Clinical and genetic correlate in childhood onset Friedreich ataxia.

We analyzed the clinical and genetic aspects of 28 FRDA patients from 20 families. 19 families were consanguineous. The onset was between 4 and 13 1/2 years of age (mean 15.4 +/- 6.2). Three patients presented with cardiomyopathy, one with weakness, and the rest with ataxia. There were two patients with preserved lower-limb deep tendon reflexes. Sensory nerve action potentials were reduced in 14/14 patients. Cardiac echograms were abnormal in 17/19 cases, and this was between 6 and 16 years of age (mean 10.1 +/- 3.5). Four families were multiplex. Clinical intra-familial variability was observed. Increased GAA repeats of the X25 gene were found in 27/28 patients studied, all in a homozygous state. 88.9% of patients had a smaller allele larger than 500 repeats, and 66.7% had more than 700 repeats. The patient who did not have increased GAA repeats in both alleles had peculiar findings. Significant correlation of expansion was obtained for the early onset, and cardiomyopathy as the onset.     

GAA repeat polymorphism in Turkish Friedreich's ataxia patients

Friedreich's ataxia (FRDA), the most common subtype of early onset hereditary spinocerebellar ataxia (SCA), is an autosomal recessive neurodegenerative disorder caused by unstable GAA tri-nucleotide expansions in the first intron of FRDA gene located at 9q13-q21.1 position. Results of GAA repeat polymorphism in 80 Turkish SCA patients and 38 family members of 11 typical FRDA patients were reported. GAA triplet repeat size ranged from approximately 7 to 34 in normal alleles and from approximately 66 to 1300 in mutant alleles. Twenty six patients were homozygous for GAA expansion and size of expanded alleles differed from approximately 425 to 1300 repeats. Children 2 and 6 years old (showing no ataxia symptoms) of one family had homozygous GAA expansions reaching approximately 925 repeats. All 11 families studied had at least 1 afflicted child and 9 parents and 2 siblings were carrier (heterozygous) with mutant alleles ranging from 66 to 850 repeats. Family studies confirmed the meiotic instability and stronger effect of expansion in the smaller alleles on phenotype and a negative correlation between GAA repeat expansion size and onset-age of the disease.     

Molecular analysis of Friedreich's ataxia locus in the Indian population

OBJECTIVES: Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by expansion of GAA repeats in the frataxin gene. We have carried out the first molecular analysis at the Friedreich's ataxia locus in the Indian population. MATERIALS AND METHODS: Three families clinically diagnosed for Friedreich's ataxia were analyzed for GAA expansion at the FRDA locus. The distribution of GAA repeats was also estimated in normal individuals of Indian origin. RESULTS: All patients clinically diagnosed for Friedreich's ataxia were found to be homozygous for GAA repeat expansion. The GAA repeat in the normal population show a bimodal distribution with 94% of alleles ranging from 7-16 repeats. CONCLUSION: Indian patients with expansion at the FRDA locus showed typical clinical features of Friedreich's ataxia. The low frequency of large normal alleles (6%) could indicate that the prevalence of this disease in the Indian population is likely to be low.     

Limited somatic mosaicism for Friedreich's ataxia GAA triplet repeat expansions identified by small pool PCR in blood leukocytes

OBJECTIVES: Friedreich's ataxia (FRDA), the most common inherited ataxia, is associated with an unstable expansion of GAA repeats in the first intron of the frataxin gene on chromosome 9. We investigated the mosaicism of expanded alleles to elucidate the basis for genotype phenotype correlations. PATIENTS AND METHODS: We studied the instability of the GAA repeat in blood leukocytes from 45 individuals including 20 FRDA patients and 20 non-affected controls using small pool PCR combined with Southern blotting and hybridization. RESULTS: Expanded GAA repeats could be resolved into distinct alleles showing differences in length up to 1,000 triplets for an individual genome. We found a significant correlation between the size of the largest allele and the range of mosaicism. CONCLUSION: The somatic mosaicism for expanded repeats observed in FRDA patients rendered the precise measurement of allele sizes more difficult and may influence the results of studies correlating the clinical spectrum with the genotype. Following, a confidential prediction of the prognosis deduced from the repeat length is hardly possible for an individual FRDA patient.     

Friedreich’s ataxia: clinical heterogeneity in two sisters

Abstract Diagnostic evaluation of two sisters affected by ataxia, with similar age of onset, revealed a characteristic trinucleotide expansion in the Friedreich’s ataxia (FRDA) locus and two different phenotypic presentations. At onset the elder sister had retained deep tendon reflexes (FARR), while the younger sister presented classic FRDA. The GAA expansion in the patients’ alleles proved to be similar in both siblings, ruling out that age at onset and clinical heterogeneity could be due to different FRDA mutations. On the whole, clinical and genetic data on these patients confirmed that FARR is a variant phenotype of FRDA.     

