Spinocerebellar ataxia type 12 (SCA12) is a late-onset autosomal dominant neurodegenerative disorder. The clinical phenotypic presentation of SCA12 typically includes bilateral upper limb tremor, dysarthria, gait ataxia, hyperreflexia, and neuropsychiatric symptoms (O’Hearn et al., 2015). The age of onset ranges from 8 to 55 years, most often between 40 and 50 years. The prevalence of SCA12 is significantly higher in India compared with other regions (Srivastava et al., 2001; Ganaraja et al., 2022). SCA12 is caused by an unstable expansion of a cytosine-adenine-guanine (CAG) trinucleotide repeat located within the PPP2R2B gene, flanking exon 7 on chromosome 5q32. Affected individuals carry 51–78 CAG repeats (Holmes et al., 1999). Studies have shown that patients carrying 43–50 CAG repeats, when compared with those above the typical pathogenic threshold of 51 repeats, exhibit clinical features similar to the classic SCA12 phenotype but with a highly variable age of onset (Srivastava et al., 2017). This study presents the clinical characteristics and neuroimaging findings of a proband with SCA12, together with a literature review, aiming to improve clinical diagnosis.

A literature search was conducted in the Wanfang, VIP, China National Knowledge Infrastructure (CNKI), and PubMed databases¹ using the search terms “Spinocerebellar Ataxia-12” and “SCA12” covering publications from 1999 to present. A total of 14 publications reporting affected individuals or pedigrees were identified (Srivastava et al., 2001; Holmes et al., 1999; Srivastava et al., 2017; Ganaraja et al., 2022; Chen et al., 2014; Li, 2011; Li et al., 2025; Xie et al., 2017; Basu et al., 2024; Kalia et al., 2014; Zhao et al., 2002; Hellenbroich et al., 2004; Zheng et al., 2024; Brussino et al., 2010) and are summarized in Table 1.

A review of the 14 publications revealed that SCA12 was first reported and named by Holmes et al. in 1999 (Holmes et al., 1999). Typical clinical manifestations of SCA12 include limb tremor, ataxia, and cerebellar dysfunction. In contrast, this case was initially presented with head and jaw tremor, accompanied by mixed tremor in both upper limbs. Kinetic tremor of the upper limbs is more commonly observed at disease onset in SA12. Although resting tremor was observed, its marked exacerbation during postural maintenance and intentional movement aligns more with a mixed tremor—primarily postural/kinetic with a superimposed resting component—rather than a classic Parkinsonian-type resting tremor. One explanation is that tremor generation is related to abnormal activity in the cerebellar–thalamic–cortical pathway. The cerebellum integrates both the sensory and motor information from the cortex and modulates the motor cortex via thalamic feedback (Li et al., 2023). Within the cerebellar–thalamic–cortical circuit, the motor cortex plays a specific role in determining tremor amplitude, acting as a “dimmer switch” to regulate its intensity (Malling et al., 2019). The inhibitory output from the basal ganglia, particularly the internal segment of the globus pallidus, exerts a crucial ‘switch’-like control over thalamic activity (Helmich et al., 2012). Motor commands are relayed to the internal globus pallidus of the basal ganglia, which then sends inhibitory signals to the thalamus, thereby regulating the motor cortex excitability and downstream corticospinal tract activity, ultimately initiating muscle contraction and movement (Jellinger, 2019).

