1-29-07 Autosomal dominant ataxias in Portugal: Review of 106 families (original) (raw)
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Low predisposition to instability of the Friedreich ataxia gene in Cuban population
Clinical Genetics, 2000
Cuba is an archipelago in the Caribbean whose population consists of the creole descendants of Spaniards mixed with sub-Saharan Africans, the Chinese, European Jews and Amerindians to a lesser degree (1). It is also the country with the world's highest prevalence of Spinocerebellar ataxia type 2 (SCA2). Recessive and sporadic ataxias, on the contrary, represent 9.16% and 2.39%, respectively among all types of ataxia (2). Worldwide, Friedreich ataxia (FRDA) is considered the most frequent form of inherited ataxia. We undertook as study to determine its prevalence in Cuba as well as to describe the characteristics of the FRDA gene in the normal population, looking for some clues about the probable origin of the disease. For these purposes, after informed consent was obtained, 87 patients affected by a recessive or sporadic ataxia, previously identified through a national survey (2), were evaluated. For clinical examination, internationally validated clinical scales, International cooperative ataxia rating scale (ICARS) and Scale for the Assessment and Rating of Ataxia (SARA) (3, 4), were used. Genomic DNA was obtained by extraction from leukocytes and PCR for FRDA gene was carried out using standard protocols, which included the primers GAA-104F and GAA-629R, together with the Elongase enzyme (Invitrogen). Gel electrophoresis was performed according to established techniques. A total of 496 chromosomes from 248 non-FRDA individuals aged 25 years or older coming from all over the island were also analyzed using the same protocol, as well as fragment analysis for the estimation of GAA repeat sizes using a ReproGel™ high resolution in an Alfexpress sequencer (GE Healthcare Bio-sciences Uppsala Sweden). Among the patients, 69 were affected by recessive ataxia and 18 by sporadic ataxia; 45 individuals were males (51.72%) and 42 females (48.28%). One of the patients presented with intermittent ataxia resulting in a metabolic disease. Six patients
Molecular and clinical study of a cohort of 110 Algerian patients with autosomal recessive ataxia
BMC medical genetics, 2015
Autosomal recessive cerebellar ataxias (ARCA) are a complex group of neurodegenerative disorders with great genetic and phenotypic heterogeneity, over 30 genes/loci have been associated with more than 20 different clinical forms of ARCA. Genetic heterogeneity combined with highly variable clinical expression of the cerebellar symptoms and overlapping features complicate furthermore the etiological diagnosis of ARCA. The determination of the most frequent mutations and corresponding ataxias, as well as particular features specific to a population, are mandatory to facilitate and speed up the diagnosis process, especially when an appropriate treatment is available. We explored 166 patients (115 families) refered to the neurology units of Algiers central hospitals (Algeria) with a cerebellar ataxia phenotype segregating as an autosomal recessive pattern of inheritance. Genomic DNA was extracted from peripheral blood samples and mutational screening was performed by PCR and direct seque...
Genetics of Ataxias in Indian Population: A Collative Insight from a Common Genetic Screening Tool
Advanced Genetics, 2022
study group Cerebellar ataxias (CAs) represent a group of autosomal dominant and recessive neurodegenerative disorders affecting cerebellum with or without spinal cord. Overall, CAs have preponderance for tandem nucleotide repeat expansions as an etiological factor (10 TREs explain nearly 30-40% of ataxia cohort globally). The experience of 10 years of common genetic ataxia subtypes for ≈5600 patients' referrals (Pan-India) received at a single center is shared herein. Frequencies (in %, n) of SCA types and FRDA in the sample cohort are observed as follows: SCA12 (8.6%, 490); SCA2 (8.5%, 482); SCA1 (4.8%, 272); SCA3 (2%, 113); SCA7 (0.5%, 28); SCA6 (0.1%, 05); SCA17 (0.1%, 05), and FRDA (2.2%, 127). A significant amount of variability in TRE lengths at each locus is observed, we noted presence of biallelic expansion, co-occurrence of SCA-subtypes, and the presence of premutable normal alleles. The frequency of mutated GAA-FRDA allele in healthy controls is 1/158 (0.63%), thus an expected FRDA prevalence of 1:100 000 persons. The data of this study are relevant not only for clinical decision making but also for guidance in direction of genetic investigations, transancestral comparison of genotypes, and lastly provide insight for policy decision for the consideration of SCAs under rare disease category.
