aberrant interactions with growth factor independent transcription repressor 1 that leads to gfi1 degradation in the proteasome. the expanded polyglutamine region results in increased affinity of the ataxin 1 axh domain for certain transcription factors, and this effect is believed to play a significant role in ataxin 1 toxicity. another protein shown to have significant interactions with ataxin 1 is the leucine-rich acidic nuclear protein or lanp. its function is unknown, but it is predominately expressed in the same neurons as ataxin 1 and has been shown to localize in the nuclei of these neurons at the same substructures as ataxin 1. lanp only interacts with the polyglutamine region of ataxin 1, and its interactions are stronger as the number of glutamine residues increases, so the two proteins are likely vital to each other's functions in neurons and lanp may also facilitate pathology of mutant ataxin 1 proteins. ataxin 1 like, also called brother of ataxin 1 or boat, has significant interactions with ataxin-1 and many associated proteins, like n-cor. ataxin 1 like has reduced expression in transgenic mice models and has been shown to moderate cytotoxicity of ataxin-1. toxicity from the mutated protein causes degradation in neural tissues. this includes loss of dendritic aborization, or branching, early in disease progression and eventual atrophy of brain tissues in later stages. sca1 causes moderate degradation of a variety of tissues, including both hemispheres of the cerebellum, the cerebellar vermis, the pons, and the brain stem. it also causes mild atrophy in cerebral cortical tissue. a recent study also found significant atrophy of the spinal cord and flattening of the posterior column and found a correlation between cord area, cag repeats, and sara scores in sca1. central nervous system tissues, unlike that of bone, muscle, or skin, lacks mechanisms for endogenously generating and differentiating new cells and for restoring long distance patterns and connections as they are lost, so as degeneration progresses the losses are permanent. diagnosis and evaluation most scas and other ataxic disorders are clinically heterogeneous, meaning clinical signs and symptoms are similar between diseases and distinguishing between diseases with a neurologic exam alone is difficult. in symptomatic persons, diagnosis of ataxia related disorders often requires a neurological exam, evaluation of neurological and family history, and molecular genetic testing. absence of a family history does not exclude hereditary causes like spinocerebellar ataxia type 1 because family history may not have been collected or may be unavailable for certain individuals and new cases may originate from anticipation in an allele with a mutable number of repeats.: 2–4 to establish a diagnosis, molecular genetic testing is currently commercially available for 14 sca types, including sca1. in cases where scas are not present in family history or where family history is unavailable, testing for the 4 most common scas will return positive results for 50% of suspected sca cases.: 11 individuals who are at risk of inheriting sca1 but are currently presymptomatic can also be screened with molecular genetic testing. genetic testing genetic testing is the only definitive way to differentiate between spinocerebellar ataxia types because of the similarity between clinical characteristics of these diseases and the large variance between cases. genetic testing is available for many sca types, including the relatively common types sca1, 2, 3, 6, and 7; and the less common sca8, 10, 12, 14, and 17. however, genetic testing is high in cost and has a low diagnostic yield, with positive diagnoses being found in only 24% of tests ordered by a subspecialist and 10% overall. genetic testing can be administered at various stages of disease progression. when genetic testing is administered after the onset of symptoms, the test is said to be diagnostic; in adults prior to onset of symptoms it is presymptomatic, and the test can be performed for prenatal or preimplantation diagnoses. the european molecular quality genetics network (emqn) recommends criteria for each type, which must be met before testing can begin. the eqmn recommends that labs receive a written clinical evaluation of symptoms by a neurologist and a disclosure of family history, or lack of history, before initiating diagnostic genetic testing. because no preventative or curative treatments are known for scas, genetic testing for at risk individuals is not recommended for all cases, and is typically issued on an individual basis. presymptomatic, prenatal, and preimplantation testing are typically requested through a genetic counsellor and require existing family history and documentation of informed consent of the consultand. spinocerebellar ataxia type 1 was one of the first late onset diseases for which presymptomatic testing was demonstrated effective and predictive; prior to the development of testing for sca1, huntington's disease was the only similar disease for which presymptomatic testing was available. molecular genetic testing of scas must be able to differentiate samples with the pathogenic allele from those without and be able to accurately measure the number of repeats in repeat expansion disorders. capillary electrophoresis (ce) is one method that has met these criteria and is recommended by the emqn. another method that is common is polyacrylamide gel electrophoresis (page). both methods require amplification of all loci of interest for a given test. amplification is done using polymerase chain reactions or pcr. the choice of primers can allow either for a single gene to be amplified or for many genes to amplified for use in a multiplex assay which can save time in cases where a panel of many tests may be required. page and ce both use timed cycles of electricity to draw pieces of dna through a porous polymer, separating analytes by a combination of ionic mobility, size and mass. ce is advantageous over page in that molecular weight measurements like mass spectrometry can be used with analytes, whereas page requires the use of southern blot to allow comparison to a sequencing ladder. for repeat lengths within the range where interruptions are relevant, assays like ce and page will not determine if the strain is pathogenic and additional testing will be required. clinical no formal diagnostic criteria exist for most scas, and genetic testing is the only certain diagnostic method, but clinical examination of signs and symptoms may be vital to distinguishing scas from non-genetic ataxias, and from other types of genetic