Spinocerebellar Ataxia Type 20

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 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 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.