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Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with mean age of onset between age ten and 15 years and usually before age 25 years. FRDA is typically associated with depressed tendon reflexes, dysarthria, muscle weakness, spasticity in the lower limbs. optic nerve atrophy, scoliosis, bladder dysfunction, and loss of position and vibration senses. About two-thirds of individuals with FRDA have cardiomyopathy, 30% have diabetes mellitus, and about 25% have an "atypical" presentation with later onset, retained tendon reflexes, or unusually slow progression of disease.
Diagnosis/testing. Individuals with FRDA have identifiable mutations in the FXN gene. The most common mutation, seen in more than 96% of individuals with FRDA, is a GAA triplet-repeat expansion in intron 1 of FXN. About 4% of individuals affected with FRDA are compound heterozygotes for a GAA expansion in the disease-causing range in one FXN allele and another inactivating FXN mutation in the other allele. Molecular genetic testing is available on a clinical basis.
Management. Treatment of FRDA includes: prostheses, walking aids and wheelchairs for mobility; speech, occupational, and physical therapy; pharmacologic agents for spasticity; orthopedic interventions for scoliosis and foot deformities; dietary modifications and placement of a nasogastric tube or gastrostomy for dysphagia; antiarrhythmic agents, anti-cardiac failure medications, anticoagulants and pacemaker insertion for cardiac disease; oral hypoglycemic agents or insulin for diabetes mellitus; hearing aids; antispasmodics for bladder dysfunction; and psychological support. Surveillance includes biannual ECG and echocardiogram, hearing assessment every two to three years, and annual fasting blood sugar to monitor for diabetes mellitus.
Genetic counseling. FRDA is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of having no mutation. Carrier testing of at-risk relatives and prenatal testing for pregnancies at 25% risk are possible if both FXN mutations have been identified in an affected family member.
Before the identification of the FXN gene, clinical diagnostic criteria for Friedreich ataxia (FRDA) were established by Geoffroy et al (1976) and refined by Harding (1981). Following identification of the FXN gene, studies have shown that up to 25% of individuals homozygous for the GAA expansion in the FXN gene exhibit clinical findings that differ from the previously established clinical diagnostic criteria [Durr et al 1996, Schols et al 1997, Filla et al 2000].
Individuals with Friedreich ataxia typically exhibit a combination of the following findings:
Progressive ataxia of gait and limbs
Absent muscle stretch reflexes in the legs (in atypical cases, reflexes may be preserved; see FRDA with retained reflexes [FARR])
Onset before age 25 years (in atypical cases, onset may be delayed; see late-onset FRDA [LOFA] and very late-onset FRDA [VLOFA])
Dysarthria, decrease/loss in position sense and/or vibration sense in lower limbs, muscle weakness
Autosomal recessive inheritance
Other signs:
Usually present: pyramidal weakness of the legs, extensor plantar responses
Frequent: scoliosis, pes cavus, hypertrophic non-obstructive cardiomyopathy
Present in 10%-25%: optic atrophy, deafness, glucose intolerance, or diabetes
The diagnosis is confirmed in those with two identifiable mutations in FXN.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. FXN (FRDA, X25) is the only gene directly implicated in the pathogenesis of Friedreich ataxia.
About 96% of individuals with FRDA are homozygous for a GAA triplet-repeat expansion in intron 1 of the FXN gene.
Approximately 4% of individuals with FRDA are compound heterozygotes for a GAA expansion in the disease-causing range in one FXN allele and another inactivating FXN gene mutation in the other allele.
To date, no affected individuals with inactivating point mutations in both FXN alleles have been reported.
Other loci. Among individuals who satisfy the clinical diagnostic criteria for FRDA and who have normal vitamin E levels, fewer than 1% have no GAA expansions in the FXN gene. It is possible that these individuals have mutations at a locus distinct from FXN [Durr et al 1996, Smeyers et al 1996, Geschwind et al 1997, Kostrzewa et al 1997, McCabe et al 2000, Christodoulou et al 2001, Marzouki et al 2001].
Christodoulou et al (2001) performed a genome-wide scan and identified genetic linkage to markers within 9p11-p23 in a large family with autosomal recessive ataxia similar to FRDA, designating the locus as FRDA2. Given the clinical similarities between FRDA and ataxia with oculomotor apraxia (AOA) type 1, which maps within the same locus (9p13.3), it remains to be determined whether FRDA2 is a distinct locus. The prevalence of disease associated with this genetic locus is unclear.
Allele sizes. Four classes of alleles are recognized for the GAA triplet repeat sequence in intron 1 of the FXN gene [Sharma et al 2004]:
Normal alleles: 5-33 GAA repeats. More than 80% of alleles contain fewer than 12 repeats (short normal; SN) and approximately 15% have 12-33 repeats (long normal; LN). Normal alleles with more than 27 GAA repeats are rare.
