SCA2 in the Indian population: Unified haplotype and variable phenotypic patterns in a large case series.

BACKGROUND: Spinocerebellar ataxia-2 is one of the most prevalent SCA type across the world and one of the commonest in India. We aimed to characterize SCA2 patients both clinically and genetically (ATXN2-CAG repeats and its haplotypic background). METHODS: A total of 436 SCA2 patients were recruited consecutively comprising individuals of multiple ethnicities and two large multigenerational families. A detailed clinical evaluation and genetic analysis for CAG repeat length estimation and two marker based haplotype analysis [rs695871 and rs695872 located 177 bp and 106 bp upstream of CAG sequence in Exon 1 of ATXN2] was performed. RESULTS: Generalized limb ataxia and slow saccades were prevalent features in majority of our patients, while hyporeflexia and extrapyramidal features were less commonly observed manifestations. Slow ocular saccades, upper limb ataxia and tremor showed significant associations with age of onset, CAG repeat length and disease duration. We observed a 100% association of C-C haplotype with the expanded ATXN2 repeats. CONCLUSION: This study represents the largest study of SCA2 Indian patients that highlights the clinico-genetic manifestations and haplotype analysis. A significant proportion of patients have not shown the characteristic slow saccades and hyporeflexia thus indicating the influences of other factors in modulation of the disease which warrants further investigations. The observation of CC haplotype in all our SCA2 patients indicates a common origin across all Indian sub populations and that also indicate a common global founder event in the past.

Intravenous immunoglobulin with prednisone and risk-adapted chemotherapy for children with opsoclonus myoclonus ataxia syndrome associated with neuroblastoma (ANBL00P3): a randomised, open-label, phase 3 trial.

Purpose: No previous clinical trial has been conducted for patients with neuroblastoma associated opsoclonus myoclonus ataxia syndrome (OMA), and current treatment is based on case reports. To evaluate the OMA response to prednisone and risk-adapted chemotherapy and determine if the addition of intravenous gammaglobulin (IVIG) further improves response, the Children's Oncology Group designed a randomized therapeutic trial. Patient and Methods: Eligible subjects were randomized to receive twelve cycles of IVIG (IVIG+) or no IVIG (NO-IVIG) in addition to prednisone and neuroblastoma risk-adapted chemotherapy. All low-risk patients were treated with cyclophosphamide. The severity of OMA symptoms was evaluated at 2, 6, and 12 months using a scale developed by Mitchell and Pike and baseline versus best response scores were compared. A single patient who did not undergo neurologic assessment was excluded from OMA response analysis. This study is registered with Clinical Trials.gov (identifier NCT00033293). Results: Of the 53 patients enrolled in the study, 62% (33/53) were female. There were 44 low-risk, 7 intermediate-risk, and 2 high-risk neuroblastoma patients. Twenty-six subjects were randomized to receive IVIG+ and 27 were randomized to NO-IVIG. The neuroblastoma 3-year event-free survival (95% confidence interval (CI)) was 94.1% (87.3%, 100%) and overall survival was 98.0% (94.1%, 100%). Significantly higher rates of OMA response were observed in patients randomized to IVIG+ compared to NO-IVIG [21/26=80.8% for IVIG+; 11/27=40.7% for NO-IVIG (odds ratio=6.1; 95% CI: (1.5, 25.9), p=0.0029)]. For the majority of patients, the IVIG+ OMA regimen combined with cytoxan or other risk-based chemotherapy was well tolerated, although there was one toxic death in a high-risk subject. Conclusion: This is the only randomized prospective therapeutic clinical trial in children with neuroblastoma-associated OMA. The addition of IVIG to prednisone and risk-adapted chemotherapy significantly improves OMA response rate. IVIG+ constitutes a back-bone upon which to build additional therapy.

Ethnicity and geographic distribution of pediatric chronic ataxia in Manitoba.

BACKGROUND: Genetic and environmental factors are important determinants of disease distribution. Several disorders associated with ataxia are known to occur more commonly in certain ethnic groups; for example, the disequilibrium syndrome in the Hutterites. The aim of this study was to determine the ethnic and geographic distribution of pediatric patients with chronic ataxia in Manitoba, Canada. METHODS: We identified 184 patients less than 17 years-of-age with chronic ataxia during 1991-2008 from multiple sources. Their diagnosis, ethnicity and place of residence were determined following a chart review. RESULTS: Most patients resided in Manitoba (N=177) and the majority in Winnipeg, the provincial capital. Thirty five Aboriginal, 29 Mennonite and 11 Hutterite patients resided in Manitoba. The latter two groups were significantly overrepresented in our cohort. Ataxia telangiectasia, mitochondrial disorders, and non-progressive ataxia of unknown etiology associated with pyramidal tracts signs and developmental delay were significantly more common in Mennonite patients. Four of five patients with neuronal migration disorders associated with chronic ataxia were Aboriginal. Few isolated disorders with chronic ataxia occurred in the 11 Hutterite patients including a Joubert syndrome related disorder. CONCLUSIONS: Three disorders associated with chronic ataxia were more prevalent than expected in Mennonites in Manitoba. Few rare disorders were more prevalent in the Hutterite and Aboriginal population. Further research is needed to determine the risk factors underlying these variations in prevalence within different ethnic groups. The unique risk factor profiles of each ethnic group need to be considered in health promotion endeavors.Ethnie et distribution géographique de l'ataxie chronique chez des patients d'âge pédiatrique au Manitoba.

