[The Nomenclature and Classification of Sporadic Spinocerebellar Degeneration].

Spinocerebellar degeneration (SCD) is a neurodegenerative disease characterized by progressive cerebellar ataxia. SCD has a wide range of clinical, pathological, and genetic features, including whether the disease is sporadic or hereditary, and whether it manifests as purely cerebellar or affects multiple systems. Therefore, the classification of SCD has been complicated and has changed over time. Recent advances in genetic testing have shed light on the classification of hereditary SCD. In contrast, the classification of sporadic SCD remains chaotic and there exist nomenclature discrepancies in sporadic SCD between Japanese and English literature. Sporadic SCD is usually divided into multiple system atrophy and cortical cerebellar atrophy in Japanese literature, but the latter nomenclature seems to be uncommon in English literature. The aim of this review is to reconsider the nomenclature and classification of sporadic SCD. At this time, sporadic adult-onset ataxia of unknown etiology is an acceptable term to describe a case of sporadic SCD that does not fit the multiple system atrophy classification.

Current concepts in the treatment of hereditary ataxias.

Hereditary ataxias (HA) represents an extensive group of clinically and genetically heterogeneous neurodegenerative diseases, characterized by progressive ataxia combined with extra-cerebellar and multi-systemic involvements, including peripheral neuropathy, pyramidal signs, movement disorders, seizures, and cognitive dysfunction. There is no effective treatment for HA, and management remains supportive and symptomatic. In this review, we will focus on the symptomatic treatment of the main autosomal recessive ataxias, autosomal dominant ataxias, X-linked cerebellar ataxias and mitochondrial ataxias. We describe management for different clinical symptoms, mechanism-based approaches, rehabilitation therapy, disease modifying therapy, future clinical trials and perspectives, genetic counseling and preimplantation genetic diagnosis.

Current concepts in the treatment of hereditary ataxias / Conceitos atuais no tratamento das ataxias hereditárias

ABSTRACT Hereditary ataxias (HA) represents an extensive group of clinically and genetically heterogeneous neurodegenerative diseases, characterized by progressive ataxia combined with extra-cerebellar and multi-systemic involvements, including peripheral neuropathy, pyramidal signs, movement disorders, seizures, and cognitive dysfunction. There is no effective treatment for HA, and management remains supportive and symptomatic. In this review, we will focus on the symptomatic treatment of the main autosomal recessive ataxias, autosomal dominant ataxias, X-linked cerebellar ataxias and mitochondrial ataxias. We describe management for different clinical symptoms, mechanism-based approaches, rehabilitation therapy, disease modifying therapy, future clinical trials and perspectives, genetic counseling and preimplantation genetic diagnosis.

RESUMO As ataxias hereditárias representam um grupo complexo de doenças neurodegenerativas, e se caracterizam por ataxia cerebelar progressiva, associada a sinais e sintomas extra-cerebelares e sistêmicos, os quais incluem: neuropatia periférica, sinais piramidais, distúrbios do movimento, convulsões e disfunção cognitiva. Não existe um tratamento efetivo para a cura das ataxias hereditárias. Até o momento os tratamentos disponíveis são apenas sintomáticos. Nesta revisão vamos abordar tratamento sintomático das principais ataxias autossômicas recessivas, ataxias autossômicas dominantes, ataxias ligadas ao X e ataxias mitocondriais. Descrevemos os diferentes sintomas, abordagens terapêuticas baseadas no mecanismo fisiopatológico, terapia de reabilitação, terapia modificadora da doença, futuros ensaios clínicos, perspectivas, níveis de evidência, aconselhamento genético e diagnóstico genético pré-implantacional.

Canine hereditary ataxia.

The hereditary ataxias are a group of neurodegenerative diseases that cause a progressive (or episodic) cerebellar ataxia. A large number of different disorders have been described in different breeds of purebred dog, and in some instances, more than one disorder occurs in a single breed, creating a confusing clinical picture. The mutations associated with these disorders are being described at a rapid rate, potentially changing our ability to prevent, diagnose, and treat affected dogs. A breed-related neurodegenerative process should be suspected in any pure bred dog with slowly progressive, symmetric signs of ataxia.

