Is caused by mutation in the gene encoding frataxin (FXN). 2% of cases of Friedreich ataxia are due to point mutations in the FXN gene, the other 98% being due to expansion of a GAA trinucleotide repeat in intron 1 of the FXN gene (OMIM).
A form of monogenic diabetes caused by mutations in FXN (PMID:21127150).
Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia with associated limb muscle weakness, absent lower limb reflexes, extensor plantar responses, dysarthria, and decreased vibratory sense and proprioception. Onset is usually in ... Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia with associated limb muscle weakness, absent lower limb reflexes, extensor plantar responses, dysarthria, and decreased vibratory sense and proprioception. Onset is usually in the first or second decade, before the end of puberty. It is one of the most common forms of autosomal recessive ataxia, occurring in about 1 in 50,000 individuals. Other variable features include visual defects, scoliosis, pes cavus, and cardiomyopathy (review by Delatycki et al., 2000). Pandolfo (2008) provided an overview of Friedreich ataxia, including pathogenesis, mutation mechanisms, and genotype/phenotype correlation. - Genetic Heterogeneity of Friedreich Ataxia Another locus for Friedreich ataxia has been mapped to chromosome 9p (FRDA2; 601992).
In FRDA, the spinocerebellar tracts, dorsal columns, pyramidal tracts and, to a lesser extent, the cerebellum and medulla are involved. The disorder is usually manifest before adolescence and is generally characterized by incoordination of limb movements, dysarthria, nystagmus, ... In FRDA, the spinocerebellar tracts, dorsal columns, pyramidal tracts and, to a lesser extent, the cerebellum and medulla are involved. The disorder is usually manifest before adolescence and is generally characterized by incoordination of limb movements, dysarthria, nystagmus, diminished or absent tendon reflexes, Babinski sign, impairment of position and vibratory senses, scoliosis, pes cavus, and hammertoe. The triad of hypoactive knee and ankle jerks, signs of progressive cerebellar dysfunction, and preadolescent onset is commonly regarded as sufficient for diagnosis. McLeod (1971) found abnormalities in motor and sensory nerve conduction. - Cardiac Manifestations Cardiac manifestations are conspicuous in some cases (Boyer et al., 1962). Hewer (1968) found that one-half of 82 fatal cases of Friedreich ataxia died of heart failure and nearly three-quarters had evidence of cardiac dysfunction in life. Twenty-three percent had diabetes and 4 developed diabetic ketosis terminally. One case had an affected parent. Age at death varied from the first (3 cases) to the eighth (1 case) decade with a mean of 36.6 years. Muscular subaortic stenosis has been described in cases of Friedreich ataxia (Elias, 1972; Boehm et al., 1970). Ackroyd et al. (1984) reviewed cardiac findings in 12 children, aged 6 to 16 years, with FA. In 10, EKG abnormalities were found. All had abnormalities of the echocardiogram in the form of symmetric, concentric, hypertrophic cardiomyopathy. Casazza and Morpurgo (1996) reviewed a 15-year experience with a large series of patients with Friedreich ataxia to determine the prevalence of hypokinetic cardiomyopathy and to define which patients among those with and without initial left ventricular hypertrophy are most likely to progress to the hypokinetic-dilated form. They concluded that a transition from the hypertrophic to the hypokinetic-dilated form is not rare. The presence of Q waves identified a subgroup of patients with wall motion abnormalities prone to develop a hypokinetic-dilated left ventricle; these patients have a poor prognosis. - Visual System Manifestations Fortuna et al. (2009) studied in detail possible involvement of visual system pathways in 26 Italian patients with FRDA between 15 and 45 years of age. Twenty-one patients were completely asymptomatic, but visual field examination showed 1 of 3 different patterns of visual field defect: severe visual field impairment with general and concentric reduction of sensitivity, mild reduction of sensitivity and a concentric superior or inferior arcuate defect, and very little depression and only an isolated small paracentral area of reduced sensitivity. Optical coherence tomography showed reduced retinal nerve fiber layer (RNFL) thickness in all patients and reduced number of axons, and approximately half of patients had abnormal visual evoked potentials. Two of the 26 patients presented with sudden bilateral loss of central vision at 25 and 29 years of age, respectively, similar