Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms.

OBJECTIVE: To identify factors that determine disease severity and clinical phenotype of the most common spinocerebellar ataxias (SCAs), we studied 526 patients with SCA1, SCA2, SCA3. or SCA6. METHODS: To measure the severity of ataxia we used the Scale for the Assessment and Rating of Ataxia (SARA). In addition, nonataxia symptoms were assessed with the Inventory of Non-Ataxia Symptoms (INAS). The INAS count denotes the number of nonataxia symptoms in each patient. RESULTS: An analysis of covariance with SARA score as dependent variable and repeat lengths of the expanded and normal allele, age at onset, and disease duration as independent variables led to multivariate models that explained 60.4% of the SARA score variance in SCA1, 45.4% in SCA2, 46.8% in SCA3, and 33.7% in SCA6. In SCA1, SCA2, and SCA3, SARA was mainly determined by repeat length of the expanded allele, age at onset, and disease duration. The only factors determining the SARA score in SCA6 were age at onset and disease duration. The INAS count was 5.0 +/- 2.3 in SCA1, 4.6 +/- 2.2 in SCA2, 5.2 +/- 2.5 in SCA3, and 2.0 +/- 1.7 in SCA6. In SCA1, SCA2, and SCA3, SARA score and disease duration were the strongest predictors of the INAS count. In SCA6, only age at onset and disease duration had an effect on the INAS count. CONCLUSIONS: Our study suggests that spinocerebellar ataxia (SCA) 1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors

Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6.

Abstract: Onset of genetically determined neurodegenerative diseases is difficult to specify because of their insidious and slowly progressive nature. This is especially true for spinocerebellar ataxia (SCA) because of varying affection of many parts of the nervous system and huge variability of symptoms. We investigated early symptoms in 287 patients with SCA1, SCA2, SCA3, or SCA6 and calculated the influence of CAG repeat length on age of onset depending on (1) the definition of disease onset, (2) people defining onset, and (3) duration of symptoms. Gait difficulty was the initial symptom in two-thirds of patients. Double vision, dysarthria, impaired hand writing, and episodic vertigo preceded ataxia in 4% of patients, respectively. Frequency of other early symptoms did not differ from controls and was regarded unspecific. Data about disease onset varied between patients and relatives for 1 year or more in 44% of cases. Influence of repeat length on age of onset was maximum when onset was defined as beginning of permanent gait disturbance and cases with symptoms for more than 10 years were excluded. Under these conditions, CAG repeat length determined 64% of onset variability in SCA1, 67% in SCA2, 46% in SCA3, and 41% in SCA6 demonstrating substantial influence of nonrepeat factors on disease onset in all SCA subtypes. Identification of these factors is of interest as potential targets for disease modifying compounds. In this respect, recognition of early symptoms that develop before onset of ataxia is mandatory to determine the shift from presymptomatic to affected status in SCA

Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings

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The First Cellular Models Based on Frataxin Missense Mutations That Reproduce Spontaneously the Defects Associated with Friedreich Ataxia

BACKGROUND:Friedreich ataxia (FRDA), the most common form of recessive ataxia, is due to reduced levels of frataxin, a highly conserved mitochondrial iron-chaperone involved in iron-sulfur cluster (ISC) biogenesis. Most patients are homozygous for a (GAA)(n) expansion within the first intron of the frataxin gene. A few patients, either with typical or atypical clinical presentation, are compound heterozygous for the GAA expansion and a micromutation. METHODOLOGY:We have developed a new strategy to generate murine cellular models for FRDA: cell lines carrying a frataxin conditional allele were used in combination with an EGFP-Cre recombinase to create murine cellular models depleted for endogenous frataxin and expressing missense-mutated human frataxin. We showed that complete absence of murine frataxin in fibroblasts inhibits cell division and leads to cell death. This lethal phenotype was rescued through transgenic expression of human wild type as well as mutant (hFXN(G130V) and hFXN(I154F)) frataxin. Interestingly, cells expressing the mutated frataxin presented a FRDA-like biochemical phenotype. Though both mutations affected mitochondrial ISC enzymes activities and mitochondria ultrastructure, the hFXN(I154F) mutant presented a more severe phenotype with affected cytosolic and nuclear ISC enzyme activities, mitochondrial iron accumulation and an increased sensitivity to oxidative stress. The differential phenotype correlates with disease severity observed in FRDA patients. CONCLUSIONS:These new cellular models, which are the first to spontaneously reproduce all the biochemical phenotypes associated with FRDA, are important tools to gain new insights into the in vivo consequences of pathological missense mutations as well as for large-scale pharmacological screening aimed at compensating frataxin deficiency