Mutable normal (premutation) alleles: 34-65 pure (uninterrupted) GAA repeats
Mutable normal alleles are not associated with Friedreich ataxia but may expand during parental transmission, resulting in disease-causing alleles.
Expansion of premutation alleles, sometimes more than tenfold the original size, has been observed in both paternal and maternal transmission.
It is not clear if every premutation allele is capable of expansion via intergenerational transmission, or indeed if expansion is more likely in a premutation allele that has expanded previously.
Alleles longer than 27 GAA triplet repeats are often interrupted by a (GAGGAA)n sequence. It has been postulated that (GAGGAA)n [Montermini, Andermann et al 1997] and perhaps also (GAAAGAA)n [Cossee, Schmitt et al 1997] interruptions of the GAA triplet repeat may stabilize premutation alleles and prevent their expansion into the abnormal range. However, clear guidelines regarding the implications of these interruptions and their clinical significance have not been established.
Full penetrance (disease-causing expanded) alleles: 66-1700 GAA repeats. The majority of expanded alleles contain between 600 and 1200 GAA repeats [Campuzano et al 1996, Durr et al 1996, Filla et al 1996, Epplen et al 1997].
Borderline alleles: 44-66 uninterrupted GAA repeats. The shortest repeat length associated with disease, i.e. the exact demarcation between normal and full penetrance alleles, has not been clearly determined (see Penetrance). Using a sensitive assay to detect somatic instability, Sharma et al (2004) showed that individuals with somatically unstable borderline alleles (in addition to a full penetrance allele) may develop LOFA / VLOFA. The shortest allele associated with FRDA is therefore 44 uninterrupted GAA triplets. Somatic instability was required for clinical expression of the FRDA phenotype, and therefore, alleles with fewer than 37 GAA triplets are unlikely to cause disease.
Note: Overlap exists between the sizes of premutation and borderline alleles, and therefore borderline alleles present a risk for intergenerational expansion. Borderline alleles may be associated with reduced penetrance (see Penetrance).
Clinical uses
Diagnosis
Preimplantation genetic diagnosis
Clinical testing
The length of the GAA repeat is estimated using either PCR or Southern blot assays [Campuzano et al 1996; Durr et al 1996; Montermini, Andermann et al 1997].
Direct sequencing is the most accurate method for analysis of the length and purity (i.e., interrupted vs uninterrupted) of premutation alleles.
Sequence analysis. Sequencing is used to identify the two types of inactivating mutations:
Nonsense mutations, errors of splicing or frameshift mutations that result in premature termination of translation
Missense mutations, mainly involving the highly conserved, carboxy-terminal domain (see Table 2; pdf)
Table 1 summarizes molecular genetic testing for this disorder.
| Test Method | Mutations Detected | Prevalence | Test Availability |
|---|---|---|---|
| Targeted mutation analysis | Homozygous GAA expansion in FXN | 96% | Clinical
 |
| Heterozygous GAA expansion in FXN | 4% | ||
| Sequence analysis | Heterozygous point mutation in FXN |
Interpretation of test results. The exact demarcation between normal and full penetrance alleles remains poorly defined. While the risk of phenotypic expression with borderline alleles is increased, it is not possible to offer exact risks. Therefore, the interpretation of test results in individuals with one large expanded allele and one allele containing fewer than 100 GAA repeats may be difficult.
Note: Interpretation is further complicated by the possibility that the size of the GAA expansion in leukocytes may not necessarily be the same as that in pathologically relevant tissues such as the dorsal root ganglia and heart.
For issues to consider in interpretation of sequence analysis results, click here. Analysis of other inactivating FXN gene mutations typically involves screening of all coding exons and their flanking splice sites. Potentially pathogenic mutations in other gene regions (e.g., gene promoter) may thus be missed.
Because the heterozygote (carrier) frequency for full penetrance alleles is estimated to be between 1/60 and 1/100 in Indo-Europeans, the possibility of another etiology should be entertained in heterozygotes if no other inactivating FXN gene mutation is detected on sequence analysis (see Differential Diagnosis).
Perform targeted mutation analysis by PCR or Southern blot analysis of the GAA repeat.
Perform sequence analysis if the individual fulfills the clinical diagnostic criteria of FRDA and is heterozygous for a full penetrance allele [Cossee et al 1999].
Consider another diagnosis if no expanded alleles are detected, i.e., the individual is homozygous for alleles of normal size. Sequence analysis is not recommended in these individuals (see Differential Diagnosis).
No other phenotypes are associated with mutations in FXN.
