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


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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Available from: Craig D Kaplan, Nov 04, 2014
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    • ", researchers have been looking for common mechanisms on a molecular level. Gene–gene interaction networks have previously shown that even when SCAs are divided into groups based on mutation type, they still show great overlap in gene co-expression mechanisms (Matilla-Dueñas et al., 2013;Orr et al., 1993) SCA2 ATXN2 Ataxin-2 RNA metabolism (CAG) n (Imbert et al., 1996;Pulst et al., 1996;Sanpei et al., 1996) SCA3 ATXN3 Ataxin-3 Deubiquitination, transcription regulation (CAG) n (Kawaguchi et al., 1994)SCA4 Unknown Unknown Unknown Unknown (Flanigan et al., 1996)Zhuchenko et al., 1997) SCA7 ATXN7 Ataxin-7 Transcription regulation (CAG) n (David et al., 1997) SCA8 KLHL1AS/ATXN8 Kelch-like 1/Ataxin-8 Unknown Intronic (CTG) n (Koob et al., 1999) SCA9 Reserved Unknown Unknown Unknown (Higgins et al., 1997) SCA10 ATXN10 Ataxin-10 Neuritogenesis (ATTCT) n (Matsuura et al., 2000) SCA11 TTBK2 Tau Tubulin Kinase 2 Implicated in tau phosphorylation Deletion (Houlden et al., 2007) SCA12 PPP2R2B Protein phosphatase 2 (formerly 2A), regulatory subunit B Regulation of PP2 activity, transcription regulation 5′-UTR (CAG) n (Holmes et al., 1999)Huang et al., 2012)SCA30 Unknown Unknown Unknown Unknown (Storey et al., 2009) SCA31 TK2 or BEAN Unknown Unknown Intronic (TGGAA) n (Sato et al., 2009) SCA32 Reserved SCA33 Reserved SCA34 ELOVL4 Elongation of very long chain fatty acids protein 4 Elongation of fatty acids MM (Cadieux-Dion et al., 2014) SCA35 TGM6 Transglutaminase 6 Crosslinking of proteins, conjugation of polyamines to proteins MM (Wang et al., 2010) SCA36 NOP56 NOP56 ribonucleoprotein homolog 60S ribosomal subunit biogenesis (early & middle stages) Intronic (GGCCTC) n (Kobayashi et al., 2011) SCA37 Unknown Unknown Unknown Unknown (Serrano-Munuera et al., 2013) SCA38 ELOVL5 Elongation of very long chain fatty acids protein 5 Elongation of fatty acids MM (Di Gregorio et al., 2014) SCA39 Unknown Unknown Unknown Chromosomal duplication (Johnson et al., 2015) SCA40 CCDC88C Coiled-coil domain containing 88C Regulation of protein phosphorylation, regulation of Wnt signaling MM (Tsoi et al., 2014) SCA41 TRPC3 Transient receptor potential cation channel, subfamily C, member 3 Receptor-activated non-selective calcium permeant cation channel MM (Fogel et al., 2015)DRPLA ATN1 Atrophin I Transcriptional corepressor (CAG) n (Koide et al., 1994) Undefined RNF170 Ring finger protein 170 E3 ubiquitin ligase activity MM (Valdmanis et al., 2011) Undefined GRID2 Glutamate receptor, Ionotropic, Delta 2 Ionotropic glutamate receptor activity MM (Coutelier et al., 2015)andVerbeek, 2014). Gene–gene interaction networks emerging in all cerebellar ataxias include neurogenesis, cell cycle and proliferation, cell communication, and synaptic transmission, all of which include calcium signaling. "
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    ABSTRACT: The spinocerebellar ataxias (SCAs) form an ever-growing group of neurodegenerative disorders causing dysfunction of the cerebellum and loss of motor control in patients. Currently, 41 different genetic causes have been identified, with each mutation affecting a different gene. Interestingly, these diverse genetic causes all disrupt cerebellar function and produce similar symptoms in patients. In order to understand the disease better, and define possible therapeutic targets for multiple SCAs, the field has been searching for common ground among the SCAs. In this review, we discuss the physiology of climbing fibers and the possibility that climbing fiber dysfunction is a point of convergence for at least a subset of SCAs.
    Full-text · Article · Jan 2016 · Neurobiology of Disease
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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.
    Full-text · Article · May 2011 · Orphanet Journal of Rare Diseases
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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.
    Full-text · Article · Jul 2009 · Human Mutation
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