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Infantile onset spinocerebellar ataxia (IOSCA) is a progressive neurological syndrome exhibiting an autosomal recessive pattern of inheritance. The characteristic features were described in Finland in the beginning of 1990s. Having shown that IOSCA does not segregate with any of the markers linked to other hereditary ataxias and thus represents a genetically distinct disease, we assigned the locus of this new hereditary ataxia to 10q23.3-q24.1. To approximate the age of the Finnish IOSCA mutation and to investigate the possible existence of more than one mutation underlying the disease, the ancestors of 13 IOSCA families were identified by use of church records dating back to the 1500s. The IOSCA pedigrees were frequently merged, providing support for these having one common ancestor. Analysis of the extended IOSCA haplotypes exposed ancient recombination events and revealed one core haplotype of four markers on a region of approximately 2 cM, which was unequivocally present in 92% of disease chromosomes. Both genealogical and haplotype data thus suggest that a single IOSCA ancestral mutation was introduced into the Finnish population most probably approximately 30-40 generations ago before the time when the general east-west migration took place within Finland.

The 2nd International Congress on Immunopharmacology was held in June of 2011 at the Conference Center of Plaza America in Varadero, Cuba. The main goal of this meeting was to provide state-of-the-art communications for scientists, manufacturers, regulators and healthcare workers, to accelerate progress in the development of biological and biotechnological products and to promote exchange/scientific cooperation between researchers. 300 delegates from 22 countries attended the conference. The wide-ranging programme commenced with a plenary session and then split into a series of parallel workshops and symposia, covering “Advances in Immunopharmacology”, “Neuroimmunology”, “Therapeutic Biological Products”, “Prophylaxis and Treatment of Helicobacter pylori”, “Pharmacology of Cytochrome P450”, “Hereditary Ataxias” and “Delivery Systems and Current Strategies for Drug Design”. In this last Symposium, a substantial body of data was presented relating to the development of delivery systems with adjuvant and vaccine potential and also to strategies focused in therapeutic and prophylactic approaches against tuberculosis. This issue is dedicated to some of the results presented in this area.

Background: Hereditary ataxias (HA) comprise a group of genetically heterogeneous rare diseases. As important public health problems to be monitored, this study analyses the morbimortality of HA in Spain. Methods: Data were extracted from the national death index (1981-2008), using the International Classification of Diseases (ICD) 9th revision code 334 until 1998, and 10th revision code G11 from 1999 onwards. ICD-9 codes were then selected from the national discharge dataset (1998-2007). Age-adjusted morbidity and mortality rates were obtained by gender and 5-year period. Results: Of the 610 HA deaths from 1981 to 2008, 277 corresponded to Friedreich's ataxia (45.4%) and 333 (54.6%) to other and unspecified ataxias (non-Friedreich group). Both groups showed an increase in mortality trend, which was more pronounced in males from 1985-1989 to 1990-1994. Geographical distribution of mortality revealed higher risk for males, mainly in the north of Spain. A total of 5,341 HA hospitalisations were identified from 1998 to 2007. The average annual age-adjusted hospitalisation rate was 1.19 per 100,000 population, with a rising trend. Conclusion: This increase in morbidity and mortality, coupled with the slight interprovincial differences, indicate that more attention should be paid to these rare diseases by public authorities and society alike.

Friedreich's ataxia (FRDA) and spinocerebellar ataxia type 2 (SCA 2) are among the most commonly diagnosed hereditary ataxias in Czech Republic. Although criteria differentiate the ataxias, disorder onset symptoms may be similar. Our goal was to determine whether and to what degree of validity posturographic examination may be utilized, with the aim of differential diagnosis; which specific posturographic parametres are suitable for differential diagnosis; and which differences in FRDA and SCA 2 patient posturographic findings may be established. 17 SCA 2 and 12 FRDA patients were examined with ten healthy controls. A multi-sensor tenzometric platform was used for posturographic examination. Toe standing position was added to basic tests, including standing position with and without visual control. There was no difference between patients in standing position with visual control but there were distinct differences between FRDA and SCA 2 patients, based on upright stance without visual control and medio-lateral deviation. There were no differences between patients in toe standing position, suggesting not only the cerebellum, but also deep sensation, helps to create the so-called adaptive controller. Posturography is attested to as a useful method for differential diagnosis of hereditary ataxias and provides neurophysiological findings in cerebellar and sensoric ataxias.