Neurologic manifestations. Individuals with typical FRDA develop progressive ataxia in childhood or in the early teens, starting with poor balance when walking, followed by slurred speech and upper-limb ataxia. The mean age of onset of symptoms is ten to 15 years [Durr et al 1996; Delatycki, Paris et al 1999], but onset can be as early as age two years and as late as the sixth decade [Durr et al 1996]. Gait ataxia, caused by a combination of spinocerebellar degeneration and loss of joint-position sense (proprioception), is the earliest symptom in the vast majority [Durr et al 1996]. The poor balance is accentuated when visual input is eliminated, such as in darkness or when the eyes are closed (Romberg sign). Ankle and knee jerks are absent and plantar responses are up-going.
Within five years of symptom onset, most individuals with FRDA exhibit "scanning" dysarthria, lower extremity weakness, and diminished or absent joint-position and vibration sense distally — neurologic manifestations that result from progressive degeneration of the dorsal root ganglia, posterior columns, corticospinal tracts, the dorsal spinocerebellar tracts of the spinal cord, and the cerebellum. Involvement of the peripheral sensory and motor neurons results in a mixed axonal peripheral neuropathy.
Muscle weakness is often present and is most prominent in hip extensors and abductors; as disease advances, distal limb muscle weakness and wasting become evident.
Spasticity in the lower limbs is common and can be significant, affecting foot plantarflexors and inverters to a greater extent than dorsiflexors and everters. Thus, in the late stages of disease equinovarus deformity is commonly seen [Delatycki et al 2005] and may result in contractures and significant morbidity. Pes cavus is common (55%) but causes little problem for affected individuals [Durr et al 1996].
Optic nerve atrophy, often asymptomatic, occurs in approximately 25% of individuals with FRDA. Reduced visual acuity was found in 13% in one study [Durr et al 1996]. Abnormal extraocular movements include irregular ocular pursuit, dysmetric saccades, square wave jerks, and failure of fixation suppression of the vestibulo-ocular reflex. Horizontal and vertical gaze palsy does not occur.
Sensorineural hearing loss occurs in 13% of individuals with FRDA [Durr et al 1996].
Scoliosis is present in about two-thirds of individuals with FRDA when assessed clinically [Durr et al 1996] and 100% when assessed radiographically [Labelle et al 1986].
Bladder symptoms including urinary frequency and urgency were reported by 41% of individuals in one study [Delatycki, Paris et al 1999].
Autonomic disturbance becomes more common with disease progression. The most common manifestation is cold, cyanosed feet; bradycardia is less common [Margalith et al 1984].
While cognition is generally not impaired in FRDA, motor and mental reaction times can be significantly slowed [Wollmann et al 2002].
Other manifestations. Hypertrophic cardiomyopathy, defined as increased thickness of the interventricular septum, is present in two-thirds of individuals with FRDA [Durr et al 1996; Delatycki, Paris et al 1999]. Echocardiographic evaluation may reveal left ventricular hypertrophy that is more commonly asymmetric than concentric [Isnard et al 1997, Bit-Avragim et al 2001, Koc et al 2005, Dutka et al 2000]. When more subtle cardiac involvement is sought by methods such as tissue Doppler echocardiography, an even larger percentage of individuals have detectable abnormalities [Dutka et al 2000]. Later in the disease course, the cardiomyopathy may become dilated. Electrocardiography (ECG) is abnormal in the vast majority, with T wave inversion, left axis deviation, and repolarization abnormalities being most commonly seen [Dutka et al 1999].
Symptoms related to cardiomyopathy usually occur in the later stages of the disease [Dutka et al 1999] but in rare instances may precede ataxia [Lamont et al 1997, Alikasifoglu et al 1999, Leonard & Forsyth 2001]. Subjective symptoms of exertional dyspnea (40%), palpitations (11%), and anginal pain may be present in moderately advanced disease. Arrhythmias (especially atrial fibrillation) and congestive heart failure frequently occur in the later stages of the disease and are the most common cause of mortality.
Diabetes mellitus occurs in up to 30% of individuals with FRDA. Those without diabetes mellitus may have impaired glucose tolerance [Ristow 2004].
Progression. The rate of progression of FRDA is variable. The average time from symptom onset to wheelchair dependence is ten years [Durr et al 1996; Delatycki, Paris et al 1999].
The average age at death was 37 years in a large study in the early 1980's [Harding 1981]. In a more recent study, the average interval from symptom onset to death was 36 years [De Michele et al 1996], perhaps suggesting increased longevity related to better management (particularly of cardiac complications) and recognition of milder phenotypes (see below). Survival into the sixth and seventh decades has been documented. Death is often related to cardiomyopathy; aspiration pneumonia caused by dysphagia may also shorten the life span.
