Spinocerebellar Ataxia Type 28

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Retrieved

2021-01-18

Source

Gene_reviews

Trials

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Genes

AFG3L2, TUBB6, SPG7, OMA1

Drugs

Acetylleucine, Alpha-tocotrienol quinone ( VINCERINONE ), Ceftriaxone

Acetylleucine, Alpha-tocotrienol quinone ( VINCERINONE ), Ceftriaxone, Trans-resveratrol

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Summary

Clinical characteristics.

Spinocerebellar ataxia type 28 (SCA28) is characterized by young-adult onset, very slowly progressive gait and limb ataxia resulting in coordination and balance problems, dysarthria, ptosis, nystagmus, and ophthalmoparesis. In most individuals, SCA28 presents as a loss of coordination of lower limbs (unsteadiness, gait ataxia). Less frequently, ptosis/ophthalmoplegia, dysarthria, or upper-limb incoordination may occur as the initial finding. The course of the disease is slowly progressive without impairment of functional autonomy even decades after onset.

Diagnosis/testing.

Because the phenotype of SCA28 is indistinguishable from many other inherited disorders with SCA, the diagnosis of SCA28 is established in a proband with typical clinical findings by the identification of a heterozygous pathogenic variant in AFG3L2 by molecular genetic testing.

Management.

Treatment of manifestations: Ambulatory aids (crutches, canes, walkers); home adaptations as needed; physical therapy to help with tasks such as eating, dressing, walking, and bathing; stretching exercise for those with pyramidal involvement to avoid contractions and lack of comfort during sleep. Speech/ language therapy is helpful for those with dysarthria and swallowing difficulties as is surgery for severe ptosis.

Prevention of secondary complications: Psychological support; weight control to facilitate ambulation; thickened feeds or gastrostomy feedings to avoid aspiration pneumonia.

Surveillance: Annual assessment to evaluate stability or progression of the cerebellar ataxia. Monitoring of speech and swallowing.

Agents/circumstances to avoid: Alcohol consumption and sedatives such as benzodiazepines that may worsen gait ataxia and coordination.

Genetic counseling.

SCA28 is inherited in an autosomal dominant manner. Most individuals diagnosed with SCA28 have an affected parent; the proportion of cases caused by de novo pathogenic variants is unknown. Each child of an individual with SCA28 has a 50% risk of inheriting the pathogenic variant. Prenatal and preimplantation genetic testing are possible if the pathogenic variant in the family has been identified.

Diagnosis

Suggestive Findings

Spinocerebellar ataxia type 28 (SCA28) should be suspected in individuals with the following:

Onset generally in young adulthood (but with a wide range: ages 3-76 years)
A slowly progressive gait disorder resulting from cerebellar impairment
Cerebellar dysarthria
Oculomotor abnormalities including ophthalmoparesis, nystagmus and ptosis
Hyperreflexia or brisk deep tendon reflexes
Brain MRI showing cerebellar atrophy predominantly of the superior vermis, with sparing of the brain stem
A family history consistent with autosomal dominant inheritance

Establishing the Diagnosis

The diagnosis of SCA28 is established in a proband with typical clinical findings and identification of a heterozygous pathogenic variant in AFG3L2 by molecular genetic testing (see Table 1).

Because the phenotype of SCA28 is indistinguishable from many other inherited disorders with SCA, recommended molecular genetic testing approaches include use of a multigene panel and more comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of AFG3L2, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended due to a likely gain-of-function or dominant-negative disease mechanism (see Molecular Genetics).

A multigene panel that includes AFG3L2 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For this disorder a multigene panel is recommended (see Table 1). At present the role for whole-gene deletions/duplication in the pathology is not supported by available data. Partial-gene deletions, if identified, would require additional studies to determine clinical significance (see Molecular Genetics).
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in SCA28

Gene ¹	Method	Proportion of Probands with a Pathogenic Variant ² Detectable by Method
AFG3L2	Sequence analysis ³	>99% ^4, ^5 ,6
AFG3L2	Gene-targeted deletion/duplication analysis ⁷	Extremely rare ⁸

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Unselected individuals, all exons analyzed [Cagnoli et al 2010, Di Bella et al 2010, Fogel et al 2014, Sawyer et al 2014, Pyle et al 2015, Coutelier et al 2017, Iqbal et al 2017]
5.: Autosomal dominant cases, all exons analyzed [Jia et al 2012, Németh et al 2013, Löbbe et al 2014, Hadjivassiliou et al 2017, Szpisjak et al 2017]
6.: Unselected individuals, only exons 15-16 analyzed [Edener et al 2010, Musova et al 2014]
7.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
8.: Smets et al [2014] reported a deletion of exons 14-16, which likely truncates the protein, in two families (likely related) with autosomal dominant transmission.

Clinical Characteristics

Clinical Description

Age of onset and progression. The usual age at onset is early adulthood (26.5 ± 17.2 years); the range is from age three to 78 years. The course of the disorder is slowly progressive without impairment of functional autonomy even decades after onset.

Presentation. In most individuals, SCA28 presents as a loss of coordination of lower limbs (unsteadiness, gait ataxia). Less frequently, ptosis/ophthalmoplegia, dysarthria, or upper-limb incoordination may occur as the initial finding.

