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Spinocerebellar Ataxia Type 1

SCA1

Spinocerebellar ataxia type 1 is an autosomal dominant genetic disease in which progressive central nervous system degeneration (primarily of the cerebellum) results in the appearance of gait disorders, dysarthria, and severe motor impairment. The severity of the disorder and clinical progression markedly varies from patient to patient. The diagnosis is made on clinical grounds, findings obtained from a detailed family history, and genetic testing to confirm ataxin-1 mutations.


Presentation

Spinocerebellar ataxias (SCAs) are a group of more than 40 distinct disorders of progressive neuronal degeneration, principally involving the cerebellum and the motor tracts involved in signaling to and from this part of the central nervous system [1] [2] [3] [4]. Each type arises due to a specific genetic mutation and in the case of spinocerebellar ataxia type 1 (SCA1), the ataxin-1 gene (located on chromosome 6) is expanded by trinucleotide repeats (CAG) [3] [4] [5], which through still unexplained mechanisms, leads to a variable degree of central nervous system damage. The onset of symptoms is reported to be around 30-40 years of age in the majority of patients, while gender predilection has not been established [1] [6]. Symptoms related to the function of the cerebellum are the cornerstone of spinocerebellar ataxia type 1, with the inability to control body movements (ataxia) resulting in gait impairment and an improper balance being the main complaints [3] [4]. In addition, dysarthria and ocular symptoms (diplopia, difficulties with focusing objects, saccadic nystagmus, gaze palsies, blepharospasm, and ptosis) are frequently encountered in this patient population [3] [4] [5]. Some reports have identified cognitive dysfunction (memory impairment, defects in executive functioning) and focal dystonias (writer's cramp) in the clinical presentation [4] [5]. Unfortunately, ataxia eventually affects all four limbs and necessitates the use of wheelchairs within 15-20 years in virtually all individuals who suffer from this condition [3].

Abnormal Eye Movement
  • Ileok Jung and Ji-Soo Kim, Abnormal Eye Movements in Parkinsonism and Movement Disorders, Journal of Movement Disorders, 10.14802/jmd.18034, 12, 1, (1-13), (2019).[doi.org]
  • In addition to ataxia, an abnormal eye movement known as nystagmus may appear on the neurological examination. SCA7 SCA7 only comprises 2 to 5 percent of autosomal dominant spinocerebellar ataxias.[verywell.com]
  • This form of hereditary cerebellar ataxia was clinically distinct from that described by Friedreich and was characterized by adult onset, abnormal eye movements, increased tendon reflexes, marked atrophy of the cerebellum and an autosomal dominant inheritance[scielo.br]
Ataxia
  • Of the 302 patients with a diagnosis of cerebellar ataxia in 3 Korean University Hospitals from June 2011 to June 2012, 48 patients with spinocerebellar ataxia types 1, 2, 3, 6, 7, or 8 or with undetermined spinocerebellar ataxias were enrolled.[ncbi.nlm.nih.gov]
  • Keywords Spinocerebellar ataxia Autosomal dominant ataxia Autosomal recessive ataxia Sporadic ataxia This is a preview of subscription content, log in to check access. Notes Disclosures There was no sponsorship for this study.[doi.org]
  • […] atrophy, Cerebellum & Ataxias, 3, 1, (2016).[doi.org]
  • We describe the unusual case of a 51-year-old woman with spinocerebellar ataxia type 1 (SCA1) who showed choreiform movements in addition to cerebellar ataxia.[ncbi.nlm.nih.gov]
Cerebellar Ataxia
  • Cerebellar ataxia was found in 25 individuals belonging only to the former community (7.2%).[ncbi.nlm.nih.gov]
  • We describe the unusual case of a 51-year-old woman with spinocerebellar ataxia type 1 (SCA1) who showed choreiform movements in addition to cerebellar ataxia.[ncbi.nlm.nih.gov]
  • Autosomal dominant cerebellar ataxia type 1 (ADCA1) is a clinical and genetic heterogeneous neurodegenerative disorder which leads to progressive cerebellar ataxia.[ncbi.nlm.nih.gov]
  • The results were correlated with the disease duration and severity of the clinical deficit assessed with the International Cerebellar Ataxia Rating Scale (ICARS) and Inherited Ataxia Clinical Rating Scale (IACRS).[doi.org]
  • Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 2010;9(9):885–94. PubMed CrossRef Google Scholar 11. Fogel BL, Perlman S. Clinical features and molecular genetics of autosomal recessive cerebellar ataxias.[doi.org]
Tremor
  • Among SCA2 patients, bradykinesia was the most frequent (35.3%), followed by reduced facial expression, postural tremor and dystonia (29.4% each), rest tremor, titubation and rigidity (23.5% each), and lip/jaw tremor and chorea (11.8% each).[ncbi.nlm.nih.gov]
  • Rating Scale: Part A Tremor location/severity rating Part B Handwriting and drawings Part C Functional disabilities resulting from tremor Questionnaires related to sleep, depression (Beck Depression Inventory) (BDI), alertness (Computerized Continuous[clinicaltrials.gov]
  • The clinical features of individuals carrying 39 uninterrupted CAG repeats did not differ from the SCA1 phenotype in general with dysphagia, pale discs, pyramidal signs and cerebellar tremor being more frequent as compared to other SCA genotypes.[ncbi.nlm.nih.gov]
  • Tremor in SCA-12 might respond to medications used for essential tremor. SCA12 is caused by a repeat expansion. If both genes have 4-32 repeats, then the individual does not have SCA12.[ataxiacenter.umn.edu]
  • A wide stance, gait difficulties, and tremor (intentional) on finger-nose testing are some of the main findings in patients with spinocerebellar ataxia type 1, whereas assessment of speech and eye movement to identify dysarthria and associated anomalies[symptoma.com]
Nystagmus
  • All patients underwent a video-oculographic recording of fixation abnormalities, gaze-evoked nystagmus, positional and head-shaking nystagmus, and dysmetric saccades.[ncbi.nlm.nih.gov]
  • All patients underwent a video‐oculographic recording of fixation abnormalities, gaze‐evoked nystagmus, positional and head‐shaking nystagmus, and dysmetric saccades.[doi.org]
  • Disease definition Spinocerebellar ataxia type 1 (SCA1) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term) characterized by dysarthria, writing difficulties, limb ataxia, and commonly nystagmus and saccadic abnormalities[orpha.net]
  • Neurological examination 5 years after onset revealed slow eye movement with nystagmus as well as limb and truncal ataxia. Magnetic resonance imaging showed atrophy of the cerebellum and brainstem.[ncbi.nlm.nih.gov]
  • In addition, dysarthria and ocular symptoms (diplopia, difficulties with focusing objects, saccadic nystagmus, gaze palsies, blepharospasm, and ptosis) are frequently encountered in this patient population.[symptoma.com]
Cerebellar Disease
  • Frohman, Neuro-ophthalmic Manifestations of Cerebellar Disease, Neurologic Clinics, 10.1016/j.ncl.2014.07.002, 32, 4, (1009-1080), (2014). Angela Jinsook Oh, Tiffany Chen, Mohammad Ali Shariati, Naz Jehangir, Thomas N.[doi.org]
  • Duration of disease was similar in the Huntington’s disease and degenerative cerebellar diseases groups.[doi.org]
  • However in cerebellar disease this response is completely absent causing to limb to continue moving in the desired direction. (Be careful that you protect the patient from the unarrested movement causing them to strike themselves.)[stanfordmedicine25.stanford.edu]
  • Register AN ATTEMPT TO CLASSIFY CEREBELLAR DISEASE, WITH A NOTE ON MARIE'S HEREDITARY CEREBELLAR ATAXIA - 24 Hours access EUR 36.00 GBP 28.00 USD 45.00 Rental This article is also available for rental through DeepDyve.[doi.org]
  • Long-term effects of coordinative training in degenerative cerebellar disease.[ncbi.nlm.nih.gov]