Neuroimaging. MRI is often normal in the early stages of FRDA. With advanced disease, atrophy of the cervical spinal cord and cerebellum may be observed [Ormerod et al 1994, De Michele et al 1996, Bhidayasiri et al 2005].
Electrodiagnostic findings
Motor nerve conduction velocity of greater than 40 m/s with reduced or absent sensory nerve action potential
Absent H reflex
Abnormal central motor conduction time after transcranial magnetic stimulation [Brighina et al 2005]
About 25% of individuals with identifiable FXN mutations have atypical findings [Durr et al 1996] that include the following:
Late-onset FRDA (LOFA) and very late-onset FRDA (VLOFA). In approximately 15% of individuals with FRDA, onset may be later than age 25 years. In individuals with LOFA the age of onset is 26-39 years [De Michele et al 1994] and in VLOFA the age of onset is over 40 years [Gellera et al 1997, Bidichandani et al 2000, Bhidayasiri et al 2005]. The oldest reported age of onset among individuals homozygous for the GAA expansion is 51 years [Durr et al 1996].
Disease progression is usually slower in LOFA than in typical FRDA, including a later age of confinement to a wheelchair and lower incidence of secondary skeletal abnormalities (e.g., scoliosis, pes cavus, pes equinovarus) [Lamont et al 1997, Lynch et al 2006].
FRDA with retained reflexes (FARR). FARR accounts for approximately 12% of individuals who are homozygous for the GAA expansion [Durr et al 1996, Coppola et al 1999]. Some individuals with FARR show brisk tendon reflexes that can be accompanied by clonus. Tendon reflexes may be retained for more than ten years after the onset of the disease [Schols et al 1997]. FARR usually has a later age of onset and lower incidence of secondary skeletal involvement and cardiomyopathy [Montermini, Richter et al 1997, Coppola et al 1999].
FRDA in Acadians. Montermini, Richter et al (1997) showed that Acadians with FRDA have a later age of onset, late age of confinement to a wheelchair, and a much lower incidence of cardiomyopathy.
Spastic paraparesis without ataxia. Individuals homozygous for GAA expansions may rarely present with spastic gait disturbance without gait or limb ataxia. These individuals usually have hyperreflexia and a later age of onset; they develop ataxia with time [Gates et al 1998, Castelnovo et al 2000, Lhatoo et al 2001, Badhwar et al 2004].
Other rare presentations of FRDA
Chorea and pure sensory ataxia [Berciano et al 1997, Hanna et al 1998, Zhu et al 2002]
Apparently isolated cardiomyopathy with ataxia only becoming evident some time later [Leonard & Forsyth 2001]
Despite the general genotype-phenotype correlations described below, it is not possible to predict the specific clinical outcome in any individual based on genotype. The remaining variability in individuals with FRDA may be caused by genetic background (e.g., Acadian individuals), somatic heterogeneity of the GAA expansion [Montermini, Richter et al 1997; Sharma et al 2002; Sharma et al 2004], and other unidentified factors.
Homozygotes for pathogenic GAA repeat expansions
GAA repeat size. The age of onset, presence of leg muscle weakness/wasting, duration until wheelchair use, and prevalence of cardiomyopathy, pes cavus, and scoliosis have all shown statistically significant correlations with GAA expansion size [Durr et al 1996; Filla et al 1996; Monros et al 1997; Montermini, Richter et al 1997]. The size of the shorter of the two expanded GAA repeats shows better correlation, accounting for about 50% of the variation in age of onset [Filla et al 1996].
Late-onset FRDA (LOFA) and very late-onset FRDA (VLOFA)
Individuals with LOFA frequently exhibit fewer than 500 GAA repeats in at least one of the expanded alleles [Durr et al 1996; Filla et al 1996; Montermini, Richter et al 1997; Bhidayasiri et al 2005]
Individuals with VLOFA usually have fewer than 300 GAA repeats in at least one of the expanded alleles [Bidichandani et al 2000, Berciano et al 2005]. However, Bidichandani et al (2000) reported an individual with VLOFA who was homozygous for expansions with greater than 800 GAA repeats, underscoring the inability to predict the clinical outcome in each individual.
FRDA in Acadians. Despite the observed clinical differences in this population, no significant differences were found either in the size of the GAA expansions or in the coding region of FXN, compared to individuals with typical FRDA [Montermini, Richter et al 1997].
Spastic paraparesis without ataxia may be seen in those with smaller expanded alleles [Berciano et al 2002], or in association with the G130V missense mutation [McCabe et al 2002].
Cardiomyopathy is more frequently seen with longer GAA repeat alleles [Durr et al 199, Filla et al 1996, Monros et al 1997].
