Spinocerebellar Ataxia Type 15

Clinical characteristics.

Spinocerebellar ataxia type 15 (SCA15) is characterized by slowly progressive gait and limb ataxia, often in combination with ataxic dysarthria, titubation, upper limb postural tremor, mild hyperreflexia, gaze-evoked nystagmus, and impaired vestibuloocular reflex gain. Onset is between ages seven and 72 years, usually with gait ataxia but sometimes with tremor. Affected individuals remain ambulatory for ten to 54 years after symptom onset. Mild dysphagia usually after two or more decades of symptoms has been observed in members of multiple affected families and movement-induced oscillopsia has been described in one member of an affected family.

Diagnosis/testing.

The diagnosis of SCA15 should be considered in individuals in whom the diagnoses of SCA5, SCA6, SCA8, SCA11, SCA12, SCA14, and SCA27 have been excluded by molecular genetic testing (if available) and who fulfill the clinical diagnostic criteria for SCA15.

ITPR1 is the only gene known to be associated with SCA15. Neuroimaging reveals atrophy of the rostral and dorsal vermis of the cerebellum with mild atrophy of the cerebellar hemispheres.

Management.

Treatment of manifestations: Physical and occupational therapy; management of neurogenic dysphagia, if it occurs.

Prevention of secondary complications: Aids for walking and home modifications to help prevent falls; prevention/treatment of osteoporosis to reduce fracture risk.

Surveillance: Follow up by a neurologist with consultation from physiatrists and physical and occupational therapists every two or three years.

Agents/circumstances to avoid: Limit alcohol intake to lessen the risk of falls.

Genetic counseling.

SCA15 is inherited in an autosomal dominant manner. If a parent of the proband is affected, the risk to each sib is 50%. Prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.

Clinical Diagnosis

The 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 postural and kinetic tremor (which are common and may be the presenting features) and mild hyperreflexia (typically without spasticity, but occasionally with extensor plantar responses)
• Family history consistent with autosomal dominant inheritance

Additional findings may include the following:

• Gaze-evoked nystagmus (sometimes transient only) in approximately 80% of affected individuals
• Impaired vestibuloocular reflex gain (even to the point of producing movement-induced oscillopsia in a minority) in approximately 50% of members of the two families in which it has been tested
• Postural head and/or truncal tremor in a minority (probably <30%) of affected individuals
• Upper-limb postural tremor that may occasionally occur early in the disease course or, rarely, be the presenting feature
• Orolingual dyskinesias, perioral myokymia, and chorea (reported in one family each)
• Cognitive impairment noted in two families; it is not clear that this extends beyond the mild (mainly executive) dysfunction common to most cerebellar disorders [Schmahmann & Sherman 1998].

Brain 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.

Note: One affected Italian individual with cognitive impairment had bifrontoparietal atrophy; however, it is not certain whether this was attributable to SCA15 or another coexistent process.

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 Testing

Gene. ITPR1 is the only gene known to be associated with SCA15 [van de Leemput et al 2007].

Testing Strategy

Establishing the diagnosis in a proband. The diagnosis of SCA15 should be considered in individuals in whom the diagnoses of SCA5, SCA6, SCA8, SCA11, SCA12, SCA14, and SCA27 have been excluded by molecular genetic testing (if available) and who fulfill the clinical diagnostic criteria for SCA15.

Serial single-gene testing. Because 96% of ITPR1 pathogenic variants are exon 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. The combination of deletion analysis and sequence analysis has identified a pathogenic variant in every individual tested to date whose family demonstrates linkage to ITPR1 [Obayashi et al 2012, Storey & Gardner 2012].

Multigene panel. Another strategy for molecular diagnosis of a proband suspected of having SCA15 is use of a multigene panel that includes genes known to cause ataxias. These panels vary by methods used and genes included; thus, the ability of a panel to detect a pathogenic variant in any given individual also varies. See Differential Diagnosis. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Clinical information on spinocerebellar ataxia type 15 (SCA15) is based on findings in 67 affected individuals from 20 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], six French pedigrees [Marelli et al 2011], five German pedigrees [Synofzik et al 2011], three Italian pedigrees [Di Gregorio et al 2010, Castrioto et al 2011], one UK pedigree [Novak et al 2010], and one Australian pedigree [Author, unpublished]. Although two other British pedigrees and one other Japanese pedigree have also been identified, clinical descriptions are limited to mention of the presence of pure, slowly progressive ataxia in all three pedigrees and additionally truncal tremor and pyramidal features in the Japanese pedigree.

Onset in all 67 affected individuals was between ages seven and 72 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 fewer than 30%. 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 to 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. All 13 members of the French pedigrees remained independently ambulatory after an average of 22 years (range 6-43 years); of these, two with an average duration of symptoms of 42 years used unilateral supports. Eight of ten members of the German pedigrees were ambulatory after an average of nine years; of these, one used a crutch after 19 years of symptoms.