The PPP2R2B gene encodes the Bβ regulatory subunit of protein phosphatase 2A (PP2A). By modulating PP2A activity toward substrates such as the microtubule-associated protein Tau, this subunit participates in tau dephosphorylation (Lin et al., 2010). Dysfunction in this process may lead to tau detachment from microtubules, its subsequent aggregation into neurofibrillary tangles (NFTs), and ultimately the disruption of the neuronal cytoskeleton. This impairs axonal transport and synaptic function, culminating in neuronal death (Chen et al., 2009). PPP2R2B dysfunction may lead to dysregulation of PP2A activity toward pathways such as MAPK/ERK, impairing neuronal growth, differentiation, survival, and synaptic function. Such dysfunction has been linked to intellectual disability and developmental delay, and represents a potential mechanism underlying spinocerebellar ataxia (Sandal et al., 2025). PP2A also plays a role in dopaminergic signaling, and dysfunction of the dopaminergic system is closely associated with movement disorders such as tremor (Rampino et al., 2017). Pathologically, PPP2R2B abnormalities predominantly affect the cerebellum and the cerebral cortex, manifesting as Purkinje cell degeneration and cortical neuronal loss (Cohen and Margolis, 2016). Based on the clinical phenotype observed in this patient, the mixed tremor suggests that PPP2R2B gene abnormalities may impair the functional synergy between the basal ganglia–thalamocortical and cerebellar–thalamocortical circuits. Previous reports have not commented on tremor asymmetry; therefore, it remains unclear whether the more pronounced right-sided tremor observed in this patient is typical. A comparison of tremor characteristics in SCA12 between previously reported cases and the present case is provided in Table 2.

Extrapyramidal symptoms such as increased muscle tone, psychiatric symptoms including dementia and depression, and Parkinsonian symptoms such as bradykinesia and rigidity, often do not appear at the onset or in the early stages of SCA12. Cognitive impairment may typically emerge as the disease progresses. The progressive neurodegeneration in SCA12 gradually affects both cortical and subcortical regions (Basu et al., 2024) but shows no correlation with age, age of onset, ataxia severity, disease duration, or CAG repeat length (Agarwal et al., 2021).

In this pedigree, the proband presented with a rare initial symptom of head, facial, and jaw tremor, followed by tremors in both upper limbs, which were also observable at rest. These symptoms were accompanied by ataxia, dysphagia, dysarthria, and cognitive impairment. In the early stages of the disease, other SCA12 patients have been diagnosed with essential tremor (ET) (O’Hearn et al., 2001). However, in this pedigree, the proband was initially diagnosed with ET-plus. The ET-plus refers to the presence of characteristic bilateral upper limb action tremor of ET, along with additional neurological signs of uncertain significance, such as impaired tandem gait, questionable dystonic posturing, memory impairment, or other mild neurological signs of unclear significance, while excluding dystonia and task-specific tremor (Zhang, 2023). Symptomatic treatment proved ineffective, and SCA12 was not initially considered.

In the elderly population, multiple neurodegenerative disorders may coexist, leading to complex clinical presentations. For example, neurodegenerative diseases such as Parkinson’s disease (PD) or Alzheimer’s disease (AD) can occur alongside cerebrovascular diseases (e.g., cerebral infarction, leukoencephalopathy), representing a mixed pathology (Narasimhan et al., 2022). In such contexts, tremor manifestations can vary and may include resting tremor (typical of PD), postural tremor, or intention tremor, which was more commonly linked to cerebellar lesions or essential tremor (Jellinger, 2025). This necessitates a comprehensive evaluation integrating clinical, imaging, neurophysiological, and genetic information. Although the patient had cerebrovascular risk factors, gait disturbance, and resting tremor—features requiring differentiation from vascular parkinsonism (VaP)—the typical clinical presentation of VaP is often characterized as a “lower-body parkinsonism” or “parkinsonism of the lower half”. The VaP involves rigidity and bradykinesia in both lower limbs and postural instability of the trunk, while upper limb function generally remains intact (Wang, 2022). However, these patterns does not align with the symptoms observed in the present case. After several medical consultations, further inquiry into the family history revealed that several family members had limb tremors. Genetic testing was recommended for the patient, which detected 69 CAG repeats, confirming the diagnosis of SCA12. However, the possibility that cerebrovascular disease contributed to certain clinical features, such as gait instability and some cognitive impairment, cannot be entirely excluded.