Isnard et al (1997) found echocardiographic evidence of left ventricular hypertrophy in 81% of those with FRDA with repeat lengths greater than 770 triplets and in only 14% of those with repeat lengths less than 770 triplets.
Significant correlation is seen between the length of the GAA expansion and the thickness of the interventricular septum and left ventricular wall [Isnard et al 1997, Dutka et al 1999, Bit-Avragim et al 2001].
Montermini, Richter et al (1996) and Delatycki, Paris et al (1999) showed that the presence of cardiomyopathy correlated with disease severity as defined by age of onset.
Cuda et al (2002) described an individual with particularly severe early childhood-onset cardiac hypertrophy that preceded the onset of ataxia; the individual was homozygous for large GAA expansions and additionally had a mutation in the cardiac troponin T gene.
Diabetes mellitus or abnormal glucose tolerance does not show a clear-cut correlation with the size of the GAA expansion. Filla et al (1996) found that individuals with diabetes mellitus tend to have larger repeat lengths; in a larger cohort, however, Durr et al (1996) did not find significant correlation either with the size of the GAA expansion or with disease duration. Despite the lack of correlation with the GAA expansion size, Delatycki, Paris et al (1999) found a correlation between the incidence of diabetes mellitus and an earlier age of onset.
Compound heterozygotes for an expansion and a point mutation. Although most compound heterozygotes are clinically indistinguishable from typical individuals with FRDA with homozygous GAA expansions [Campuzano et al 1996, Filla et al 1996, Cossee et al 1999, Zuhlke et al 2004], exceptions have been observed.
Compound heterozygosity for the G130V or D122Y missense mutations, each located near the amino end of the highly conserved carboxy-terminal domain of frataxin, results in an atypically mild FRDA phenotype [Bidichandani et al 1997, Cossee et al 1999]. Affected individuals have slowly progressive disease, absence of dysarthria, retention of reflexes, and mild or absent cerebellar ataxia.
Two individuals who were compound heterozygous for the 2delT mutation presented with chorea [Zhu et al 2002, Spacey et al 2004].
Compound heterozygotes for an expansion and a borderline "mutable" allele. Individuals with somatically unstable borderline alleles present with LOFA/VLOFA, mild and gradually progressive disease, and normal reflexes/hyperreflexia [Sharma et al 2004].
Penetrance is complete in homozygotes with typical GAA repeat expansions and in compound heterozygotes for an expansion and another deleterious mutation. However, because of wide variability in the size of pathogenic expanded alleles, and for other unknown reasons, onset can range from before age five years to older than age 50 years. This variability in age-dependent penetrance can occasionally occur within the same sibship.
Note: Because the allele size at the lower end of the mutant allele range has not been clearly defined, it is possible that incomplete penetrance is associated with borderline alleles and expanded alleles containing fewer than 100 GAA repeats. However, alleles of this size are rare.
Friedreich ataxia is inherited in an autosomal recessive manner; therefore, anticipation is not observed because the disease is almost never observed in more than one generation.
The prevalence of Friedreich ataxia is 2/100,000-4/100,000. The carrier frequency is 1/60-1/100.
FRDA is the most common inherited ataxia in Europe, the Middle East, South Asia (Indian subcontinent), and North Africa.
FRDA has not been documented in Southeast Asia, in sub-Saharan Africa, or among Native Americans. A lower than average prevalence of FRDA is noted in Mexico.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Peripheral neuropathy. FRDA is most frequently confused with Charcot-Marie-Tooth type 1 (CMT1), also known as the demyelinating form of hereditary motor and sensory neuropathy type I (HMSN1). Some individuals with CMT1 present in childhood with clumsiness, areflexia, and minimal distal muscle weakness. In children with FRDA who have not developed dysarthria or extensor plantar responses, the diagnosis of CMT1 may be difficult to exclude solely on clinical findings. Inheritance of CMT1 is autosomal dominant.
Spinocerebellar ataxia with axonal neuropathy (SCAN1) is an autosomal recessive disease characterized by ataxia, axonal sensorimotor polyneuropathy, distal muscular atrophy, pes cavus, and steppage gait — signs that may collectively mimic FRDA. SCAN1 is caused by a mutation in TDP1, the gene encoding tyrosyl-DNA phosphodiesterase 1, a topoisomerase I-dependent DNA damage repair enzyme [El-Khamisy et al 2005].