Workup

Because of the rare occurrence of spinocerebellar ataxia type 1 in clinical practice (1-2 per 100,000 individuals) [5], the diagnosis may be difficult to establish without a comprehensive clinical investigation. One of the most important components of the workup is a thorough patient history, during which the familial presence of symptoms can be the first sign pointing toward an inherited disorder. The age of onset, as well as the progression of symptoms, should be noted. A detailed physical examination must follow and the physician must particularly focus on the neurological exam and evaluation of the cerebellum. A wide stance, gait difficulties, and tremor (intentional) on finger-nose testing are some of the main findings in patients with spinocerebellar ataxia type 1 [3], whereas assessment of speech and eye movement to identify dysarthria and associated anomalies, respectively, are equally important steps. Once sufficient evidence toward this disorder is attained, genetic testing may be indicated [3] [5]. Confirmation of trinucleotide repeats on the ataxin-1 gene through various molecular methods are a definite measure for establishing a diagnosis of spinocerebellar ataxia type 1 [3] [5].

MRI Shows Cerebellar Atrophy
  • Clinical features Late-onset ataxia Slowly progressive Lower limb more affected than upper limb Dysarthria, ocular dysmetria Spasmodic torticollis in some Brain MRI shows cerebellar atrophy in some No anticipation Cognitive deterioration, epilepsy, signs[emedicine.com]
Microcytosis
  • Abstract We report a family affected by autosomal dominant ataxia, in which numerous members also showed microcytosis.[ncbi.nlm.nih.gov]

Treatment

  • There is currently not a cure for SCA1, but treatments are available to help manage symptoms.[rarediseases.info.nih.gov]
  • We occasionally observe long-term remission of cervical dystonia after several botulinum toxin treatments. However, botulinum toxin transiently acts on neuromuscular junctions.[ncbi.nlm.nih.gov]
  • Abstract We occasionally observe long-term remission of cervical dystonia after several botulinum toxin treatments. However, botulinum toxin transiently acts on neuromuscular junctions.[doi.org]
  • […] of Spinocerebellar Ataxia Medical research yet now unable to discover the curative treatment for spinocerebellar ataxia, even the available treatment is not able to control the disease progression.[healthsaline.com]
  • ., any condition can be approved for medical marijuana as long as a DC-licensed physician recommends the treatment.[medicalmarijuanainc.com]

