Clinical 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 proposed 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 pathogenic variant.

Suggestive Findings

Spinocerebellar ataxia type 20 (SCA20) should be considered in individuals with a slowly progressive ataxia without sensory features who have the following findings:

• Onset with dysarthria (rather than with gait ataxia) that may be abrupt in onset (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 vestibuloocular 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. CT scan showing heavy dentate calcification and pan cerebellar atrophy in an individual age 62 years with mild ataxia, three years after symptom onset III:16. CT scan slices at two levels of the dentate showing heavy dentate calcification and (more...)

Figure 2.

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

Neurophysiology. Nerve conduction studies are normal.

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

Establishing the Diagnosis

The diagnosis of SCA20 is established in a proband with the above Suggestive Findings and the following characteristic radiographic features:

• Brain CT. Pronounced dentate calcification, typically without concomitant pallidal calcification
• Brain MRI. Mild-to-moderate pan cerebellar atrophy and normal cerebrum and brain stem (except for increased inferior olivary T₂ signal in those with palatal tremor)

Note: The candidate region for SCA20 lies within the pericentromeric region of chromosome 11, encompassing chr11:44,045,910-69,634,192 (loci D11S903-FGF3). Although the candidate region includes SPTBN2 (pathogenic variants in which are responsible for SCA5), SPTBN2 pathogenic variants were excluded as the cause of SCA20 [Lorenzo et al 2006]. Knight et al [2008] reported a 260-kb heterozygous duplication within the candidate region, at 11q12.2-11q12.3 (chr11:61,453,940-61,746,019), cosegregating with SCA20 in the index family. It remains unknown whether this cosegregating duplication contains a locus or loci that are pathogenic in the duplicated state, or the duplication is merely in linkage disequilibrium with a closely linked locus that is the actual basis of the cerebellar phenotype (or whether there is another more complex genetic explanation).

Molecular genetic testing approaches can include a combination of chromosomal microarray analysis or exome array.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications that cannot be detected by sequence analysis.

Clinical Description

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, Storey & Gardner 2012].

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 includes palatal tremor ("myoclonus") without ear click (10/16), although this finding can be subtle. Gaze-evoked nystagmus is unusual (3/16). In two it was impersistent; in another affected individual persistent downbeating nystagmus was evident. Saccades are typically hypermetric into downgaze (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 involved 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; it is assumed to be very rare, given that no further individuals have been reported since the publication of the original family in 2008.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 20 (SCA20), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Careful clinical and neurologic evaluation
• Speech assessment
• Consultation with a clinical geneticist and/or genetic counselor

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 in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

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

Risk to Family Members

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 de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include neurologic assessment and CT scan of brain.
• 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. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation has been performed on the parents of the proband.

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

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

Offspring of a proband. The risk to offspring of an individual with SCA20 is 50%.

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

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, the causative genetic alteration is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing

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

Molecular Pathogenesis

Introduction. 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.

Mechanism of disease causation is unknown, but suspected to be a dosage effect of one or more genes in the 11q12.2-12.3 region.

Genes of interest in this region. One of the known genes in the duplicated region, DAGLA, is potentially an attractive candidate as it is highly expressed in murine Purkinje cells.

Revision History

• 18 April 2019 (sw) Comprehensive update posted live
• 7 June 2012 (me) Comprehensive update posted live
• 6 January 2009 (es) Revision: 260-kb duplication of 11q12.2-11q12.3 identified as suspected cause of SCA20
• 27 February 2007 (me) Review posted live
• 6 February 2007 (es) Original submission

Literature Cited

• 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]
• 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]
• 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]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
• 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]
• Knight MA, Hernandez D, Diede SJ, Dauwerse HG, Rafferty I, van de Leemput J, Forrest SM, Gardner RJM, 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]
• 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]
• Sperling MR, Herrmann C Jr. Syndrome of palatal myoclonus and progressive ataxia: two cases with magnetic resonance imaging. Neurology. 1985;35:1212–4. [PubMed: 4022358]
• Storey E, Gardner RJM. Spinocerebellar ataxia type 20. Handb Clin Neurol. 2012;103:567–73. [PubMed: 21827916]
• Storey E, Knight MA, Forrest SM, Gardner RJ. Spinocerebellar ataxia type 20. Cerebellum. 2005;4:55–7. [PubMed: 15895561]