Diagnosis Of Friedreich Ataxia Research Articles

Early onset of Friedreich's ataxia in a compound heterozygote

Friedreich's ataxia (FA) is an autosomal recessive condition caused by a GAA trinucleotide repeat expansion in the X25 gene on chromosome 9. We describe an unusual form of “pseudodominant” inheritance...

Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families.

To determine the incidence of spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7 and Friedreich's ataxia (FA) among a large panel of ataxia families. The ataxias are a clinically and genetically heterogeneous group of neurodegenerative diseases that variably affect the cerebellum, brainstem, and spinocerebellar tracts. Trinucleotide repeat expansions have been shown to be the mutational mechanism for five dominantly inherited SCAs as well as FA. We collected DNA samples and clinical data from patients representing 361 families with adult-onset ataxia of unknown etiology. Patients with a clinical diagnosis of FA were specifically excluded from our collection. Among the 178 dominant kindreds, we found SCA1 expansion at a frequency of 5.6%, SCA2 expansion at a frequency of 15.2%, SCA3 expansion at a frequency of 20.8%, SCA6 expansion at a frequency of 15.2%, and SCA7 expansion at a frequency of 4.5%. FA alleles were found in 11.4% of apparently recessive and 5.2% of apparently sporadic patients. Among these patients the repeat sizes for one or both FA alleles were relatively small, with sizes for the smaller allele ranging from 90 to 600 GAA repeats. The clinical presentation for these patients is atypical for FA, with one or more of the following characteristics: adult onset of disease, retained tendon reflexes, normal plantar response, and intact or partially intact sensory perceptions. Pathogenic trinucleotide repeat expansions were found among 61% of the dominant kindreds. Among patients with apparently recessive or negative family histories of ataxia, 6.8% and 4.4% tested positive for a CAG expansion at one of the dominant loci, and 11.4 and 5.2% of patients with apparently recessive or sporadic forms of ataxia had FA expansions. Because of the significant implications that a dominant versus recessive inheritance pattern has for future generations, it is important to screen patients who do not have a clearly dominant inheritance pattern for expansions at both the FA and the dominant ataxia loci.

Identification of a missense mutation in a Friedreich's ataxia patient: Implications for diagnosis and carrier studies

Approximately 95% of all Friedreich's ataxia (FA) patients are homozygous for a large GAA triplet-repeat expansion in the first intron of the Friedreich's ataxia gene (FRDA). The remaining cases are expected to be compound heterozygous with a GAA expansion on one allele and a point mutation on the other. Generally, the clinical diagnostic profile in this group of patients is indistinguishable from that in classic FA patients with homozygous expansions. This study describes a mildly affected patient who presents with only one expanded allele by Southern blot analysis. Point mutation screening shows a single base change in FRDA exon 3 resulting in a nonconservative amino acid replacement in the N-terminal portion of the frataxin protein. Extended family studies show that two of the patient's sibs are carriers of the expanded allele and one is a carrier of the missense mutation. This case study demonstrates the benefits of implementing a combined Southern blot and point mutation diagnostic protocol for compound heterozygous patients. By identifying both mutations, this procedure confirms the diagnosis of FA in patients with an atypical disease course and allows for more complete family studies.

Long range polymerase chain reaction-based diagnosis of friedreich ataxia in the clinical molecular diagnostics laboratory

Long range polymerase chain reaction-based diagnosis of friedreich ataxia in the clinical molecular diagnostics laboratory

GAA trinucleotide repeat expansion in variant Friedreich's ataxia families

Phenotypic variants in Friedreich's ataxia include late onset, preservation of the lower limbs tendon reflexes, and slow progression. We describe clinical and electrophysiological features from three families with Friedreichlike phenotypes. Friedreich's ataxia diagnosis was confirmed by finding two allelic expansions of the GAA trinucleotide repeat at the X25 gene. In family 1 both patients had a late-onset phenotype with preservation of knee and ankle jerks, lack of cardiomyopathy, and preserved H reflex. One of them did not have electrophysiologic evidence of sensory axonal neuropathy. Patients from family 2 showed variability in the age of onset, and 2 out of 3 affected children had hyperactive lower limbs reflexes with preserved H reflex. Disease progression in a patient from family 3 was very slow after onset at the age of 21. The finding of two expanded alleles in these families confirms the wide variability of the clinical spectrum of Friedreich's ataxia.

Prenatal diagnosis of friedreich ataxia: Improved accuracy by using new genetic flanking markers

Friedreich ataxia is a neurodegerative disorder with autosomal recessive inheritance. Since the gene causing mutation has not yet been identified, prenatal, predictive, and carrier diagnoses are based on indirect haplotype analysis with closely linked markers. Until recently, only distal markers were available and their physical distance to the Friedreich ataxia (FRDA) gene remained elusive. The identification of close flanking markers that mark out the boundaries of the FRDA locus and reduce the critical genomic region which contains the gene allows for the first time misdiagnosis due to undetectable recombination to be avoided and diagnosis accuracy to be greatly improved. In this sense, we have verified a prenatal diagnosis in which the fetus was diagnosed as an unaffected carrier last year with a confidence of 95 per cent. By using the new flanking markers, the diagnosis improved and confidence reached almost 100 per cent.

Dysarthria in Friedreich's ataxia: Syllable intensity and fundamental frequency patterns

Friedreich's ataxia (FA), a degenerative disease of the nervous system, gives rise to speech motor deficits. With respect to the regulation of pitch and loudness controversial findings have been reported so far, including ‘monopitch’ and ‘monoloudness’, on the one hand, and ‘fluctuations of pitch and loudness', on the other. Seven subjects with established diagnosis of FA underwent acoustic analysis of sentence utterances. Based upon digitally computed contours of fundamental frequency (F0) and sound intensity (sound pressure level, SPL), measures of intra-utterance variation of these parameters were derived. Moreover, realization of sentence accent by means of F0 and SPL was analysed. A subgroup of patients presented with increased values of intra-utterance variation of SPL. Presumably, the bulbocerebellar dysfunction concomitant with FA resulted in disturbances of proprioceptive control reflexes required for the maintenance of a constant subglottal air pressure. In contrast, intra-utterance variation of...

Friedreich's Ataxia With Acute Cardiomyopathy

Friedreich's ataxia (FA) is a progressive, spinocerebellar degenerative disease. Onset is generally in the second decade of life, occurring as a neurologic degenerative process. Most, if not all, patients have an associated cardiomyopathy, which is frequently the cause of death. We studied two siblings who had FA with acute cardiomyopathy at 3 and 5 years of age, respectively, and in whom the classic nervous system signs developed, only later. The diagnosis of FA should be considered in patients of any age who have unexplained cardiomyopathy.