ataxias. clinical examination can also help distinguish between sca types to some extent, so genetic tests for certain types can be prioritized over others. diagnosis of scas often begins with the detection of symptoms that suggest a cerebellar disorder, like progressive ataxia or dysarthria, or with recognition of similar symptoms to a case identified in the individuals family history, especially in first or second degree relatives. many laboratory studies can be used to further narrow the potential cause of ataxia; imaging of brain and spinal cord and various electrophysiology exams may be useful for identifying disease phenotypes and blood and urine studies may rule out acquired causes.: 4 when evaluating ataxic disorders and their treatments, there are numerous tests that a neurologist may perform. tests may be evaluated individually or follow a scale for evaluating the ataxia. a cerebellar exam may include saying phrases with many consonants to detect scanning speech, detecting horizontal gaze nystagmus by following a finger with the eyes, performing rapid alternating movements like rotating a hand from palm to back repeatedly, testing the holmes rebound phenomenon, and testing patellar reflex for hypotonia or hypertonia. common scales include the international cooperative ataxia rating scale (icars) and scale for the assessment and rating of ataxic disorders (sara) for evaluating the severity of ataxia as a symptom. icars measures on a 100 scale, where 0 is normal function and 100 is the highest possible impairment, assigning different point values for different tests. the tests are divided into categories evaluating posture and gait, kinetic functions, speech, and oculomotor functions. while these categories create useful categorization to assess which areas need to be focused on in therapies, this redundancy results in a longer test time, which can skew results of tests performed at the end of a session; and can result in contradictory scores. sara is a shorter exam, evaluated on a scale of 0 to 40, where again zero is normal function and 40 is highest possible impairment. it comprises eight tests: gait, stance, finger chase, finger-to-nose test, fast alternating hand movements, heel-shin slide, and three limb kinectic function tests. differential diagnosis differential diagnosis of scas by clinical methods is difficult because these diseases are clinically heterogenous and there is significant variance between the expression of individual cases. using clinical information for differential diagnosis is used to prioritize genetic testing not as a stand-alone diagnosis. many potential differentiating symptoms have been found, and methods of assessing many symptoms and their progression to guide genetic testing have been developed. even if a specific type of spinocerebellar ataxia cannot be immediately determined clinical history, family history, clinical examination can help distinguish between other ataxias and can help reduce the number of genetic tests needed to identify a type of sca. examination of relatives of individuals thought to have sporadic ataxia can often reveal enough family history to identify a transmission mode. there are some common trends that may be useful to discriminate scas. sca1 tends to progress faster than sca2, 3, and 6, with greater annual change in sara scores and earlier loss of functions after onset. in the diagnostics of clinical ataxia, imaging may not be useful to distinguish sca1 from other scas as there is significant variance between individual cases and significant overlap between diseases. vestibulo-ocular reflex can be tested using a video recorded head impulse test or vhit. in this test, sca1 typically has normal reflex latency, and does not consistently show a deficit in vor function, distinguishing it from sca3 and friedreich's ataxia. certain patterns in ocular motor disorders, detectable with video-oculography, appear to typify certain sca types. while sca1 was not significantly correlated with a unique pattern, other possible scas can be linked and absence of a vertical nystagmus following horizontal head shaking reduces the likelihood of an sca6 diagnosis, while the absence of a square wave pattern during fixation reduces the likelihood of sca3. one possible system for the differential diagnosis of sca types is to record the progression of symptoms and use bayesian probability to build a predictive model, or a bayesian classifier, that compares the observed data to trends like those described above to find the likelihood of each diagnosis to be correct. one such bayesian classifier was shown to accurately predict 78% of sca cases out of a cohort with known types of sca. the sensitivity and specificity for sca1 within this model was 76.9% and 98.2% respectively. regional variance in prevalence, symptoms and clinical assessment might still limit the use of this system on large scales, though the system may implemented by individual clinics using their own regional data. management there is currently no cure for spinocerebellar ataxia type 1. however, some of its symptoms may be managed with physical, occupational or speech therapies, lifestyle and dietary changes, or with medications. managing symptoms will not prevent the disease from progressing but can be important for maintaining quality of life.: 48 it is important to note, however, that many disorders that cause ataxia and related symptoms exist, and that management strategies that work for some, such as vitamin e supplements for certain acquired ataxias, will not work for hereditary ataxias like sca1 and can be dangerous to a person's health.: 52 small cohort studies have shown that individuals with cerebellar disorders recover coordination and have lower sara scores regardless of stage or severity of their ataxia before therapy when they are regularly participating in physiotherapy or exergaming over individuals who are not. these studies suggest that multidomain physical therapy, more focused coordinative training, and exergaming routines all produced improvements in sara scores equivalent to at least one year of normal progression, 2.2 points or more on average, over the course of several weeks. while these results are promising, larger scale studies may be necessary to validate these results. overall, physical therapy for individuals with ataxia has modest evidence supporting its efficaciousness, but current practice uses custom treatments without a standard decision making procedure between clinics, which limits the ability to reproducibly assess the quality of routines in literature. among the earliest developed neurorehabilitation practices is