1. Muscular dystrophies; 2. Congenital muscular dystrophies; 3. Congenital myopathies; 4. Distal myopathies; 5. Other myopathies; 6. Myotonic syndromes; 7. Ion channel muscle diseases; 8. Malignant hyperthermias; 9. Metabolic myopathies; 10. Hereditary cardiomyopathies; 11. Congenital myasthenic syndromes; 12. Spinal muscular atrophies; 13. Hereditary ataxias; 14. Hereditary motor and sensory neuropathies; 15. Hereditary paraplegias; 16. Other neuromuscular disorders

The hereditary ataxias comprise a very large spectrum of genetically determined neurodegenerative disorders with progressive ataxia as the prominent symptom. In order to measure the severity of cerebellar ataxia in an easier and more practical way, it was proposed a new scale: the Scale for the Assessment and Rating of Ataxia (SARA). The objective of this study was to translate and validate SARA into Brazilian Portuguese. METHOD: The SARA was translated into Brazilian Portuguese, analyzed, back translated to English, and compared to the original version. It was applied to 30 patients. In addition to SARA, we applied the International Cooperative Ataxia Rating Scale (ICARS) in all subjects. RESULTS: SARA scale was translated into Brazilian version with adequate internal consistence, but a significant correlation between ICARS and SARA was not found. CONCLUSION: SARA was translated and validated into Brazilian Portuguese language, showing good reliability and validity. As ataxias hereditárias compreendem grande espectro de doenças neurodegenerativas geneticamente determinadas, tendo como sintoma preponderante a ataxia de instalação progressiva. No sentido de avaliar a gravidade da ataxia cerebelar através de forma mais fácil e prática, foi proposta uma nova escala: a Escala para Avaliação e Graduação de Ataxia (SARA). O objetivo deste estudo foi traduzir e validar a SARA para o português brasileiro. MÉTODO: A escala SARA foi traduzida para o português brasileiro, analisada, traduzida novamente para o inglês e comparada com sua versão original. A escala foi aplicada em 30 pacientes. Além disso, nós aplicamos também a Escala Cooperativa Internacional para Graduação de Ataxia (ICARS) em todos os pacientes. RESULTADOS: A escala SARA foi traduzida para a versão brasileira com adequada consistência interna, mas uma correlação significativa com a escala ICARS não foi encontrada. CONCLUSÃO: A escala SARA foi traduzida e validada para o português brasileiro, demonstrando boa confiabilidade e validade.

Predictive testing protocols are intended to help patients affected with hereditary conditions understand their condition and make informed reproductive choices. However, predictive protocols may expose clinicians and patients to ethical dilemmas that interfere with genetic counseling and the decision making process. This paper describes ethical dilemmas in a series of five cases involving predictive testing for hereditary ataxias in Cuba. The examples herein present evidence of the deeply controversial situations faced by both individuals at risk and professionals in charge of these predictive studies, suggesting a need for expanded guidelines to address such complexities.