A distinct autosomal recessive ataxia maps to chromosome 12in an inbred family from Jordan
Brain and Development, 2006
Autosomal recessive ataxias are a heterogeneous group of rare disorders characterized by early onset ataxia associated with neurologic, ophthalmologic or systemic signs. The ataxias associated with myoclonus, epilepsy and progressive neurological degeneration are usually included with the progressive myoclonus epilepsies, one of which is Unverricht-Lundborg disease. We identified four siblings with ataxia, juvenile onset progressive action tremor and atonic seizures from a Jordanian family. The mode of inheritance of this syndrome is autosomal recessive. We performed a genome-wide screen for linkage and fine mapped the region that contains the disease locus. The four affected siblings have ataxia noted at the onset of walking with dysarthria and bulbar features, but no cerebellar hypoplasia on MRI. They all developed a fine tremor that progressed to a coarse action tremor, as well as atonic seizures. Treatment with valproate fully controlled the seizures and improved the tremor, but did not change the course of the ataxia. We mapped the gene responsible for this disorder to the pericentromeric region of chromosome 12. A recently described autosomal recessive variant of Unverricht-Lundborg disease also maps to the same region. We discuss the similarities and differences between our family and the family with the Unverricht-Lundborg disease variant. q
American journal of …, 1990
The locus for autosomal dominant ataxia with a diagnosis of olivo-ponto-cerebellar atrophy at autopsy has been previously assigned to chromosome 6p. However, evidence for two alternative locations has been reported. We have recently described a large potential founder-effect population of such patients in the Holguin province of Cuba. With an estimated 1,000 patients available for analysis, this extensive cluster of families provides a unique opportunity for the definitive localization of the genetic mutation. Linkage analysis between the disease locus in this population and markers within and flanking the HLA region on chromosome 6 were undertaken in 12 families comprising over 100 affected individuals. Despite similarity in the clinical phenotype between those families where the disease locus has been reported to be linked to the HLA locus and the Cuban patients, no evidence of linkage to this region could be demonstrated in the latter. The disease locus was excluded from a 96-cM genetic interval of the short arm of chromosome 6, encompassing the F13A1-HLA-GLO1-MUT/D6S4 loci. These data strongly support the existence of genetic heterogeneity for the disease.
Clinical and molecular genetic findings in a Friedreich's Ataxia Tunisian family
The most common mutation in Friedreich's ataxia (FA) is an expanded GAA trinucleotide repeat in the first intron of the FXN (Frataxin) gene. A clear correlation between the size of the expanded alleles and phenotype severity was found as the major determining factor. The objective of this study was to report clinical and molecular data of 10 patients homozygous for pathological FXN GAA expansions. Clinical evaluation was preformed for all the patients. GAA expansions were detected by Tripled Primed PCR (TP-PCR) and GAA allele size was estimated by Long Range PCR (XL-PCR). Clinical features were variable within the same family with no correlation between age at onset, worsening score or tendon reflexes status. All patients were homozygous for the pathological GAA expansions. No obvious relationship was found between the different clinical features and size of GAA repeats. In conclusion, factor controlling phenotypic expression in FA may be related to other factors than FXN GAA ex...
American Journal of Human Genetics, 2001
Ataxia with oculomotor apraxia (AOA) is characterized by early-onset cerebellar ataxia, ocular apraxia, early areflexia, late peripheral neuropathy, slow progression, severe motor handicap, and absence of both telangiectasias and immunodeficiency. We studied 13 Portuguese families with AOA and found that the two largest families show linkage to 9p, with LOD scores of 4.13 and 3.82, respectively, at a recombination fraction of 0. These and three smaller families, all from northern Portugal, showed homozygosity and haplotype sharing over a 2-cM region on 9p13, demonstrating the existence of both a founding event and linkage to this locus, AOA1, in the five families. Three other families were excluded from this locus, demonstrating nonallelic heterogeneity in AOA. Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA), so far described only in Japan, is characterized by marked cerebellar atrophy, peripheral neuropathy, mental retardation, and, occasionally, oculomotor apraxia. Two unrelated Japanese families with EOCA-HA were analyzed and appeared to show linkage to the AOA1 locus. Subsequently, hypoalbuminemia was found in all five Portuguese patients with AOA1 with a long disease duration, suggesting that AOA1 and EOCA-HA correspond to the same entity that accounts for a significant proportion of all recessive ataxias. The narrow localization of AOA1 should prompt the identification of the defective gene.
Journal of the Neurological Sciences, 2002
Fifteen Moroccan families with a phenotype resembling Friedreich Ataxia (FA) were studied. Seven families (13 patients) had the 744 del A mutation in the alpha-tocopherol transfer protein (a-TTP) gene, characteristic of ataxia with vitamin E deficiency (AVED). The other eight families (16 patients) had GAA expansions in the first intron of the frataxin gene. The clinical differences between the two groups differed. AVED caused by the 744 del A could be distinguished by head titubation, lower frequency of the neuropathy and slower disease progression, decreased visual activity and retinitis pigmentosa, which has also been associated with a His 101 Gln missense mutation in the a-TTP gene. The neurological disorder associated with vitamin E deficiency can be improved by the alpha-tocopherol treatment.