to Leber hereditary optic neuropathy (LHON; 535000). Two additional patients had had severe ophthalmologic features, close to those with the LHON-like visual loss, manifest by consistent reduction of RNFL thickness, bilateral central visual field involvement, and reduced visual acuity. Overall, the findings indicated that visual field involvement can occur in FRDA, resulting from a slowly progressive degenerative process involving the optic nerve and optic radiations. Fortuna et al. (2009) concluded that loss of central vision associated with poor visual acuity may occur late in the course of FRDA, with a predilection for patients who are compound heterozygotes. - Late-onset Form De Michele et al. (1994) found age of onset greater than age 20 in 19 of 114 of their patients with the classic form of FA as defined by autosomal recessive or sporadic occurrence, progressive unremitting ataxia of limbs and gait, and absence of knee and ankle jerks. Each of the described patients had at least one of the following signs: dysarthria, extensor plantar response, and echocardiographic evidence of hypertrophic cardiomyopathy. Linkage analysis was performed for 16 patients and 25 healthy members from 8 of the 17 affected families studied. No recombination was found (maximum lod score of 5.17 at theta = 0.0) with the extended MLS1-MS-GS4 haplotype. This suggests that late-onset FA is likely to be an allelic disorder with classic FA for which the upper limit for age of onset was given as 20 years by Geoffroy et al. (1976) and as 25 years by Harding (1981). Eleven of the patients reported by De Michele et al. (1994) had onset after age 25; 2 of these patients had onset after age 30. The only significant differences between these late-onset patients and the more typical early-onset patients were a lower occurrence of skeletal deformities in the late-onset groups and normal visually evoked potentials which were abnormal in 69% of individuals presenting with FA before age 20. The disease progression was slower in the late-onset group. The Ataxia Study Group (Pujana et al., 1999) in Spain found no spinocerebellar ataxia (see 164400) or DRPLA (125370)-type mutations (unstable CAG repeat expansions) in 60 late-onset sporadic cases of spinocerebellar ataxia. One of the 60 cases carried a homozygous GAA repeat expansion in the FRDA gene. In this case, the disease began with vertigo episodes at 30 years of age, whereas the onset for gait ataxia was 35 years, with progression of other signs such as dysarthria, areflexia, pes cavus, and reduced motor and sensory conduction velocity. Magnetic resonance imaging (MRI) showed moderate cerebellar cortical atrophy. Lhatoo et al. (2001) reported a case of 'very late onset' Friedreich ataxia, confirmed by genetic testing, in a man who presented with a history of lower limb spasticity beginning at age 40. The features were unusual in that he did not have ataxia (although he did have a spastic gait), nystagmus, areflexia, or sensory neuropathy, and brain scans were normal. - Friedreich Ataxia with Retained Reflexes (FARR) Harding (1981) described absence of lower limb tendon reflexes as an absolute criterion for the diagnosis of Friedreich ataxia, setting aside early-onset cerebellar ataxia with retained tendon reflexes (EOCA; 212895) as a separate category. Palau et al. (1995) presented 6 sibships in which 2 affected probands fulfilled all of Harding's criteria for the diagnosis of Friedreich ataxia, except for the preservation of deep tendon reflexes in the lower extremities. In 3 of these sibships, affected sibs were discordant for the presence or absence of deep tendon reflexes. They considered the presence of cardiomyopathy by ECG or echocardiogram as an essential criterion for this diagnostic category, which they described as Friedreich ataxia with retained reflexes (FARR). A maximum lod score of 3.38 at a recombination fraction theta equal to 0.00 was obtained, suggesting that FARR is an allelic variant of Friedreich ataxia. Coppola et al. (1999) found that among 101 patients homozygous for GAA expansion within the FRDA gene, 11 from 8 families had FARR. These patients had a lower occurrence of decreased vibration sense, pes cavus, and echocardiographic signs of left ventricular hypertrophy than did the 90 Friedreich ataxia patients with areflexia. Furthermore, the mean age at onset was significantly later (26.6 years vs 14.2 years) and the mean size of a smaller allele was significantly less (408 vs 719 GAA triplets) in FARR patients. The neurophysiologic findings were consistent with milder peripheral neuropathy