Spinocerebellar ataxia type 14 (SCA14) [OMIM: 605361] (Yamashita et al., 2000; Brkanac et al., 2002) (Rossi et al., 2014) is an autosomal dominant disorder characterized by progressive cerebellar degeneration, dysarthria, and nystagmus. Symptoms, such as axial myoclonus (Yamashita et al., 2000), cognitive impairment (Wedding et al., 2013; Bolton and Lacy, 2019), tremors (Koht et al., 2012), and impaired sensibility (Klebe et al., 2005; Koht et al., 2012), may also be observed. Furthermore, Parkinson’s disease (Sailer et al., 2012; Chen et al., 2022), which is characterized by muscle rigidity and tremors, has also been reported in some family pedigrees. Patients with SCA14 may exhibit further ataxic conditions such as dysphagia (Ueda et al., 2013). The incidence of SCA14 is from 1% to 4% in all autosomal genetic disorders (Chelban et al., 2018), and it was first reported in a Japanese family in 2000 (Yamashita et al., 2000). It was also reported in a 4th generation American family of English and Dutch origin who displayed pure cerebellar ataxia (Brkanac et al., 2002). SCA14 has also been reported in various countries such as Australia (Kang et al., 2019), Norway (Koht et al., 2012), Germany (Ganos et al., 2014), Japan (Ueda et al., 2013), and China (Chen et al., 2022). There is an ambiguous correlation between clinical manifestations and ethnicity, while the age of onset occurs between childhood and 60 years old. Diagnosis is mainly based on clinical manifestations, physical examination, and laboratory tests, and genetic testing is required to confirm the diagnosis. SCA14 is caused by PRKCG variants encoding protein kinase C γ (PKCγ) (Yabe et al., 2003). Although missense and deletion mutations have been found in PRKCG (Chelban et al., 2018), the specific molecular mechanism underlying pathogenesis remains poorly understood (Shimobayashi and Kapfhammer, 2021). Here, we identified a c.1232G>C mutation in PRKCG in a Chinese family to extend the genotype and phenotype of SCA14. Our results emphasize the importance of detecting PRKCG mutations in patients with episodic ataxia.

The clinical manifestations of SCAs, which are a unique type of cerebellar degenerative disease, range from typical ataxia disturbance to abnormal ocular movements. Many patients exhibit cerebellar ataxia, but this may not be an early symptom. In a previous case, dystonia was reported as the only symptom present in the early stages (De Michele et al., 2022). In this case, the proband had a speech disorder and cognitive impairment since birth and suffered from episodic ataxia over the last 3 years. Clinical manifestations and imaging results revealed that there were no traces of postoperative complications such as hydrocephalus and herniation. Furthermore, we consulted a neurosurgeon and a neurologist at Dushu Lake Hospital Affiliated with Soochow University. Furthermore, it has been 10 years since the right-sided parietooccipital tumorectomy was performed, and the cerebellar ataxia of the patient was not considered to be caused by a craniotomy. Considering the episodic ataxia, mild cognitive impairment, and speech disorder, it was recommended that the patient undergo genetic testing. Whole genomic extraction showed mutations in PRKCG with no mutations in KCNA1 or CACNA1A, which are commonly observed in episodic ataxia. Based on the genotype and phenotype, it was concluded that repeated falls were caused by ataxia rather than hypokalemia. Moreover, during previous episodic ataxia, the patient did not undergo strenuous exercise or exhibit a loss of appetite, vomiting, diarrhea, and other causes of low potassium levels. Additionally, no relationship between SCA14 and hypokalemia was reported. The absence of ataxia and cognitive dysfunction in the patient’s father, who had the same genotype, may be explained by the decreased penetrance of the disorder (Yabe et al., 2003).

