‘Idiopathic’ late onset cerebellar ataxia: A clinical and genetic study of 36 cases

doi:10.1016/0022-510X(81)90104-0

Journal of the Neurological Sciences

Volume 51, Issue 2, August 1981, Pages 259-271

https://doi.org/10.1016/0022-510X(81)90104-0 Get rights and content

Abstract

The clinical features of 36 patients with late onset cerebellar ataxia of unknown cause are described. Overall, the age of onset ranged from 30 to 74 years and there was a significant excess of males. The patients were divided into 3 groups on clinical grounds. The first was composed of 12 cases in whom truncal ataxia was more marked than limb ataxia and onset was relatively late (mean 54.75 years); these correspond to the Marie-Foix-Alajouanine type of cerebellar degeneration. The second group contained 6 individuals who had prominent tremor in the upper limbs, both resting and during action. The 18 individuals in the 3rd group were clinically similar to patients previously reported as sporadic examples of olivopontocerebellar atrophy. It was this latter category which contributed the excess of males. None of the patients had similarly affected relatives. Both the 3rd group, and all 36 cases were compared with 36 other patients with dominantly inherited late onset cerebellar ataxia in order to establish which clinical features might indicate the presence of new dominant mutations in the “sporadic” cases. Optic atrophy, ophthalmoplegia and pigmentary retinal degeneration were more frequent in the familial cases.