C9ORF72 repeat expansion is not a significant cause of late onset cerebellar ataxia syndrome.

The GGGGCC hexanucleotide expansion in the C9ORF72 gene is the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Caucasian populations. The phenotypic spectrum of C9ORF72 hexanucleotide repeat expansion mutation has been reported to include parkinsonian syndrome, Huntington's disease-like syndrome and dementia syndrome. Although few individuals with cerebellar ataxia have also anecdotally been found to harbor the mutation, the relationship between the mutation and cerebellar ataxia awaits further clarification. We hereby screened for the presence of the C9ORF72 hexanucleotide repeat expansion in 331 patients with multiple system atrophy-cerebellar variant and 98 unrelated patients with molecularly un-assigned spinocerebellar ataxia in Taiwan utilizing a repeat-primed polymerase chain reaction assay. We found that none of the 429 patients had the C9ORF72 hexanucleotide repeat expansion mutation. Therefore, our study does not support that the mutation plays a significant role in cerebellar ataxia.

A mitochondrial implication in a Tunisian patient with Friedreich's ataxia-like.

Genes encoding the DNA helicase TWINKLE (C10orf2) or the two subunits of mtDNA polymerase γ (POLγ) (POLG1 and POLG2) have a direct effect on the mitochondrial DNA replication machinery and were reported in many mitochondrial disorders. Friedreich's ataxia (FRDA) is the common cause of ataxia often associated with the expansion of a GAA repeat in intron 1 of the frataxin gene (FXN). Mitochondrial DNA could be considered as a candidate modifier factor for FRDA disease, since mitochondrial oxidative stress is thought to be involved in the pathogenesis of this disease. We screened the FXN, POLG1 and C10orf2 genes in a Tunisian patient with clinical features of Friedreich's ataxia-like. The results showed the absence of the expansion of a GAA triplet repeat in intron 1 of the FXN gene. Besides, the sequencing of all the exons and their flanking regions of the FXN, POLG1 and C10orf2 genes revealed the presence of intronic polymorphisms. In addition, screening of the mtDNA revealed the presence of several mitochondrial known variations and the absence of mitochondrial deletions in this patient. The detected m.16187C>T and the m.16189T>C change the order of the homopolymeric tract of cytosines between 16184 and 16193 in the mitochondrial D-loop and could lead to a mitochondrial dysfunction by inhibiting replication and affecting protein involved in the replication process of the mtDNA which could be responsible for the clinical features of Friedreich ataxia observed in the studied patient.

Peripheral nerve involvement in hereditary cerebellar and multisystem degenerative disorders.

Hereditary ataxias (HA) encompass an increasing number of degenerative disorders characterized by progressive cerebellar ataxia usually accompanied by extracerebellar semeiology including peripheral nerve involvement. Classically, HA were classified according to their pathological hallmark comprising three main forms: (1) spinal form predominantly with degeneration of spinocerebellar tracts, posterior columns, and pyramidal tracts (Friedreich's ataxia, FA); (2) olivopontocerebellar atrophy (OPCA); and (3) cortical cerebellar atrophy (CCA). In the 1980s Harding proposed a clinico-genetic classification based upon age of onset, modality of transmission, and clinical semeiology. The main categories in this classification were as follows: (1) early onset cerebellar ataxia (EOCA) with age of onset below 25 years and usually with autosomal recessive (AR) transmission (this group encompasses FA and syndromes different from FA); (2) autosomal dominant cerebellar ataxia (ADCA) with adult onset and with either cerebellar-plus syndrome or pure cerebellar semeiology; and (3) idiopathic late onset onset cerebellar ataxia (ILOCA). With the advent of molecular genetics, the nosology of HA has been in a state of constant flux. At present EOCA comprises at least 17 genotypes (designated with the acronym of ARCA derived from AR cerebellar ataxia), whereas under the umbrella of ADCA 30 genotypes have been reported. In this chapter we will review peripheral nerve involvement in classical pathological entities (OPCA and CCA), ARCA, ADCA, and ILOCA paying special attention to the most prevalent syndromes in each category. As a general rule, nerve involvement is relatively common in any form of ataxia except ILOCA, the most common pattern being either sensory or sensorimotor neuronopathy with a dying-back process. An exception to this rule is AR spastic ataxia of Charlevoix-Saguenay where nerve conduction studies show the characteristic pattern of intermediate neuropathy implying that sacsin mutation causes both axonal and Schwann cell dysfunction.