Väitöskirjatutkimuksessa kuvattiin kaksi uutta perinnöllisen ataksian tautimuotoa ja selvitettiin niiden molekyyligeneettinen syy. Ataksia on neurologinen oire, joka tarkoittaa liikkeiden hallinnan ja tasapainon heikkenemistä. Toinen tässä tutkimuksessa kuvatuista taudeista MIRAS-ataksia (Mitochondrial recessive ataxia syndrome) on osoittautunut yleisimmäksi perinnölliseksi ataksiaksi suomalaisväestössä ja yleiseksi Pohjois-Euroopassa. Suomessa MIRAS-mutaation kantajia arvioidaan olevan peräti 40 000, ja ataksiaan sairastuminen on seurauksena, jos geenivirheen saa molemmilta kantajavanhemmilta. Geenivirheiden löytyminen on tärkeä lähtökohta aivojen rappeutumasairauksien tautimekanismien ymmärtämiseksi ja hoidon kehittämiseksi. Tutkimustulosten avulla voitiin huomattavasti parantaa aikuisiässä alkavan perinnöllisen ataksian taudinmäärittelyn mahdollisuuksia Suomessa ja maailmalla. Perinnölliset ataksiat ovat vaikeita keskushermoston sairauksia, jotka johtuvat pikkuaivojen, aivorungon ja/tai selkäytimen asentotuntoa välittävien ratayhteyksien etenevästä vauriosta ja joiden merkittävin oire on tasapainohäiriö. Ataktisen horjuvan kävelyn ja liikuntakyvyn heikkenemisen lisäksi sairastuneilla voi esiintyä puheen puuromaisuutta, silmien liikehäiriöitä, raajojen kömpelyyttä ja vaihtelevasti myös muita hermostoperäisiä löydöksiä, kuten ääreishermoston rappeutumaa eli polyneuropatiaa. Aikuisalkuiset suvussa väistyvästi periytyvät tai yksittäisinä ilmenevät ataksiat muodostavat puutteellisesti kuvatun sairausryhmän niin suomalaisväestössä kuin maailmanlaajuisestikin. Ataksian spesifinen diagnoosi jää usein puuttumaan ja samalla myös täsmällinen tieto sairauden syystä, laadusta, ennusteesta ja sen periytyvyydestä jälkipolville. Kliinisessä neurologisessa työssä havaitsimme useita tapauksia ja perheitä, joiden ataksian kuva ei sopinut tiedossa oleviin tauteihin ja diagnoosi jäi avoimeksi huolimatta erittäin laajoista tutkimuksista. MIRAS-ataksian löytymiseen johtaneet tutkimukset käynnistyvät eteläpohjalaisesta perheestä vuonna 1997. Molekyyligeneettisen tutkimuksen osalta pääsimme läpimurtoon kansainvälisen tutkimusyhteistyön avulla vuonna 2003: sairauden syyksi löytyi tuman POLG1-geenistä uusi mutaatio W748S. Kyseisen geenivirheen seurauksena mitokondrioiden DNA:ta monistavaan polymeraasi gamma -entsyymiin (POLG) tulee toimintahäiriötä, minkä seurauksena mitokondrioiden DNA-aines alkaa katkeilla ja mitokondrioiden toiminta solujen energialaitoksina alkaa heikentyä. Suomalaisten ja muiden eurooppalaisten MIRAS-potilaiden jatkotutkimukset täydensivät kuvaamme sairauden kliinisistä piirteistä: MIRAS on väistyvästi periytyvä aikuis- tai nuoruusalkuinen ataksia, johon liittyy tuntohermojen polyneuropatia ja mahdollisina lisäpiirteinä silmien liikehäiriöt, myokloniset lihasnykäykset, vapina, epileptiset kohtaukset, psykiatriset oireet ja myöhäisvaiheessa kognitiivisen tason heikkeneminen. MIRAS-taudille tyypillisiä aivojen magneettikuvauslöydöksiä ovat pikkuaivojen ja aivojen syvissä osissa sijaitsevien thalamus-tumakkeiden kirkassignaalimuutokset. Toinen väitöskirjatutkimuksessa kuvattu uusi perinnöllinen ataksiasyndrooma löytyi pohjalaisperheestä ja sen syyksi selvisi mitokondriaalisen DNA:n mutaatio 8993T>C, ensimmäistä kertaa aikuisalkuisen ataksian ja polyneuropatian syynä. Havainnon julkaisemisen jälkeen kyseistä ataksiaa on löydetty myös muualta. During the last 15 years the causative mutations of many hereditary ataxias have been identified. However, adult-onset non-dominant ataxias are less well characterized. Despite comprehensive investigations, the majority of adult patients presenting with sporadic or apparently recessive ataxia have previously remained without a final genetic diagnosis. In this thesis, two distinct new types of non-dominant ataxias are clinically and genetically characterized. One of them, the mitochondrial recessive ataxia syndrome (MIRAS), proved to be common in Northern European countries and the most common single hereditary ataxia disease in the Finnish population. The scientific research of this thesis started with the unique clinical observations in patients showing recessive progressive adult-onset ataxia and bilateral thalamic lesions detected by MRI. This ataxia was found to be caused by recessive mutations in the POLG1 gene, encoding mitochondrial polymerase gamma. Further explorations revealed other clinical features of these patients, that together with long term follow-up, completed the phenotype of the MIRAS disease: adult- or juvenile onset spinocerebellar type ataxia combined with sensory neuropathy, late cognitive impairment, oculomotor defects, myoclonus, tremor, psychiatric symptoms, and seizures. Because the carrier frequency of the W748S mutation in POLG1 gene proved to be very high in the Finnish population, and some family members reported neurological symptoms, we also investigated possible disease manifestations in heterozygote carriers belonging to the large original MIRAS family. Sensory neuropathy was a frequent subclinical finding, but definite clinical signs were not determined. In our clinical cohort of non-dominant adult-onset patients we also identified a heteroplasmic 8993T>C mitochondrial DNA mutation underlying a separate new distinct ataxia entity presented in this thesis. This is another adult-onset slowly progressive spinocerebellar type ataxia with axonal polyneuropathy, and without mitochondrial histochemical abnormalities in skeletal muscle. Appropriate genetic diagnosis is important for the individual patients and their families and helps addressing the prognosis, genetic counselling and possible therapeutic implications of the disease. This research effort has improved the diagnostic strategy and accuracy for adult ataxia patients in Finland and elsewhere. However, there are still unsolved genetic backgrounds that will need further research in order to find additional causes for adult-onset ataxia.

