SCA15 is an autosomal dominant, adult-onset, very slowly progressive form of cerebellar ataxia. Most patients also have disabling action and postural tremor, and some have pyramidal tract affection, dorsal column involvement, and gaze palsy. Brain imaging shows cerebellar ... SCA15 is an autosomal dominant, adult-onset, very slowly progressive form of cerebellar ataxia. Most patients also have disabling action and postural tremor, and some have pyramidal tract affection, dorsal column involvement, and gaze palsy. Brain imaging shows cerebellar atrophy mainly affecting the vermis (summary by Synofzik et al., 2011). Heterozgous mutation in the ITPR1 gene can also cause SCA29 (117360), which is distinguished by onset in infancy of delayed motor development followed by nonprogressive ataxia and mild cognitive impairment. Autosomal dominant 'pure' cerebellar ataxia, classified as ADCA type III by Harding (1983, 1993), is a genetically heterogeneous disorder (see, e.g., 117210). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Storey et al. (2001) described an Australian kindred with a dominantly inherited 'pure' cerebellar ataxia in which linkage to known spinocerebellar ataxia loci was excluded by linkage studies and testing for trinucleotide repeat expansions. In 8 subjects studied, ... Storey et al. (2001) described an Australian kindred with a dominantly inherited 'pure' cerebellar ataxia in which linkage to known spinocerebellar ataxia loci was excluded by linkage studies and testing for trinucleotide repeat expansions. In 8 subjects studied, a notable clinical feature was slow progression, with the 3 least affected having only a mild degree of gait ataxia after 3 or more decades of disease duration. The name spinocerebellar ataxia-15 (SCA15) was applied. Miyoshi et al. (2001) reported a 4-generation Japanese family with autosomal dominant spinocerebellar ataxia. The ages at onset of the 9 affected members (5 men and 4 women) ranged from 20 to 66 years. All showed pure cerebellar ataxia, and 3 patients also had head tremor. Head MRI demonstrated cerebellar atrophy without brainstem involvement. Mutation analysis by PCR excluded mutations in previously identified genes causing SCA. Based on initial mapping, the disorder was designated SCA16. Miura et al. (2006) provided follow-up on the family reported by Miyoshi et al. (2001). Three additional patients were ascertained and 1 individual previously reported as affected was determined to be unaffected. The main common clinical features were saccadic eye movements, horizontal gaze-evoked nystagmus, dysarthria, and limb and truncal ataxia. Two affected individuals had evidence of mental impairment. Hara et al. (2004) reported 2 families with autosomal dominant spinocerebellar ataxia characterized by ataxic gait, cerebellar atrophy, and very slow progression. Several affected individuals also showed hyperreflexia and postural and action tremor of the hand, neck, and trunk. Both families originated from a northern province of Japan. Synofzik et al. (2011) reported 5 German families in which 10 patients with SCA15 presented with slowly progressive cerebellar ataxia, requiring a walker or wheelchair 15 to 17 years after onset, and vermal cerebellar atrophy. Seven of 10 patients had action and postural tremor of the hands or head, while all had intention tremor. Clinical and electrophysiological signs of extracerebellar affection, including pyramidal tract or dorsal column involvement, were mild and more variable. Two had psychiatric manifestations before onset of ataxia.