Analysis of the factors influencing the cardiac phenotype in Friedreich's ataxia

Friedreich's ataxia (FRDA) has been associated with both cardiac hypertrophy and to a lesser degree dilated cardiomyopathy. We have conducted a cross sectional magnetic resonance imaging (MRI) study of 25 patients with clinically and genetically confirmed FRDA and 24 healthy controls to analyse how disease parameters influence cardiac features in FRDA. MR cine imaging in the long and short axis planes was performed alongside clinical assessments. LV mass was most pronounced in FRDA patients with a larger genetic mutation (GAA1 repeats >600), earlier age of onset (<16years) and a shorter disease duration (<15 years). LV mass decreased with longer disease duration (>15 years), and independent of GAA1 repeat size and age of onset, suggesting cardiac thinning occurred with prolonged disease. Heart function was lower in patients with larger GAA1 repeat number and longer disease duration. Consequently, cardiac hypertrophy was more marked in FRDA patients with a larger GAA1 repeat number and younger age of onset, while prolonged disease duration was associated with lower LV mass and decreased heart function. It is important not only to understand the biochemical basis for these cardiac changes but also allow for these changes when assessing the effect of treatment of FRDA patients. © 2010 Movement Disorder Society     

Novel,complex interruptions of the GAA repeat in small,expanded alleles of two affected siblings with late‐onset Friedreich ataxia

Friedreich ataxia (FA) is an autosomal recessive disorder associated with expanded GAA repeats in intron 1 of the FRDA gene. Two siblings presented with a mild form of FA at >60 years of age. Both had a large expansion (>600 repeats) and a small expansion (120 repeats) by long‐range PCR. Sequence analysis of the small allele revealed multiple, complex interruptions in the GAA repeat. These 2 patients presented later than predicted from their allele size alone, when compared with a large cohort of FA patients. Accounting for the interruptions in the GAA repeat, though, did not make the age of onset consistent with that noted in other patients. Three additional patients with late onset FA and small expanded alleles also exhibited interrupted GAA repeats that were not associated with inappropriately late onset. Our observations suggest that interrupted GAA repeats do not clearly impact the age of onset in FA. © 2008 Movement Disorder Society     

Very late-onset Friedreich ataxia despite large GAA triplet repeat expansions

BACKGROUND: Most patients with Friedreich ataxia (FRDA) have abnormal GAA triplet repeat expansions in both X25 genes. The size of the GAA expansion in the shorter of the 2 expanded alleles correlates significantly with parameters of clinical severity and is inversely related to the age at onset. OBJECTIVES: To describe the clinical and molecular genetic findings in a patient with very late-onset FRDA and to review the literature. PATIENT AND METHODS: A 58-year-old white woman with mild progressive gait disturbance of 15 years' duration whose examination revealed mild incoordination was analyzed for mutations in the X25 gene. A combination of long-range polymerase chain reaction and genomic Southern blot analyses were used to identify GAA expansions in intron 1 of the X25 gene. To uncover evidence of somatic variability in triplet repeat length, DNA isolated from several tissue samples was similarly analyzed. Single-strand conformational polymorphism analysis was used to screen for mutations spanning the entire coding sequence of frataxin and all intron-exon junctions of the X25 gene. RESULTS: DNA isolated from blood leukocytes revealed GAA triplet repeat expansions in both X25 genes, which were estimated to contain 835 and 1200 repeats. Similar expansions were detected in DNA isolated from lymphoblasts, fibroblasts, buccal cells, and sural nerve, with estimated mean (+/- SD) lengths of the shorter and longer expansions being 854 (+/-69) and 1283 (+/-72) triplets, respectively. A review of reported cases of late-onset Friedreich ataxia (25-39 years) and very late-onset Friedreich ataxia (> or =40 years) demonstrated that this is the first instance of a patient presenting with very late-onset FRDA despite carrying more than 800 GAA repeats in both expanded X25 alleles. CONCLUSIONS: This unique case of very late-onset FRDA highlights a limitation in our ability to accurately predict the phenotype in FRDA based solely on the size of the GAA expansion. Other genetic or environmental factors may significantly modify disease severity in FRDA.     