When symptoms such as resting tremor, ataxia, and hippocampal atrophy are present in a patient with a significant family history, SCA12 should be considered. Differentiating SCA12 from essential tremor can be clinically challenging;in such cases, eliciting a detailed family history is crucial. Additionally, epidemiological clues, such as Indian ancestry, may also raise suspicion for SCA12 (Kalia et al., 2014). Genetic counseling should be provided to family members regarding autosomal dominant cerebellar ataxia (ADCA).

In patients with SCA12, structural MRI primarily reveals atrophy of the cerebral cortex and the cerebellum. The degree of cerebral cortical atrophy is generally more severe than that of the cerebellar cortex (Holmes et al., 1999; Chen et al., 2014), with the vermis more prominently affected than the cerebellar hemispheres. Atrophy rarely involves the basal ganglia, thalamus, brainstem nuclei, and subcortical regions of the cerebrum (Li et al., 2012; Yao et al., 2022). In this case, the proband exhibited more pronounced cerebral cortical atrophy compared to cerebellar hemispheric atrophy, consistent with some reports related to SCA12. Although hippocampal atrophy was observed—particularly noteworthy given the family history and tremor—and raised suspicion for a hereditary degenerative ataxia such as SCA12, it should be noted that hippocampal atrophy is a common imaging finding in the elderly population. This study lacked quantitative volumetric measurements or comparison with an age-matched control group. Therefore, we cannot determine whether this represents a specific neuroimaging marker of SCA12 or reflects age-related or vascular changes.

In clinical practice, the presence of mixed tremor, characterized by postural/kinetic and resting components, alongside hippocampal atrophy, particularly in the context of a positive family history, should prompt consideration of SCA12. Early genetic testing enables accurate diagnosis and prevents misdiagnosis as ET or other neurodegenerative disorders.

No specific targeted therapy for SCA12 has been identified to date. According to international reports (Ganaraja et al., 2022), drug treatments for SCA12 patients often involve a combination therapy with agents such as amantadine, propranolol, clonazepam, primidone, levodopa, trihexyphenidyl, and baclofen. However, no objective evaluations of these treatments are available. An earlier study on the use of propranolol for SCA12 showed no significant improvement in tremor symptoms (O’Hearn et al., 2001). In contrast, a case report of an SCA2 patient with severe action tremor demonstrated marked symptom improvement following combined deep-brain stimulation (DBS) of the thalamus and subthalamic nucleus (Freund et al., 2007). In the present case, the proband showed minimal symptomatic change after treatment with the antitremor agent Arotinolol.

In summary, this familial case and literature review reaffirm that upper limb tremor is the most frequent initial symptom in SCA12, often accompanied with head and voice tremors. This case exhibits that SCA12 can manifest with a mixed tremor phenotype—prominent postural/intentional tremor with a significant resting component—together with pyramidal and extrapyramidal signs and cognitive impairment. Notably, hippocampal atrophy was observed, whether this finding is specific to SCA12 or relates to aging or vascular changes remains unclear and requires further investigation.

This case report is limited to a single family, which constrains the generalizability of the findings. Furthermore, the available imaging and genetic data for the family are incomplete. There is also a lack of documentation regarding early symptoms and signs, as well as early-stage and familial neuroimaging data. Importantly, definitive evidence of familial co-segregation is absent, as genetic testing was not performed on other symptomatic relatives, preventing confirmation of the phenotype–genotype link within the family.

Therefore, in clinical practice, it is essential to develop a systematic diagnostic approach for tremor by obtaining detailed patient histories, emphasizing neuroimaging evaluation, exploring functional imaging assessments, and applying genetic testing selectively. Future prospective multicenter cohort studies with large sample sizes are warranted for SCA12. The use of quantitative MRI techniques, such as volumetric measurement and diffusion tensor imaging, combined with refined neuropsychological testing batteries, may help determine the specific hippocampal involvement in SCA12.