Spinocerebellar ataxia type 12 in a 52-year-old female

Spinocerebellar ataxia type 12 (SCA12) is a rare autosomal dominant neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the PPP2R2B gene. It typically presents with tremor, progressive ataxia, dysarthria and, in some cases, cognitive impairment. Most reported cases have originated from India; the condition has only rarely been described outside that context.

Case presentation

A 52-year-old woman of Indian descent was referred in March 2022 for evaluation of progressive tremor, cognitive changes and movement difficulties. Symptoms began 2 years earlier, initially with tremor of the lips, followed by tremor of the upper limbs and head. The tremor was most prominent during posture maintenance, interfering with daily tasks such as holding objects or pouring tea. She was initially diagnosed with essential tremor; however, the progressive nature of her symptoms prompted referral for a second opinion.

Her husband reported an impaired ability to walk in a straight line. Additional features included slowed speech, word-finding difficulty and memory impairment.

Family history was notable for multiple relatives overseas in India diagnosed with movement disorders initially thought to be Parkinson’s disease. Her father developed symptoms in his late 40s, with subsequent cognitive decline until his death at 63. Other affected relatives included her paternal grandfather and several paternal uncles (see Figure 3 pedigree chart).

Past medical history included type 2 diabetes mellitus, gastro-oesophageal reflux disease and spondyloarthritis. Medications were atorvastatin, salazopyrin, oxybutynin and metformin.

Examination revealed disrupted pursuit eye movements with saccadic intrusions, consistent with broken pursuit. She exhibited postural tremor of the upper limbs and head, without bradykinesia or rigidity. Gait was slow but without shuffling or reduced arm swing. On the Mini-Addenbrooke’s Cognitive Examination, she scored 20/30.

A range of investigations was performed to rule out other potential causes of progressive tremor and ataxia. Routine blood tests including full blood count, electrolytes, liver and thyroid function, vitamin B12 and vitamin E were normal, excluding metabolic, nutritional or endocrine causes. Ceruloplasmin and serum copper levels were within normal range, making Wilson’s disease unlikely. Autoimmune and paraneoplastic antibody panels were negative, excluding immune-mediated cerebellar ataxia. No exposure history or medication use suggested a toxin- or drug-induced tremor.

Magnetic resonance imaging of the brain (March 2022) demonstrated global brain volume reduction, most marked in cortical grey matter and the cerebellum. Symmetrical T2 hyperintensities were noted in the superior cerebellar peduncles. Volumetric analysis revealed whole brain and brainstem volume at the first centile, cerebellar grey matter at the fifth centile and cortical grey matter at the sixth centile (see Figure 1 and 2).

Genetic analysis confirmed a CAG repeat expansion in one allele of PPP2R2B, establishing the diagnosis of SCA12.

By September 2024, symptoms had progressed with further impairment in daily living. Broken pursuit eye movements persisted, and she developed persistent hiccups likely due to brainstem involvement.

Diagnosis

The diagnosis of SCA12 was confirmed by genetic testing. Neuroimaging findings of cerebellar and brainstem/cord atrophy supported the diagnosis.

Management

She was commenced on propranolol for tremor and low-dose amitriptyline for mood disturbance and muscle stiffness. She was referred to physiotherapy and clinical psychology for supportive care, and to gastroenterology for evaluation of persistent hiccups. A multidisciplinary approach was established to optimise function and quality of life. There is currently no curative treatment for SCA12.

Discussion

SCA12 is a slowly progressive autosomal dominant ataxia caused by a CAG repeat expansion in the PPP2R2B gene on chromosome 5q32.^1,2 The disease has a distinctive clinical profile, with tremor frequently presenting as the initial symptom in mid-life, followed by the gradual emergence of ataxia, dysarthria, cognitive decline and, occasionally, psychiatric symptoms.

Although rare worldwide, SCA12 has been reported with notable frequency in India,^2–5 particularly among members of the Agarwal community, an endogamous business group originally from Northern India. In this population, SCA12 is considered the second most common form of spinocerebellar ataxia after SCA2. This clustering suggests a strong founder effect. Other neurogenetic disorders, such as limb–girdle muscular dystrophy and megalencephalic leukodystrophy, have also been observed at higher prevalence in the same community.

The clinical spectrum of SCA12 is wide and overlaps with more common conditions such as essential tremor and Parkinson’s disease. Tremor is usually action-induced, is often of slower frequency and higher amplitude compared with essential tremor and may include proximal “wing-beating” movements. Ataxia, dysarthria and eye movement abnormalities tend to evolve later, which can delay recognition. Misdiagnosis as essential tremor is well documented, particularly when ataxia develops over years.

Neuropsychiatric symptoms including depression, irritability, apathy and occasionally psychosis have been reported, and functional decline is common over time. Imaging typically shows cerebellar and cortical atrophy, though this is not uniformly present. While longer repeats may be associated with earlier onset, severity does not consistently correlate with expansion size.

There is no disease-modifying therapy for SCA12. Management focusses on tremor suppression, gait rehabilitation, cognitive support and psychiatric symptom control within a multidisciplinary framework. Recognition of its distinctive clinical and ethnic associations is essential for timely diagnosis, genetic counselling and supportive planning.

Conclusion

This case highlights the importance of considering genetic ataxia in patients with progressive tremor, particularly when there is a strong family history. Early recognition and genetic confirmation allow for appropriate counselling, supportive care and family risk assessment.

View Figure 1–3.