Ataxia and Hereditary DisordersAtaxia and hereditary disorders
Section snippets
Inherited Ataxias
The last decade has seen great changes in the diagnosis of inherited ataxias. Previously mysterious diseases are now recognized to be caused by specific mutations for which genetic screening is readily available. In many cases, the discovery of the molecular basis has broadened our definition of the possible clinical manifestations of particular inherited ataxias. Moreover, the type of mutation underlying the more common forms of inherited ataxia—unstable trinucleotide repeat expansions—helps
Ataxia and Genetics: Asking the Right Questions
The Online Mendelian Inheritance in Man, or OMIM (http://www3.ncbi.nlm.nih.gov/Omim/) lists over 400 genetic illnesses associated with ataxia. This is a daunting number, the great majority of which the neurologist will never see. When assessing whether a patient has a genetic form of ataxia, concentrating on the answers to a few fundamental questions helps narrow the focus:
1) Is there a family history of similar disease? If so, does the list of affected family members suggest an
Early Onset Ataxias
Recessive metabolic disorders often manifest as intermittent ataxia, for which the differential diagnosis is extensive. Certain tests will narrow the list, including serum lactate, pyruvate, and ammonia levels; serum amino acids and urine organic acids; serum cholesterol, lipoprotein, and vitamin E levels; and, in some cases, enzymatic assays and rectal, skin or muscle biopsies. A brain MRI may reveal evidence of leukodystrophy or congenital/developmental abnormalities. Here the authors discuss
Classification of Late–Onset Ataxias
In the past, adult onset hereditary ataxias were classified according to pathology, for example “olivopontocerebellar atrophy” (OPCA) and “cerebellar–cortical atrophy.” This descriptive classification has been abandoned in favor of ones that take into account clinical and genetic features.
Most of the well characterized, inherited forms of adult onset ataxia are dominantly inherited. This, in part, reflects the fact that studies require sufficient numbers of affected persons to successfully find
Treatment
Unfortunately, advances in the therapy of ataxia lag far behind the remarkable progress in understanding the genetics of the disease. The field lacks well-designed clinical trials showing symptomatic or preventive benefit for progressive ataxia. Perhaps, the only widely accepted therapy is acetazolamide for episodic ataxia; even though the beneficial response may be greater in EA-2, patients with any form of episodic ataxia deserve a trial of acetazolamide. Likewise, patients with spasticity
Summary
Recent advances in molecular genetics have eliminated much of the confusion that previously plagued the diagnostic workup of inherited ataxia. The remarkable phenotypic variability among ataxias—and even within the same type of ataxia—are now explained by the dynamic nature of trinucleotide repeat mutations. The finding that DNA expansions underlie disease has resulted in straightforward and inexpensive genetic testing for the more common forms of dominantly inherited ataxia. For many patients,
References (61)
- et al.
Iron–dependent self–assembly of recombinant yeast frataxin: Implications for Friederich's Ataxia
Am J Hum Genet
(2000) - et al.
SCA1 transgenic mice: A model for neurodegeneration caused by an expanded CAG trinucleotide repeat
Cell
(1995) - et al.
Xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy: do the genes explain the diseases?
Trends Genet
(1996) - et al.
Mapping of spinocerebellar ataxia 13 to chromosome 19q13.3–q13.4 in a family with autosomal dominant cerebellar ataxia and mental retardation
Am J Hum Genet
(2000) - et al.
Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice
Cell
(1996) Molecular genetics and pathogenesis of Friedreich's ataxia
Neuromuscul Disord
(1998)- et al.
Effect of idebenone on cardiomyopathy in Friedreich's ataxia: A preliminary study
Lancet
(1999) - et al.
Myoclonic epilepsy and ragged–red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA (Lys) mutation
Cell
(1990) - et al.
Autosomal dominant cerebellar ataxia type III: linkage in a large British family to a 7.6–cM region on chromosome 15q14–21.3
Am J Hum Genet
(1999) - et al.