Van de Leemput et al. (2007) identified heterozygous deletions involving the ITPR1 gene in affected members of 3 unrelated families with autosomal dominant spinocerebellar ataxia, including the SCA15 family of Australian origin used to map the locus (Storey ... Van de Leemput et al. (2007) identified heterozygous deletions involving the ITPR1 gene in affected members of 3 unrelated families with autosomal dominant spinocerebellar ataxia, including the SCA15 family of Australian origin used to map the locus (Storey et al., 2001; Knight et al., 2003). Using high-density genomewide SNP genotyping, Van de Leemput et al. (2007) identified a large deletion removing the first 3 exons of the SUMF1 gene (607939) and the first 10 exons of the ITPR1 gene in the family reported by Knight et al. (2003). Affected members of 2 additional families were found to have even larger deletions removing exons 1-44 and 1-40 of the ITPR1 gene, respectively. As homozygous mutations in the SUMF1 gene lead to a different phenotype (MSD; 272200) and heterozygous carriers of SUMF1 mutations do not exhibit a movement disorder, the authors concluded that deletions of the ITPR1 gene underlie the ataxia phenotype. Van de Leemput et al. (2007) noted that direct gene sequencing failed to identify mutations in the ITPR1 gene and that gene dosage studies were required for accurate diagnosis. In affected members of a large Japanese family with autosomal dominant spinocerebellar ataxia reported by Miyoshi et al. (2001) and Miura et al. (2006), Iwaki et al. (2008) identified a heterozygous deletion of exons 1 to 48 of the ITPR1 gene (147265.0001). The SUMF1 gene was not affected. The findings indicated that SCA15 and SCA16 are the same disorder, due to haploinsufficiency of ITPR1. In affected members of a Japanese family with SCA15 originally reported by Hara et al. (2004), Hara et al. (2008) identified a 414-kb deletion of chromosome 3p26 including all of the ITPR1 gene and exon 1 of the SUMF1 gene. Breakpoint analysis indicated that the deletion was mediated by nonhomologous end joining. RT-PCR showed that expression levels of both ITPR1 and SUMF1 in the patients were half of levels in normal controls. In affected members of a second unrelated Japanese family reported by Hara et al. (2004), Hara et al. (2008) identified a heterozygous mutation in the ITPR1 gene (147265.0002). Synofzik et al. (2011) identified pathogenic ITPR1 deletions in 5 (8.9%) of 56 German families with autosomal dominant SCA who were negative for common SCA repeat expansions. All deletions detected by multiplex ligation-dependent probe amplification (MLPA) were confirmed by SNP array and spanned approximately 183 to 423 kb, and each family had a unique deletion. In 3 families, the deletions affected partly both the ITPR1 and SUMF1 genes, without including the 3-prime region of the ITPR1 gene. One family had a deletion preserving exons 1 and 2 in the 5-prime untranslated region of the ITPR1 gene. Marelli et al. (2011) identified ITPR1 deletions in 6 (1.8%) of 333 families of European origin with autosomal dominant SCA who were negative for common SCA repeat expansions. In 3 families, the deletion included ITPR1 and SUMF1; in 1 family, the deletion included ITPR1, SUMF1, and SETMAR (609834); and in 2 families, the deletion was limited to ITPR1. Most presented with cerebellar gait ataxia and later developed ocular movement abnormalities and dysarthria. Two patients from 1 family had pyramidal signs, 2 additional patients from another family showed some executive decline, and some patients reported dysphagia.
Based on their finding of SCA15 in 5 (8.9%) of 56 German families with unexplained SCAs, Synofzik et al. (2011) noted that SCA15 is the most common non-trinucleotide repeat SCA in Central Europe.
The diagnosis of spinocerebellar ataxia type 15 (SCA15) should be considered in individuals with the following findings:...
DiagnosisClinical DiagnosisThe diagnosis of spinocerebellar ataxia type 15 (SCA15) should be considered in individuals with the following findings:Very slowly progressive ataxia (e.g., still independently ambulant after 20-30 years of symptoms)No other neurologic signs beyond tremor or mild hyperreflexia (typically without spasticity or extensor plantar responses)Family history consistent with autosomal dominant inheritanceAdditional findings include:Gaze-evoked nystagmus in approximately 60% of affected individualsImpaired vestibulo-ocular reflex gain in approximately 50%, even to the point of producing movement-induced oscillopsia in a minorityPostural head and/or truncal tremor in approximately 40% of affected individualsUpper-limb postural tremor that may occasionally occur early in the disease courseBrain MRI. Neuroimaging typically reveals atrophy of the rostral and dorsal vermis of the cerebellum. The cerebellar hemispheres may appear normal or be mildly atrophic. The brain stem and cerebral hemispheres are unaffected.Neurophysiology. Nerve conduction studies are typically normal, although minor slowing of sural sensory and median motor conduction velocity was noted in members of one Japanese pedigree.Molecular Genetic TestingGene. ITPR1 is the only gene known to be associated with SCA15 [van de Leemput et al 2007]. Clinical testingDeletion/duplication analysis and sequence analysis. SCA15 is defined by the presence of an ITPR1 disease-causing mutation. In all but one pedigree a deletion of at least several exons is causative (see Molecular Genetics) and therefore not detectable on sequence analysis. The combination of deletion analysis and sequence analysis has identified a disease-causing mutation in every individual tested to date whose family demonstrates linkage to the SCA15 locus [Storey & Gardner, in press].Table 1. Summary of Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 15View in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityITPR1Sequence analysisSequence variants 21/7ClinicalDeletion/ duplication analysis 3Exonic or whole-gene deletions6/71. 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.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyEstablishing the diagnosis in a probandThe diagnosis of SCA15 should be considered in individuals in whom the diagnoses of SCA5, 6, 8, 11, 12, 14, and 27 have been excluded by molecular genetic testing (if available) and who fulfill the clinical diagnostic criteria for SCA15.Because 86% of ITPR1 mutations are exonic or whole-gene deletions that are not detected by sequence analysis, molecular genetic testing begins with deletion/duplication analysis followed by sequence analysis if a deletion is not identified.Genetically Related (Allelic) DisordersThe locus for a dominantly inherited congenital nonprogressive ataxia with cognitive impairment in a large Australian pedigree overlaps that of SCA15 [Dudding et al 2004]. However, this phenotype seems to be sufficiently different from SCA15 in that the disorders are probably distinct, although the possibility that they are allelic cannot yet be excluded, as the members of this pedigree have not yet undergone ITPR1 genetic testing.
