What is Spinal Cerebellar Ataxia type 14 (SCA14)?

Spinocerebellar Ataxia Type 14 (SCA14)

Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant hereditary cerebellar ataxia caused by mutations in the protein kinase C gamma (PKCγ, PRKCG) gene, typically presenting in early to mid-adult life with slowly progressive pure cerebellar ataxia, normal lifespan, and characteristic cerebellar atrophy on brain MRI. 1

Genetic Basis and Molecular Pathology

• SCA14 results from point mutations in the PRKCG gene encoding protein kinase C gamma, with a hotspot for mutations located in exon 4 1, 2
• The disease demonstrates genetic heterogeneity with over 40 distinct disease-causing mutations identified, including mutations in the C1 domain such as H36R, H101Q, Gly128Asp, and Ser119Phe 3, 2, 4
• The pathological mechanism involves both loss-of-function and gain-of-function processes: mutant PKCγ undergoes cytoplasmic mislocalization and aggregation, becomes hyper-activated with increased substrate phosphorylation, and resists efficient degradation 4
• Genetic testing for SCA14 is clinically available and should target PRKCG exon 4 screening as the initial approach 1, 2

Clinical Presentation and Natural History

• Onset typically occurs in early to mid-adult life (around age 40s), though some patients report symptoms since early childhood, with very slow progression over decades 1, 3, 5
• The hallmark presentation is pure cerebellar ataxia manifesting as gait imbalance, dysarthria, and nystagmus 1, 3
• Disease severity correlates positively with age, demonstrating gradual worsening measured by SARA scores 5
• Patients maintain ambulation for extended periods—one documented case remained ambulatory after more than 20 years of disease progression 3
• Lifespan is normal despite progressive neurological decline 1

Associated Clinical Features Beyond Pure Cerebellar Ataxia

• Mild dystonia (focal, task-specific, or segmental) occurs in some patients 5
• Myoclonus, particularly intermittent axial myoclonus, may be present 1, 5, 2
• Occasional sensory loss and hyperactive tendon reflexes can develop 1
• Subtle pyramidal signs may emerge during disease course 5
• Cognitive decline occurs in a minority of cases 1
• Rare presentations include intractable epilepsy with early onset and severe walking disturbance 2

Neuroimaging and Neuropathology

• Brain MRI demonstrates cerebellar atrophy as the characteristic finding 1
• The single autopsy case reported showed loss of cerebellar Purkinje cells as the primary pathological substrate 1
• Imaging patterns align with the autosomal dominant spinocerebellar ataxias showing progressive cerebellar hemispheric and vermian volume loss 6

Neurophysiological Abnormalities

• Transcranial magnetic stimulation reveals reduced short interval intracortical inhibition (SICI), reflecting abnormalities of intracortical inhibitory circuits 5
• Unlike healthy controls where SICI increases with increasing conditioning pulse intensities, SCA14 patients fail to show this normal response pattern 5
• Other neurophysiological parameters including motor thresholds, contralateral silent period, intracortical facilitation, interhemispheric inhibition, and short afferent inhibition remain normal 5
• Somatosensory, acoustic, and visual evoked potentials do not differ from controls 5

Epidemiology and Ethnic Considerations

• SCA14 is a rare form of autosomal dominant cerebellar ataxia with very low frequency in the Japanese SCA population (approximately 2 in 882 screened patients) 2
• Clinical features and disease-causing mutations in PRKCG demonstrate heterogeneity even within the same ethnic background 3
• Specific mutations may show phenotypic consistency—both patients with the Gly128Asp mutation exhibited pure cerebellar ataxia without additional features 3

Diagnostic Approach

• MRI of the head without IV contrast is the preferred initial imaging modality to detect cerebellar atrophy 7, 6
• Genetic testing should focus on PRKCG exon 4 screening using PCR-based methods with denaturing high-performance liquid chromatography and subsequent direct sequencing 2
• Clinical diagnosis relies on the combination of slowly progressive cerebellar ataxia with adult onset, family history consistent with autosomal dominant inheritance, and exclusion of other causes 8, 1
• Spine imaging may be warranted if motor spasticity or sensory ataxia develops, though this is less common in SCA14 compared to other SCA subtypes 6

Key Distinguishing Features from Other Ataxias

• Unlike sensory ataxia, cerebellar ataxia in SCA14 does not worsen with eye closure (negative Romberg test) 7, 9
• The slow progression and normal lifespan distinguish SCA14 from more aggressive cerebellar degenerations 1
• Pure cerebellar presentation without significant extrapyramidal signs, ophthalmoplegia, or intellectual disturbance differentiates many SCA14 cases from other SCA subtypes 2