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Spinocerebellar Ataxia Type 20

Synonym: SCA20
, DPhil, FRACP
Director, Van Cleef Roet Centre for Nervous Diseases
Head, Department of Neuroscience
Department of Medicine (Neuroscience)
Monash University (Alfred Hospital Campus)
Neurologist to Neurogenetics Clinics, Alfred, Saint Vincent's and Royal Melbourne Hospitals
Melbourne, Victoria, Australia

Initial Posting: ; Last Update: June 7, 2012.

Summary

Disease characteristics.

Spinocerebellar ataxia type 20 (SCA20) is characterized by a slowly progressive ataxia and dysarthria. Approximately two thirds of those affected also display palatal tremor ("myoclonus") and/or abnormal phonation clinically resembling spasmodic adductor dysphonia. Dysarthria, which may be abrupt in onset, precedes the onset of ataxia in about two thirds of affected individuals, sometimes by a number of years. Hypermetric horizontal saccades (without nystagmus or disturbance of vestibulo-ocular reflex gain) are seen in about half of affected persons. Although minor pyramidal signs (brisk knee jerks, crossed adductor spread) may be seen, spasticity and extensor plantar responses are not. Cognition is normal. Clinical information is based on the findings in 16 personally examined affected members of a single Australian family of Anglo-Celtic descent.

Diagnosis/testing.

The diagnosis of SCA20 is based on clinical findings and neuroimaging. Within five years of disease onset CT scan shows pronounced dentate calcification, typically without concomitant pallidal calcification. In addition to evidence of dentate calcification, MRI shows mild to moderate pan cerebellar atrophy and normal cerebrum and brain stem (except for increased inferior olivary T2 signal in those with palatal tremor). The locus for SCA20 lies within the pericentromeric region of chromosome 11; the gene is unknown. A 260-kb duplication of 11q12.2-11q12.3 has been identified as the probable cause of SCA20 in the index family.

Management.

Treatment of manifestations: Physical and occupational therapy; guidance from a speech pathologist expert in the management of neurogenic dysphagia.

Prevention of secondary complications: Prevention of falls by using appropriate gait aids and home modifications; personal alarm system.

Genetic counseling.

SCA20 is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the mutation.

Diagnosis

Clinical Diagnosis

Clinical information on spinocerebellar ataxia type 20 (SCA20) derives from studies of the index pedigree, an Australian family of Anglo-Celtic descent [Knight et al 2004].

The diagnosis should be considered in individuals with a slowly progressive ataxia without sensory features who have the following findings:

  • Onset with dysarthria that may be of abrupt onset, rather than with gait ataxia (seen in ~66%)
  • Palatal tremor (in ~66%)
  • Family history consistent with autosomal dominant inheritance

Additional findings may include the following:

  • Hypermetric horizontal saccades (without nystagmus or disturbance of vestibulo-ocular reflex gain) in about half
  • Mild hyperreflexia (typically without spasticity or extensor plantar responses) in a minority
  • Postural tremor of arms with or without involvement of the head (seen in a minority; may be the first symptom)

Neuroimaging

  • CT scan (Figure 1) shows pronounced dentate calcification, typically without concomitant pallidal calcification, at an early stage of the illness (≤3 years from onset).
  • MRI (Figure 2) shows mild to moderate pan cerebellar atrophy, with low dentate signal on T1 and T2-weighted sequences (consistent with calcification) and normal cerebrum and brain stem (apart from increased inferior olivary T2 signal in some, as a correlate of palatal tremor).
Figure 1. 
III:12.

Figure 1


III:12. CT scan showing heavy dentate calcification and pan cerebellar atrophy in a 62-year-old individual with mild ataxia; three years after symptom onset
III:16. CT scan slices at two levels of the dentate showing heavy dentate calcification (more...)

Figure 2.. MRI axial proton density images showing (a) inferior olivary hypertrophy and (b) low dentate signal consistent with dentate calcification in a 54-year-old individual 16 years after onset
Note: Roman:arabic numeral combinations refer to pedigree numbers.

Figure 2.

MRI axial proton density images showing (a) inferior olivary hypertrophy and (b) low dentate signal consistent with dentate calcification in a 54-year-old individual 16 years after onset
Note: Roman:arabic numeral combinations refer to pedigree (more...)