Spinocerebellar degenerations.

The spinocerebellar ataxias (SCA) are a large group of inherited disorders affecting the cerebellum and its afferent and efferent pathways. Their hallmark symptom is slowly progressive, symmetrical, midline, and appendicular ataxia. Some may also have associated hyperkinetic movements (chorea, dystonia, myoclonus, postural/action tremor, restless legs, rubral tremor, tics), which may aid in differential diagnosis and provide treatable targets to improve performance and quality of life in these progressive, incurable conditions. The typical dominant ataxias with associated hyperkinetic movements are SCA1-3, 6-8, 12, 14, 15, 17, 19-21, and 27. The common recessive ataxias with associated hyperkinetic movements are ataxia telangiectasia and Friedreich's ataxia. Fragile X tremor-ataxia syndrome (FXTAS) and multiple-system atrophy (a sporadic ataxia which is felt to have a genetic substrate) also have hyperkinetic features. A careful work-up should be done in all apparently sporadic cases, to rule out acquired causes of ataxia, some of which can cause hyperkinetic movements in addition to ataxia. Some testing should be done even in individuals with a confirmed genetic cause, as the presence of a secondary factor (nutritional deficiency, thyroid dysfunction) can contribute to the phenotype.

[Autosomal recessive cerebellar ataxias]. / Les ataxies cérébelleuses autosomiques récessives.

INTRODUCTION: Autosomal recessive cerebellar ataxias (ARCA) are heterogeneous and complex inherited neurodegenerative diseases that may affect the cerebellum and/or the spinocerebellar tract, the posterior column of the spinal cord and the peripheral nerves. Cerebellar ataxia is frequently proeminent and mostly associated with several neurological or extra-neurological signs, leading to a major disability before the age of 30. STATE OF ART: Friedreich's ataxia (FRDA) is clearly the most frequent ARCA and several rarer entities have been described during the past fifteen years such as ataxia with oculomotor apraxia type 1 (AOA1) and type 2 (AOA2), ataxia with vitamin E deficiency (AVED) and autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The ACAR are characterized by both allelic and non-allelic genetic heterogeneity. They may be divided into three groups: spino-cerebellar ataxia with pure sensory neuropathy; cerebellar ataxia with sensori-motor axonal neuropathy; pure cerebellar ataxia (i.e. ataxia of purely cerebellar origin that may be associated with other symptoms). Common physiological pathways are involved in several ARCA, such as DNA repair deficiency (AOA1, ataxia telangiectasia [AT]…), RNA termination disorder (AOA2), mitochondrial defect (FRDA, sensory ataxic neuropathy with dysarthria and ophthalmoplegia [Sando]…), lipoprotein assembly defects (AVED, abetalipoproteinemia [ABL]), chaperon protein disorders (ARSACS, Marinesco-Sjögren syndrome [MSS]) or peroxysomal diseases (Refsum disease [RD]). PERSPECTIVES: New nanotechnology methods and high throughput gene analysis as well as bioinformatics should lead to the identification of several new ARCAs in the next few years despite the rarity of these entities. However, the challenge of the next decades will be the discovery of efficient treatments for these disabling neurodegenerative disorders. CONCLUSION: Clinicians should be aware of the more frequent ARCAs, especially FRDA, in addition to ARCAs for which treatment is available (FRDA, AVED, ABL and RD for instance).

Difference in the effects of tandospirone on ataxia in various types of spinocerebellar degeneration: an open-label study.