Prognosis

  • Prognosis Prognosis is poor. In the late stages of the disease, usually 10 to 15 years following onset, bulbar dysfunction secondary to affection of lower medullary nuclei results in aspiration which is life-threatening.[orpha.net]
  • The prognosis is bleak, with a gradual progression to disability and death within 10-20 years. Ref: Orr, H.T. et al. (1993). Expansion of an unstable CAG trinucleotide repeat in spinocerebellar ataxia type I. Nature Genet. 4, 221-26.[gpnotebook.co.uk]

Etiology

  • Etiology SCA1 is caused by CAG repeat expansions in the ATXN1 gene region on chromosome 6p23. Prognosis Prognosis is poor.[orpha.net]
  • Given that these were cases of sporadic ataxia, acquired causes would be predicted to be more common etiologies in this population (Fogel and Perlman, 2006 ; Klockgether, 2010 ; Fogel and Perlman, 2011 ).[doi.org]

Epidemiology

  • Summary Epidemiology Prevalence is estimated to be 1-2 in 100,000 with significant geographical and ethnic variations. Clinical description The disease typically presents in the 4th decade (age range 4-74 years).[orpha.net]
  • An epidemiological study of cerebellar ataxia was done in two villages in the Indian state of Tamilnadu where its prevalence was observed to be high. All the people were screened and the clinical characteristics of those with ataxia were recorded.[ncbi.nlm.nih.gov]
Sex distribution
Age distribution

Pathophysiology

  • This suggests a possible pathophysiologic relationship between SCA1 and familial occurrence of spontaneous pneumothorax.[ncbi.nlm.nih.gov]
  • However, both the sporadic and inherited cases of cerebellar ataxia exhibit common pathophysiological characteristics such as the specific degeneration of the main cerebellar neurons; the Purkinje cells.[neurodegenerationresearch.eu]
  • Clinical, genetic, molecular, and pathophysiological insights into spinocerebellar ataxia type 1. Cerebellum. 2008;7(2):106-14. doi: 10.1007/s12311-008-0009-0. Review. Zoghbi HY, Orr HT.[ghr.nlm.nih.gov]
  • Ruegsegger C et al (2016) Impaired mTORC1-dependent expression of homer-3 influences SCA1 pathophysiology. Neuron 89(1):129–146 CrossRef Google Scholar 25.[doi.org]
  • – A saccade study on pathophysiology, Clinical Neurophysiology, 10.1016/j.clinph.2015.07.035, 127, 2, (1491-1502), (2016).[doi.org]

Prevention

  • Notably, MitoQ slowed down the appearance of SCA1-linked neuropathology such as lack of motor coordination as well as prevented oxidative stress-induced DNA damage and PC loss.[ncbi.nlm.nih.gov]
  • Therefore, synthesis and review of research from the SCA1 field is valuable for future clinical and diagnostic work in the treatment and prevention of SCA1.[ncbi.nlm.nih.gov]
  • RNA interference (RNAi) of ataxin-1 preserved cerebellar lobule integrity and prevented disease-related transcriptional changes for over a year. Notably, RNAi therapy also preserved rotarod performance and neurohistology.[ncbi.nlm.nih.gov]
  • We reported previously that mutant ataxin-1, a causative gene product of spinocerebellar ataxia type 1 (SCA1), prevents Bergmann glia proliferation in mutant ataxin-1 knockin mice and that suppressed Bergmann glia function leads to Purkinje cell degeneration[ncbi.nlm.nih.gov]
  • Appropriate counseling, prenatal evaluation and therapy will prevent the spread of disease to the next generation.[ncbi.nlm.nih.gov]

References

Article

  1. Ashizawa T, Figueroa KP, Perlman SL, et al. Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US; a prospective observational study. Orphanet J Rare Dis. 2013;8:177.
  2. Rüb U, Bürk K, Timmann D, et al. Spinocerebellar ataxia type 1 (SCA1): new pathoanatomical and clinico-pathological insights. Neuropathol Appl Neurobiol. 2012;38(7):665-680.
  3. Paulson HL. The Spinocerebellar Ataxias. J Neuroophthalmol. 2009;29(3):227-237.
  4. Khwaja GA, Srivastava A, Ghuge VV, Chaudhry N. Writer’s cramp in spinocerebellar ataxia Type 1. J Neurosci Rural Pract. 2016;7(4):584-586.
  5. Subramony SH, Ashizawa T. Spinocerebellar Ataxia Type 1. 1998 Oct 1 [Updated 2014 Jul 3]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  6. Jacobi H, Bauer P, Giunti P, et al. The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: A 2-year follow-up study. Neurology. 2011;77(11):1035-1041.

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Last updated: 2019-07-11 20:17