Ataxia. Ataxia with vitamin E deficiency (AVED) (caused by mutations in TTPA, encoding α-tocopherol transfer protein), abetalipoproteinemia, or other fat malabsorptive conditions should be considered in individuals with the FRDA phenotype without GAA expansions [Cavalier et al 1998, Hammans & Kennedy 1998]. Most individuals with AVED fulfill the diagnostic criteria for FRDA, although titubation and hyperkinesia are more frequently seen in AVED [Cavalier et al 1998]. Although less frequent than in FRDA, cardiomyopathy is seen in 19% of those with AVED [Cavalier et al 1998]. It is important to differentiate FRDA from AVED because, unlike FRDA, AVED can be effectively treated with continuous lifelong vitamin E supplementation. Serum concentration of vitamin E and lipid-adjusted vitamin E may also be used to differentiate AVED from FRDA [Feki et al 2002]. Inheritance of AVED is autosomal recessive.
Ataxia with oculomotor apraxia type 1 (AOA1) (oculomotor apraxia and hypoalbuminemia; early-onset cerebellar ataxia with hypoalbuminemia) is characterized by childhood onset of slowly progressive cerebellar ataxia followed by oculomotor apraxia and a severe axonal sensorimotor peripheral neuropathy. The initial manifestation is progressive gait imbalance in childhood (age 2-18 years) that may be associated with chorea. All affected individuals have generalized areflexia followed by a peripheral neuropathy. Cognitive impairment may be noted. The clinical phenotype of AOA1 may be highly variable; however, the presence of chorea, severe sensorimotor neuropathy, oculomotor anomalies, cerebellar atrophy on MRI and absence of the Babinski sign can help to distinguish AOA1 from Friedreich ataxia [Le Ber et al 2003]. AOA1 is associated with mutations in the APTX gene [Moreira et al 2001]. Inheritance is autosomal recessive. AOA1 is the most common recessively inherited ataxia in Japan, and in Portugal it is second to FRDA. AOA1 has also been reported in France, Germany, Italy, Taiwan, Tunisia, and Australia with variable frequencies [Le Ber et al 2005].
Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by ataxia with onset between age ten and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, choreiform or dystonic movement, and elevated alpha-fetoprotein (AFP) levels [Le Ber et al 2004]. It is caused by mutations in SETX, the gene encoding senataxin [Moreira et al 2004]. Inheritance is autosomal recessive. Among Europeans, AOA2 is the most common non-FRDA, autosomal recessive cerebellar ataxia.
Other early-onset ataxias may be distinguishable by virtue of their characteristic clinical features. See also Ataxia Overview.
Ataxias associated with mitochondrial DNA mutations
Behr syndrome (spasticity, ataxia, optic atrophy, and mental retardation)
Marinesco-Sjogren syndrome (cerebellar ataxia, cataracts, mental retardation, short stature, and delayed sexual development)
Late-onset hexosaminidase A deficiency (ataxia, upper and lower motor neuron disorders, dementia, and psychotic episodes) [Perlman 2002]
Spasticity. FRDA is rare among individuals with uncomplicated (isolated) autosomal recessive spastic paraparesis [Wilkinson et al 2001, Badhwar et al 2004] (see also Hereditary Spastic Paraplegia Overview). However, autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) may present with early-onset ataxia and areflexia, Babinski sign, loss of vibratory sensation, and pes cavus without spasticity [Shimazaki et al 2005].
Multisystem atrophy. VLOFA caused by a shorter GAA expansion allele may mimic multiple system atrophy of the cerebellar type [Berciano et al 2005].
Autosomal dominant ataxia with sensory neuropathy. Spinocerebellar ataxia type 4 (SCA4) [Flanigan et al 1996] and SCA25 [Stevanin et al 2004] may present with FRDA-like phenotypes.
To establish the extent of disease in an individual diagnosed with Friedreich ataxia (FRDA), the following are recommended:
Neurologic assessment
Physical therapy and occupational therapy assessment of strength, balance, and need for adaptive aids
Speech and swallowing assessment
ECG and echocardiogram for evidence of cardiomyopathy; assessment by a cardiologist if abnormal
Assessment of significant scoliosis by an orthopedic surgeon
Bladder function
Hearing
Random blood glucose concentration for evidence of diabetes mellitus
There is little objective evidence regarding management of FRDA. A multidisciplinary approach is essential for maximal benefit as FRDA affects multiple organ systems:
Prostheses, walking aids, wheelchairs, and physical therapy as prescribed by physiatrist (rehabilitation medicine specialist) to maintain an active lifestyle
Occupational therapy assessment to ensure a safe home and work environment
To manage spasticity: physical therapy including stretching programs, standing frame and splints, pharmacologic agents such as baclofen and botulinum toxin. Orthopedic interventions, both operative and non-operative, for scoliosis [Labelle 1986] and foot deformities [Delatycki et al 2005] may be necessary.