Publisher Summary This chapter summarizes the current understanding of the main hereditary ataxias and spastic parapareses that are particular to northeastern Canada. The following neurogenetic disorders were first identified in patients from northeastern Canada: ataxia with oculomotor apraxia type 2, autosomal recessive spastic ataxia of Charlevoix–Saguenay, hereditary sensory and autonomic neuropathy type 2, recessive ataxia of the Beauce, spastic ataxia 1, hereditary motor and sensory neuropathy with agenesis of the corpus callosum, and autosomal dominant sensory ataxia. It has been demonstrated for many inherited diseases that historical events have shaped the various regional gene pools of Quebec and the Maritime Provinces. In doing so, it has given rise to the increased prevalence of some rare diseases due to founder effects. The study of the more common and homogenous of these diseases has been largely completed. The regional populations of Canada will still allow the identification of new rarer forms of ataxias and parapareses and contribute to the uncovering of their mutated genes.

Machado–Joseph disease [MJD, also spinocerebellar ataxia type 3 (SCA3)] and familial amyloid polyneuropathy type I (FAP-I or ATTR V30M) are neurodegenerative disorders, inherited in an autosomal dominant fashion, which have a high prevalence in Portugal, probably due to a founder effect. MJD and FAP-I are late-onset diseases, with symptoms emerging usually during adulthood. CGPP, which is the national reference centre for these disorders, has a genetic lab that offers diagnostic, pre-symptomatic and prenatal testing and an outpatient clinic to counsel and follow relatives at risk for hereditary ataxias, FAP- I and Huntington disease (HD). The present work is a review of our 10- year experience with psychological counselling of individuals at risk for MJD and FAP-I. Persons at risk for FAP-I may show a better response to pre-symptomatic testing than those who are at risk for MJD and HD because of the availability of liver transplantation, which may improve their health and life expectancy. Psychological well-being and specific distress of MJD and FAP-I test applicants, before undergoing genetic testing (baseline level) and 3 to 6 months after disclosure of test results, have shown a low level of change, both in identified carriers and non-carriers. A major goal of psychological characterization of at-risk individuals for MJD and FAP-I is to determine the factors that influence the uptake of genetic testing.

Olfactory function is affected in different neurodegenerative diseases. Recently, it has been found that some hereditary ataxias are also associated with significant olfactory impairment. However, the initial findings did not examine the nature of the olfactory impairment associated with these ataxias. In the present article the effect of spinocerebellar ataxia type 2 (SCA2) on olfactory function was studied in 53 SCA2 patients and 53 healthy control subjects from Holguin, Cuba. Several tests were applied to evaluate olfactory threshold, description, identification and discrimination. The results show significant impairment in SCA2 patients on all olfactory measurements, and the pattern of olfactory deficits found suggests that they have much in common with those reported for other neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases.

Hereditary ataxias are recognized as a heterogeneous group of diseases based on their clinical and histopathological features. Diagnosis of specific disorders is complicated by the considerable phenotypic variability and marked overlap of clinical features among the hereditary ataxias. Recent progress in the field of molecular and human genetics allowed for identification of genetic loci or mutations responsible for many of these diseases, and DNA testing can now identify the mutation in 60–70% of patients with hereditary ataxia. An increasing number of genetic animal models of hereditary ataxias are becoming available. These genetically engineered animals provide a powerful means to study disease mechanisms that is essential for the development of rational treatment strategies. These animal models are also used to screen available drugs for their efficacy in treating the disease. This chapter aims at reviewing the clinical and histopathological features of inherited ataxias. For the most part, the chapter focuses on the diseases for which the causative genetic mutation is identified.

Two groups of hereditary ataxias are most relevant to humans — the autosomal recessive ataxias and the autosomal dominant spinocerebellar ataxias. Recessive ataxias are multisystem disorders that are characterized by inactivating mutations that result in loss of protein function. By contrast, cell death associated with dominant spinocerebellar ataxias is mostly restricted to the CNS, and cellular control of protein folding and processing is affected. The purpose of this review is to provide an integrated view of the field, encompassing the similarities — which are few — and the differences — which are many — between pathological processes that cause ataxia. In reviewing the current knowledge of ataxias, we discuss recent insights into the pathogenic mechanisms that lead to specific neuronal dysfunction and neurodegeneration.

Harding's classification takes credits for defining the homogeneous phenotypes that have been essential for the genetic linkage studies and it is still useful for didactic purposes. The advances in pathogenetic knowledge make it now possible to modify Harding's classification. Five main pathogenetic mechanisms may be distinguished: 1) mitochondrial; 2) metabolic; 3) defective DNA repair; 4) abnormal protein folding and degradation; 5) channelopathies. The present attempt to classify ataxia disorders according to their pathogenetic mechanism is a work in progress, since the pathogenesis of several disorders is still unknown. A pathogenetic classification may be useful in clinical practice and when new therapeutic strategies become available.

