Clinical Diagnosis

The diagnosis of spinocerebellar ataxia type 28 (SCA28) should be considered in the presence of the following:

• Onset generally in young adulthood (but wide range: ages 3-60 years)

• A slowly progressive gait disorder resulting from cerebellar impairment

• Oculomotor abnormalities, especially ptosis

• An MRI showing cerebellar atrophy predominantly of the superior vermis, with sparing of the brain stem

• A family history consistent with autosomal dominant inheritance

No features of SCA28 are pathognomonic; therefore, diagnosis depends on molecular genetic testing.

Molecular Genetic Testing

Gene. AFG3L2, encoding for ATPase family gene 3-like 2, is the only gene in which mutations are known to cause SCA28.

Clinical testing

• Sequence analysis has identified different disease-causing sequence variants in 12 families published to date [Mariotti et al 2008, Cagnoli et al 2010, Edener et al 2010].

Table 1. Summary of Molecular Genetic Testing Used in SCA 28

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
AFG3L2	Sequence analysis	Sequence variants 2	12/12 3	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Mariotti et al [2008], Cagnoli et al [2010], Edener et al [2010]

Testing Strategy

Individuals with a positive family history of autosomal dominant cerebellar ataxia should be tested for mutations in the genes associated with the most common inherited ataxias, including SCA1, 2, 3, 6, 7, 17, DRPLA, and SCA14 (See Hereditary Ataxia Overview).

Individuals who represent simplex cases (i.e., a single occurrence of ataxia in a family) rarely have a mutation in one of the known genes [Fogel & Perlman 2007, Klockgether 2010].

To confirm/establish the diagnosis in a proband. Because exons 15 and 16 of AFG3L2 seem to be mutational hotspots [Cagnoli et al 2010, Di Bella et al 2010], sequence analysis of these two exons could be the first step in testing, followed by sequence analysis of the whole coding region and intron-exon boundaries in individuals in whom no mutation is identified.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

The phenotype of two brothers from a consanguineous relationship, who were homozygous for the c.1847A>G (p.Tyr616Cys) sequence variant in AFG3L2, appears to be complex and severe, including spastic gait and epilepsy leading to death of one of the two affected brothers at age 13 years. Mitochondrial DNA depletion was also noted. It is not clear if the phenotype results from the sequence variant in AFG3L2 alone or from mutation of another gene or genes as well.

Natural History

No prospective natural history study has yet been published. The following discussion of the natural history of spinocerebellar ataxia type 28 (SCA28) is based on the findings reported in 12 families (43 individuals) published to date [Mariotti et al 2008, Cagnoli et al 2010, Edener et al 2010].

The phenotype is characterized by young-adult onset, slowly progressive gait and limb ataxia, dysarthria, hyperreflexia of the lower limbs, nystagmus, and ophthalmoparesis.

The usual age at onset is early adulthood (24.4 ± 14.9 years); the range is from age three to 60 years. The course of the disease is slowly progressive without impairment of functional autonomy even decades after onset.

Cerebellar ataxia is associated with dysarthria.

Reflexes are usually increased in the lower limbs (31/41; 76%), and Babinski sign is present in 10/37 (27%).

Oculomotor abnormalities are present in 32/40 (80%), including limited gaze (~50%) and gaze-evoked nystagmus (19/39; 49%).

Ptosis is present in 15/31 (48%).

Decreased vibration sense at the ankles is present in 9/20 (45%), but superficial sensation is always normal.

Extrapyramidal signs, either parkinsonism (mainly rigidity and/or bradykinesia) or dystonia, were observed in 6/25 (24%).

Low IQs, cognitive difficulties, and/or behavior problems have been reported in 8/43 (19%).

Electrophysiologic studies. Conduction velocities were normal in seven affected individuals, some neurogenic changes have been observed in two [Cagnoli et al 2010]. At present, there is no evidence of peripheral neuropathy.

Genotype-Phenotype Correlations

For the most part, each mutation reported to date has occurred in a single family only.

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

Penetrance

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

Three individuals with a mutation in AFG3L2 were not symptomatic.

• In one case, this could be attributed to the young age of the tested individual, who may therefore be presymptomatic [Cagnoli et al 2010].

• The other two are the mother and maternal uncle of a symptomatic individual: in this family, it has been proposed that a variant in SPG7 may modify the phenotype caused by mutation of AFG3L2 [Di Bella et al 2010].
  Note: The possibility of a sequence variant in SPG7 modifying the phenotype caused by mutation of AFG3L2 is yet to be confirmed.

Prevalence

One to three Europeans in 100,000 have autosomal dominant cerebellar ataxia (ADCA) and, to date, causative mutations in 18 genes have been identified. The most frequent subtype is SCA3.

Testing for the most common ADCAs (SCA1, 2, 3, 6, 7, and 17) identifies a mutation in approximately 44% (ranging from 1 to 90% in different published reports), but the diagnosis remains unknown in many patients [Durr 2010].

According to published data, point mutations in AFG3L2 account for approximately 1.5% of ADCA in individuals of European origin [Di Bella et al 2010, Cagnoli et al 2010, Edener et al 2010], with an estimated incidence of approximately 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:

• 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

• Examination by an ophthalmologist

• Evaluation of cognitive abilities

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

• Speech/language therapy for dysarthria and swallowing difficulties

• Physical therapy to ameliorate coordination difficulties, especially with tasks such as eating, dressing, walking, and bathing

• 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 performe 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 exacerbate gait ataxia and coordination difficulties.

Testing 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 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

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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 new mutation. The proportion of cases caused by de novo mutations is unknown.

• If the disease-causing mutation 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 mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include genetic counseling with psychological support. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with SCA28 have an affected parent, the family history may appear to be negative because of early death of the parent before the onset of symptoms or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred, s/he may have somatic mosaicism for the mutation 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 or has an AFG3L2 mutation, the risk to the sibs of inheriting the mutation is 50%.

• The sibs of a proband with clinically unaffected parents are still at risk for SCA28 because of the theoretic possibility of reduced penetrance in a parent.

• If the disease-causing mutation found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the theoretic possibility of germline mosaicism.

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

Other family members. 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 may be 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.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for SCA28 is available 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 disease-causing mutation 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 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 resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

Family planning

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

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

No laboratories offering molecular genetic testing for prenatal diagnosis of SCA28 caused by mutation of AFG3L2 are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see .

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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Suggested Reading

1. Brice G, Child AH, Evans A, Bell R, Mansour S, Burnand K, Sarfarazi M, Jeffery S, Mortimer P. Milroy disease and the VEGFR-3 mutation phenotype. J Med Genet. 2005;42:98–102. [PMC free article: PMC1735984] [PubMed: 15689446]
2. Lichtenstein L, Kaplan L. Alkaptonuria and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease, Vol 2. 8 ed. New York: McGraw-Hill; 2001:2109-23.
3. Muntoni F. Journey into muscular dystrophies caused by abnormal glycosylation. Acta Myol. 2004;23:79–84. [PubMed: 15605948]
4. Wolfsdorf JI, Weinstein DA. Glycogen storage diseases. Rev Endocr Metab Disord. 2003;4:95–102. [PubMed: 12618563]

Acknowledgments

Telethon Foundation support is gratefully acknowledged (grant GGP07110)

Revision History

• 17 May 2011 (me) Review posted live

• 7 February 2011 (ab) Original submission