Familial SCA14: A case report with review

gene, which encodes protein kinase Cγ (PKCγ). The clinical manifestations are heterogeneous, ranging from slowly progressive pure cerebellar ataxia to complex phenotypes with sensory or extrapyramidal involvement. To the best of our knowledge, the present report is the first to describe a Han Chinese family carrying the PRKCG c.424T>G (p.C142G) mutation, which has previously only been described in Danish and Japanese cohorts. The proband, a 72-year-old man, developed gait instability in his 40s, progressing to dysarthria, intention tremor, oculomotor slowing and sensory impairment. Brain MRI revealed severe diffuse cerebellar atrophy. The siblings and daughter of the patient presented with variable ataxic symptoms, confirming autosomal dominant inheritance. Genetic testing by next-generation sequencing identified the heterozygous c.424T>G mutation, co-segregating in affected family members. This mutation localizes to the C1 regulatory domain of PKCγ, a zinc-finger structure critical for diacylglycerol binding and kinase autoinhibition. Substitution of cysteine by glycine at codon 142 destabilizes zinc coordination, impairs protein stability and disrupts membrane recruitment. Functional evidence suggests that C142G induces aberrant kinase activity, misfolding and altered MAPK signaling, resulting in chronic cellular stress without rapid neuronal death, thus accounting for the indolent course of the disease compared with that of polyglutamine SCAs. The present findings expand the knowledge regarding the ethnic and geographic distribution of the codon 142 mutation and highlight the complexity of genotype-phenotype associations, as clinical presentations varied from mild gait ataxia to cognitive impairment and bulbar involvement. The report underscores the value of early genetic testing in unexplained ataxia, facilitating accurate diagnosis, genetic counseling and individualized management. Further functional studies are warranted to clarify the pathogenic mechanisms and to explore potential targeted therapies for SCA14.