Clinical information on spinocerebellar ataxia type 15 (SCA15) is based findings in 28 affected individuals from five families: the index pedigree (an Australian family of Anglo-Celtic descent [Storey et al 2001]), three Japanese pedigrees [Hara et al 2008, Iwaki et al 2008], and an Australian pedigree [Author, unpublished]. Although two British pedigrees have also been identified, clinical descriptions are limited to mention of the presence of pure, slowly progressive ataxia. ...
Natural HistoryClinical information on spinocerebellar ataxia type 15 (SCA15) is based findings in 28 affected individuals from five families: the index pedigree (an Australian family of Anglo-Celtic descent [Storey et al 2001]), three Japanese pedigrees [Hara et al 2008, Iwaki et al 2008], and an Australian pedigree [Author, unpublished]. Although two British pedigrees have also been identified, clinical descriptions are limited to mention of the presence of pure, slowly progressive ataxia. Onset in all 28 affected individuals was between ages seven and 66 years (mean 31 years). SCA15 typically presents with very slowly progressive gait ataxia, often in combination with ataxic dysarthria. Head and/or truncal tremor with or without upper extremity tremor is seen in approximately 40%. It may begin simultaneously with — or even occasionally precede — gait ataxia. Deterioration in handwriting, motion-induced instability (e.g., on escalators), and myoclonus were the first symptoms in one individual each.Progression of SCA15 is notably slow. All nine affected members of the two Australian pedigrees remained independently ambulant after an average of 31 years of symptoms (range 10-54 years); of these nine, two used canes. Most of the affected members of one Japanese pedigree were ambulant 20 years after onset; in another, one affected individual required a wheelchair when assessed after 40 years of symptoms. After ten years of gait ataxia, two affected individuals from the Australian pedigree were able perform tandem gait, but were unable to hop on one foot within a 30-cm (1 foot) square; one had minor difficulties on the half-turn.Two of nine members of the Australian pedigrees reported mild dysphagia that developed after several decades of symptoms; one reported onset of a movement-induced oscillopsia 40 years after initial symptoms of movement-induced unsteadiness.Life-threatening complications such as severe bulbar dysfunction have not become evident during the disease course. From the limited clinical information available, cognition does not appear to be affected.Neuropathology. No pathologic material is available in SCA15.
The differential diagnosis of SCA15 is that of a (relatively) pure, slowly progressive, dominantly inherited ataxia, perhaps with early tremor. SCA5, SCA6, SCA8, SCA11, SCA12, SCA14, SCA19/22, SCA21, SCA23, SCA26, SCA27, SCA28, and SCA30 may also fall into this category [Schöls et al 2004, Stevenin et al 2004, Verbeek et al 2004, Manto 2005, van de Warrenburg et al 2005, Cagnoli et al 2006, Storey et al 2008]. Some of these disorders can be excluded by molecular genetic testing, if available. SCA8 and SCA30, in particular, may result in phenotypes almost identical to SCA15. Clinical differentiation of SCA15 from SCA5, SCA11, SCA19/22, SCA21, SCA23, SCA26, and SCA27 may also be impossible, based on the reported details of these disorders....