Over 25 autosomal dominant and autosomal recessive spinocerebellar ataxias have been isolated over the last decade. The recognition of paediatric ataxia phenotypes and, in addition, other movement disorders including hereditary choreiform and parkinsonian syndromes, has improved our knowledge of these diseases. Advances in molecular genetics has allowed fuller delineation and better recognition of these diseases.

The hereditary ataxias are a group of genetic neurological disorders, characterized by motor incoordination, resulting from dysfunction of the cerebellum and its connections. These syndromes can be divided into childhood-ataxias that often result from underlying enzymatic defects and late-onset progressive ataxias that are due to specific gene function. Both groups comprise a large group of diseases that can be further divided based on the mode of inheritance. For a few hereditary ataxias, particularly those due to specific metabolic or enzymatic defects, the underlying pathological mechanism may be reversed by treatment. For the rest, the treatment is currently limited to symptomatic therapies to manage the patients' disabilities. In this chapter, we have stressed the importance of basic science research that promises to bring advances to the bedside.

The lateral reticular nucleus (LRT) of the medulla oblongata is a precerebellar nucleus involved in proprioception and somatomotor automatisms. We investigated this nucleus in five individuals with clinically diagnosed and genetically confirmed spinocerebellar ataxia type 3 (SCA3, Machado-Joseph disease). Polyethylene glycol-embedded 100 micro m thick sections stained for lipofuscin granules and Nissl material as well as Nissl-stained paraffin-embedded sections revealed severe destruction of the LRT in all SCA3 brains examined. Some of the few surviving neurones contained ataxin-3-immunopositive intranuclear inclusion bodies, as noted in other affected brain regions in SCA3. Along with the severe neuronal depletion, obvious astrogliosis was seen in the LRT of all SCA3 patients. The findings suggest that the LRT is a consistent target of the pathological process underlying SCA3. In view of its afferent and efferent connections, destruction of the LRT probably contributes to gait ataxia in individuals suffering from SCA3.

Item does not contain fulltext BACKGROUND: International prevalence estimates of autosomal dominant cerebellar ataxias (ADCA) vary from 0.3 to 2.0 per 100,000. The prevalence of ADCA in the Netherlands is unknown. Fifteen genetic loci have been identified (SCA-1-8, SCA-10-14, SCA-16, and SCA-17) and nine of the corresponding genes have been cloned. In SCA-1, SCA2, SCA3, SCA6, SCA7, SCA-12 and SCA-17 the mutation has been shown to be an expanded CAG repeat. Previously, the length of the CAG repeat was found to account for 50 to 80% of variance in age at onset. Because of heterogeneity in encoded proteins, different pathophysiologic mechanisms leading to neurodegeneration could be involved. The relationship between CAG repeat length and age at onset would then differ accordingly. METHOD: Based on the results of SCA mutation analysis in the three DNA diagnostic laboratories that serve the entire Dutch population, the authors surveyed the number of families and affected individuals per SCA gene, as well as individual repeat length and age at onset. Regression analysis was applied to study the relationship between CAG repeat length and age at onset per SCA gene. The slopes of the different regression curves were compared. RESULTS: On November 1, 2000, mutations were found in 145 ADCA families and 391 affected individuals were identified. The authors extrapolated a minimal prevalence of 3.0 per 100,000 (range 2.8 to 3.8/100,000). SCA3 was the most frequent mutation. CAG repeat length contributed to 52 to 76% of age at onset variance. Regression curve slopes for SCA-1, SCA2, SCA3, and SCA7 did not differ significantly. CONCLUSIONS: The estimated minimal prevalence of ADCA in the Netherlands is 3.0 per 100,000 inhabitants. Except for SCA6, the relationship between age at onset and CAG repeat expansion does not differ significantly between SCA-1, SCA2, SCA3, and SCA7 patient groups in our population, indicating that these SCA subtypes share similar mechanisms of polyglutamine-induced neurotoxicity, despite heterogeneity in gene products.

Spinocerebellar ataxia type 7 (SCA7) is a neuro-degenerative disorder characterised by progressive cerebellar ataxia and macular degeneration. SCA7 is one of the least common genetically verified autosomal dominant cerebellar ataxias (ADCAs) in the world (4.5 to 11.6%), but in Sweden and Finland SCA7 is the most commonly identified form of ADCA. In an inventory of hereditary ataxias in Scandinavia (Sweden, Norway, Denmark and Finland) we identified 15 SCA7 families, eight in Sweden and seven in Finland, while no cases of SCA7 could be found in Norway or Denmark. We examined whether the relatively high frequency of SCA7 families in Sweden and Finland was the result of a common founder effect. Only two out of 15 families could be connected genealogically. However, an extensive haplotype analysis over a 10.2 cM region surrounding the SCA7 gene locus showed that all 15 families studied shared a common haplotype over at least 1.9 cM. This strongly suggests that all Scandinavian SCA7 families originate from a common founder pre-mutation.