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La ataxia cerebelosa es un síndrome caracterizado por inestabilidad de la marcha, pérdida de coordinación y alteraciones oculomotoras y del habla. Son enfermedades muy heterogéneas clínica y genéticamente. Se han descrito más de 200 genes causales y se requieren distintas técnicas para analizar los diferentes tipos de mutaciones: expansiones dinámicas, mutaciones puntuales o variaciones en el número de copias. La aplicación en los últimos años de las nuevas técnicas de secuenciación genética masiva ha aumentado de forma exponencial nuestro conocimiento sobre las bases moleculares de las ataxias. Ha permitido la identificación de nuevos genes causales y ha redefinido el espectro fenotípico de genes conocidos. No obstante, para interpretar la patogenicidad de las variantes identificadas, sigue siendo fundamental la recogida detallada de la historia familiar y el fenotipo de los pacientes. En esta actualización revisamos las manifestaciones clínicas de las formas más frecuentes y la estrategia diagnóstica más apropiada en la práctica clínica habitual.
Cerebellar ataxia is a syndrome characterized by gait instability, loss of coordination, and oculomotor and speech abnormalities. These diseases are highly heterogeneous both clinically and genetically. More than 200 causal genes have been described and different techniques are required for analyzing the various types of mutations: dynamic expansions, point mutations, or copy number variations. The use of new massive parallel gene sequencing techniques in recent years has exponentially increased our knowledge of the molecular bases of ataxias. It has allowed for the identification of new causal genes and has redefined the phenotypic spectrum of known genes. Nevertheless, in order to interpret the pathogenicity of the variants identified, taking a detailed family history and the phenotype of patients continue to be fundamental. This update will review the clinical manifestations of the most common forms and the most appropriate diagnostic strategy in routine clinical practice.
An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14
2023, American Journal of Human Genetics
Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA)_>300 and a further nine individuals with (GAA)_>250. PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA)_>300 and only 2/311 control individuals (0.6%) had a pure (GAA)_>250. In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA)_>335 and a further six had (GAA)_>250, whereas 10/190 (5.3%) control subjects had (GAA)_>250 but none were (GAA)_>335. The combined data suggest (GAA)_>335 are disease causing and fully penetrant (p = 6.0 × 10⁻⁸, OR = 72 [95% CI = 4.3–1,227]), while (GAA)_>250 is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R² = 0.44, p = 0.00045, slope = −0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA27B/ATX-FGF14 as a frequent cause of adult-onset ataxia.
A novel clinicopathologic entity causing rapidly progressive cerebellar ataxia?
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Citation Excerpt :
From a clinical perspective, several disease names have been used in the literature for CCA. Harding, in 1981, proposed the term “idiopathic late-onset cerebellar ataxia” (ILOCA), which was defined as progressive cerebellar ataxia developing in those over 20 years of age and with no family history of neurologic disease [7]. She also indicated that alcoholism, hypothyroidism, chronic anticonvulsant therapy, and paraneoplastic processes needed to be excluded [7].
Sporadic, adult-onset cerebellar ataxia is a disease with multiple etiologies. In addition to cortical cerebellar atrophy (CCA), which is often used for the pathological diagnosis, other terms such as idiopathic late-onset cerebellar ataxia (ILOCA) and sporadic adult-onset ataxia of unknown etiology (SAOA) have been used to refer to this disorder. These names describe key features of the disease, including degeneration limited to the cerebellar cortex (with or without secondary involvement of inferior olivary nuclei), a slowly progressive ataxia, and absence of a clear etiology, such as multiple system atrophy, as well as paraneoplastic, autoimmune, infectious and inherited ataxias. In this Point of View article, we describe two patients with sporadic, adult-onset ataxia with rapidly progressive disease course in addition to extracerebellar symptoms resembling prion disease, including the reevaluation of one patient who was previously reported. Pathological findings are mostly consistent with CCA, but also have degenerative changes in the thalamus. Whole genome sequencing in two patients with rapidly progressive CCA did not reveal any pathogenic variants associated with cerebellar ataxia. Although the underlying etiology behind rapidly progressive CCA is unknown, we suggest that the unique combination of clinical and pathological features of CAA with a short disease course defines a new disease entity, rapidly progressive cerebellar cortical and thalamic degeneration. This viewpoint article draws attention to this rare sporadic cerebellar ataxia with the hope that highlighting clinical and pathologic findings in a typical case will lead to improved recognition and research.
Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS
2019, American Journal of Human Genetics
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CANVAS is a cerebellar ataxia with combined cerebellar, vestibular, and somatosensory dysfunction.11,12 Historically, individuals with CANVAS have been assigned the diagnosis of idiopathic late-onset cerebellar ataxia.13 More recently, CANVAS is clinically recognized and has been incorporated into the contemporary research and teaching of both cerebellar and vestibular diseases.14,15
Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)_exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)₁₁ short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.
Sporadic adult-onset ataxia
2018, Handbook of Clinical Neurology
Citation Excerpt :
Only one case series reported a higher female proportion (Abele et al., 2007). The mean age of onset reported in the available case series ranged from 41 to 56 years (Harding, 1981; Klockgether et al., 1990; Abele et al., 2002, 2007; Burk et al., 2004, 2005; Muzaimi et al., 2004; Lin et al., 2016; Giordano et al., 2017). SAOA is a progressive disorder, but according to general clinical experience, progression rate is considerably smaller than in MSA-C.
Sporadic adult-onset ataxia (SAOA) is a nongenetic neurodegenerative disorder of the cerebellum of unknown cause which manifests with progressive ataxia. It is distinguished from hereditary ataxias and from acquired ataxias. SAOA also needs to be differentiated from multiple system atrophy of cerebellar type (MSA-C). Thus, the diagnosis of SAOA can only be made by exclusion. Although cerebellar ataxia is the prominent symptom in SAOA, patients often have additional nonataxia signs, including pyramidal tracts signs, decreased or absent ankle reflexes, sensory disturbances, mainly in the form of reduced vibration sense, and mild urinary symptoms that do not the fulfill the criteria for severe autonomic failure required for the diagnosis of MSA-C. Disease progression in SAOA is considerably slower than in MSA-C. Brain imaging typically shows isolated cerebellar atrophy. Nerve conduction studies provide evidence for polyneuropathy in about one-third of SAOA patients. As the etiology and pathogenesis of SAOA are unknown, there is no specific treatment approach to this condition.
The aetiology of Idiopathic Late Onset Cerebellar Ataxia (ILOCA): Clinical and imaging clues for a definitive diagnosis
2016, Journal of the Neurological Sciences

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^☆: This work was financially supported by the Friedreich's Ataxia Group and the Medical Research Council.

^∗: Present address: Department of Neurology, The Middlesex Hospital, Mortimer Street, London W1, Great Britain.

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‘Idiopathic’ late onset cerebellar ataxia: A clinical and genetic study of 36 cases☆

Abstract

Parenchymatous atrophy of the cerebellum

J. nerv. ment. Dis.

Parenchymatous cortical cerebellar atrophy

J. nerv. ment. Dis.

Dyssynergia cerebellaris progressiva

Trans. amer. neurol. Ass.

Olivo-ponto-cerebellar atrophy

Brain

L'atrophie olivo-pontocérébelleuse

Nouv. Icon. Salpêtrière

Olivopontocerebellar atrophy (Déjerine-Thomas type)

Spinocerebellar degeneration — A clinical survey of 74 cases

Canad. med. Ass. J.

Olivopontocerebellar atrophy

Neurology (Minneap.)

Clinical description and roentgenologic evaluation of patients with Friedreich's ataxia

Canad. J. neurol. Sci.