The aim of this study was to investigate the effects of tandospirone on ataxia in various types of spinocerebellar degeneration (SCD). Fifteen milligram per day of tandospirone was administered to 39 patients with SCD (spinocerebellar atrophy (SCA) 1, five patients; SCA2, six patients; Machado-Joseph disease (MJD), 14 patient; SCA6, five patients; multiple system atrophy-cerebellar type (MSA-C), seven patients; and multiple system atrophy-Parkinson type (MSA-P), two patients). All patients were assessed before and 4 weeks after administration of the drug using the international cooperative ataxia rating scale total score (ARS), total length traveled (TLT) of body stabilometry, and a self-rating depression scale. Statistically, ARS showed a significant difference in MJD (p = 0.005) and SCA6 (p = 0.043). TLT also showed a significant difference in MJD (p = 0.002) and SCA6 (p = 0.043). Eight of 39 patients (SCA1, 1/5; SCA2, 0/6; MJD, 4/14; SCA6, 3/5; MSA-C, 0/7; and MSA-P, 0/2) showed more than a five point reduction in ARS, and 13 of 39 patients (SCA1, 0/5; SCA2, 1/6; MJD, 8/14; SCA6, 4/5; MSA-C, 0/7; and MSA-P, 0/2) showed a reduction of TLT. Our data indicate that the effects of tandospirone on ataxia are different between types of SCD. Therefore, tandospirone is useful for cerebellar ataxia in patients with MJD and SCA6.

Prevalence of spinocerebellar degenerations in the Hokuriku district in Japan.

BACKGROUND: The prevalence of disease subtypes of spinocerebellar degenerations (SCDs) varies between countries, and even between areas within a country. We report unprecedented epidemiologic data on SCDs in the Hokuriku district, which is located in the central, western part of Japan. METHODS: Clinical and genetic data on SCD patients were obtained via questionnaires distributed to all the departments of neurology, psychiatry and internal medicine in the Hokuriku district (n = 418). RESULTS: Among the SCD patients, autosomal dominant cerebellar ataxias (ADCAs) were noted in 40.4%, multiple system atrophy in 24.7%, cortical cerebellar atrophy in 13.3% and autosomal recessive cerebellar ataxia in 0.3%. Genetically confirmed ADCA patients included those with Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3; 63.3%), SCA6 (20.0%), ADCA linked to chromosome 16q22.1 (10.0%), dentatorubral pallidoluysian atrophy (4.4%), SCA1 (1.1%) and SCA2 (1.1%). MJD/SCA3 was highly prevalent in the Toyama prefecture of the Hokuriku district, accounting for 90% of genetically confirmed ADCAs by birthplace; MJD/SCA3 patients were concentrated in the Gosei area, the western part of the Toyama prefecture, giving an estimated prevalence of 19.1 per 100,000 inhabitants. CONCLUSIONS: The Hokuriku district, especially the Gosei area of Toyama, had a surprisingly high relative frequency and prevalence of MJD/SCA3, which is comparable to that in the Azores, Portugal.

Diagnosis and management of early- and late-onset cerebellar ataxia.

Cerebellar ataxias represent a heterogeneous group of neurodegenerative disorders. Two main categories are distinguished: hereditary and sporadic ataxias. Sporadic ataxias may be symptomatic or idiopathic. The clinical classification of hereditary ataxias is nowadays being replaced by an expanding genotype-based classification. A large spectrum of degenerative and metabolic disorders may also present with ataxia early or late in the course of disease. We present a diagnostic algorithm for the adult patient presenting with subacute cerebellar ataxia, based on family history and straightforward clinical characteristics of the patient. Along with the algorithm, an overview of the autosomal dominant, autosomal recessive, X-linked, mitochondrial, symptomatic and idiopathic subtypes of cerebellar ataxia is presented. An appropriate diagnosis is of utmost importance to such considerations as prognosis, genetic counselling and possible therapeutic implications.

Neurophysiologic studies in early-onset cerebellar ataxia.