Frataxin gene point mutations in Italian Friedreich ataxia patients

Friedreich ataxia (FRDA) is associated with a GAA-trinucleotide-repeat expansion in the first intron of the FXN gene (9q13-21), which encodes a 210-amino-acid protein named frataxin. More than 95% of patients are homozygous for 90-1,300 repeat expansion on both alleles. The remaining patients have been shown to be compound heterozygous for a GAA expansion on one allele and a micromutation on the other. The reduction of both frataxin messenger RNA (mRNA) and protein was found to be proportional to the size of the smaller GAA repeat allele. We report a clinical and molecular study of 12 families in which classical FRDA patients were heterozygous for a GAA expansion on one allele. Sequence analysis of the FXN gene allowed the identification of the second disease-causing mutation in each heterozygous patient, which makes this the second largest series of FRDA compound heterozygotes reported thus far. We have identified seven mutations, four of which are novel. Five patients carried missense mutations, whereas eight patients carried null (frameshift or nonsense) mutations. Quantitation of frataxin levels in lymphoblastoid cell lines derived from six compound heterozygous patients showed a statistically significant correlation of residual protein levels with the age at onset (r = 0.82, p < 0.05) or the GAA expansion (r = -0.76, p < 0.1). In the group of patients heterozygous for a null allele, a strong (r = -0.94, p < 0.01) correlation was observed between the size of GAA expansion and the age at onset, thus lending support to the hypothesis that the residual function of frataxin in patients' cells derive exclusively from the expanded allele.     

Variations of frataxin protein levels in normal individuals

Friedreich’s ataxia (FRDA) is the most common of the inherited ataxias and is associated with GAA trinucleotide repeat expansions within the first intron of the frataxin (FXN) gene. There are expanded FXN alleles from 66 to 1,700 GAA·TTC repeats in FRDA patients and correlations between number of GAA repeats and frataxin protein levels are assumed. Here, we present for the first time frataxin protein levels as well as analysis of GAA triplet repeats in the FXN gene in a population of 50 healthy Austrian people. Frataxin protein levels were measured in lymphocytes from blood samples by ELISA and GAA repeats were analyzed by capillary electrophoresis. Rather unexpectedly, we found a high variation of frataxin protein levels among the individuals. In addition, there was no correlation between frataxin levels, GAA repeats, age and sex in this group. However, these findings are of great importance for better characterization of the disease.     

Unstable triplet repeat and phenotypic variability of spinocerebellar ataxia type 1

A Siberian kindred with spinocerebellar ataxia genetically linked to the SCA1 locus on chromosome 6p has been screened for the CAG triplet expansion within the coding region of the SCA1 gene. The kindred includes 1,484 individuals, 225 affected and 656 at risk, making this collection the largest spinocerebellar ataxia type 1 (SCA1) pedigree known. Each of the studied 78 SCA1 patients carried an expanded allele containing a stretch of 39 to 72 uninterrupted CAG repeats. Normal alleles had 25 to 37 trinucleotide repeats. Expanded alleles containing 40 to 55 repeats were found in 26 atrisk relatives. The number of CAG repeats in the mutated allele was inversely correlated with age at disease onset. Cerebellar deficiency was present in each patient and its severity was moderately affected by the number of CAG repeats. In contrast, the associated signs, dysphagia, diffuse skeletal muscle atrophy with fasciculations, and tongue atrophy were absent or mild in patients with low CAG repeat numbers, but severely complicated the course of illness in patients with a larger number of repeat units. One female mutation carrier was asymptomatic at age 66, more than 2 standard deviations beyond the average age of risk, suggesting incomplete penetrance. In 2 symptomatic individuals who had an expanded number of CAG repeats on both chromosomes, age at onset, rate of progression, and clinical manifestation corresponded to the size of the larger allele.     

Typical Friedreich's ataxia without GAA expansions and GAA expansions without typical Friedreich's ataxia

