasticity, hypertonia, or dystonia of the limbs. None were able to walk independently. All had cerebellar ataxia and 2 had dysmetria. Three patients had oculomotor apraxia with strabismus and the fourth had hyperopia. Variable dysmorphic features included small or upslanted palpebral fissures, hypertelorism, deep-set eyes, enophthalmia, short nose, small nares, prognathism, anteverted ears, sparse hair, thick hair, low posterior hairline, and distal abnormalities of the fingers and toes. Two patients had mild microcephaly (-2 and -2.5 SD), and 2 had early-onset seizures consistent with epileptic encephalopathy.

▼ Molecular Genetics

In 4 unrelated girls with SCA42ND, Chemin et al. (2018) identified de novo heterozygous missense mutations in the CACNA1G gene (A961T, 605065.0002 and M1531V, 605065.0003). Three patients carried the A961T variant, suggesting a mutation hotspot. The mutation in the first patient was found by whole-exome sequencing and confirmed by Sanger sequencing. The other patients were identified through collaborative data sharing of patients with a similar phenotype who underwent exome sequencing. Electrophysiologic studies in HEK293 cells showed that the mutant currents activated at more negative potentials and had markedly slowed inactivation kinetics compared to wildtype. This resulted in increased calcium influx, consistent with a gain of function. Computational modeling of the mutations confirmed that the mutations would promote increased firing activity in deep cerebellar neurons. These currents were blocked in vitro in the presence of TTA-P2, a selective T-type calcium channel blocker.

Tags: 17q21.33