and milder impairment of the somatosensory pathways in FARR patients. Marzouki et al. (2001) described 3 Tunisian families with early-onset cerebellar ataxia with retained tendon reflexes in which Friedreich ataxia, vitamin E deficiency ataxia (AVED; 277460), and known forms of autosomal dominant cerebellar ataxia were excluded by linkage analysis. - Chorea Hanna et al. (1998) described 2 patients with a generalized chorea in the absence of cerebellar signs who were homozygous for the trinucleotide repeat expansion in intron 1 of the FXN gene that is typical of Friedreich ataxia. Chorea as a rare manifestation of Friedreich ataxia had previously been controversial. This was the first report of chorea in patients confirmed to have the FA genetic abnormality. One patient was a 21-year-old student in whom the diagnosis of idiopathic structural thoracic scoliosis was made at the age of 10 years. The scoliosis was treated surgically at age 14 years by insertion of Harrington rods. Neurologic symptoms developed at age 19 years. He noticed that his gait had become abnormal. He described involuntary jerks of his legs interfering with normal gait and causing occasional falls. Similar involuntary movements of his upper arms had stopped him from playing the guitar. His father described him as generally 'twitchy.' Neurologic examination revealed facial and generalized chorea but no cerebellar signs. Eye movements, speech, and optic discs were normal. He was areflexic. Genetic analysis showed repeat sizes of 500 and 800 repeats in the 2 alleles of the FXN gene. The second case was that of a 13-year-old boy who at the age of 10 years developed recurrent palpitations and was found to have ventricular arrhythmias secondary to a mild hypertrophic cardiomyopathy. His parents described him as generally twitchy and clumsy over the past year, but there was no history of gait disturbance. Neurologic examination revealed mild generalized chorea involving particularly his head, neck, and shoulders. Eye movements, speech, and optic discs were normal. Although he was generally mildly clumsy, there were no unequivocal cerebellar signs. Genetic analysis confirmed that he was homozygous for the FA intron 1 expansion with both alleles measuring 4.5 kb corresponding to a repeat size of approximately 1,000 repeats.
Filla et al. (1996) studied the relationship between the trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. The length of the FA alleles ranged from 201 to 1,186 repeat units. There was no overlap between the ... Filla et al. (1996) studied the relationship between the trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. The length of the FA alleles ranged from 201 to 1,186 repeat units. There was no overlap between the size of normal alleles and the size of alleles found in FA. The lengths of both the larger and the smaller alleles varied inversely with the age of onset of the disorder. Filla et al. (1996) reported that the mean allele length was significantly higher in FA patients with diabetes and in those with cardiomyopathy. They noted that there was meiotic instability with a median variation of 150 repeats. Isnard et al. (1997) examined the correlation between the severity of left ventricular hypertrophy in Friedreich ataxia and the number of GAA repeats. Left ventricular wall thickness was measured in 44 patients using M-mode echocardiography and correlated with GAA expansion size on the smaller allele (267 to 1200 repeats). A significant correlation was found (r = 0.51, p less than 0.001), highlighting an important role for frataxin in the regulation of cardiac hypertrophy. In a study of 187 patients with autosomal recessive ataxia, Durr et al. (1996) found that 140, with ages at onset ranging from 2 to 51 years, were homozygous for a GAA expansion that had 120 to 1,700 repeats of the trinucleotides. About one-quarter of the patients, despite being homozygous, had atypical Friedreich ataxia; they were older at presentation and had intact tendon reflexes. Larger GAA expansions correlated with earlier age at onset and shorter times to loss of ambulation. The size of the GAA expansions (and particularly that of the smaller of each pair of alleles) was associated with the frequency of cardiomyopathy and loss of reflexes in the upper limbs. The GAA repeats were unstable during transmission. Thus, the clinical spectrum of Friedreich ataxia is broader than previously recognized, and the direct molecular test for the GAA expansion is useful for the diagnosis, prognosis, and genetic counseling. Pianese et al. (1997) presented data suggesting that (1) the