Speech therapy to maximize communication skills
Management of dysphagia that may include dietary modification and, in the late stages of disease, use of nasogastric or gastrostomy feeding
Treatment of cardiac disease to reduce morbidity and mortality, including anti-arrhythmic agents, anti-cardiac failure medication, anti-coagulants, and pacemaker insertion. Cardiac transplantation is more controversial [Sedlak et al 2004].
Treatment of diabetes mellitus with oral hypoglycemic agents or insulin as needed
Hearing aids as needed
Antispasmodic agents for bladder dysfunction
Psychological support for affected individuals and family
The measures outlined in Treatment of Manifestations can reduce the impact of some complications such as joint contractures.
If ECG and echocardiogram performed at the time of initial diagnosis are normal, ECG should be repeated annually and echocardiogram every two years [English & Gibbs 2006].
Hearing assessment should be performed every two to three years or more often if symptoms are present.
Fasting blood sugar should be performed yearly to monitor for diabetes mellitus.
Deficiency of frataxin results in abnormal accumulation of intramitochondrial iron, defective mitochondrial respiration, and overproduction of oxygen free radicals with evidence of oxidant-induced intracellular damage (see Molecular Genetic Pathogenesis).
Antioxidant therapy by free radical scavengers such as coenzyme Q10, vitamin E, idebenone (a short-chain analog of coenzyme Q10), and more recently, mitochondrial-targeted idebenone (MitoQ) have been considered potential therapies for slowing the progression of FRDA.
Coenzyme Q10 and vitamin E. Following three to six months' antioxidant treatment with coenzyme Q10 and vitamin E, Lodi et al (2001) showed improved ATP production in the heart and skeletal muscle of individuals with FRDA. An open label trial of these agents in ten individuals for 47 months resulted in sustained improvement in bioenergetics and improved cardiac function as assessed by increased fractional shortening [Hart et al 2005].
Idebenone. Small clinical trials with idebenone have shown that the drug can reduce the left ventricular mass and wall thickness in some individuals with cardiac hypertrophy [Rustin et al 1999, Hausse et al 2002, Buyse et al 2003, Mariotti et al 2003]. Some early evidence indicates that idebenone may improve cardiac function [Buyse et al 2003]; better-designed trials are needed to address this question definitively.
In the studies cited, idebenone did not modify neurologic manifestations of the disease; however, the studies were not sufficiently large to detect even modest slowing of disease progression. Larger trials are to commence shortly.
Idebenone was well tolerated when 5 mg/kg/day was administered orally for up to 12 months.
Idebenone was also shown to delay the onset of cardiac pathology and prolong the life span of a transgenic mouse model of cardiomyopathy in FRDA; however, a much larger per kilogram dose was used than in human studies [Seznec et al 2004].
MitoQ and MitoVitE. In an effort to improve the delivery of antioxidants to the mitochondria, idebenone [Kelso et al 2001] and vitamin E [Smith et al 1999] were linked to a lipophilic cation to produce MitoQ and MitoVitE, respectively. In a cell culture model using fibroblasts from affected individuals, Jauslin et al (2003) showed that MitoQ was 800-fold more active than idebenone in protecting cells from endogenous oxidative stress. Although MitoVitE was less effective, it was still 20-fold more effective than idebenone. A trial of MitoQ in FRDA is planned to commence shortly.
Oral MitoQ accumulates in the heart and brain of mice [Kelso et al 2001].
Iron chelators have been proposed as a possible therapy for lowering the intramitochondrial iron overload. Nonspecific iron chelators (such as desferrioxamine) for the specific reduction of mitochondrial iron overload may not be effective; a clinical trial was terminated for lack of efficacy. In vitro studies using a mitochondrial-specific iron chelator (2-pyridylcarboxaldehyde) showed promising results [Richardson et al 2001].
Upregulation of frataxin expression. Because the GAA repeat expansion results in reduced quantities of normal frataxin, a number of studies have been conducted to identify compounds that increase frataxin expression. Agents that have been found to increase frataxin expression in cellular models include hemin, butyric acid [Sarsero et al 2003], and erythropoietin [Sturm et al 2005]. More work is required before such therapies can be recommended for individuals with FRDA.
Gene therapy to supplement the loss of function of frataxin is also under consideration. However, a significant amount of basic research is needed before gene therapy can be feasible in a clinical setting.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Friedreich ataxia (FRDA) is inherited in an autosomal recessive manner.
Parents of a proband
Depending on the mutations present in the proband, each parent may have one of the following:
A pathogenic expanded allele (i.e., a GAA trinucleotide repeat allele that is in the disease-causing range)
Another deleterious FXN mutation
A premutation allele (i.e., a GAA trinucleotide repeat allele that is predisposed to expand into the abnormal range)
Carriers of all FXN gene mutations are asymptomatic.
