Autosomal dominant cerebellar ataxia type I: a review of the phenotypic and genotypic characteristics. Orphanet J Rare Dis 6:33

Tri State Mountain Neurology, 105 Woodlawn Dr, Johnson City, TN 27604, USA.
Orphanet Journal of Rare Diseases (Impact Factor: 3.36). 05/2011; 6(1):33. DOI: 10.1186/1750-1172-6-33
Source: PubMed


Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds.

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    • "The authors’ technique of ultrasound measurement of BCM can be a reliable screening tool for patients suspected to have CAG expansion and AR resistance. BCM ultrasonography may prevent the indiscriminate use of CAGn analysis that tends to be expensive and not covered by most health insurances.33 Even though androgenic activity can be inferred from a patient's symptoms, objective clinical measurement at the tissue level is proven to be difficult to measure. "
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    ABSTRACT: Serum testosterone does not correlate with androgen tissue activity, and it is critical to optimize tools to evaluate such activity in males. Ultrasound measurement of bulbocavernosus muscle (BCM) was used to assess the relationship between the number of CAG repeats (CAGn) in the androgen receptor (AR) and the BCM size; the changes in the number of CAGn over age were also evaluated. Transperineal ultrasound measurement of the BCM was also performed. AR CAGn were determined by high performance liquid chromatography, and morning hormone levels were determined using immunoassays. Forty-eight men had CAG repeat analysis. Twenty-five were <30 years of age, mean 23.7 years (s.d. = 3.24) and 23 were >45 years of age, mean 53 years (s.d. = 5.58). The median CAGn was 21 (13-29). BCM area was greater when the number of CAGn were <18 as compared to the number of CAGn >24 (P = 0.04). There was a linear correlation between the number of CAGn and the BCM area R 2 = 16% (P = 0.01). In the 45 to 65-years-old group, a much stronger negative correlation (R 2 = 29%, P = 0.01) was noticed. In the 19 to 29-years-old group, no such correlation was found (R 2 = 4%, P = 0.36). In older men, the number of CAGn increased with age (R 2 = 32%, P = 0.01). The number of CAGn in the AR correlates with the area of the BCM. Ultrasound assessment of the BCM is an effective surrogate to evaluate end-organ activity of androgens. The number of CAGn may increase with age.
    Full-text · Article · Feb 2014 · Asian Journal of Andrology
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    • "spasticity in SCA1, peripheral neuropathy in SCA2 or dystonia in SCA3 *Address correspondence to this author at the Department of Neurology, Knappschaftskrankenhaus, Ruhr-University of Bochum, In der Schornau 23-25, D-44892 Bochum, Germany; Tel: 49 234-299-3704; Fax: 49 234-299-3719; E-mail: [7] [8] [9] [10], the development of speech impairment in the course of the disease has mainly been attributed to dysfunction of cerebellar motor control circuits [11]. In other SCA subtypes, however, the disease process is confined to the cerebellum resulting in a " pure " ataxia phenotype, that in case of SCA6 has a particularly late onset [2] [3]. "
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    ABSTRACT: Objective: Abnormalities in vowel articulation have been reported to be a common feature of dysarthria in spinocerebellar ataxia (SCA); however, findings about the degree and pattern of impaired vowel production are inconsistent. Therefore, the aim of the current study was to characterize the pattern of dysfunctional vowel production in patients with SCA by the means of acoustic analysis. Methods: 31 patients SCA and 32 healthy subjects were tested. Description of vowel articulation was based upon the frequencies of the first and second formant (F1 and F2) of the German vowels /􀀁/, /i/ and /u/ extracted severalfold from defined words within a given reading passage. The mean as well as the coefficient of variance of the respective F1 and F2 values of each single vowel were taken as measures of distinctiveness and steadiness of vowel articulation. Results: In the SCA group, F1 and F2 values showed increased variability and a specifically restricted range which was particularly seen in the vowel /i/. Furthermore, the dysfunctional pattern differed between male and female patients with SCA. Conclusions: Measurement of F1 and F2 revealed dysfunctional vowel articulation in SCA – however, with some genderrelated specifities – that can be explained by imprecision and reduced range of articulatory movements in ataxic speakers. Therefore, objective measurement of vowel formant frequencies provided additional information to the overall perceptual speech score. According to these preliminary findings, acoustic analysis of speech could be a promising tool for diagnosis, monitoring and detection of therapeutic effects in ataxic dysarthria.
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    • "It is noted that cerebellar atrophy on MRI is an important argument in favor of a neurodegenerative disease diagnosis such as ADCA in contrast to a secondary cause of cerebellar ataxia. Secondary cerebellar ataxias have been previously discussed [2]. After alternate causes for ataxia have been excluded, genetic testing may be conducted for a definitive diagnosis. "
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    ABSTRACT: Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally, by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments.
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