FRDA GAA repeat is highly unstable during meiosis, (2) contractions outnumber expansions, (3) both parental source and sequence length are important factors in variability of FRDA expanded alleles, and (4) the tendency to contract or expand does not seem to be associated with particular haplotypes. Thus, they concluded that FRDA gene variability appears to be different from that found with other triplet diseases. Bidichandani et al. (1997) found an atypical FRDA phenotype associated with a remarkably slow rate of disease progression in a Caucasian family. It was caused by compound heterozygosity for a G130V missense mutation (606829.0005) and the GAA expansion of the FXN gene. The missense mutation G130V was the second mutation to be identified in the FXN gene and the first to be associated with a variant FRDA phenotype. This and the other reported missense mutation (I154F; 606829.0004) mapped within the highly conserved sequence domain in the C-terminus of the frataxin gene. Since the G130V mutation was unlikely to affect the ability of the first 16 exons of the neighboring STM7 gene to encode a functional phosphatidylinositol phosphate kinase, Bidichandani et al. (1997) questioned the role of STM7 in Friedreich ataxia. McCabe et al. (2002) reported phenotypic variability in 2 affected sibs with compound heterozygosity for the G130V mutation and a GAA expansion. The first sib, a 34-year-old man, first presented at age 10 with leg stiffness and mild gait ataxia and later developed significant limb spasticity. His sister had onset of disease at age 15, with progressive ataxia and lack of limb spasticity. Since Friedreich ataxia is an autosomal recessive disease, it does not show typical features observed in other dynamic mutation disorders, such as anticipation. Monros et al. (1997) analyzed the GAA repeat in 104 FA patients and 163 carrier relatives previously defined by linkage analysis. The GAA expansion was detected in all patients, most (94%) of them being homozygous for the mutation. They demonstrated that clinical variability in FA is related to the size of the expanded repeat: milder forms of the disease (late-onset FA and FA with retained reflexes) were associated with shorter expansions, especially with the smaller of the 2 expanded alleles. Absence of cardiomyopathy was also associated with shorter alleles. Dynamics of the GAA repeat were investigated in 212 parent-offspring pairs. Meiotic instability showed a sex bias: paternally transmitted alleles tended to decrease in a linear way that depended on the paternal expansion size, whereas maternal alleles either increased or decreased in size. All but 1 of the patients with late-onset FA were homozygous for the GAA expansion; the exceptional individual was heterozygous for the expansion and for another unknown mutation. All but 1 of the FA patients with retained reflexes exhibited an axonal sensory neuropathy. However, preservation of their tendon reflexes suggested that the physiologic pathways of the reflex arch remained functional. A close relationship was found between late-onset disease and absence of heart muscle disease. Delatycki et al. (1999) studied FRDA1 mutations in FA patients from Eastern Australia. Of the 83 people studied, 78 were homozygous for an expanded GAA repeat, while the other 5 had an expansion in one allele and a point mutation in the other. The authors presented a detailed study of 51 patients homozygous for an expanded GAA repeat. They identified an association between the size of the smaller of the 2 expanded alleles and age at onset, age into wheelchair, scoliosis, impaired vibration sense, and the presence of foot deformity. However, no significant association was identified between the size of the smaller allele and cardiomyopathy, diabetes mellitus, loss of proprioception, or bladder symptoms. The larger allele size was associated with bladder symptoms and the presence of foot deformity.
Delatycki et al. (1999) stated that 2% of cases of Friedreich ataxia are due to point mutations in the FXN gene (606829), the other 98% being due to expansion of a GAA trinucleotide repeat in intron 1 of ... Delatycki et al. (1999) stated that 2% of cases of Friedreich ataxia are due to point mutations in the FXN gene (606829), the other 98% being due to expansion of a GAA trinucleotide repeat in intron 1 of the FXN gene (606829.0001). They indicated that 17 mutations had so far been described. Similarly, Lodi et al. (1999) cited data indicating that the GAA triplet expansion in the first intron of the FXN gene is the cause of Friedreich ataxia in 97% of patients.