Differential DiagnosisThe differential diagnosis of SCA15 is that of a (relatively) pure, slowly progressive, dominantly inherited ataxia, perhaps with early tremor. SCA5, SCA6, SCA8, SCA11, SCA12, SCA14, SCA19/22, SCA21, SCA23, SCA26, SCA27, SCA28, and SCA30 may also fall into this category [Schöls et al 2004, Stevenin et al 2004, Verbeek et al 2004, Manto 2005, van de Warrenburg et al 2005, Cagnoli et al 2006, Storey et al 2008]. Some of these disorders can be excluded by molecular genetic testing, if available. SCA8 and SCA30, in particular, may result in phenotypes almost identical to SCA15. Clinical differentiation of SCA15 from SCA5, SCA11, SCA19/22, SCA21, SCA23, SCA26, and SCA27 may also be impossible, based on the reported details of these disorders.Head tremor, if present in addition, suggests SCA15 more strongly than the other types of inherited ataxia. SCA1, SCA2, and SCA3 have much more aggressive clinical course, and SCA2 is also characterized by clinically obvious slow saccades (not seen in SCA15). Also, approximately 60% of individuals with SCA15 display gaze-evoked nystagmus, which is rare in SCA2.The radiologic picture of SCA15 is that of a pure cerebellar atrophy, which may also be seen in SCA4, SCA5, SCA6, SCA8, SCA10, SCA11, SCA14, SCA18, SCA21, SCA22, SCA23, SCA25, SCA28, and SCA30 [Stevanin et al 2004, Verbeek et al 2004, Manto 2005, Cagnoli et al 2006, Storey et al 2008]. Some of these disorders can be excluded by molecular genetic testing, if available. The clinical characteristics of the other hereditary ataxias can be found in Hereditary Ataxia Overview.
To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 15 (SCA15), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 15 (SCA15), the following evaluations are recommended:Clinical evaluationMRI to determine the pattern and extent of cerebellar atrophy and confirm the absence of extra-cerebellar changes.Treatment of ManifestationsEducation for affected individuals and their families is the cornerstone of management.Physical and occupational therapy, as used for ataxic syndromes of any etiology, may be employed.Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals should maintain activity. To date significant dysphagia has not been an issue for individuals with SCA15; however, if significant dysphagia were to develop, a speech pathologist expert in the management of neurogenic dysphagia should be asked to help guide management.Prevention of Secondary ComplicationsSecondary complications are unlikely in the early years of the disease.Weight control is important because obesity can exacerbate difficulties with ambulation and mobility. Later, risk of falls can be reduced via appropriate gait aids and home modifications; if falls are frequent, a personal alarm system could be required. To limit the likelihood of fractures resulting from falls, bone density should be estimated and osteoporosis treated if present.SurveillanceFollow-up by a neurologist with consultation from physiatrists and physical and occupational therapists every two or three years is appropriate.Agents/Circumstances to AvoidBecause individuals with ataxic syndromes in general have abnormal sensitivity to the motor effects of alcohol, it is reasonable to limit alcohol intake to lessen the risk of falls.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.OtherTreatment of symptomatic tremor has not been reported in SCA15. At least in the Australian pedigrees, tremor did not cause major functional disability.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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 15: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDITPR13p26.1Inositol 1,4,5-trisphosphate receptor type 1ITPR1 homepage - Mendelian genesITPR1Data 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 15 (View All in OMIM) View in own window 147265INOSITOL 1,4,5-TRIPHOSPHATE RECEPTOR, TYPE 1; ITPR1 606658SPINOCEREBELLAR ATAXIA 15; SCA15Normal allelic variants. ITPR1, encoding inositol 1,4,5-triphosphate receptor type 1, has 58 exons. Eleven spliced and two unspliced mRNAs putatively encode valid proteins. Pathologic allelic variants. The known pathogenic allelic variants almost all involve deletion of part, or all, of ITPR1, often in association with partial deletion of the adjacent SUMF1 [van de Leemput et al 2007, Hara et al 2008, Iwaki et al 2008]. Known variants include exons 1-10 of ITPR1 and 1-3 of SUMF1; 1-40 of ITPR1 and 1-3 of SUMF1; 1-44 of ITPR1 and 1-3 of SUMF1; 1-48 of ITPR1 without any deletion of SUMF1; and all of ITPR1 with exon 1 of SUMF1. A p.Pro1059Leu mutation (disturbing a highly conserved residue) has also been presumptively linked with a Japanese SCA15 pedigree [Hara et al 2008]. See Table 2.Table 2. Selected ITPR1 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference Sequences c.3176C>Tp.Pro1059LeuNM_002222.4 NP_002213.4 Partial- and whole-gene deletions; see Pathologic allelic variantsDeletions of varying lengthSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). Normal gene product. The archetypal protein is 2758 residues in length and forms a homotetramer. The C-terminal domains form an intracellular transmembrane channel that mediates calcium release from the endoplasmic reticulum following binding by inositol 1,4,5-trisphosphate receptor type 1. The cytoplasmic N-terminal domain contains the inositol 1,4,5-trisphosphate receptor type 1 binding domain. The protein is particularly abundant in Purkinje cells, but is also found in other brain areas apparently unaffected in SCA15 including CA1 hippocampus, striatum, and cerebral cortex.Abnormal gene product. On the basis that deletions of part or all of ITPR1 are the most frequent causes of SCA15, it is presumed that the pathogenic mechanism is haploinsufficiency.