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Spinocerebellar Ataxia Type 11 Summary

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Spinocerebellar Ataxia Type 11 Summary NLM Citation: Chen Z, Puzriakova A, Houlden H. Spinocerebellar Ataxia Type 11. 2008 Jul 22 [Updated 2019 Oct 31]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Bookshelf URL: https://www.ncbi.nlm.nih.gov/books/ Spinocerebellar Ataxia Type 11 Synonym: SCA11 Zhongbo Chen, MA, BM BCh, MRCP,1 Arina Puzriakova, BSc, MSc,2 and Henry Houlden, MD, PhD2 Created: July 22, 2008; Updated: October 31, 2019. Summary Clinical characteristics Spinocerebellar ataxia type 11 (SCA11) is characterized by progressive cerebellar ataxia and abnormal eye signs (jerky pursuit, horizontal and vertical nystagmus). Pyramidal features are seen on occasion. Peripheral neuropathy and dystonia are rare. Six families have been reported to date, one each from the UK, Pakistan, France, Germany, Denmark, and China. Age of onset ranged from early childhood to the mid-40s. Life span is thought to be normal. Diagnosis/testing The diagnosis of spinocerebellar ataxia type 11 (SCA11) is established in a proband with a heterozygous pathogenic variant in TTBK2 identified by molecular genetic testing. Management Treatment of manifestations: Management is supportive; there are no known disease-modifying treatments to date. Physiotherapy and assessment for assistive devices for ambulation; occupational therapy, including home adaptations; speech and language therapy for dysarthria and dysphagia; ankle-foot orthotics if required and good foot care for those with neuropathy; treatment per ophthalmologist for vision issues; prism glasses may be helpful for diplopia. Surveillance: Annual neurologic evaluation; evaluations with physiotherapist, occupational therapist, speech and language therapist, and ophthalmologist as indicated. Author Affiliations: 1 Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom; Email: [email protected]. 2 Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom; Email: [email protected]; Email: [email protected]. Copyright © 1993-2019, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved. 2 GeneReviews® Genetic counseling SCA11 is inherited in an autosomal dominant manner. The proportion of SCA11 caused by de novo mutation is unknown. Each child of an individual with SCA11 has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for at-risk pregnancies is possible if the diagnosis has been established by molecular genetic testing in an affected family member. Diagnosis Suggestive Findings Spinocerebellar ataxia type 11 (SCA11) should be considered in individuals with the following clinical features: • Progressive cerebellar ataxia • Abnormal eye signs (jerky pursuit, horizontal and vertical nystagmus) • Dysarthria • Pyramidal features (mild-to-moderate lower-extremity hyperreflexia; in very rare cases, a positive Babinski sign or other pyramidal features) • Swallowing difficulties Rare findings in SCA11: • Peripheral neuropathy • Dystonia Establishing the Diagnosis The diagnosis of spinocerebellar ataxia type 11 (SCA11) is established in a proband with a heterozygous pathogenic variant in TTBK2 identified by molecular genetic testing (see Table 1). Because the phenotype of SCA11 is indistinguishable from many other inherited disorders with ataxia, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing. Note: Single-gene testing (sequence analysis of TTBK2, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. • An ataxiamultigene panel that includes TTBK2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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. Of note, given the rarity of SCA11, some panels for ataxia may not include this gene. (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 an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. Spinocerebellar Ataxia Type 11 3 • Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing is most commonly used; genome sequencing is also possible. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. Table 1. Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 11 Proportion of Probands with a Pathogenic Gene 1 Method Variant 2 Detectable by Method Sequence analysis 3 6/6 families 4 TTBK2 Gene-targeted deletion/duplication Unknown 6 analysis 5 1. See Table A. Genes and Databases for chromosome locus and protein. 2. See Molecular Genetics for information on allelic variants detected in this gene. 3. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4. Houlden et al [2007], Bauer et al [2010], Lindquist et al [2017], Deng et al [2019] 5. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6. No data on detection rate of gene-targeted deletion/duplication analysis are available. Clinical Characteristics Clinical Description To date, 28 individuals from six families have been identified with a pathogenic variant in TTBK2 [Houlden et al 2007, Bauer et al 2010, Lindquist et al 2017, Deng et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports. Table 2. Clinical Features of Spinocerebellar Ataxia Type 11 Feature Number of Persons w/Feature Comment Cerebellar ataxia 28/28 Variable truncal &/or gait ataxia Limb ataxia 21/28 Dysarthria 22/28 Jerky pursuit 18/28 Nystagmus 20/28 Ophthalmoplegia 2/28 Diplopia 4/28 • Most prominent in the British family Hyperreflexia 18/28 • Lower > upper limbs Extrapyramidal • Laterocollis 1/28 features • "No-no" head tremor Onset. In the six families described with spinocerebellar ataxia type 11 (SCA11), age of onset ranged from age nine years in the family of Danish origin to age 40-50 years in the families from France, Germany, and China. Most individuals present with a pure ataxia phenotype, with few additional features. Abnormal eye findings were identified in a third of individuals, a small proportion of whom presented with diplopia at onset. 4 GeneReviews® Ataxia. The cerebellar ataxia was clinically similar in all six families. All individuals presented with an ataxia- predominant disorder and difficulty walking due to unsteadiness and maintaining balance. In approximately a third of individuals, limb ataxia was also present. Ataxia was usually slowly progressive. For example, in the British family described, the mean disease duration was 26.8 years [Houlden et al 2007]. Abnormal eye findings include jerky pursuit and horizontal and vertical nystagmus. All of the individuals with SCA11 from Devon had abnormal eye movements at presentation, with jerky pursuit and vertical nystagmus more prevalent than horizontal nystagmus [Houlden et al 2007]. Half of the individuals with vertical nystagmus had an upbeat nystagmus [Giunti et al 2012]. Only a very small proportion were found to be symptomatic with ophthalmoplegia and diplopia. No members of the French family had abnormal eye findings. One individual in the German family had oculomotor disturbances with jerky pursuit, gaze-evoked nystagmus, dysmetric saccades, and impaired optokinetic nystagmus on presentation, nine years after symptom onset [Bauer et al 2010]. In the Danish family, one individual presented with diplopia and nystagmus at age nine years [Lindquist et al 2017]. A sib presented at age four years with ataxia and was found to have nystagmus at age nine years [Lindquist et al 2017]. Three individuals of Chinese descent had nystagmus at the time of presentation [Deng et al 2019]. It is unclear if abnormal eye findings progress, but ocular symptoms were the only presenting feature for one individual out of 28 affected. Although abnormal eye findings may be seen
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