Since the discovery of the first mutations that cause hereditary ataxias in the early 1990s, there has been continuous progress in deciphering the molecular pathogenesis of degenerative ataxias. Recent research in Friedreich's ataxia, the most frequent recessive ataxia, has provided further evidence that the clinical phenotype of this disorder is caused by abnormal oxidative phosphorylation due to mitochondrial dysfunction. The dominantly inherited spinocerebellar ataxias (SCAs) are genetically heterogeneous. Up to now, 11 distinct loci have been identified. The mutations that cause SCA1, SCA2, SCA3, SCA6 and SCA7 share the common feature of an expanded CAG sequence, encoding an abnormally long polyglutamine tract within the respective gene products. Recent pathogenetic research points to the importance of abnormal protein-protein interaction and altered gene transcription. The aetiology of many sporadic ataxias remains obscure. In some patients, association of ataxia with specific serum antibodies (antigliadin, antiglutamic acid decarboxylase) suggests an immune pathogenesis.

One of us (MP) learned about the mapping of Huntington disease gene to chromosome 4 from the late Dr. Anita Harding. She got the news over the phone from her London office during a visit to Italy for a meeting on hereditary ataxias. In Britain, they receive Nature at least a week earlier than us. Dr. Harding was very excited, and she immediately said that that was the way to go if we wanted to understand the causes of hereditary ataxias, classify these diseases in a rational way, and eventually find a treatment. At that time, the challenge seemed, and indeed was, formidable. No clue was then available about the genetic basis of what Dr. Harding aptly called "hereditary ataxias of unknown cause," their classification was confused and controversial, and all attempts to find specific biochemical abnormalities had failed. Fourteen years later, the success of the molecular genetic studies is astounding. The defective genes have been identified for Friedreich ataxia, the major recessive "hereditary ataxia of unknown cause," and for five dominantly inherited "hereditary ataxias of unknown cause." Three more dominant ataxia genes have been mapped. The molecular pathogenesis of the dominant ataxias begins to be unraveled and animal models have been and are being developed. Information is also quickly accumulating about the defective protein in Friedreich ataxia. Direct molecular diagnosis is now possible. Classification has been revolutionized. Diagnostic criteria are being redefined in the light of the molecular discoveries. The goal of this review, dedicated to the memory of the late Dr. Harding, is to offer a concise summary of current knowledge about the molecular genetics of some of the hereditary ataxias that used to be classified as of "unknown cause."

To the Editor: The editorial by Rosenberg [1] is a superb analysis of the current genotype situation in the field of the hereditary ataxias. Rosenberg is quite right in his comments that the genotype has great importance in clarifying the issue of correlation …

There are a number of conditions having ataxia as the prime characteristic. Friedrich’s ataxia is thought to be the most common of the hereditary ataxias. Approximately one in every 50 000 babies born are likely to be affected. Boys and girls can be affected equally.

Autosomal recessive hereditary ataxias belong to a group of heterogeneous disorders, for which detailed clinical evaluation, ancillary exams, and sometimes, genetic tests, are required for diagnosis. After literature review, an algorithm was built to help the investigation of this group […] Contribution to clinical characterization of autosomal recessive hereditary ataxias (Abstract). Theses. Sao Paulo, 2009

An epidemiological survey of hereditary ataxias and paraplegias was conducted in Molise, a region of Italy (335, 211 inhabitants on 1 January 1989). Total prevalence was 7.5 x 10(-5) inhabitants (95\% confidence limits 4.8-11.1). There were 7 patients with Friedreich's disease, 5 with early onset cerebellar ataxia with retained tendon reflexes, 4 with ataxia-telangiectasia, 9 with hereditary spastic paraplegias (2 autosomal dominant and 7 autosomal recessive cases). There was no patient with autosomal dominant cerebellar ataxia.

s of the 5th Latin American Congress of Clinical Neurophysiology / Clinical Neurophysiology 119 (2008), S143–S177 S161 P01.10 Sleep pathology characterization in the asymptomatic carriers of the SCA2 mutation L. Velazquez Perez 1, R. Rodriguez Labrada1, N. Canales Ochoa1, G. Sanchez Cruz1, L. Galicia Polo2, R. Garcia Aguilera1 , L.E. Almaguer Mederos 1, H. Reyes Valencia2 , J. Rodriguez1 1Centre for Research of Hereditary Ataxias, Holguin, Cuba; 2UNAM, DF

In recent years, several authors have proposed new classifications of inherited ataxias, some of them being based on systematic clinical studies of large groups of patients. This methodic approach has led to the identification of new types of ataxias and helped the development of molecular biology research in these diseases. Up to now, nerve conduction velocity and evoked potential studies have not been considered in the classification of hereditary ataxias. We have studied the results of short latency evoked potentials in 102 patients affected by a early onset, progressive cerebellar ataxia. Based on the results of this study and a review of the literature on this subject, we will evaluate the utility of nerve conduction velocity and evoked potential recordings in the classification of this group of diseases.

