Search

Friedreich Ataxia (FA) is the most common hereditary ataxia, caused by abnormal expansion of the GAA triplet of the first intron of the X25 gene on chromosome 9. Clinically it occurs in patients under the age of 25 and it is frequently associated with musculoskeletal, endocrine and myocardial disorders. Among their phenotypic variants there are patients starting their symptoms after the age of 25. The latter group is defined as late onset Freidreich ataxia (LOFA). The objective of this work is to present three siblings affected by late onset Friedreich ataxia. Their symptoms began between the ages of 32 and 34, with gait disturbance and dysarthria of cerebellar type, which worsened, thus becoming more evident in the course of 6-12 months. None had musculoskeletal or myocardial involvement. There was no family history of ataxia or other neurological disorders. Two of these patients underwent genetic study that showed abnormal expansion of GAA triplet confirming the diagnosis of FA. A magnetic resonance imaging (MRI) of the brain was performed. Proximal spinal cord atrophy, sparing cerebellar structures, was found in two of the cases and vermian atrophy associated with proximal spinal cord atrophy was observed in the third one. Molecular testing GAA expansions in the FA gene should be considered in cerebellar ataxia with dysarthria and loss of proprioception.

Introduction: Friedreich's ataxia (FA) is the most frequent of the recessive hereditary ataxias. AIMS. Our aim was to analyse the findings from electrooculography studies in subjects with FA attended in our Service over a 30-year period., Patients and Methods: Between the years 1970 and 1999, 51 patients with FA diagnosed in the Neurology Service of our hospital were examined. All of them were submitted to an electronystagmography study and an examination of the oculomotor system using electrooculography (EOG). In the EOG study, saccades, (square-wave) saccadic intrusions, spontaneous, triggered, positional and optokinetic nystagmus (OKN), visual suppression of the vestibulo-ocular reflex (VOR) and following were all evaluated., Results: The disorders that were found most often were ataxic following (72.5%), abnormalities in rotational testing (56.8%) and dysmetria in the saccades (52.9%). The presence of square waves was observed in just over half the traces (52.9%)., Conclusions: In FA the predominant EOG findings are those suggesting a cerebellar disease.

Friedreich's ataxia is an autosomal recessive disease generally characterized by the presence of microsatellite expansion in a GAA triplet. The patients inherit a pathologic allele from each one of their parents, that may sometimes show GAA triplet expansions or contractions. Two familial studies of typical Friedreich's ataxia are described. Their molecular study demonstrated marked intergenerational instability and an abnormally long expansion of the GAA triplet in the father in the other one. In the first case, there were expansions of 680/815 repetitions, being characterized by an expansion of 290 repetitions GAA in the father-patient transmission. The second case presented GAA of 1,260/1,095 expansions, while the expanded allele of the father was 1,350 repetitions. These cases illustrate that there can be both expansion as well as contraction of the GAA triplet from alleles of paternal origin in the disease, without any apparent phenotypic changes.

Background: To establish the distribution of the different forms of dominant ataxias and Friedreich ataxia in Spanish population., Patients and Methods: We have performed a molecular study in 121 patients presenting ataxia as the first sign of neurodegenerative disease. In these patients, we have performed a molecular study of SCA 1, SCA 2, SCA 3, SCA 6, SCA 7, SCA 8, DRPLA, alpha-TTP (tocopherol transfer protein) and Friedreich's ataxia genes., Results: The study showed that the Friedreich ataxia is the most frequent form representing 34.4% of the total of the hereditary ataxias. One patient presented mutation in alpha-TTP gene. Among the dominant forms SCA 3 was the most frequent (27.3%) followed by SCA 7 (16%), SCA 6 (9%) and SCA 2 (4.5%). We have not found mutations in SCA 1 and DRPLA genes. Two of 60 apparently sporadic cases presented mutations in the SCA 6 and SCA 8., Conclusions: The genetic analysis is the principal method to distinguish the different clinic forms of ataxia. We have not found mutations in 41.2% of dominant forms and in 43.3% of recessive forms. These results suggest the existence of new candidates genes.