Neurophysiology. Nerve conduction studies are normal.

Testing

Indices of calcium metabolism (serum concentrations of calcium, phosphate, magnesium, alkaline phosphatase, parathyroid hormone, 25-hydroxy vitamin D) are normal.

Molecular Genetic Testing

Locus. Knight et al [2008] reported a 260-kb duplication of 11q12.2-11q12.3 as the probable cause of SCA20 in the index family. The locus for SCA20 lies within the pericentromeric region of chromosome 11. The gene is unknown. Although the candidate region includes SPTBN2 (the gene in which mutation is responsible for SCA5), SPTBN2 mutations have been excluded as the cause of SCA20 [Lorenzo et al 2006].

Table 1.

Summary of Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 20

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency
UnknownLinkage analysisN/A N/A
Direct DNA 1260-kb duplicationUnknown

N/A = not applicable

1. Direct DNA methods may include mutation analysis, mutation scanning, sequence analysis, or other means of molecular genetic testing.

Testing Strategy

To confirm/establish the diagnosis in a proband. Because the gene in which mutations cause SCA20 has not been identified, the diagnosis of SCA20 is based on clinical findings.

Clinical Description

Natural History

Clinical information on spinocerebellar ataxia type 20 (SCA20) is based on the index pedigree, an Australian family of Anglo-Celtic descent that is the only family with SCA20 reported to date [Knight et al 2004, Storey et al 2005].

The 16 affected family members had onset between age 19 and 64 years (mean 47).

SCA20 presents with dysarthria without ataxia in a majority (10/16); the dysarthria may be of abrupt (2/16) or subacute (1/16) onset. It often combines the clinical appearance of spasmodic adductor dysphonia with cerebellar dysarthria. Other initial symptoms were dysarthria with simultaneous gait ataxia (2/16), gait ataxia alone (2/16), upper limb kinetic and isometric tremor (1/16), and episodic vertigo (1/16).

Progression of SCA20, as judged by cross-sectional data, appears to be relatively slow; all affected members of this family were able to walk with or without gait aids except one, who became wheelchair dependent after 40 years of symptoms. Another required a feeding gastrostomy after 15 years of symptoms.

The clinical picture usually (10/16) includes palatal tremor ("myoclonus") without ear click, although this finding can be subtle. Gaze-evoked nystagmus is unusual (3/16). In two it was impersistent; in another affected individual persistent down-beating nystagmus was evident. Saccades are typically hypermetric into down gaze (10/16) and horizontally (8/16). The vestibulo-ocular reflex gain, as judged by dynamic vs static visual acuity, is normal, correlating with absence of movement-induced oscillopsia. Minor pyramidal signs (brisk knee jerks, crossed adductor spread) are seen in a minority (5/16), but none have spastic tone or extensor plantar responses. Postural and kinetic tremor of the upper limbs, the presenting feature in one individual, was evident in only one other family member. Only one displayed intention tremor (as distinct from dysmetria and dyssynergia) on the finger/nose test.

Other extrapyramidal features (apart from slowing of repetitive movements without movement decay) are absent. None had a history of cognitive decline.

Penetrance

The penetrance is unknown, as the invovled gene has not been identified.

Anticipation

Only four parent-child pairs could be documented by self-report regarding age of onset, which was younger by an average of 12 years in the offspring. This information is inadequate to confirm or refute anticipation. Large CAG/CTG and ATTCT/AGAAT repeats have been excluded in the region of interest [Knight et al 2004].

Prevalence

The prevalence of SCA20 is unknown and must await discovery of the involved gene. The clinical and radiologic picture is very distinctive; thus, given that it has only been reported in the index family, the disorder is likely to be rare.

Differential Diagnosis

The differential diagnosis of spinocerebellar ataxia type 20 (SCA20) is essentially that of its component features, as the constellation of progressive, dominantly inherited ataxia, early dentate calcification, and (often) palatal tremor is distinctive.

Inherited ataxia. See Ataxia Overview.

Dentate calcification appears early in SCA20; it was seen in five affected individuals who had been symptomatic for five years or less.

