DiagnosisClinical 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 ptosisAn MRI showing cerebellar atrophy predominantly of the superior vermis, with sparing of the brain stemA 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 testingSequence 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 View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityAFG3L2Sequence analysisSequence variants 212/12 3Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 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.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].

Differential DiagnosisThe 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, 2, 3, 7, 17 and DRPLA), usually begin before age 30 years, are more rapidly progressive, and have brain stem involvement on MRI. SCA6 has adult-onset, slowly progressive ataxia and gaze-evoked nystagmus findings that overlap with those of SCA28.Friedreich ataxia and ataxia with oculomotor apraxia types 1 and 2 (AOA1 and AOA2) are autosomal recessive and more rapidly progressive than SCA28, and usually have childhood onset. Mitochondrial disorders, especially those associated with external ophthalmoplegia and ptosis, should be considered as well (see Mitochondrial DNA Deletion Syndromes and Mitochondrial Disease Overview). Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations 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 assessmentExamination by an ophthalmologistEvaluation of cognitive abilitiesTreatment of ManifestationsAt present, only symptomatic treatments are available. These include the following:Crutches (less often canes) and walkersHome adaptations including grab bars for the bathtub or shower chairs and raised toilet seats as neededSpeech/language therapy for dysarthria and swallowing difficulties Physical therapy to ameliorate coordination difficulties, especially with tasks such as eating, dressing, walking, and bathingSurgical intervention as needed for severe ptosisPrevention of Secondary ComplicationsPsychological 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.SurveillanceAnnual 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 AvoidAlcohol consumption and sedatives such as benzodiazepines may exacerbate gait ataxia and coordination difficulties. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Spinocerebellar Ataxia Type 28: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDAFG3L218p11​.21AFG3-like protein 2AFG3L2 homepage - Mendelian genesAFG3L2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Spinocerebellar Ataxia Type 28 (View All in OMIM) View in own window 604581ATPase FAMILY GENE 3-LIKE 2; AFG3L2 610246SPINOCEREBELLAR ATAXIA 28; SCA28Normal allelic variants. AFG3L2 has 17 exons.Pathologic allelic variants. All pathologic allelic variants known are missense or small in/dels.Table 2. Selected AFG3L2 Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change
(Alias ¹) Protein Amino Acid ChangeReference SequencesPathologicc.1295A>Cp.Asn432ThrNM_006796​.2
NP_006787​.2c.1961C>Tp.Thr654Ilec.1996A>Gp.Met666Valc.1997T>Gp.Met666Argc.1997T>Cp.Met666Thrc.2011G>Ap.Gly671Argc.2012G>Ap.Gly671Gluc.2021_2022delCCinsTA
(2021_2022CC>TA)p.Ser674Leuc.2071G>Ap.Glu691Lysc.2081C>Ap.Ala694Gluc.2098G>Ap.Glu700Lysc.2105G>Ap.Arg702GlnSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal gene product. AFG3L2 encodes an ATP-dependent metalloprotease belonging to the AAA-superfamily (ATPases associated with a variety of cellular activities). This gene was cloned as a paralog of SPG7 (paraplegin) [Banfi et al 1999], whose homozygous inactivation causes an autosomal recessive form of hereditary spastic paraplegia (HSP) [Casari et al 1998]. (See Spastic Paraplegia 7). Both AFG3L2 and paraplegin are mitochondrial proteins, and are highly conserved through evolution, the orthologous protein FtsH being present in E. coli [Ito & Akiyama 2005]. The two proteins have been extensively studied in yeast models (orthologous genes are Yta10 (SPG7) and Yta12 (AFG3L2). Yta10p-12p constitutes a membrane-embedded complex of approximately 850 kd (m-AAA protease), active on the matrix side of the inner mitochondrial membrane (IMM) [Arlt et al 1996, Arlt et al 1998].Studies in yeast assigned a dual activity to the m-AAA protease for protein degradation and activation (cleavage) [Nolden et al 2005]: 1.It conducts protein quality surveillance in the IMM and degrades non-assembled membrane proteins to peptides [Arlt et al 1996, Leonhard et al 2000]; 2.It mediates protein processing and thereby activates certain mitochondrial proteins [Koppen et al 2009].Abnormal gene product. Except for one mutation (c.1295A>C; p.Asn432Thr), all known mutations are located in the M41-protease domain of the AFG3L2 protein [Cagnoli et al 2010, Di Bella et al 2010, Edener et al 2010]. The clustering of missense and small indel mutations in a narrow region of the gene suggests that this particular region encodes a critical functional domain. Several mutations occur on the same two codons: Met666 and Gly671. Yta10-Yta12 deficient yeast cells fail to be complemented by expression of mutated human AFG3L2 protein [Di Bella et al 2010].