Gait and limb ataxia

Reflexes may be increased in the lower limbs and Babinski sign is present in some.
Decreased vibration sense at the ankles is present in some, but superficial sensation is always normal.
Extrapyramidal signs, either parkinsonism (mainly rigidity and/or bradykinesia) or dystonia, have been observed.

Dysarthria. Severity can vary from individual to individual and changes with progression of the disorder.

During the initial phases of the disease individuals may have impaired speech, but be easy to understand.
Later on, speech becomes slurred so that the affected individual is difficult to understand.

Dysphagia. Mild dysphagia has been occasionally reported [Löbbe et al 2014, Zühlke et al 2015, Szpisjak et al 2017].

Ocular problems

Ptosis
Nystagmus
Ophthalmoparesis with limited horizontal and vertical gaze

Intellectual disability, cognitive difficulties, and/or behavior problems have been reported [Cagnoli et al 2010, Edener et al 2010, Musova et al 2014], but are not considered hallmarks of SCA28. Some individuals have memory and attention deficits [Szpisjak et al 2017].

Electrophysiologic studies. Some neurogenic changes have been observed in two individuals [Cagnoli et al 2010], impaired vibration sense in five [Zühlke et al 2015, Svenstrup et al 2017], impaired thermo- and nociception in two [Zühlke et al2015], and metatarsal pallanesthesia in one [Löbbe et al 2014].

Imaging studies. Cerebellar atrophy can be prominent, affecting the vermis with sparing of the brain stem on brain MRI.

Genotype-Phenotype Correlations

No genotype-phenotype correlations can be proposed based on published studies, although persons with the p.Met666Arg, p.Glu700Lys, and p.Gly671Arg pathogenic variants have early-onset disease (i.e., in infancy/childhood), whereas the other pathogenic missense variants are mainly associated with onset in the second to fourth decade [Mariotti et al 2008, Cagnoli et al 2010, Edener et al 2010, Szpisjak at al 2017].

Penetrance

From the studies of SCA28 published to date, disease penetrance appears to be complete.

Prevalence

According to published data, heterozygous pathogenic variants in AFG3L2 account for approximately 1.5% of autosomal dominant cerebellar ataxia (ADCA) in individuals of European origin [Cagnoli et al 2010, Di Bella et al 2010, Edener et al 2010], with an estimated incidence of 0.045 in 100,000.

Differential Diagnosis

The ataxic gait of persons with SCA28 is indistinguishable from that seen in other adult-onset inherited or acquired ataxias. When the family history suggests autosomal dominant inheritance, all other autosomal dominant cerebellar ataxias (ADCAs) have to be considered (see Hereditary Ataxia Overview).

The most commonly occurring SCAs, those caused by polyglutamine expansions (i.e., SCA1, SCA2, SCA3, SCA7, SCA17 and DRPLA), usually begin before age 30 years, are more rapidly progressive, and have brain stem involvement on MRI.
SCA6 is characterized by adult-onset slowly progressive ataxia and gaze-evoked nystagmus findings that overlap with those of SCA28.
SPG7 is characterized by adult-onset slowly progressive ataxia with increased reflexes (or even spasticity), ophthalmoparesis, and optic atrophy.
Friedreich ataxia and ataxia with oculomotor apraxia type 1 and type 2 (AOA1 and AOA2) are autosomal recessive and more rapidly progressive than SCA28, and usually have childhood onset and severe peripheral involvement (polyneuropathy).

Mitochondrial disorders, especially those associated with external ophthalmoplegia and ptosis, should be considered as well (see Mitochondrial DNA Deletion Syndromes and Mitochondrial Disorders Overview).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with spinocerebellar ataxia type 28 (SCA28) the following evaluations are recommended if they have not already been completed:

Neurologic examination (including scales to evaluate the severity of cerebellar ataxia and to allow subjective follow up)
Cerebral MRI
Note: MRI is part of the routine evaluation of persons with ataxia; however, in SCA28 no association between the extent of cerebellar atrophy and disease severity or progression has been proven.
Speech assessment and evaluation for swallowing difficulties
Examination by an ophthalmologist
Evaluation of cognitive abilities
Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

At present, only symptomatic treatments are available. These include the following:

Crutches (less often canes) and walkers
Home adaptations including grab bars for the bathtub or shower chairs and raised toilet seats as needed
Physical therapy to ameliorate coordination difficulties, especially with tasks such as eating, dressing, walking, and bathing
Stretching exercise for those with pyramidal involvement to avoid contractions and lack of comfort during sleep
Speech/language therapy for dysarthria and swallowing difficulties
Surgical intervention as needed for severe ptosis

Prevention of Secondary Complications

Psychological support helps affected individuals cope with the consequences of the disease.

Weight control can facilitate ambulation.

To avoid complications such as aspiration pneumonia, thickened feeds or gastrostomy should be considered.

Surveillance

Annual assessment of the cerebellar ataxia using SARA (Scale for the Assessment and Rating of Cerebellar Ataxia), CCFS (Composite Cerebellar Functional Severity Score), or similar scales should be performed to evaluate stability or progression of the disease.

Monitoring of speech and swallowing difficulties is recommended.

Agents/Circumstances to Avoid

Alcohol consumption and sedatives such as benzodiazepines may worsen gait ataxia and coordination difficulties.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

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.