A case of a novel CACNA1G mutation from a Chinese family with SCA42

Abstract

Rationale:Spinocerebellar ataxia (SCA), a genetically inherited heterogeneous disorder, is characterized by gait ataxia, dysarthria, parkinsonism, choreic movements, dystonia, epilepsy, cognitive and psychiatric symptoms. Spinocerebellar ataxia-42 (SCA42), caused by heterozygous mutation in the calcium channel 1G (CACNA1G) gene, is a rare SCA subtype and the transmission pattern is autosomal dominant inheritance.Patient concerns:We presented a novel mutation (c.4721T>A; p.Met1574Lys) in 3 patients from a Chinese family using whole-exome sequencing. All patients exhibited cerebellar ataxia and the clinical manifestations were similar to those that were previously reported in the French and Japanese families. In addition, cerebral magnetic resonance imaging (MRI) showed cerebellar atrophy, and the hot cross bun sign of brainstem was found in the proband and her sister.Diagnoses:The clinical features and MRI findings indicated the diagnosis of SCA. Taken together, the symptoms, MRI findings, as well as whole-exome sequencing made the diagnosis of SCA42 most likely candidate.Interventions and outcomes:The patient was treated with cobamamide (1.5 mg once daily) for nerve nutrition and further physical therapy. At the 4-month follow-up visit, the patient's condition did not improve obviously.Lessons:Recently, a missense mutation in CACNA1G gene (c.5144G4A; p.Arg1715His) was identified in French and Japanese families with SCA42. However, there has been no report of SCA42 or its mutant loci in Chinese patients. Our finding showed a novel mutation in CACNA1G gene and provided important insights into the pathogenesis of SCA42.

Neuronal Cav3 channelopathies: recent progress and perspectives

“…SCA42 is characterized by a slowly progressive ataxia with a variable onset but mainly in young adulthood. Athough the prevalence of SCA42 is very low, the association of this p.Arg1715His-Cav3.1 mutation with SCA42 was subsequently confirmed in Japanese and Chinese families [82,88,104,109]. Additional CACNA1G missense mutations have been identified in other SCA42 patients, including p.Arg1068Cys, p.His1611Gln, and p.Pro2273His variants.…”

Novel Missense CACNA1G Mutations Associated with Infantile-Onset Developmental and Epileptic Encephalopathy

“…The CACNA1G gene has been associated with various forms of cerebellar ataxia and neurological comorbidities [ 2 , 3 , 4 , 6 , 18 , 19 ]. Our study further validates CACNA1G in the group of pathogenic neuronal ion channel genes associated with DEE [ 20 , 21 , 22 , 23 ].…”

“…Inherited variants in the CACNA1G gene were first suggested as risk alleles in families with idiopathic generalized epilepsy, although this still awaits definitive confirmation [ 1 ]. Pathogenic variants in CACNA1G were subsequently reported in familial spinocerebellar ataxia [ 2 , 3 , 4 ], a clinically heterogeneous neurodegenerative disorder [ 5 ]. In patients harboring the recurrent p.R1715H mutation and exhibiting spinocerebellar ataxia, the disease symptoms were primarily attributed to CACNA1G loss of function (LoF) and reduced neuronal excitability [ 2 , 3 ].…”

Clinical Characteristics and Possible Drug Targets in Autosomal Dominant Spinocerebellar Ataxias

“…The most prevalent symptom at onset was gait instability, whereas a relatively pure cerebellar phenotype with additional pyramidal signs, orbicular myokymia and rarely, with mild sensory deficits, dysphagia and urinary dysfunction may also be observed in the course of the disease. Brain MRI demonstrated cerebellar atrophy with vermal predominance, whereas postmortem pathological studies have not been performed so far [126][127][128].…”