Friedreich ataxia occurs with a prevalence of approximately 1/50,000 in Caucasian populations, but is rare among sub-Saharan Africans and does not exist in the Far East (Koenig, 1998). Dean et al. (1988) found a particularly high frequency of ... Friedreich ataxia occurs with a prevalence of approximately 1/50,000 in Caucasian populations, but is rare among sub-Saharan Africans and does not exist in the Far East (Koenig, 1998). Dean et al. (1988) found a particularly high frequency of FA in Cyprus. A relatively high frequency of Friedreich ataxia has been found in the Rimouski area of the Province of Quebec (Barbeau, 1978). It has been differentiated from a spastic ataxia that occurs particularly in the Charlevoix-Saguenay region of that province (see 270550). Friedreich ataxia in 'typical' French-Canadian patients (i.e., those in the province of Quebec) shows clinical differences from FA in the Acadian population of Louisiana, which likewise came originally from France: following an initial period of parallel development of the disease, the latter exhibits a more slowly progressive peripheral involvement (muscle weakness and loss of vibratory perception) and a lower incidence or absence of cardiomyopathy leading to a longer life span than commonly found among FA patients (Barbeau et al., 1984). From the frequency of parental consanguinity, Romeo et al. (1983) estimated that the incidence of FA in Italy as a whole is between 1 in 22,000 and 1 in 25,000. The incidence in southern Italy, where 16 of the 18 consanguineous marriages were concentrated, was similar (between 1 in 25,000 and 1 in 28,000). Leone et al. (1988) did a complete ascertainment of this disorder in a defined area of northwestern Italy. They found a 30-year survival rate of 61%, suggesting a better prognosis than previously reported. Females fared better than males. Leone et al. (1990) ascertained 59 cases in a defined area of northwestern Italy. The patients were distributed in 39 families. The proportion of first-cousin marriages among parents of the patients (3%) was lower than expected from Dahlberg's formula (8%). This finding was thought to be incompatible with genetic heterogeneity. In a nationwide survey of Japanese patients, Hirayama et al. (1994) estimated the prevalence of all forms of spinocerebellar degeneration to be 4.53 per 100,000; of these, 2.4% had Friedreich ataxia. However, their definition of Friedreich ataxia is at variance from that proposed by Harding (1981), which was in common usage at the time of the study. Specifically, they referred to family history which is 'usually present' as unusual for a recessive disorder. Furthermore, they did not exclude patients who had retained knee jerks nor did they require the presence of Babinski sign. Juvonen et al. (2002) 'dissected' the epidemiology of Friedreich ataxia in Finland by combining results from a nationwide clinical survey and a molecular carrier testing study. In the general population of Finland, the carrier frequency was only 1 in 500, corresponding to a birth incidence of 1 in a million. In the more sparsely populated northern Finland, the carrier frequency was 5 times higher and 4 of the 7 Finnish FRDA patients originated from this region. Haplotype analysis revealed the major universal risk haplotype in all of the investigated patients. Alleles in the uppermost end of the normal variation (28-36 GAA) were totally missing in the Finnish population. The relative enrichment of the FRDA mutation in the north was thought to date back to the internal migration movement and the settling of northern Finland in the 1500s. The missing reservoir of expansion-prone large normal alleles in the frataxin gene found in this study was thought to be one explanation for the rarity of Friedreich ataxia in Finland. The same phenomenon had been seen in Huntington disease, which is rare in Finland and is associated with a low frequency of large normal CAG repeats. Using linkage disequilibrium analysis based on haplotype data of 7 polymorphic markers close to the frataxin gene, Colombo and Carobene (2000) estimated the age of FRDA founding mutation event(s) to be at least 682 +/- 203 generations (95% confidence interval: 564-801 generations), a dating that is consistent with little or no negative selection and provides further evidence for an ancient spread of a premutation (at-risk alleles) in western Europe. Assuming 20 to 30 years per generation, these results dated the spread of the premutation in western Europe at least back to 9,000 to 14,000 years B.C., but also as far as 17,000 to 24,000 years ago, a period of time following the Upper Paleolithic population expansion (Harpending et al., 1998). However, the estimated age may not actually be the age of the mutation event(s) per se, but the age of a population bottleneck through which the western European ancestors passed. Furthermore, since the intronic expansion is documented in non-western European populations as well, the basic founder event(s) behind the FRDA mutation (i.e., generation of chromosomes bearing LN alleles, probably of sub-Saharan African origin) may well be somewhat older in order to account for the wide spread throughout the whole of Europe, the Middle East, and North Africa. In 110 unrelated Portuguese and Brazilian families with spinocerebellar ataxia due to a trinucleotide repeat expansion, Silveira et al. (2002) found that 64% of recessively inherited cases had an expansion in the FRDA gene. Anheim et al. (2010) found that FRDA accounted for the largest percentage of autosomal recessive cerebellar ataxia by far in a cohort of 102 patients from Alsace, France. Of 57 patients for whom molecular diagnosis could be determined, 36 were affected with FRDA. The authors estimated the prevalence of FRDA to be 1 in 50,000 in this region. Marino et al. (2010) found that 5 (7.25%) of 87 Cuban patients with autosomal recessive ataxia had expanded alleles at the FXN gene. The estimated prevalence of the disorder was 1 in 2,200,000, with a carrier frequency of 1 in 745, suggesting it is rare on the island. The affected families were located in western Cuba. Genotyping of the GAA repeat in 248 controls showed that 8 repeats was the most common, with a range of 5 to 31. Premutated or expanded alleles were not observed in the control population. Marino et al. (2010) concluded that there is a low predisposition to instability of the GAA repeat allele in Cuba.