  • While dentate calcification is common in the general population with increasing age, affecting 0.7% of those older than age 65 years in one study [Harrington et al 1981], it rarely occurs in the absence of basal ganglia calcification (as it did in 9/11 individuals in the family with SCA20).
  • Hyperparathyroidism and pseudohypoparathyroidism with basal ganglia (and dentate) calcification may be dominantly inherited, and can be excluded on biochemical testing.
  • Dentatorubral-pallidoluysian atrophy can include pallidal microcalcification in the Haw River phenotype.
  • Dominant "familial idiopathic brain calcification" (OMIM 213600) (see Familial Idiopathic Basal Ganglia Calcification) has been reported in several families, but basal ganglia calcification dominates, and the clinical presentation includes cognitive decline and parkinsonism rather than ataxia.

Palatal tremor ("myoclonus") may be seen in the following situations, while dentate calcification is not:

  • In conjunction with progressive ataxia in sporadic (i.e., not inherited) cases, possibly representing a unique degenerative syndrome [Sperling & Herrmann 1985]
  • Rarely, in multiple system atrophy-cerebellar type (MSAC)
  • In early adult-onset Alexander disease, in which bulbar palsy and spastic tetraparesis are also seen. Inheritance is autosomal dominant.
  • In a dominant branchial myoclonus syndrome with ataxia [de Yebenes et al 1988], which may be a phenotypic variant of adult-onset Alexander disease

Dysphonia (which is apparent in SCA20 rather than confirmed on formal voice analysis) may also be seen with ataxia and motor neuropathy [Barbieri et al 2001]; this latter syndrome appears to be inherited in an autosomal recessive manner. The presence of motor neuropathy and the absence of dentate calcification and palatal tremor also serve to distinguish this syndrome from SCA20.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to SimulConsult®, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 20 (SCA20), the following evaluations are recommended:

  • Careful clinical and neurologic evaluation
  • Speech assessment

Treatment of Manifestations

Affected persons should be followed by a neurologist with consultation from physiatrists and physical and occupational therapists.

Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals should maintain activity.

Canes and walkers help prevent falls. Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary.

Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria or dysphonia.

Weighted eating utensils and dressing hooks help maintain a sense of independence.

Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.

When dysphagia becomes troublesome, videofluoroscopic swallow evaluation can identify the consistency of food least likely to trigger aspiration.

Prevention of Secondary Complications

Secondary complications are unlikely in the early years of the disease.

Later, prevention of falls via appropriate gait aids and home modifications, and (if falls are frequent) a personal alarm system may be required. To limit the likelihood of fractures resulting from falls, bone density should be estimated and osteoporosis treated if present.

Vitamin supplements are recommended, particularly if caloric intake is reduced.

Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.

Surveillance

The following are appropriate:

  • Periodic speech assessment if dysphagia becomes a problem
  • Routine follow up with a neurologist about every two years or as needed

Agents/Circumstances to Avoid

Affected individuals should avoid alcohol as well as medications known to cause nerve damage (e.g., isoniazid).

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Tremor-controlling drugs do not work well for cerebellar tremors.

Education for affected individuals and their families is the cornerstone of management.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Spinocerebellar ataxia type 20 (SCA20) is inherited in an autosomal dominant manner.

Risk to Family Members

This section is written from the perspective that clinical testing for this disorder is available and results can be used for clinical purposes. However, it is the responsibility of the clinician to ascertain whether such testing is available for a specific patient.— ED.

Parents of a proband

  • Almost all individuals diagnosed with SCA20 have an affected parent.
  • A proband with SCA20 may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include neurologic assessment and CT scan of brain.

Note: Although almost all individuals diagnosed with SCA20 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

Offspring of a proband. Each child of an individual with SCA20 has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Because the gene in which mutations are responsible for SCA20 has not been identified, prenatal testing is not possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • NCBI Genes and Disease
  • Ataxia UK
    Lincoln House
    1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: 0845 644 0606 (helpline); 020 7582 1444 (office); +44 (0) 20 7582 1444 (from abroad)
    Email: helpline@ataxia.org.uk; office@ataxia.org.uk
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    9 Winchester House
    Kennington Park
    London SW9 6EJ
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: marco.meinders@euro-ataxia.eu
  • International Network of Ataxia Friends (INTERNAF)
    Email: internaf-owner@yahoogroups.com
  • Spanish Ataxia Federation (FEDAES)
    Spain
    Phone: 34 983 278 029; 34 985 097 152; 34 634 597 503
    Email: sede.valladolid@fedaes.org; sede.gijon@fedaes.org; sede.bilbao@fedaes.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Spinocerebellar Ataxia Type 20: Genes and Databases

