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Spinocerebellar ataxia 1(SCA1)

MedGen UID:
155703
Concept ID:
C0752120
Disease or Syndrome
Synonyms: Cerebelloparenchymal disorder 1; CEREBELLOPARENCHYMAL DISORDER I; Olivopontocerebellar atrophy 1; Olivopontocerebellar atrophy 4; OLIVOPONTOCEREBELLAR ATROPHY I; OLIVOPONTOCEREBELLAR ATROPHY IV; SCA1; Spinocerebellar atrophy 1; SPINOCEREBELLAR ATROPHY I
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
Genetic anticipation with paternal anticipation bias
MedGen UID:
319018
Concept ID:
C1834002
Finding
Source: HPO
A type of genetic anticipation observed predominantly upon transmission from affected males.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Spinocerebellar ataxia type 1 (715748006)
 
Gene (location): ATXN1 (6p22.3)
OMIM®: 164400
Orphanet: ORPHA98755

Definition

Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions. Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia. Later signs include slowing of saccadic velocity, development of up-gaze palsy, dysmetria, dysdiadochokinesia, and hypotonia. In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction are seen. Onset is typically in the third or fourth decade, although childhood onset and late adult onset have been reported. Those with onset over age 60 years may manifest a pure cerebellar phenotype. Interval from onset to death varies from ten to 30 years; individuals with juvenile onset show more rapid progression and more severe disease. Anticipation is observed. An axonal sensory neuropathy detected by electrophysiologic testing is common; brain imaging typically shows cerebellar and brain stem atrophy. [from GeneReviews]

Additional descriptions

From OMIM
The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias,' (SCAs) even though 'spinocerebellar' is a hybrid term, referring to both clinical signs and neuroanatomical regions (Margolis, 2003). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord, and the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (Schols et al., 2004; Taroni and DiDonato, 2004). Historically, Harding (1982) proposed a clinical classification for autosomal dominant cerebellar ataxias (ADCAs). ADCA I was characterized by cerebellar ataxia in combination with various associated neurologic features, such as ophthalmoplegia, pyramidal and extrapyramidal signs, peripheral neuropathy, and dementia, among others. ADCA II was characterized by the cerebellar ataxia, associated neurologic features, and the additional findings of macular and retinal degeneration. ADCA III was a pure form of late-onset cerebellar ataxia without additional features. SCA1, SCA2 (183090), and SCA3, or Machado-Joseph disease (109150), are considered to be forms of ADCA I. These 3 disorders are characterized at the molecular level by CAG repeat expansions on 6p24-p23, 12q24.1, and 14q32.1, respectively. SCA7 (607640), caused by a CAG repeat expansion in the ATXN7 gene (607640) on chromosome 3p13-p12, is a form of ADCA II. SCA5 (600224), SCA31 (117210), SCA6 (183086), and SCA11 (600432) are associated with phenotypes most suggestive of ADCA III. However, Schelhaas et al. (2000) noted that there is significant phenotypic overlap between different forms of SCA as well as significant phenotypic variability within each subtype. Classic reviews of olivopontocerebellar atrophies and of inherited ataxias in general include those of Konigsmark and Weiner (1970), who identified 5 types of olivopontocerebellar atrophy, Berciano (1982), Harding (1993), Schelhaas et al. (2000), and Margolis (2003).  http://www.omim.org/entry/164400
From GHR
Spinocerebellar ataxia type 1 (SCA1) is a condition characterized by progressive problems with movement. People with this condition initially experience problems with coordination and balance (ataxia). Other signs and symptoms of SCA1 include speech and swallowing difficulties, muscle stiffness (spasticity), and weakness in the muscles that control eye movement (ophthalmoplegia). Eye muscle weakness leads to rapid, involuntary eye movements (nystagmus). Individuals with SCA1 may have difficulty processing, learning, and remembering information (cognitive impairment).Over time, individuals with SCA1 may develop numbness, tingling, or pain in the arms and legs (sensory neuropathy); uncontrolled muscle tensing (dystonia); muscle wasting (atrophy); and muscle twitches (fasciculations). Rarely, rigidity, tremors, and involuntary jerking movements (chorea) have been reported in people who have been affected for many years.Signs and symptoms of the disorder typically begin in early adulthood but can appear anytime from childhood to late adulthood. People with SCA1 typically survive 10 to 20 years after symptoms first appear.  https://ghr.nlm.nih.gov/condition/spinocerebellar-ataxia-type-1