Familial episodic ataxia: Clinical heterogeneity in four families linked to chromosome 19p
Ann Neurol
(1997)
Very late–onset Friedreich's ataxia despite large GAA triplet repeat expansions
Arch Neurol
Friedreich's ataxia: Autosomal recessive disease caused by an intronic GAA triplet repeat expansion
Science
Molecular and clinical correlation in spinocerebellar ataxia 2: A study of 32 families
Hum Mol Genet
Fourteen and counting unraveling trinucleotide repeat diseases
[Review] Hum Mol Genet
Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7)
Hum Mol Genet
Spinocerebellar ataxia type 8: Clinical features in a large family
Neurology
Friedreich's ataxia: An overview
J Med Genet
Clinical and genetic abnormalities in patients with Friedreich's ataxia
N Engl J Med
ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF
Nat Genet
The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich's ataxia
Am J Hum Genet
The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia
Am J Hum Genet
Molecular analysis of new mutations for Huntington's disease: Intermediate alleles and sex of origin effects
Nat Genet
Spinocerebellar ataxia type 6: Gaze-evoked and vertical nystagmus, Purkinje's cell degeneration, and variable age of onset
Ann Neurol
Calcium channels in neurological disease
Ann Neurol
Related articles, clinical features and classification of inherited ataxias
Adv Neurol
Human alpha-tocopherol transfer protein: Gene structure and mutations in familial vitamin E deficiency
Ann Neurol
Spinocerebellar ataxia type 7 (SCA7): A neurodegenerative disorder with neuronal intranuclear inclusions
Hum Mol Genet
Expansion of a novel CAG trinucleotide repeat in the 5' region of PPP2R2B is associated with SCA12
Nat Genet
Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats
Nat Genet
CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1
Nat Genet
Cited by (43)
Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7
2013, Progress in NeurobiologyCitation Excerpt :Since these elongated CAG-repeats encode pathologically expanded polyglutamine tracts in the disease proteins, these SCA are also designated polyglutamine or CAG-repeat diseases (Table 1) (Banfi et al., 1994; Bauer and Nukina, 2009; Clark and Orr, 2000; David et al., 1997; Dürr, 2010; Gilman, 2000; Imbert et al., 1996; Jonasson et al., 2002; Kawaguchi et al., 1994; Klockgether, 2003; Klockgether and Paulson, 2011; Lebre and Brice, 2003; Mauger et al., 1999; Orr et al., 1993; Pang et al., 2002; Paulson and Ammache, 2001; Paulson, 2007; Pulst et al., 1996; Riess et al., 1997a; Robitaille et al., 1997; Schöls et al., 2004; Soong and Paulson, 2007; Stevanin et al., 2000; Zhuchenko et al., 1997). SCA1, SCA2, SCA3, SCA6 and SCA7 (Table 1) are clinically characterized by an insidious and predominantly adult onset, a progressive worsening of classic cerebellar and non-cerebellar symptoms and an average disease duration of 15–30 years (Dürr, 2010; Klockgether, 2003; Klockgether and Paulson, 2011; Paulson and Ammache, 2001; Paulson, 2009; Schöls et al., 2004; Soong and Paulson, 2007; Stevanin et al., 2000). SCA1, SCA2, SCA3, SCA6 are associated with a prevalence of comorbid depressive symptoms of approximately 20% (Schmitz-Hübsch et al., 2011).
Therapeutic RNA interference for neurodegenerative diseases: From promise to progress
2007, Pharmacology and TherapeuticsConsistent affection of the central somatosensory system in spinocerebellar ataxia type 2 and type 3 and its significance for clinical symptoms and rehabilitative therapy
2007, Brain Research ReviewsCitation Excerpt :Furthermore, the severe and consistent involvement of all of the somatosensory pathways that subserve transmission of nociceptive, thermal, and epicritic information sufficiently explains the occurrence of the well-known somatosensory clinical deficits of SCA2 and SCA3 patients as well as the paraclinical finding that the somatosensory evoked potentials may be altered in these ataxic patients (Abele et al., 1997; Bürk et al., 1996; Bürk et al., 1997; Cancel et al., 1997; Klockgether, 2003; Paulson and Ammache, 2001; Schöls et al., 1997b, 2004; Yamamoto et al., 1997). Ingestive dysfunctions leading to dysphagia represent frequent clinical symptoms in SCA2 and SCA3 patients (Abele et al., 1997; Bürk et al., 1996; Bürk et al., 1997; Cancel et al., 1997; Dürr et al., 1995; Geschwind et al., 1997; Paulson and Ammache, 2001; Schöls et al., 1997a,b) and are commonly associated with weight loss, dehydration, and with the occurrence of an aspiration pneumonia. This in turn represents a life-threatening complication in patients suffering from SCA2 and SCA3 and other diseases associated with neurogenic dysphagia (Langmore et al., 1998; Leopold and Kagel, 1983; Lind, 2003; Marik and Kaplan, 2003; Martin et al., 1994; Palmer et al., 2000; Ramsey and Smithard, 2004).
Progression rates of dominant spinocerebellar ataxias
2011, NeurologyClinical, imaging, and laboratory markers of premanifest spinocerebellar ataxia 1, 2, 3, and 6: A systematic review
2021, Journal of Clinical Neurology (Korea)
Address reprint requests to, Henry Paulson MD, PhD, Assistant Professor, Department of Neurology, University of Iowa College of Medicine, Iowa City, IA 52242-1101