SCAs are a group of progressive neurogenetic disorders caused by gene mutations. SCA14 is a rare autosomal dominant inherited disease involving PRKCG mutation. PRKCG encodes protein kinase C γ (PKCγ), which is a member of the serine/threonine enzyme family, plays a vital role in cell growth and signal transduction, and is highly expressed in Purkinje cells (Winkler et al., 2020; Shimobayashi and Kapfhammer, 2021). The activity of PKCγ also plays a major role in dendritic development and synaptic maturation of cerebellar Purkinje cells (Winkler et al., 2020). In vitro studies and studies on transgenic mice (Winkler et al., 2020) support the functional gain hypothesis, which indicates that increased PKCγ activity leads to dendritic dysplasia, neuronal death, and aggregation effects. The effect of PKCγ is related to the membrane residence duration (Wong et al., 2018). However, a study has shown that PKCγ exerts toxic effects by inducing endoplasmic reticular stress (Seki et al., 2007). Shimobayashi (Shimobayashi and Kapfhammer, 2017) reported that SCA14 depends on the activity of PKCγ, and mutations in different domains occur due to different pathways.

Until now, many mutation sites have been reported (Chen et al., 2022; De Michele et al., 2022; Tada et al., 2022) (Schmitz-Hübsch et al., 2021) (Figure 4) in PRKCG. However, we pioneered the determination of a novel heterozygous mutation in PRKCG c.1232G>C (p.G411A). PRKCG consists of two domains, namely, the regulatory domain and the catalytic domain. The regulatory domain consists of the C1 and C2 regions. The majority of the mutations discovered in the C1 region are missense variants (De Michele et al., 2022). Variants in the catalytic domain are rare, and the clinical phenotype is much more complex (Chelban et al., 2018) because of the inhibition of calcium ion inflow (Adachi et al., 2008), which in turn prevents dendritic processes, as reported in this case. The mutation gene is located in exon11, which is in the catalytic domain. The patient had a speech disorder and cognitive impairment since birth. The disease progressed and ataxia initially occurred 3 years ago. However, his father had the same mutation that only manifested as a speech disorder. Transgenic mice (Ji et al., 2014) with PKCγ mutations located in the catalytic domain (S361G) have shown pathological changes and motility defects typical of cerebellar ataxia, which is consistent with this case. However, the mutation (p.G411A) reported here requires further functional verification.

Many patients diagnosed with SCA14 display progressive cerebellar syndrome, which is rarely associated with severe disabilities (Koht et al., 2012). Dysarthria, abnormal ocular movements, and dysmetria are the most common clinical manifestations, and cognitive impairment is rare and is usually mild (De Michele et al., 2022) in these patients. To summarize the clinical features of SCA14 reported thus far, they can be divided into two categories as follows: the classic type and the atypical type. The characteristics of the classic type are as follows: 1) cerebellar ataxia, most patients present with slowly progressive ataxia; 2) dysarthria or a speech disorder; 3) ocular symptoms, abnormal ocular movements, and dysmetria; and 4) cerebellar atrophy in the MRI. The characteristics of the atypical type include cognitive impairment, depression, and epilepsy. All affected subjects that were considered in this article had a speech disorder, and the proband exhibited progressive ataxia and mild cognitive dysfunction, which is consistent with the clinical manifestations of a previously reported case of SCA14 (Wedding et al., 2013). The proband had no cerebellar atrophy, as revealed by a CT scan on 1 October 2009, and he refused to undergo more MRI scans due to personal reasons. However, if the patient exhibits the development of cerebellar atrophy in the future, a further examination will be required. To summarize, SCA14 should be considered when patients exhibit the following features: slowly progressive cerebellar ataxia, dysarthria or a speech disorder, abnormal ocular movement, extrapyramidal systemic syndrome, and mild to severe atrophy of the cerebellum revealed by brain magnetic resonance. Presently, a diagnosis for the same relies on gene detection. The majority of patients with SCA14 have a long history of the disease; thus, ordinary life is unaffected. However, many patients may die from dysphagia or falls. Currently, there is no targeted therapy for SCA14. Supportive treatment includes heteropathy, such as rehabilitation treatment, and antisecosis to reduce the risk of asphyxia.

We reported on this family of Chinese origin with episodic ataxia, speech disorders, and cognitive impairment with an extended genetic profile and clinical features of SCA14, and emphasize the importance of gene sequencing in patients with episodic ataxia regardless of the absence of classic dysmetria and nystagmus and also independent of familial history.