Ataxia aguda em idade pediátrica? revisão retrospectiva de cinco anos / Acute ataxia in childhood? a five year retrospective review

Objetivos: Caracterizar os casos de ataxia aguda internados em um Serviço de Pediatria e avaliar a sua abordagem no Departamento de Urgência.Métodos: Análise retrospectiva dos registos clínicos das crianças internadas entre janeiro de 2006 e dezembro de 2010 com quadro clínico de alteração da marcha e/ou dos movimentos motores finos com início dentro das últimas 72 horas.Resultados: Foram incluídas 82 crianças, 44 do sexo feminino. A mediana de idade foi de 4 anos. Trinta crianças apresentaram pródromos e 18 tinham história de infecção prévia. Os sintomas concomitantes mais frequentes foram sonolência (46 casos), vômitos (18 casos) e irritabilidade (14 casos). O exame físico não mostrou alterações em dois terços dos casos. Setenta crianças foram sujeitas a pelo menos um exame complementar de diagnóstico. As principais causas identificadas foram intoxicações (53 casos) e ataxia pós-infecciosa (15 casos). Só 16% necessitaram de tratamento específico e a maioria das internações foi de curta duração. Foram referenciados para seguimento em consulta hospitalar 32 casos. Registrou-se uma evolução benigna na maioria dos casos.Conclusões: A atitude face a uma criança com ataxia aguda deve ser ponderada e individualizada, tornando-se difícil a implementação de um protocolo de abordagem uniforme. A maioria dos casos tem um curso benigno e autolimitado, com internação de curta duração e apenas tratamento de suporte. No entanto, causas mais graves devem ser devidamente excluídas. História clínica minuciosa, exame físico e neurológico completos e internação visando a vigilância da evolução clínica são aspectos fundamentais.

Aims: To characterize the cases of acute ataxia hospitalized in a Pediatric Department and to evaluate its approach in the Emergency Department.Methods: Retrospective analysis of medical records of children admitted between January 2006 and December 2010 with clinical gait and/or fine motor movements with onset within the last 72 hours.Results: We included 82 children, 44 girls. The median age was 4 years. Thirty children had prodromes and 18 had a history of previous infection. The most frequent accompanying symptoms were somnolence (46 cases), vomiting (18 cases) and irritability (14 cases). Physical examination showed no changes in two thirds of cases. Seventy children have been subjected to at least one further diagnostic examination. The main causes were poisoning (53 cases) and post-infectious ataxia (15 cases). Only 16% needed specific treatment and most admissions were of short duration. Thirty-two cases were referred for follow-up consultation. The course was benign in most cases.Conclusions: The attitude towards a child with acute ataxia should be careful and individualized, making it difficult to implement a uniform protocol for approach. Most cases have a benign and self-limiting course, with short duration admission and only supportive care. However, serious causes must be properly excluded. Detailed clinical history, complete physical and neurological examination, and hospitalization for monitoring of clinical course are crucial.

Tremor-ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3-10q23.31.

Leukodystrophies are a heterogeneous group of disorders associated with abnormal central nervous system white matter. The clinical features invariably include upper motor neuron signs and developmental regression with or without other neurological manifestations. The objective of this study was to characterize clinically and genetically a new form of childhood-onset leukodystrophy with ataxia and tremor. We recruited seven French-Canadian cases belonging to five families affected by an unknown form of childhood-onset leukodystrophy. Genome-wide scans (GWS) were performed using the Illumina Hap310 or Hap610 Bead Chip to identify regions of shared homozygosity that were further studied for linkage with STS markers. All cases presented between the ages of 1 and 5 years with spasticity along with other upper motor neuron signs, prominent postural tremor, and cerebellar signs. Though motor regression is a constant feature, cognitive functions are relatively preserved, even late in the course of the disease. The higher frequency of founder diseases in the French-Canadian population and the segregation in pedigrees are suggestive of a recessive mode of inheritance. By homozygosity mapping, we established linkage to a 12.6-Mb SNP-haplotyped region on chromosome 10q22.3-10q23.31 (maximum LOD score: 5.47). We describe an autosomal recessive childhood-onset leukodystrophy with ataxia and tremor mapping to a 12.6 Mb interval on chromosome 10q22.3-10q23.31. Identification of the mutated gene will allow precise diagnosis and genetic counseling and shed light on how its perturbed function leads to white matter abnormalities.

