Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant disorder, which, like other spinocerebellar ataxias, is characterized by neurological symptoms including dysarthria, hypermetric saccades, and ataxia of gait and stance. This cerebellar dysfunction is progressive and permanent. First onset of symptoms is normally between 30 and 40 years of age, though juvenile onset can occur. Death typically occurs within 10 to 30 years from onset.
SCA1 is typically inherited from the parents in an autosomal dominant regime; the children of a person with the disease have a 50% chance of inheriting it themselves, and new mutations can occur in some cases. It is caused by an expanded number of trinucleotide repeats in the polyglutamine tract of the ATXN1 gene, which encodes the ataxin 1 protein. This expansion results in a larger than normal number of repeats of the nucleotide sequence cytosine, adenine, guanine, or CAG, in the gene which, in turn, results in a larger than normal number of consecutive glutamine amino acid residues in the protein. This mutant protein causes degradation in certain types of neurons, like Purkinje neurons, which are common in the cerebellum, spinal cord, and related parts of the brain. While the mechanism is not fully understood, it is suspected that changes in the interactions between ataxin 1 and other proteins result in a toxic gain of function.
The mutation can be detected before or after the onset of symptoms by genetic testing. Currently, no cure for SCA1 is known, so treatment of the disease focuses primarily on management of symptoms to maintain quality of life, focusing on physical therapy to retrain and replace lost functions. Research to develop treatments is ongoing and in addition to conventional pharmaceutical treatment, SCA1 has been the subject of research into more advanced treatment options such as gene therapy and stem cell therapy. Worldwide, an expected 1 to 2 people in 100,000 have spinocerebellar ataxia type 1, however, the prevalence varies between populations and is often linked to the founders effect.
Ataxia as a symptom has been known since the mid 19th century and the heterogeneous group of diseases now known as spinocerebellar ataxias was the subject of extensive research in the latter part of that century. Advances in molecular genetics in the 20th century allowed distinct causes of these diseases to be identified. In the early 1990s the gene causing SCA1 was localized to the human leukocyte antigen complex on chromosome 6 and by 1993, ataxin 1 was identified as the causative gene. It was the first spinocerebellar ataxia-causing gene to be localized and identified.
Signs and symptoms Ataxia refers to a lack of coordinated muscle movements that include gait abnormality and is the cerebellar sign that typifies all spinocerebellar ataxia (SCA) types, though individuals with SCA1 also develop pyramidal and bulbar signs as the disease progresses. The average age of onset is between 30 and 40 years of age, though exceptions exist. From the first symptoms, duration is typically between one and three decades, where earlier onset correlates with faster progression.
Spinocerebellar ataxia 1, like other SCAs, often causes dysarthria, a motor disorder of speech often manifest as slurring of words; pathological nystagmus, a disorder in which eyes drift involuntarily affecting vision; and gait and balance issues. SCA1 is also commonly present with dysphagia, a swallowing disorder that can cause choking while eating and drinking; and hypermetric saccades, where the eye tends to move faster or further than intended as it tracks an object or moves from one focus to another. As the disease progresses, more severe neurologic symptoms can appear like dysmetria, where limb movements consistently overshoot the desired position; dysdiadochokinesia, where repeated body movements become uncoordinated; or hypotonia, where muscles atrophy. While new symptoms appear as SCA1 progresses, nystagmus may disappear as eye movements and saccades slow down. Fatality may ultimately be caused by loss of bulbar functions, but complications from symptoms, such as pneumonia from swallowing problems, or trauma from falls, can be fatal as well. The severity and exact phenotype of these symptoms may vary between types of SCA. SCA 1 dysarthria may vary in severity depending on the task and is often associated with more strained, strangled or harsh sounding vocalization than that of other disorders.
Because of the significant variance between cases of SCA1, typical signs and symptoms may appear alongside more subtle or rare symptoms. Maculopathy has been reported in rare cases, and may be linked effects from the mutation on the ATXN1 locus on genes in neighboring loci. Task specific dystonias have been reported in individual cases, often in the form of writer's cramps or cervical dystonia.