The mutations causing SCA2, SCA6 and Friedreich's ataxia are unstable expansions of trinucleotide repeats.

INTRODUCTION Implementation of quantitative techniques to study disorders of coordination of movements in hereditary ataxias permits an objective description of the disease. OBJECTIVES To make an objective evaluation of the main disorders of coordination in patients with ataxia and compare healthy persons with those affected. PATIENTS AND METHODS We made a prospective transverse study of 43 normal persons and 50 patients with type 2 spinocerebellar ataxia (SCA2). In all cases we made a qualitative examination of Romberg's sign in two stages to increase the sensitivity. We observed how long the person could keep his balance or whether he swayed and fell. The finger-nose test and diadochokinesia were also quantitatively analyzed using a specially designed system connected to a computer which permitted quantitative analysis. RESULTS We showed that the patients with SCA2 swayed when standing upright. However, they swayed and fell more when the test became more sensitive. This showed loss of postural sense. The maximum variables of the period and standard deviation were increased, whilst the effectiveness was significantly reduced in the group of patients (finger-nose test). Quantitative examination of diadochokinesia showed increased values for the maximum period, standard deviation and integral. CONCLUSIONS The techniques developed allow measurement of the main disorders of coordination in patients with SCA2, help to differentiate affected persons from healthy ones and are useful for the detection of moderate changes in severity during progression of the disorder.

INTRODUCTION The hereditary ataxias in Cuba make up the highest concentration of these patients in the world. The spinocerebellar ataxia type 2 (SCA2) molecular form is predominant. OBJECTIVES To determine the prevalence and incidence of hereditary ataxias. PATIENTS AND METHODS We made a descriptive study of 440 patients and 1,633 members of families at risk from this disorder in the province of Holguin. We calculated the prevalence rate and incidence. RESULTS The rate of prevalence of patients in the province is 43 cases per 100,000 inhabitants; the highest rate was 503 cases per 100,000 inhabitants in part of the municipality of Baguanos. The age group that was most affected was that of 30-39 years, with a prevalence of 63.97 cases per 100,000 inhabitants. The rural population showed the highest incidence (62.04 cases per 100,000 inhabitants). The risk of members of affected families showing the disorder was 159.33 cases per 100,000 inhabitants in this province. The highest incidence was 18.08 cases per 100,000 inhabitants in Cacocum, where the incidence in the province was 4.39. CONCLUSIONS On average the disorder passes from one state to the next every year, which suggests that the extent of the disorder worsens with time. The prevalence and incidence are the highest in the world. This together with the dominant pattern of inheritance, the effect of anticipation and inexorably progressive course of the disorder shows the serious health problem that affects the Eastern region of Cuba.

OBJECTIVE This review has been designed to describe the main clinical, epidemiological, electrophysiological, molecular and quantitative neurological characteristics in SCA2. DEVELOPMENT The prevalence rate of patients with ataxia in Holguin province is 43 per 100,000 inhabitants. The prevalence of family members at risk of having this disorder is 159.33 per 100 thousand in this province. The main neurophysiological abnormality observed was reduction in the amplitudes of sensory potentials. These alterations are the expression of a predominantly axonal peripheral lesion with signs of myelin damage. Techniques of quantitative neurology were developed for evaluation of the main disorders of coordination such as asymmetry and adiadochokinesis. In Cuba 125 families have hereditary ataxia, 772 patients and 8 to 10,000 family members are at risk of developing this condition. Seventy percent of the patients with ataxia are concentrated in Holguin province. The most severely affected towns are Baguanos (a rate of 129.20 per 100,000 inhabitants), Holguin (71.85 per 100,000) and Cacocum (69.83 per 100,000). These are the highest rates in the world. CONCLUSIONS The commonest molecular form in Cuba is the SCA2, observed in 120 families. Clinically it is characterized by a cerebellar syndrome associated with disorders of eye movements and osteotendinous reflexes.

