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.

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 a heterozygous pathogenic (or likely pathogenic) variant in AFG3L2 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous AFG3L2 variant of uncertain significance does not establish or rule out the diagnosis.

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 because of 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 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 multigene panels click here. More detailed information for clinicians ordering genetic tests 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.

Clinical Description

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.

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.

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.

Mode of Inheritance

Spinocerebellar ataxia type 28 (SCA28) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with SCA28 have an affected parent.
• A proband with SCA28 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.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
• The family history of some individuals diagnosed with SCA28 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 molecular genetic testing has been performed on the parents of the proband.

Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.

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 of inheriting the variant is 50%.
• If the parents have been tested for the AFG3L2 pathogenic variant identified in the proband and:
  • A parent of the proband has the AFG3L2 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. The intrafamilial phenotypic variability reported among affected individuals is usually related to onset age or disease duration.
  • The AFG3L2 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic risk of parental germline mosaicism.
• If the parents have not been tested for the AFG3L2 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. The sibs of a proband with clinically unaffected parents are still at increased risk for SCA28 because of the possibility of reduced penetrance in a parent or the theoretic risk of parental germline mosaicism.

Offspring of a proband. Each child of an individual with SCA28 is at 50% risk of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the AFG3L2 pathogenic variant, the parent's family members may be 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 it is likely that the proband has the disorder as a result of a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for SCA28 is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in accurately predicting age of onset, disease severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for SCA28 an affected family member should be tested first to confirm the molecular diagnosis in the family.

Testing for the pathogenic variant in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members should involve pre-test interviews in which the motives for requesting the test, the individual's knowledge of SCA28, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations.

Molecular genetic testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

For more information, see also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the AFG3L2 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Acknowledgments

Telethon Foundation support is gratefully acknowledged (grant GGP07110)

Revision History

• 22 March 2018 (ha) Comprehensive update posted live
• 7 February 2013 (cd) Revision: prenatal diagnosis available
• 17 May 2011 (me) Review posted live
• 7 February 2011 (ab) Original submission

Published Guidelines / Consensus Statements

• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 6-27-22.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 6-27-22.

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