Clinical features

Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Muscular hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength. Hypotonia is characterized by a diminished resistance to passive stretching.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Bulbar palsy
MedGen UID:
220977
Concept ID:
C1301959
Disease or Syndrome
Bulbar weakness (or bulbar palsy) refers to bilateral impairment of function of the lower cranial nerves IX, X, XI and XII, which occurs due to lower motor neuron lesion either at nuclear or fascicular level in the medulla or from bilateral lesions of the lower cranial nerves outside the brain-stem. Bulbar weakness is often associated with difficulty in chewing, weakness of the facial muscles, dysarthria, palatal weakness and regurgitation of fluids, dysphagia, and dysphonia.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVSpinocerebellar ataxia 1
Follow this link to review classifications for Spinocerebellar ataxia 1 in Orphanet.

Professional guidelines

PubMed

van de Warrenburg BP, van Gaalen J, Boesch S, Burgunder JM, Dürr A, Giunti P, Klockgether T, Mariotti C, Pandolfo M, Riess O
Eur J Neurol 2014 Apr;21(4):552-62. Epub 2014 Jan 13 doi: 10.1111/ene.12341. PMID: 24418350
Gasser T, Finsterer J, Baets J, Van Broeckhoven C, Di Donato S, Fontaine B, De Jonghe P, Lossos A, Lynch T, Mariotti C, Schöls L, Spinazzola A, Szolnoki Z, Tabrizi SJ, Tallaksen CM, Zeviani M, Burgunder JM, Harbo HF; EFNS.
Eur J Neurol 2010 Feb;17(2):179-88. Epub 2009 Dec 28 doi: 10.1111/j.1468-1331.2009.02873.x. PMID: 20050888

Recent clinical studies

Etiology

Öz G, Kittelson E, Demirgöz D, Rainwater O, Eberly LE, Orr HT, Clark HB
Neurobiol Dis 2015 Feb;74:158-66. Epub 2014 Nov 29 doi: 10.1016/j.nbd.2014.11.011. PMID: 25446943Free PMC Article
Kumaran D, Balagopal K, Tharmaraj RG, Aaron S, George K, Muliyil J, Sivadasan A, Danda S, Alexander M, Hasan G
BMC Med Genet 2014 Oct 25;15:114. doi: 10.1186/s12881-014-0114-5. PMID: 25344417Free PMC Article
Reetz K, Costa AS, Mirzazade S, Lehmann A, Juzek A, Rakowicz M, Boguslawska R, Schöls L, Linnemann C, Mariotti C, Grisoli M, Dürr A, van de Warrenburg BP, Timmann D, Pandolfo M, Bauer P, Jacobi H, Hauser TK, Klockgether T, Schulz JB; axia Study Group Investigators.
Brain 2013 Mar;136(Pt 3):905-17. Epub 2013 Feb 18 doi: 10.1093/brain/aws369. PMID: 23423669
Prakash N, Hageman N, Hua X, Toga AW, Perlman SL, Salamon N
Neuroimage 2009 Aug;47 Suppl 2:T72-81. Epub 2009 May 14 doi: 10.1016/j.neuroimage.2009.05.013. PMID: 19446636
Savić D, Topisirović I, Keckarević M, Keckarević D, Major T, Culjković B, Stojković O, Rakocević-Stojanović V, Mladenović J, Todorović S, Apostolski S, Romac S
Psychiatr Genet 2001 Dec;11(4):201-5. PMID: 11807410

