Flanigan, K., Gardner, K., Alderson, K., Galster, B., Otterud, B., Leppert, M. F. et al. Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am. J. Hum. Genet. 59, 392-399

Department of Neurology, University of Utah Medical Center, Salt Lake City 84112, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 09/1996; 59(2):392-9.
Source: PubMed

ABSTRACT The hereditary ataxias represent a clinically and genetically heterogeneous group of neurodegenerative disorders. Various classification schemes based on clinical criteria are being replaced as molecular characterization of the ataxias proceeds; so far, seven distinct autosomal dominant hereditary ataxias have been genetically mapped in the human genome. We report linkage to chromosome 16q22.1 for one of these genes (SCA4) in a five-generation family with an autosomal dominant, late-onset spinocerebellar ataxia; the gene is tightly linked to the microsatellite marker D16S397 (LOD score = 5.93 at theta = .00). In addition, we present clinical and electrophysiological data regarding the distinct and previously unreported phenotype consisting of ataxia with the invariant presence of a prominent axonal sensory neuropathy.

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    • "This syndrome typically starts in middle age adults and presents with cerebellar ataxia, pyramidal signs, and peripheral sensory loss [52]. SCA4 has been linked to chromosome 16q22.1 in kindreds from Utah and Germany [53,54]. The mutation is yet unknown but does not appear to be a trinucleotide repeat disorder though anticipation has been suggested in both kindreds. "
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    ABSTRACT: 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.
    Orphanet Journal of Rare Diseases 05/2011; 6(1):33. DOI:10.1186/1750-1172-6-33 · 3.36 Impact Factor
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    • "Autosomal dominant cerebellar ataxia (ADCA)-I, a more heterogeneous group that includes SCA1, SCA2, SCA3, SCA4, SCA8, SCA12, SCA13, SCA18-25, SCA27-29, and dentatorubral-pallidoluysian atrophy (DRPLA), presents with pyramidal features, extrapyramidal signs, and amyotrophy [Orr et al., 1993; Imbert et al., 1996; Pulst et al., 1996; Kawaguchi et al., 1994; Flanigan et al., 1996; Koob et al., 1999; Holmes et al., 1999; Waters et al., 2006; Devos et al., 2001; Verbeek et al., 2004; Knight et al., 2004; Vuillaume et al., 2002; Chung et al., 2003; Schelhaas et al., 2004; Swartz et al., 2002; Stevanin et al., 2005; Yu et al., 2005; van Swieten et al., 2003; Cagnoli et al., 2006; Koide et al., 1994]. Additionally, pigmentary retinal degeneration and seizures are observed in ADCA-II (SCA7) and ADCA-IV (SCA10 and SCA17), respectively [David et al., 1997; Matsuura et al., 2000; Nakamura et al., 2001]. "
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    ABSTRACT: Repeat expansion has been implicated in 10 out of 17 candidate genes identified for autosomal dominant cerebellar ataxias (ADCAs)-commonly referred as spinocerebellar ataxias (SCAs). Though genetically distinct, the SCAs share a large number of features that confound their clinical classification. In addition, there is a difference in the prevalence and phenotypic expression of ataxias between different ethnic groups. We have created a new SCA-locus-specific variation database (LSVD) that aims to catalog and integrate information on SCAs associated with trinucleotide repeat expansion (SCA1, SCA 2, SCA 3, SCA 6, SCA 7, SCA 8, SCA 12, SCA 17, Friedreich's ataxia [FRDA], and dentatorubral-pallidoluysian atrophy [DRPLA]) from all over the world. The database has been developed using the Leiden Open (source) Variation Database (LOVD) software (Leiden University Medical Center, Leiden, the Netherlands). The database houses detailed information on clinical features, such as age and symptom at onset, mode of inheritance, and genotype information, pertaining to the SCA patients from more than 400 families across India. All the compiled genotype data conforms to the HGVS Nomenclature guidelines. This would be a very useful starting point for understanding the molecular correlates of phenotypes in ataxia-a multilocus disease in which related molecular mechanisms converge to overlapping phenotypes.
    Human Mutation 07/2009; 30(7):1037-42. DOI:10.1002/humu.21006 · 5.14 Impact Factor
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    • "No variants in coding sequence or splice sites of VAC14 were observed (C Chow, M Meisler, M Khajavi, K Szigeti and JR Lupski, unpublished data). We also investigated the function of VAC14 in the human neurological disorder SCA4, which maps to a region of chromosome 16q22 that contains the VAC14 gene (Flanigan et al, 1996). We sequenced the exons of VAC14 in an affected member of the original SCA4 family, but did not detect any coding or splice site mutations (C Chow, M Meisler, and Y-H Fu, unpublished data). "
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    ABSTRACT: The signalling lipid PI(3,5)P(2) is generated on endosomes and regulates retrograde traffic to the trans-Golgi network. Physiological signals regulate rapid, transient changes in PI(3,5)P(2) levels. Mutations that lower PI(3,5)P(2) cause neurodegeneration in human patients and mice. The function of Vac14 in the regulation of PI(3,5)P(2) was uncharacterized previously. Here, we predict that yeast and mammalian Vac14 are composed entirely of HEAT repeats and demonstrate that Vac14 exerts an effect as a scaffold for the PI(3,5)P(2) regulatory complex by direct contact with the known regulators of PI(3,5)P(2): Fig4, Fab1, Vac7 and Atg18. We also report that the mouse mutant ingls (infantile gliosis) results from a missense mutation in Vac14 that prevents the association of Vac14 with Fab1, generating a partial complex. Analysis of ingls and two additional mutants provides insight into the organization of the PI(3,5)P(2) regulatory complex and indicates that Vac14 mediates three distinct mechanisms for the rapid interconversion of PI3P and PI(3,5)P(2). Moreover, these studies show that the association of Fab1 with the complex is essential for viability in the mouse.
    The EMBO Journal 12/2008; 27(24):3221-34. DOI:10.1038/emboj.2008.248 · 10.43 Impact Factor
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