We clinically assessed and performed polymerase chain reaction analysis for the GAA trinucleotide repeat expansion in 103 patients from 73 families in Ireland, with a prior clinical diagnosis of Friedreich's ataxia (FA) or an unclassified progressive ataxic syndrome. The patients were classified as “typical” or “atypical” FA according to Harding's mandatory clinical diagnostic criteria. All patients underwent blood glucose analysis, and electrocardiography and echocardiography was performed in 99 and 101 patients, respectively. Mutation screening for expanded CAG trinucleotide repeats, associated with spinocerebellar ataxia (SCA) 1, 2, 3 and 6 was performed in 86 patients overall, including all GAA negative patients. Forty-nine of 56 typical patients and 13 of 47 atypical patients were either homozygous or heterozygous for the GAA expansion. Seven patients with a typical FA phenotype were negative for the GAA expansion. Although one of these patients had vitamin E deficiency, and two had raised α-fetoprotein levels, three other GAA negative patients with a typical FA phenotype had no other identifiable cause for their ataxia, once again raising the possibility of locus heterogeneity in FA. It is also possible that these patients have two point mutations in the X25 gene, or that they have another ataxic syndrome mimicking the FA phenotype. Two families who were homozygous for the GAA expansion exhibited intrafamilial phenotypic variability. Only one GAA negative patient had the SCA 3 mutation, and this was the only patient in the study with a possible autosomal dominant inheritance pattern. In the homozygous GAA population typical patients had significantly more repeats on the smaller allele than atypical patients, and there was an inverse relationship between the number of repeats on the smaller allele and the age at presentation. There was also an inverse relationship between the repeat size on both the larger and the smaller of the two alleles and the age at becoming wheelchair bound. There was no significant relationship between repeat size and the other indices of disease severity, including the presence or absence of diabetes or cardiomyopathy. This is the first large study of an Irish population with progressive ataxia that has shown a similar phenotype/genotype relationship to studies of FA in other European and non-European populations. The relatively low sensitivity and specificity of Harding's clinical diagnostic criteria must be appreciated when clinically assessing patients with a progressive ataxic patients with a progressive ataxic syndrome. Although molecular genetic analysis now plays an essential role in diagnosis and classification, patients with a typical FA phenotype without any identifiable cause for their ataxia exist. Received: 23 June 1999, Received in revised form: 1 December 1999, Accepted: 12 January 2000     

Friedreich ataxia: The clinical picture

Friedreich ataxia (FRDA) is a rare autosomal recessive hereditary disorder that affects approximately 1 in 50,000 Caucasians. It is caused by hyperexpansion of GAA repeats in the first intron of the frataxin gene. Initial symptoms of FRDA usually appear around the beginning of the second decade of life. In addition to neuropathological disabilities such as ataxia, sensory loss, and muscle weakness, common signs are scoliosis, foot deformity, and hypertrophic cardiomyopathy. Approximately 10 % of patients with FRDA develop diabetes. The neuronopathy in the dorsal root ganglia, accompanied by the loss of peripheral sensory nerve fibres and the degeneration of posterior columns of the spinal cord, is a hallmark of the disease and is responsible for the typical combination of signs and symptoms specific to FRDA. Variation in neurophysiological abnormalities is correlated with the size of the GAA repeat expansion and likely accounts for individual variation in the progression of FRDA. Despite a range of disease severity, most patients will lose their ability to walk, stand, or sit without support within 10 to 15 years of disease onset. In addition to a review of the clinicopathological features of FRDA, a discussion of recent advances in our understanding of the underlying molecular mechanisms is provided.     

Frataxin point mutations in two patients with Friedreich's ataxia and unusual clinical features

Two patients with a progressive ataxia are presented with clinical features consistent with classic Friedreich's ataxia (FRDA), but also with features unusual for FRDA. Analysis of DNA showed that each patient is heterozygous for the expanded GAA repeat of FRDA, but carries a base change on his other frataxin allele. For one patient a non-conservative arginine to cysteine amino acid change is predicted at amino acid 165 whereas the other mutation is found at the junction of exon one and intron one. Muscle biopsy showed an absence of frataxin immunoreactivity in the patient harbouring the intronic mutation, confirming the pathological nature of the base change. These mutations extend the range of point mutations seen in FRDA, and agree with recent reports suggesting phenotypic variation in patients with FRDA harbouring point mutations in conjunction with an expanded GAA repeat.     

Friedreich Ataxia: Executive Control Is Related to Disease Onset and GAA Repeat Length

Friedreich ataxia (FRDA) is the most frequent inherited ataxia. Neuropsychological studies suggest that FRDA may be associated with specific cognitive impairment. Very little is known about the relation between cognitive performance, demographics and disease-related parameters, such as GAA repeat size, age of onset and disease duration. The present investigation aimed at assessing cognitive functions in a representative sample of FRDA patients and at identifying the most relevant disease-related parameters. Twenty-nine adult FRDA patients underwent neuropsychological tests assessing executive functions, attention, memory and visual perception. Performance was compared with 28 age- and education-matched controls as well as with standardized norms. The relation between neuropsychological outcome, demographical variables and disease-related parameters was assessed. Cognitive impairment affected only a subgroup of patients and mostly concerned attentional and executive functions. Good cognitive performance was associated with a later disease onset, shorter GAA repeat length and lower burden of disease. Age at disease onset has been found to be a good predictor when a cut-off of 14 years was chosen. No correlation was found between cognitive performance and education, age or disease duration. The present study extends earlier findings in FRDA showing that performance in attentional and executive function tasks is best predicted by the age at disease onset. Moreover, executive functions show a clear relationship to disease severity and repeat size of the shorter GAA allele. These findings therefore have important implications for patient counselling regarding education and career choices.     