Genetic markers controlled by 21 genetic systems were studied in 13 families containing members suffering from various hereditary disorders involving ataxia. Classical cerebellar ataxia was present in four, Friedreich ataxia in two, hereditary spastic paraplegia in four, and the Charcot-Marie-Tooth syndrome in three families. In each family, every available member above the lowest age at onset observed in that family, was subjected to a thorough clinical investigation and blood was sampled for investigation of genetic markers.

We present a working and flexible classification of inherited ataxic syndromes based on the use of simple tools available to every clinician: a good history (particularly pinpointing the age of onset, the rate of progression and the mode of inheritance) and a neurological examination (identifying the presence of ataxia, deep tendon reflexes in the knee, optic nerve, retinal and/or 8th nerve signs). This classification is easily coded for computer translation on any personal computer. The place occupied by a given disorder may, by contiguity, give a clue to its pathophysiology.

We studied multimodal evoked potentials (EPs) longitudinally in a series of children with Friedreich’s ataxia and ataxia telangiectasia to determine both their diagnostic utility and their correlation with clinical regression.The auditory brainstem responses (ABRs) were abnormal only in the children with Friedreich’s ataxia. The abnormality seen in these patients was a rostral-caudal loss of the ABR waves. The visual EPs (VEPs) were abnormal in many of the patients; those with ataxia telangiectasia had unusually low amplitude or absent VEPs, occasionally with increased latencies, whereas those with Friedreich’s ataxia had normal amplitude VEPs, often at increased latencies. The somatosensory EPs were usually of increased latency or absent in these patients. Unlike the ABR and VEPs, they did not serve to differentiate the groups.Changes in the EPs appeared to reflect clinical deterioration; patients with little change in their EPs over several years were regressing very slowly, whereas others had rapid deterioration in both EPs and clinical status. We suggest that the EPs are diagnostically of value in degenerative ataxias and may be of value in monitoring these patients and their response to therapy.

In this paper the author reviews the progress accomplished in the understanding of Friedreich's disease since the start of the “Quebec Cooperative Study of Friedreich's Ataxia” in 1974. The last ten years have indeed seen important strides taken in the definition and nosography of the hereditary ataxias and the characterization of a number of new entities. Biochemically, the principal leads uncovered during the initial prospective survey, have been pursued to great detail. Unfortunately no clear-cut constant and severe enzyme block in the principal metabolic pathways has yet been identified, despite intensive studies. It is postulated that the defect may instead be a regulatory one and involve a decreased availability or utilization of one of the vitamin cofactors that are known experimentally, or clinically, to produce central nervous system damage with ataxia: Vitamin E, Biotin or Pantothenic Acid. Studies in that direction and in molecular genetics to localize the Friedreich's disease gene are being untertaken for the next phase of the Cooperative Study.

Degenerative disorders of the extrapyramidal and spinocerebellar system often have a genetic cause; however, pathogenesis usually is still unknown. Disturbance of neurotransmitter metabolism in Parkinson disease or in some dystonic syndromes offers new therapeutic approaches; in choreatic or athetoid syndromes biochemical factors are only known in some parts. Clinical and neurophysiological differentiation of various dyskinetic disorders is essential to reach better understanding. In children early signs and symptoms are seen which may be caused by different factors and are difficult to diagnose. Similar problems are to be seen in hereditary ataxias which sometimes begin in childhood: Clinical findings are essential to plan for additional investigations.

Pattern-reversal visual evoked potentials (PRVEP) were evaluated in 24 patients from 18 separate families with various forms of hereditary ataxia and spinal degeneration. Abnormally delayed latencies were found in 3 of 5 patients with classic Friedreich's ataxia, 1 patient with dominant spastic paraparesis, and 1 patient with recessive dentatorubrospinal degeneration. Fifteen other patients with several different types of dominant and recessive hereditary ataxias had normal PRVEP latencies, including 1 patient with bilateral optic atrophy. Testing of PRVEP will be useful in the clinical delineation of the genetic ataxias and spinal degenerations, and, when interpreted with caution, should be an additional variable evaluated in the differentiation of these disorders from multiple sclerosis.

• Autosomal dominant hereditary ataxias are heterogeneous groups of disorders in which cerebellar ataxia and pyramidal, extrapyramidal, and extraocular signs predominate. We studied a family with this type of disorder with evidence supporting a large-fiber sensory neuronopathy. Electrophysiologic, histologic, radiologic, and biochemical features were studied. Neuropathic features of some forms of autosomal dominant spinocerebellar degeneration are, therefore, believed to be due to a ganglioneuropathy similar to that described in Friedreich's ataxia.

Clinical, biochemical, and genetic studies have brought clarity to many issues concerning the inherited ataxias. The classification, diagnosis, and therapy of hereditary ataxias are now better understood although many questions remain. Basic defects are identified in some disorders.