Spinocerebellar ataxia (SCA) is a subtype of a group of clinically, pathologically, and genetically heterogeneous neurodegenerative disorders of the cerebellum and its afferent and efferent connections, called autosomal dominant cerebellar ataxias.1 Of nearly 30 variations of SCA, type 2 (SCA2) is the second most prevalent variant worldwide.
Clinical features of SCA2 include a wide range of motor neuron disturbances and slow saccadic eye movements, as well as nonmotor signs such as peripheral neuropathy, autonomic dysfunction, sleep disturbances, and cognitive dysfunction, leading to significantly impaired quality of life.2-4
The symptoms are progressive, marked by increased cerebellar signs and saccade slowing, as well as worsening gait ataxia that renders many patients wheelchair- or bed-bound, and is associated with early mortality approximately 15 to 20 years after the initial onset of symptoms, most often as a result of bronchopneumonia (63%).5
A recent review published in Movement Disorder examined preclinical signs of SCA2 to identify features of a prodromal stage in which early interventions could have potential significance.6 Researchers led by Luis Velázquez-Pérez, DSc, PhD, from the Center for the Research and Rehabilitation of Hereditary Ataxias in Holguin, Cuba, and colleagues from the Karolinska Universitetssjukhuset in Stockholm, Sweden, evaluated research into SCA2 conducted between 2000 and 2016 to identify the most common preclinical features in genetically susceptible populations and establish a prodromal timeline of occurrence before onset of ataxia.
As with other neurological diseases, SCA2 develops over time, with the progression of both motor and nonmotor symptoms helping to define clinical stages of the disease. The preclinical phases are harder to define. Stage 1 is asymptomatic and largely undetectable, despite underlying pathophysiologic processes. During prodromal stage 2 SCA2, positive functional nonmotor and motor signs may be detected on clinical examination, along with evidence of atrophy on imaging studies to the brain stem and cerebellum,7 although none of these signs reaches levels sufficient to confirm a diagnosis of SCA2.
Genetic Mutations to the ATXN2
The ataxin-2 gene (ATXN2) is directly associated with the development of SCA2. More than 32 cytosine, adenine, and guanine trinucleotide repeats are known in SGA2, after which further alleles are highly unstable, with expansion involving dropped interrupting CAA-triplets most commonly at allele 37 (72%).5 The vast majority (89%) of offspring of SGA2 confirmed patients have been shown to have expansions, whereas the remaining 11% have contracted cytosine, adenine, and guanine repeats with incomplete penetrance.5
Limited epidemiologic studies have pointed to families of SCA2 genetically susceptible individuals in India, Martinique, Australia, Tunisia, Germany, Italy, Mexico, and Poland,8-10 as well as founder effect documents in populations found in Cuba.11-13
According to a 2009 publication by Dr Velázquez-Pérez, SCA2 represents 87% of autosomal dominant cerebellar ataxias in Cuba.13
“If asymptomatic at-risk individuals are included in the prevalence analysis, the prevalence rate increases up to 28.51 cases per 105 inhabitants, with remarkable values in various eastern provinces, especially in Holguin,” he wrote. The ATXN2 mutation affects an estimated 600 patients from 163 families in Cuba, for a national prevalence rate of 28.51 cases per 10,000 inhabitants, including at-risk, asymptomatic individuals. In Holguin, that rate increases exponentially to 183 per 10,000.3,12 This extraordinarily high prevalence has driven research into the Holguin population, where a presymptomatic diagnostic research program has provided molecular diagnoses of 1200 individuals since 2003.14