Two of nine members of the two Australian pedigrees, two of nine members of the six French pedigrees in whom it was ascertained, four of ten members of the five German pedigrees, and five of nine members of two of the Italian pedigrees in whom it was ascertained reported mild dysphagia that typically developed after two or more decades of symptoms. One Australian family member 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 typically appear to be affected. While cognitive impairment has been noted in two families, this may represent the mild executive dysfunction commonly seen in many cerebellar disorders.

Genotype-Phenotype Correlations

A Japanese family with a single-nucleotide variant c.3176C>T [Hara et al 2008] had a progressive course and has been classified as SCA15.

Contiguous gene deletions of 3p26. Some individuals with SCA15 have larger microdeletions that encompass portions of both ITPR1 and SUMF1, a gene that causes autosomal recessive multiple sulfatase deficiency. Such individuals are at risk of developing features of SCA15 but are not at risk of having features of multiple sulfatase deficiency, unless the nondeleted homologue of SUMF1 harbors a pathogenic variant [Obayashi et al 2012, Storey & Gardner 2012].

Penetrance

The penetrance is unknown. Based on the even segregation ratio in older generations of the known SCA15 pedigrees, penetrance is likely to be high or complete in these families. The late age of onset in some cases (≤72 years) may confound attempts to establish penetrance. Apparently unaffected parents of three affected sibs were reported in one Japanese pedigree, although detailed information on the parents was not available [Obayashi et al 2012]. Based on pedigree analysis, a parent who would have been predicted to have a pathogenic variant in one of the German families died young (age 31) and was asymptomatic at the time of death, potentially concealing disease development [Synofzik et al 2011].

Anticipation

First-hand information from each member of the 22 parent-offspring pairs for whom age of onset information is available [Storey et al 2009, Di Gregorio et al 2010, Marelli et al 2011, Synofzik et al 2011] reveals that onset was an average of nine years younger in the offspring than the parents; however, information is inadequate to support or refute anticipation. The age of onset in affected children ranged between 40 years earlier to 34 years later than their affected parent.

Note: The molecular mechanism of most pathogenic variants (i.e., deletion) does not suggest that anticipation is likely.

Nomenclature

The sole family in which SCA16 was originally described has now been shown by molecular genetic testing to have SCA15; therefore, the designation SCA16 has been subsumed by SCA15.

The designation SCA16 is currently an "empty" term, as are SCA9 and SCA24 [van de Leemput et al 2007, Gardner 2008, Iwaki et al 2008].

Prevalence

Preliminary information from Ganesamoorthy et al [2009] suggests that approximately 2%-3% of Australian familial ataxias can be attributed to SCA15 after molecular genetic testing has ruled out SCA1, SCA2, SCA3, SCA6, and SCA7, which together are responsible for approximately 50% of dominantly inherited ataxias in Australia.

In a German series of 56 families with autosomal dominant ataxias in whom the SCA conditions caused by trinucleotide repeat expansion (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, and dentatorubral-pallidoluysian atrophy [DRPLA]) and SCA conditions caused by other pathogenic variant types (SCA10, SCA11, SCA14 and SCA27) had been excluded, five (9%) families had SCA15. The rate among all dominant SCA conditions was 1.8% [Synofzik et al 2011].

An Italian series of 60 pedigrees segregating an autosomal dominant SCA phenotype, in which testing for SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12, and DRPLA was negative, reported one family with SCA15 (1.7%) [Di Gregorio et al 2010].

A French series of 333 pedigrees segregating an autosomal dominant SCA phenotype, in which testing for SCA1, SCA2, SCA3,SCA 6, SCA7, SCA17, and DRPLA was negative and for which testing in some pedigrees was also negative for SCA5, SCA10, SCA11, SCA12, SCA13, SCA14, and SCA28, revealed six pedigrees with SCA15 – a rate of 1.8% [Marelli et al 2011].

A Japanese series of 74 pedigrees (with at least 2 affected members) with SCA, in which SCA1, SCA2, SCA3, SCA6, SCA31, and DRPLA had been excluded, reported one pedigree with SCA15, for a rate of 1.4% [Obayashi et al 2012].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 15 (SCA15), the following evaluations are recommended:

• Clinical evaluation
• MRI to determine the pattern and extent of cerebellar atrophy and confirm the absence of extracerebellar changes
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Education 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 Complications

Secondary 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 may be required.

To limit the likelihood of fractures resulting from falls, bone density should be estimated and osteoporosis treated if present.

Surveillance

Follow up by a neurologist with consultation from physiatrists and physical and occupational therapists every two or three years is appropriate.

Agents/Circumstances to Avoid

Because 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 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.

Other

Treatment of symptomatic tremor has not been reported in SCA15. At least in the Australian pedigrees, tremor did not cause major functional disability.