Diagnosis

Öz G, Kittelson E, Demirgöz D, Rainwater O, Eberly LE, Orr HT, Clark HB
Neurobiol Dis 2015 Feb;74:158-66. Epub 2014 Nov 29 doi: 10.1016/j.nbd.2014.11.011. PMID: 25446943Free PMC Article
Kumaran D, Balagopal K, Tharmaraj RG, Aaron S, George K, Muliyil J, Sivadasan A, Danda S, Alexander M, Hasan G
BMC Med Genet 2014 Oct 25;15:114. doi: 10.1186/s12881-014-0114-5. PMID: 25344417Free PMC Article
Reetz K, Costa AS, Mirzazade S, Lehmann A, Juzek A, Rakowicz M, Boguslawska R, Schöls L, Linnemann C, Mariotti C, Grisoli M, Dürr A, van de Warrenburg BP, Timmann D, Pandolfo M, Bauer P, Jacobi H, Hauser TK, Klockgether T, Schulz JB; axia Study Group Investigators.
Brain 2013 Mar;136(Pt 3):905-17. Epub 2013 Feb 18 doi: 10.1093/brain/aws369. PMID: 23423669
Prakash N, Hageman N, Hua X, Toga AW, Perlman SL, Salamon N
Neuroimage 2009 Aug;47 Suppl 2:T72-81. Epub 2009 May 14 doi: 10.1016/j.neuroimage.2009.05.013. PMID: 19446636
Barnes CS, Yan J, Wilmot GR
Doc Ophthalmol 2009 Jun;118(3):247-56. Epub 2008 Nov 21 doi: 10.1007/s10633-008-9156-3. PMID: 19023607

Therapy

Hearst SM, Shao Q, Lopez M, Raucher D, Vig PJ
J Neurochem 2014 Oct;131(1):101-14. Epub 2014 Jun 23 doi: 10.1111/jnc.12782. PMID: 24903464
Tanaka M, Machida Y, Nukina N
J Mol Med (Berl) 2005 May;83(5):343-52. Epub 2005 Mar 10 doi: 10.1007/s00109-004-0632-2. PMID: 15759103

Prognosis

Németh AH, Kwasniewska AC, Lise S, Parolin Schnekenberg R, Becker EB, Bera KD, Shanks ME, Gregory L, Buck D, Zameel Cader M, Talbot K, de Silva R, Fletcher N, Hastings R, Jayawant S, Morrison PJ, Worth P, Taylor M, Tolmie J, O'Regan M; UK Ataxia Consortium., Valentine R, Packham E, Evans J, Seller A, Ragoussis J
Brain 2013 Oct;136(Pt 10):3106-18. Epub 2013 Sep 11 doi: 10.1093/brain/awt236. PMID: 24030952Free PMC Article
Frontali M, Sabbadini G, Novelletto A, Jodice C, Naso F, Spadaro M, Giunti P, Jacopini AG, Veneziano L, Mantuano E, Malaspina P, Ulizzi L, Brice A, Durr A, Terrenato L
Ann Hum Genet 1996 Sep;60(Pt 5):423-35. PMID: 8912795

Clinical prediction guides

Kumaran D, Balagopal K, Tharmaraj RG, Aaron S, George K, Muliyil J, Sivadasan A, Danda S, Alexander M, Hasan G
BMC Med Genet 2014 Oct 25;15:114. doi: 10.1186/s12881-014-0114-5. PMID: 25344417Free PMC Article
Hearst SM, Shao Q, Lopez M, Raucher D, Vig PJ
J Neurochem 2014 Oct;131(1):101-14. Epub 2014 Jun 23 doi: 10.1111/jnc.12782. PMID: 24903464
Reetz K, Costa AS, Mirzazade S, Lehmann A, Juzek A, Rakowicz M, Boguslawska R, Schöls L, Linnemann C, Mariotti C, Grisoli M, Dürr A, van de Warrenburg BP, Timmann D, Pandolfo M, Bauer P, Jacobi H, Hauser TK, Klockgether T, Schulz JB; axia Study Group Investigators.
Brain 2013 Mar;136(Pt 3):905-17. Epub 2013 Feb 18 doi: 10.1093/brain/aws369. PMID: 23423669
Vig PJ, Shao Q, Subramony SH, Lopez ME, Safaya E
Cerebellum 2009 Sep;8(3):231-44. Epub 2009 Jul 11 doi: 10.1007/s12311-009-0125-5. PMID: 19593677Free PMC Article
Frontali M, Sabbadini G, Novelletto A, Jodice C, Naso F, Spadaro M, Giunti P, Jacopini AG, Veneziano L, Mantuano E, Malaspina P, Ulizzi L, Brice A, Durr A, Terrenato L
Ann Hum Genet 1996 Sep;60(Pt 5):423-35. PMID: 8912795

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