Second polar body inclusion results in diploid/triploid mixoploidy

Second polar bodyinclusion results in diploid/triploid mixoploidy. We report three cases with a typical diploid/triploid mixoploidy. Cytogenetic analysis showed a normal diploid karyotype in peripheral blood lymphocytes and a mixture of diploid and triploid cells in skin fibroblasts. We analysed microsatellite markers in patients blood lymphocytes and skin fibroblasts and compared the results with the microsatellite markers in the parents. The extra haploid set was in all three cases of maternal origin. In one case the markers were not very informative but in two cases pericentromeric markers showed a single dose of one paternal allele and a double dose of one maternal allele, more telomeric markers showed one paternal allele and two different maternal alleles. These observations can only be explained by the inclusion of the second polar body in one of the blastomeres at the cleavage stage

Chorea associated with anti-phospholipid antibodies: case report.

peer reviewedA seventeen year-old boy developed left sided chorea in a few days, subsequently involving the four limbs. Although he presented a marfanoid phenotype, genetic analysis of the Fibrillin 1 was normal. The genes for familial chorea and Huntington's disease were also negative. Biological tests showed normal serum homocystein, but revealed very high levels of anti-beta2-GP1 IgG, anticardiolipin and lupus anticoagulant, which remained at similar values for a period of over three months. Electroencephalogram and cerebral magnetic resonance imaging (MRI) showed no abnormalities. Brain PET-scan disclosed bilateral striatal hypermetabolism. The patient was treated with methylprednisolone and low dose of acetylsalicylic acid. He improved markedly after six weeks of treatment, and choreic movements disappeared completely after two months. A control PET-scan performed at this time showed reversion of striated hypermetabolism to a normal pattern. The pathogenic aspects of this relatively rare case of chorea are discussed

Ischemic stroke associated with adenoviral infection in a 4-year-old boy

We present a case of childhood arterial ischemic stroke associated with proven adenoviral upper respiratory tract infection in a previously healthy 4-year-old boy. Adenoviral meningitis and encephalitis have been reported repeatedly, thus confirming the neuroinvasive capability of these viruses. However, an association between adenoviral infection and arterial ischemic stroke has not been described thus far. HIV and varicella zoster virus are the only microorganisms that have been consistently associated with arterial ischemic stroke in the absence of acute central nervous system infection. In HIV-infected individuals ischemic stroke can be caused by vasculitis and hypercoagulability. Granulomatous arteritis of the vessel wall causes post-varicella cerebral infarction and ischemic stroke after herpes zoster ophthalmicus. We suggest that in our patient a post-varicella cerebral infarction-like mechanism of adenoviral spread to the affected artery wall occurred through the ophthalmic branch of the trigeminal nerve. Adenoviruses are neuroinvasive and inflamed conjunctiva might have permitted introduction of the virus into ophthalmic nerve tissue. In consequence, the stenotic lesion of the artery might have been induced by the presence of adenovirus and the subsequent inflammatory reaction. We recommend a prompt quest for adenoviral infection in all previously healthy children with fever and clinical presentation compatible with ischemic stroke, because timely diagnosis and treatment could improve the outcome and hasten neurological recovery

Scale for the assesment and rating of ataxia / Development of a new clinical scale

Abstract OBJECTIVE: To develop a reliable and valid clinical scale measuring the severity of ataxia. METHODS: The authors devised the Scale for the Assessment and Rating of Ataxia (SARA) and tested it in two trials of 167 and 119 patients with spinocerebellar ataxia. RESULTS: The mean time to administer SARA in patients was 14.2 +/- 7.5 minutes (range 5 to 40). Interrater reliability was high, with an intraclass coefficient (ICC) of 0.98. Test-retest reliability was high with an ICC of 0.90. Internal consistency was high as indicated by Cronbach's alpha of 0.94. Factorial analysis revealed that the rating results were determined by a single factor. SARA ratings showed a linear relation to global assessments using a visual analogue scale, suggesting linearity of the scale (p < 0.0001, r(2) = 0.98). SARA score increased with the disease stage (p < 0.001) and was closely correlated with the Barthel Index (r = -0.80, p < 0.001) and part IV (functional assessment) of the Unified Huntington's Disease Rating Scale (UHDRS-IV) (r = -0.89, p < 0.0001), whereas it had only a weak correlation with disease duration (r = 0.34, p < 0.0002). CONCLUSIONS: The Scale for the Assessment and Rating of Ataxia is a reliable and valid measure of ataxia, making it an appropriate primary outcome measure for clinical trials. Comment in SARA--a new clinical scale for the assessment and rating of ataxia. [Nat Clin Pract Neurol. 2007