The discovery of the gene for Friedreich's ataxia (FRDA) has not only broadened the FRDA phenotype, but has also identified patients with early-onset cerebellar ataxia who resemble FRDA clinically but who do not carry a mutation in the frataxin gene. In order to identify subgroups that may represent a uniform underlying disorder, we performed neurophysiologic studies, including nerve conduction studies, electromyography, and transcranial magnetic stimulation, in 15 patients with a slowly progressive, unexplained, early-onset cerebellar ataxia (EOCA). In addition, sural nerve biopsy data were available in four patients. The neurophysiologic data identified three distinctive groups of EOCA patients: three patients with normal motor and sensory conduction velocities and borderline sensory amplitudes (group 1); three patients with a mild, predominantly motor, axonal neuropathy (group 2); and nine patients with a highly uniform syndrome characterized by pyramidal features and a severe sensory and motor axonal neuropathy (group 3). We conclude that, on the basis of neurophysiologic studies, distinctive groups of patients with EOCA can be delineated, and that differentiation between patients with EOCA can be useful for differential diagnostic consideration. Whether this splitting also reflects a fundamental phenotypic difference and, therefore, may direct future DNA studies, remains to be established.

Size bias of fragile X premutation alleles in late-onset movement disorders.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by premutation expansions (55-200 CGG repeats) of the FMR1 gene, shares clinical features with other movement disorders, particularly in the domains of gait ataxia, intention tremor and parkinsonism. However, the prevalence of FXTAS within other diagnostic categories is not well defined. METHODS: A meta-analysis was conducted of all published (n = 14) genetic screens for expanded FMR1 alleles to assess the prevalence and CGG-repeat size bias of FMR1 premutation alleles in those populations. RESULTS: In men with late-onset cerebellar ataxia, the prevalence of premutation alleles (1.5%; 16/1049) was 13 times greater than expected based on its prevalence in the general population (2%; 16/818 for age of onset >50 years; odds ratio 12.4; 95% confidence interval 1.6 to 93.5). Meta-analysis of CGG-repeat data for screened patients with premutation alleles shows a shift to larger repeat size than in the general population (p<0.001). 86% (19/22) of premutation alleles were larger than 70 repeats in the patients screened, whereas only approximately 22% of premutation alleles are larger than 70 repeats in the general population. CONCLUSIONS: Expanded FMR1 alleles contribute to cases of late-onset sporadic cerebellar ataxia, suggesting that FMR1 genetic testing should be carried out in such cases. The biased distribution of FMR1 allele sizes has substantial implications for genetic counselling of carriers with smaller alleles who are at a low risk of developing FXTAS, and suggests that the estimated prevalence of FXTAS among men >50 years of age in the general population may be two to threefold lower than the initial figure of 1 in 3000.

Hereditary ataxia and behavior.

Recognizing cognitive deficits and psychiatric disorders in patients with autosomal dominant ataxias is relatively new. At this time, the percentage of patients with these disorders who experience changes in cognition or psychiatric symptoms is unknown. Cognitive impairment, when seen, is often found on tests of executive function, probably reflecting disruption of afferent and efferent pathways of the prefrontal cortex and subcortical structures, including the cerebellum. Widespread global dysfunction does occur in some cases, especially later in the disease course. Psychiatric symptoms including depression, aggression, irritability, and psychosis have all been reported. As these behavioral changes receive further study, one hopes that guidelines for treating these symptoms will emerge. Clinicians should be mindful of the psychosocial effects that genetic testing for the hereditary ataxias may have, especially in cases of predictive testing for those who are asymptomatic but at risk because of family history. Guidelines established for genetic testing in HD may be helpful when approaching these cases.

Problems and possibilities in the differential diagnosis of Syndrome Spinocerebellar Ataxia.