SCAs can also be detected before serious atrophy with electrophysiologic techniques, using electrodes on the scalp to detect changes in electric potential within the brain in response to sensations or movements. Individuals with SCA1 often exhibit abnormal brainstem auditory evoked potential, including prolonged latency and absent or poorly defined waveforms, with one study reporting 73.3% of test subjects exhibiting abnormalities. The same study also found abnormalities in visual evoked potential and median somatosensory evoked potential in some SCA1 persons. These results were similar to those exhibited in other SCAs and differences between the SCAs were not statistically significant, so electrophysiologic techniques cannot replace genetic testing for specific diagnoses of SCAs.
All SCAs cause atrophy in various neural tissues that are detectable using magnetic resonance imaging, computed tomography, or other imaging techniques. In SCA1 some degradation in the grey matter of the cerebellum and brain stem can sometimes be detected in presymptomatic individuals with the expansion in ATXN1. Typically, grey matter loss can be observed in cerebellar vermis in all lobules of the cerebellum and in the paramedian portions of both hemispheres. White matter loss can also be observed in the middle cerebellar peduncles. The volume loss can be correlated to severity and duration.
An estimated 77% of cases of progressive cerebellar disease are reported to have one or more mental health disorders, and 19% exhibit cognitive disorders. These estimates are consistently higher than the portion with mental health disorders in the general population, but still follow other general patterns, like correlations between depression frequency and sex or age. It is unclear if depression can be linked causally to cerebellar degeneration; one study reports data consistent with depression primarily being a response to the disability, not a symptom of it, while another reports evidence that depression may have a causal link; prevalence of depression varies differently between SCA types than does the rate of progression of disability.
Genetics
Spinocerebellar ataxia type 1 is caused by a mutation in the ATXN1 gene. This mutation is passed down through an autosomal dominant inheritance pattern, meaning that the disease does not skip generations, at least one parent must have the disease for the children to inherit it, and that the odds of any given child inheriting SCA 1, regardless of gender or other phenotypes, is 50% if the affected parent is heterozygous. The ATXN1 gene on chromosome 6 encodes the ataxin 1 protein, which is used in signaling pathways and gene regulation, and is heavily expressed in Purkinje neurons. The coding region for Ataxin 1 (6p22.3) contains a polyglutamine tract of variable length. SCA1 is present in individuals where the region on at least one copy of chromosome 6 contains 39 or more continuous repeats of glutamine in which more repeats are correlated to earlier onset and faster progression. Histidine interruptions in the polygluatamine tract can mitigate or prevent SCA1.
SCA1 is known to exhibit genetic anticipation, where one generation with the disease may exhibit earlier onset and faster progression than the previous generation. This is typically caused by expansions in the polyglutamine tract between generations and is more common in cases of patrilineal inheritance. This non-Mendelian inheritance is similar to that observed in Huntington's disease and is believed to be caused by differences in various mechanisms in gamete production between the sexes that result in increased mosaicism in the male germline. DNA with CAG repeats are prone to forming secondary structures, including hairpin loops and R-loops, which can result in mutations and mosaicism if DNA repair mechanisms fail. These secondary structures cause somatic mosaicism by lagging DNA polymerase in Okazaki fragments and by disrupting DNA mismatch repair, base excision repair, nucleotide excision repair and double strand break repair mechanisms. The mechanism for germline expansions is not well understood, but it is believed that only mismatch repair pathways effect germline instability and the MSH2 repair protein has been linked to expansions in male gametes in mice models.
Pathophysiology Normal ataxin 1 is intimately involved in a number of signaling pathways, in protein ubiquitination, RNA metabolism, in transcription regulation, protein transformation, and protein stabilization. Among other interactions, it forms a transcription complex with Retinoid-related Orphan nuclear-receptor transcription factor α (RORα) following interactions with an activator, Histone acetyltransferase KAT5, sometimes referred to as TIP60, and it is in the signaling mediated by metabotropic glutamate receptor 1 (mGluR1). Resonant Recognition Modeling of the ataxin 1 protein has shown possible binding sites for growth factor independent transcription repressor 1 (Gfi-1). The predictions of this computational model reveal an interaction that could play a role in SCA1 pathology, because the Gfi-1 protein is known to cause selective degradation of Purkinje cells. It is the extensive involvement of ataxin 1 in many different functions that make understanding the biochemical pathophysiology of its mutant form difficult to identify and understand.