Friedreich's ataxia with chorea and myoclonus caused by a compound heterozygosity for a novel deletion and the trinucleotide GAA expansion.

Friedreich's ataxia (FRDA) is the most common hereditary ataxia, affecting about 1 in 50,000 individuals. It is caused by mutations in the frataxin gene; 98% of cases have homozygous expansions of a GAA trinucleotide in intron 1 of the frataxin gene. The remaining 2% of patients are compound heterozygotes, who have a GAA repeat expansion in one allele and a point mutation in the other allele. FRDA patients with point mutation have been suggested to have atypical clinical features. We present a case of compound heterozygotes in a FRDA patient who has a deletion of one T in the start codon (ATG) of the frataxin gene and a GAA repeat expansion in the other allele. The patient presented with chorea and subsequently developed FRDA symptoms. The disease in this case is the result of both a failure of initiation of translation and the effect of the expansion. This novel mutation extends the range of point mutations seen in FRDA patients, and also broadens the spectrum of FRDA genotype associated with chorea.     

Phenotypic variability in friedreich ataxia: Role of the associated GAA triplet repeat expansion

We studied genotype-phenotype correlations in a group of 100 patients with typical Friedreich ataxia (FRDA), and in three groups of patients with atypical clinical presentations, including 44 Acadian FRDA, 8 late-onset FRDA (LOFA), and 6 FRDA with retained reflexes (FARR). All patients, except 3 with typical FRDA, carried two copies of the FRDA-associated GAA triplet repeat expansion. Overall, the phenotypic spectrum of FRDA appeared to be wider than defined by the currently used diagnostic criteria. Our study indicated the existence of several sources of variability in FRDA. Patients with larger GAA expansions tended to have earlier onset and were more likely to show additional manifestations of the disease. Mitotic instability of the expanded GAA repeats may partially account for the limited degree of correlation between expansion sizes as determined in lymphocytes and clinical parameters. Some clinical variants associated with specific FRDA haplotypes, such as Acadian FRDA and FARR, turned out to be unrelated to expansion sizes. No polymorphism in the frataxin coding sequence could be associated with these clinical variants.     

Different phenotypes of Friedreich's ataxia within one 'pseudo-dominant' genealogy: relationships between trinucleotide (GAA) repeat lengths and clinical features

We examined a large Turkmen family with 'pseudo-dominant' inheritance of Friedreich's ataxia resulting from consanguineous marriage of a Friedreich's ataxia patient to a heterozygote carrying an ancestral mutated allele. Two distinct phenotypes of the disease co-segregated within this genealogy. Two brothers from the younger generation exhibited 'classical' Friedreich's ataxia with onset of symptoms before 10 years and a rapidly progressive course. In contrast, three patients (two sisters from the younger generation and their father) had a more benign phenotype of late-onset Friedreich's ataxia with the onset at 26, 45 and 48 years and slow progression over decades. The patients with 'classical' Friedreich's ataxia were homozygous for a common ancestral expanded allele of the X25 gene containing 700-800 GAA repeats, while the patients with late-onset Friedreich's ataxia had two different mutated alleles, the shorter 250-repeat expansion of paternal origin and the longer 700-repeat expansion of maternal origin. One may conclude that clinical variability of Friedreich's ataxia in our patients is accounted for predominantly by a modifying effect of one of the two (shorter or longer) expanded alleles inherited from their affected father. Our observation clearly demonstrates the significance of variable-sized alleles for the phenotypic expression of the disease.     

Expanded GAA repeats and clinical variation in Friedreich's ataxia

INTRODUCTION: One of the main features of Friedreich's ataxia (FA) is phenotypic variability that can now be explained by the molecular mechanism (GAA expansion) underlying the disease. MATERIALS AND METHODS: We have analyzed genotype-phenotype correlations in a group of 40 patients homozygous for the GAA expansion. RESULTS : The smaller GAA expansion (GAA1 allele) size correlated with age at onset and progression disease rate, but we found no correlation between the larger GAA expansion (GAA2 allele) size and these clinical parameters. The frequency of pes cavus, scoliosis, axonal sensory neuropathy and areflexia increased with the size of GAA1, whereas some signs such as sphincter disturbances, cerebellar atrophy on MRI, amyotrophy, dysarthria and decreased vibration sense were associated with increased duration of the disease. CONCLUSION: GAA1 size is the main determinant of FA phenotype and GAA2 size is a poor predictor of clinical variation. Some clinical features are independent of GAA1 and GAA2 sizes and are determined by the duration of the disease.