[Neuromyelopathy in the population of Noir-marron of Saint-Laurent du Maroni in French Guiana]. / Neuromyélopathies dans la population de Noirs marrons de Saint-Laurent du Maroni en Guyane française.

The neurological observations have been reported at André Bouron Hospital of Saint-Laurent du Maroni and at General Hospital of Cayenne during a period of 5 years. All patients belonged to the "Noir Marron" ethnic group and lived in the area of Saint-Laurent. There were six women and four men, aged 15-35 years. Neurological symptoms were isolated or associated to other organ failure. Neurological manifestations included retrobulbar optic neuropathy, spastic paraparesis, sensitive ataxia and cerebellar ataxia, psychiatric symptoms were observed. Other organs affected were cardiovascular, digestive, cutaneous or endocrinologic (thyroid). Diet consist mainly in cassava. Thiamin deficiency has been observed several times. Improvement of neurological deficits following thiamin administration points towards Thiamin as an etiological factor. Ethnological specificity of Saint-Laurent area may explain that such neurological manifestation have not been observed in the rest of the department.

Is ataxic gait the predominant presenting manifestation of Creutzfeldt-Jakob disease? Experience of 14 Chinese cases from Taiwan.

Creutzfeldt-Jakob disease (CJD) is caused by an unusual prion protein. Rare CJD cases have been reported in Chinese individuals. This report describes the clinical manifestations of 14 Chinese individuals with clinically definite CJD from the National Taiwan University Hospital during the period 1976-1995. It is the largest case series of Chinese CJD up to now. All these patients fulfil the clinical definite diagnosis of CJD proposed by Brown et al. (1986), including rapidly evolving dementia, myoclonus, periodic electroencephalographic (EEG) activity (0.5-2 Hz) and death within 12 months. The clinical characteristics of the present series, including age at onset, sex ratio, duration, initial symptoms, neurological signs, EEG abnormalities, and neuroimaging studies were similar to those reported in other countries. However, there is a high incidence of initial ataxic gait as the presentation in our patients. Eight (57%) out of 14 patients initially had gait ataxia alone or in association with dementia. CJD should be considered in the differential provisional diagnosis of any middle-aged patient with a progressive ataxic syndrome.

Serum albumin levels and intraethnic variations in susceptibility to a seasonal ataxia in Nigerians.

A seasonal ataxic syndrome occurs annually, predominantly among the Ijeshas of Western Nigeria, characterized by intention tremors, cerebellar ataxia, nystagmus, and varying levels of impaired consciousness. There are evidences for intraethnic variations in susceptibility to the ataxic syndrome among the Ijeshas. The reasons for such intraethnic variations in susceptibility are unclear. To test the notion that the protein nutritional status of individuals may presage susceptibility to disease, we have undertaken a controlled study of serum albumin levels as an index of protein nutriture in patients presenting with the disease. Our study shows that the mean serum albumin level in susceptible individuals on admission was significantly lower than at discharge (Mann-Whitney test: P = .0019), was significantly lower than in controls (P = .0004), and was in no single case higher than 34 g/L (laboratory reference value 35 to 50 g/L). These results imply that the protein nutriture of individuals predicts susceptibility to the seasonal ataxia.

A dominant hereditary ataxia resembling Machado-Joseph disease in Arnhem Land, Australia.

A dominant ataxia among four families of the Arnhem Land Aboriginal people of Northern Australia has many clinical features in common with Machado-Joseph disease. Neuropathology on one case showed multiple system involvement, with sparing of the inferior olives and cerebellar cortex, consistent with Machado-Joseph disease. Portuguese ancestry is possible, although not proven.

Classifications of hereditary ataxias. A critical overview.

The classifications of hereditary ataxias (HA) proposed from 1907 to 1984 are reviewed. An analysis is provided of the possible variables in the classification of HA, including inheritance, known metabolic or other cause, localization of pathological lesions, clinical signs, natural history, epidemiology, diagnostic tools. Harding's classification is assumed to be the best clinical tool to support molecular genetics studies. However, we suggest the inclusion of Late Onset Recessive Cerebellar Ataxias in Harding's classification. Some exceptions must be considered for the diagnostic criteria of Friedreich's disease. Early Onset Cerebellar Ataxia with retained tendon reflexes (EOCA) is probably a heterogeneous entity.