Locus NameGene SymbolChromosomal LocusProtein Name
SCA20Unknown11p13-q11Unknown

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Spinocerebellar Ataxia Type 20 (View All in OMIM)

608687SPINOCEREBELLAR ATAXIA 20; SCA20

Normal allelic variants. None identified

Pathologic allelic variants. The 260-kb duplicated segment reported by Knight et al [2008] includes ten known and two unknown genes. It was not found in 1,129 control samples, suggesting that it is not merely a copy number variant.

Normal gene product. One of the known genes in the duplicated region, DAGLA, is potentially an attractive candidate as it is highly expressed in murine Purkinje cells.

Abnormal gene product. It is presumed that, if the duplication is indeed causative, the mechanism would be a gene dosage effect, with 150% of the normal level of product from a gene or genes within the duplicated segment resulting in cerebellar dysfunction. Other examples of a pathogenic effect from increased gene dosage include Parkinson disease from α-synuclein duplications and Alzheimer disease from trisomy 21 (and therefore effective “duplication” of APP).

References

Literature Cited

  1. Barbieri F, Pellecchia MT, Esposito E, Di Stasio E, Castaldo I, Santorelli F, Perretti A, Santoro L, De Michele G. Adult-onset familial laryngeal abductor paralysis, cerebellar ataxia, and pure motor neuropathy. Neurology. 2001;56:1412–4. [PubMed: 11376202]
  2. de Yebenes JG, Vazquez A, Rabano J, de Seijas EV, Urra DG, Obregon MC, Barquero MS, Arribas MA, Moreno JL, Alenda JR. Hereditary branchial myoclonus with spastic paraparesis and cerebellar ataxia: a new autosomal dominant disorder. Neurology. 1988;38:569–72. [PubMed: 3352913]
  3. Harrington MG, Macpherson P, McIntosh WB, Allam BF, Bone I. The significance of the incidental finding of basal ganglia calcification on computed tomography. J Neurol Neurosurg Psychiatry. 1981;44:1168–70. [PMC free article: PMC491242] [PubMed: 7334414]
  4. Knight MA, Gardner RJ, Bahlo M, Matsuura T, Dixon JA, Forrest SM, Storey E. Dominantly inherited ataxia and dysphonia with dentate calcification: spinocerebellar ataxia type 20. Brain. 2004;127:1172–81. [PubMed: 14998916]
  5. Knight MA, Hernandez D, Diede SJ, Dauwerse HG, Rafferty I, van de Leemput J, Forrest SM, Gardner RJ, Storey E, van Ommen GJ, Tapscott SJ, Fischbeck KH, Singleton AB. A duplication at chromosome 11q12.2-11q12.3 is associated with spinocerebellar ataxia type 20. Hum Mol Genet. 2008;17:3847–53. [PMC free article: PMC2588641] [PubMed: 18801880]
  6. Lorenzo DN, Forrest SM, Ikeda Y, Dick KA, Ranum LP, Knight MA. Spinocerebellar ataxia type 20 is genetically distinct from spinocerebellar ataxia type 5. Neurology. 2006;67:2084–5. [PubMed: 17159129]
  7. Sperling MR, Herrmann C. Syndrome of palatal myoclonus and progressive ataxia: two cases with magnetic resonance imaging. Neurology. 1985;35:1212–4. [PubMed: 4022358]
  8. Storey E, Knight MA, Forrest SM, Gardner RJ. Spinocerebellar ataxia type 20. Cerebellum. 2005;4:55–7. [PubMed: 15895561]

Chapter Notes

Revision History

  • 7 June 2012 (me) Comprehensive update posted live
  • 6 January 2009 (es) Revision: 260-kb duplication of 11q12.2-11q12.3 identified as probable cause of SCA20
  • 27 February 2007 (me) Review posted to live Web site
  • 6 February 2007 (es) Original submission
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