Differential diagnosis in neurologic patients with spinocerebellar syndrome is complex as a result of the great degree of variability in phenotypic and genetic aspects of more than 200 nosological entities. In the past decade, genetic etiology has been discovered in part of the diseases and the term ''spinocerebellar ataxia'' has become, from a neurologic point of view, a loose definition applied to a group of autosomal dominant diseases. Topical extensive literature about differential diagnoses of ataxias usually refers to genetics classification or is produced by a group of radiologists, elektrophysiologists and biologists as well as others in the field. A further problem is that the majority of studies do not take into account other acquired illnesses and diseases which may fundamentally alter the symptomology and course of a primary disease, not to mention the possibility of concomitancy in hereditary diseases. The following article was prompted by daily contact with ataxic patients and related issues raised by colleagues; its goal is to clarify problems faced by child neurologists and neurologists in clinical practice.

Influence of repetitive transcranial magnetic stimulation on disease severity and oxidative stress markers in the cerebrospinal fluid of patients with spinocerebellar degeneration.

Ataxia severity, cerebellar hemispheric blood flow (CHBF), ascorbate free radical (AFR), superoxide dismutase protein, superoxide scavenging activity, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in cerebrospinal fluid (CSF) were compared before and after an 8-week course of repetitive transcranial magnetic stimulation (rTMS) in 20 patients with spinocerebellar degenerations (SCD). SCD patients showed higher AFR, 8-OHdG, and superoxide scavenging activity than 19 controls. In SCD patients, AFR and ataxia severity declined, and CHBF increased after rTMS. As the SCD patients showed negative correlations between ataxia severity and CHBF or superoxide scavenging activity, the therapeutic mechanism of rTMS may involve decreased oxidative stress and increased CHBF.

[Autosomal dominant spinocerebellar degeneration--new forms and pathomechanisms].

In our country, hereditary spinocerebellar degeneration accounted for approximately 30% of the total cases. Most of them are autosomal dominant and include more than 20 diseases. The outlines of some new members, namely autosomal dominant cortical cerebellar atrophy linked to chromosome 16 (16q-ADCCA), SCA14, an ataxia caused by FGF14 mutation and a form of neuroferritinopathy were described. The etiology of many autosomal dominant SCDs has been identified as the abnormal expansion of CAG repeat. The latter three diseases are caused by missense mutations of the causative genes, which clearly shows the presence of other new mechanisms of cerebellar degeneration than repeat expansion. 16q-ADCCA is the most frequent after Machado-Joseph disease and SCA6 according to our genetic diagnosis of 185 SCD patients. The disease is characterized by Purkinje cell degeneration and atrophy with somatic sprouts as well as the halo-like structure surrounding the soma. The halo is positive for synaptophysin. These features are so unique that 16q-ADCCA may be diagnosed by neuropathology alone.

[At the crossroads between developmental and degenerative diseases: the cerebellar disorders of early infancy. Classification and practical approach]. / Au carrefour de la pathologie développementale et de la pathologie dégénérative: les maladies cérébelleuses de la première enfance. Démembrement et approche pratique.

The developmental characteristics of the cerebellum, including its histogenesis which persists well beyond birth, explain, at least in part,why the mechanisms of cerebral disorders of infancy remain equivocal. The nosology of certain congenital ataxias, especially those with cerebellar hypoplasia, remains ambiguous, at the crossroads between early degenerative disease and congenital non-progressive anomalies. We have revisited the clinical approach to the most frequent situations: (1) the careful dysmorphology work-up must search for any element of various recognizable syndromes, especially those transmitted by autosomal recessive inheritance. An update of list of such syndromes is provided. (2) Cerebellum imaging must be obtained as early as possible and re-documented with a long-term follow-up. Emerging 3D techniques should help improve morphological evaluation. (3) One the contrary, a complex biochemical work-up, looking for metabolic diseases, is required only when the clinical and radiological evaluations provide unusual data. (4) Mental status is always the most relevant element of prognosis. t is frequently compromised, including in congenital non-progressive ataxia with normal imaging. Beyond the classical strategies, the genetic approach must take into consideration possible phenotypic homologies with natural or experimental animal models. This approach is illustrated by the recent discovery of mutations with the human homolog of the Reeler gene in a subset of cerebellar agenesis associated with other dysgenetic elements.