Clinical, genetic, and neuroimaging profiles of autosomal recessive spinocerebellar ataxia type 4 caused by novel VPS13D variants in Chinese

Abstract Autosomal recessive spinocerebellar ataxias (SCARs) are a heterogeneous group of neurodegenerative disorders. VPS13D gene is currently the only gene associated with autosomal recessive spinocerebellar ataxia type 4 (SCAR4), also known as VPS13D dyskinesia. SCAR4 is a rare inherited disease, with only 34 reported cases reported worldwide. In this study, we reported three independent SCAR4 cases with adolescent onsets caused by five novel variants of the VPS13D gene. Each patient carried one frameshift and one missense variant: Patient 1 with c. 10474del and c. 9734C > A (p. Leu3492Tyrfs*43 and p. Thr3245Asn), Patient 2 with c. 6094₆107delGTTCTCTTGATCCC and c. 9734C > A (p. Val2032Argfs*7 and p. Thr3245Asn), and Patient 3 with c. 11954₁1963del and c. 9833 T > G (p. Phe3985Serfs*10 and p. Ile3278Ser). Two of the three patients shared nystagmus with an identical variant c. 9734C > A. Magnetic resonance imaging indicated thoracic spinal atrophy in all three patients and corpus callosum atrophy in one patient, along with other typical manifestations of white matter degradation, cerebral atrophy, and cerebellar atrophy. These findings expanded the genetic, clinical, and neuroimaging spectrum of SCAR4, and provided new insights into the genetic counseling, molecular mechanisms, and differential diagnosis of the disease.