Dynamic mutations are a new type of genetic alteration identified in recent years. They are due to an increased number of repetitions of a particular trinucleotide and are associated with a particular group of neurological and/or neuromuscular disorders. They are characterized by intergenerational and intragenerational instability. There is an inversely proportional relationship between the number of repetitions and the age at which the first symptoms are seen (genetic anticipation). To date 13 disorders, due to this type of mutation, have been described. Some, such as sex-linked mental retardation (fragile X), myotonic dystrophy or Friedreich's ataxia involve an anomalous number of repetitions, reaching over a thousand of a given trinucleotide. Another group known as the polyglutamine disorders, since the CAG trinucleotide is repeated in all cases (dominant and familial ataxias, Huntington's disease) have an increased number of repetitions but there are less than a hundred of them. Finally, recently a third group has been described, oculo-pharyngeal dystrophy with less than a dozen repetitions. Why an increased number of repetitions of a trinucleotide found in or out of a gene is associated with a particular disorder is one of the questions raised by these mutations and which is starting to be discovered.

Charcot-Marie-Tooth disease (CMT) is a hereditary motor-sensory neuropathy with a large genetic heterogeneity. Type 1 (CMT1), or demyelinating CMT, and type 2 (CMT2), or neuronal CMT, are two genetically and clinically distinct entities. CMT1 is the more prevalent and better understood of the two from a genetic standpoint. At least three genes have been shown to be implicated: the 22Kda (PMP22) gene for peripheral myelin protein located in the 17p11.2 chromosome (the CMT1A locus), the P0 myelin protein gene located in the 1q23 chromosome (the CMT1B locus), and the connexin 32 (Cx32) gene located in the Xq13 chromosome (CMTX locus). The most common mutation in CMT1, found in 70% of cases, is a tandem duplication of 1,500 kb at the CMT1A locus. Point mutations have also been described in the PMP22 gene and in P0 and Cx32. Déjerine-Sortas syndrome (DSS) is caused by point mutations in PMP22 and P0 genes, whereas familial neuropathy with liability to pressure palsies (FNPP) or tomacular neuropathy are caused mainly by deletion of 1,500 kb at the CMT1A locus, although point mutations have also been described in the PMP22 gene. Altogether, we can say that CMT1, DSS and FNPP are different clinical expressions of the same genetic pathology and reflect a phenotypic spectrum of related myelin disorders. Hereditary ataxias constitute a wide ranging and heterogeneous set of clinical entities with different ages of onset, patterns of system involvement and type of inheritance. The most common form is Friedreich's ataxia, a autosomally recessive inherited disease whose gene is located in the 9q13 chromosome, though it has not yet been isolated. This disease has various clinical presentations, which does not imply genetic heterogeneity. Dominant autosomal cerebellar ataxias, on the other hand, are extremely heterogeneous. Seven genetic loci have been described, some of which are associated to cerebellar plus forms and expanded unstable triplet sequences of CAG in SCA1 and SCA3/MJD. One locus has been described for the "pure cerebellar form" (ACAD type III) (locus SCA5) and another for the form with retinopathy (ACAD type II) (locus SCA7).

Friedreich's ataxia (FA) is a progressive degenerative disease involving both central and peripheral nervous system. It is an autosomal recessive hereditary disorder, which begins around puberty and has an unknown genetic basis and biochemical defect. The recent mapping of FA locus in human chromosome 9 by means of the analysis of the molecular genetic linkage has permitted to evaluate FA genetics with polymorphic genetic markers (RFLPs) that are secreted linked with the FA gene. The normal and mutant allele secretion of FA was evaluated in ten Spanish families with one or two members with FA by means of several cloned probes (MCT112, DR47, D9S1 and HHH220), localized in chromosome 9 and strongly linked to FA gene, with the aim of achieving a predictive diagnosis of relatives in the pediatric age and to detect healthy carriers. In 9 out of 10 families some totally or partially informative RFLP were found. In 5 of 6 relatives in pediatric age the future development of the disease could be ruled out. By contrast, the carrier status could only be identified in three relatives. In a family with two affected children a genetic recombinant for D9S1 was found. Remarkably, one of them had a better clinical evolution and preserved tendon reflexes in lower limbs.