Note: Carriers of premutation alleles are rare, and although their exact prevalence is unknown, they are less common than carriers of pathogenic expanded alleles. Consequently, hyperexpansion of premutation alleles as a means of transmitting FRDA is very unusual.
Sibs of a proband
Both parents carry a full penetrance allele or one parent carries a full penetrance allele and the other parent carries another deleterious FXN gene mutation.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be clinically unaffected, the risk of his/her being a carrier is 2/3. The wide range in age of onset and variable intergenerational instability of the GAA expansion dictate the use of caution in diagnosing an at-risk sib as unaffected.
One parent carries a full penetrance allele or another deleterious FXN gene mutation and the other parent carries a mutable normal (premutation) allele.
At conception, each sib of a proband whose parent is a carrier of a mutable normal (premutation) allele has a 25% chance of inheriting both parental mutations. Since the mutable normal (premutation) allele may remain unchanged or undergo minimal change (i.e., not expand to produce a full penetrance allele), the sibs have a less than 25% chance of being affected. Each sib also has a 50% chance of being an asymptomatic carrier of one of the parental alleles and a 25% chance of being unaffected and having two normal alleles.
Offspring of a proband
All offspring inherit one mutant allele from the affected parent.
Offspring have a 50% chance of being affected only if the reproductive partner of the proband is a carrier of a full penetrance allele or another deleterious FXN gene mutation.
If the reproductive partner of the proband carries a mutable normal (premutation) allele, the risk to each offspring of developing FRDA is less than 50%.
Carrier testing of at-risk family members is available on a clinical basis once the mutations have been identified in the proband.
Carrier testing for the GAA expansion is available for individuals whose reproductive partner is a carrier of a FXN mutation; however, testing for point mutations is not generally available. If the reproductive partner does not have an expansion of the GAA repeat, the chance of his/her being a carrier of a point mutation is about 1:2,250.
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Prenatal diagnosis for pregnancies at 25% risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed in weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| FXN | 9q13 | Frataxin |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| FXN | 2395 (MIM No. 606829) | FXN |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
Pathology in Friedreich ataxia results from deficiency of frataxin or its function.
Frataxin is required for biogenesis of iron-sulfur cluster (ISC), and therefore for the synthesis of enzymes of the respiratory chain complexes I-III and aconitases. Endocardial biopsies of individuals with FRDA revealed a deficiency of ISC proteins [Rotig et al 1997].
Frataxin is also thought to play a role in regulation of mitochondrial iron content. Affected individuals show evidence of abnormal accumulation of mitochondrial iron. However, it is likely that mitochondrial iron accumulation may be a secondary manifestation.
Frataxin deficiency leads to reduced antioxidant defense, deficient mitochondrial function, and increased oxidative damage. Affected individuals show deficient ATP production and cellular oxygenation in post-exercise skeletal muscle [Lodi et al 1999, Lynch et al 2002] and defective myocardial energy production [Lodi et al 2001, Bunse et al 2003].
Complete deficiency of mouse frataxin leads to early embryonic lethality without evidence of iron accumulation [Cossee et al 2000], indicating that frataxin is essential for early embryonic development and that iron accumulation is unlikely to be a primary pathophysiologic event. This may also be the reason why humans with both null alleles (such as inactivating point mutations) have not been identified to date; indeed, even homozygosity for very large GAA expansions results in some residual frataxin expression. Development of "tissue-specific, conditional knockouts" of mouse frda have resulted in models of specific features of the FRDA phenotype, such as neurodegeneration in the dorsal root ganglia, cardiomyopathy, and diabetes mellitus [Puccio et al 2001, Ristow et al 2003, Seznec et al 2004, Simon et al 2004]. Seznec et al (2004) showed that idebenone treatment delayed the onset of cardiac pathology and even prolonged the life span in a cardiac-specific frda knockout mouse (see Management).
Normal allelic variants: The FXN gene consists of seven alternatively spliced exons, six of which encode one of two open reading frames [Campuzano et al 1996]. Exons 1-4 spliced to exon 5A produce the major transcript that encodes the 210-amino acid protein, frataxin.
The GAA trinucleotide repeat sequence is situated at the center of an Alu repeat element in intron 1 and displays length polymorphism [Campuzano et al 1996; Cossee, Schmitt et al 1997; Montermini, Andermann et al 1997]. Normal alleles have 5-33 GAA repeats. A bimodal distribution exists among normal alleles in which 85% have fewer than 12 GAA repeats (short normal) and the remainder have 12-33 repeats (long normal). Alleles longer than 27 GAA repeats are usually interrupted by a (GAGGAA)n sequence. The homopurine/homopyrimidine nature of the GAA tract is maintained in all individuals.
Ohshima et al (1999) reported a rare variation of the GAA triplet repeat sequence: two individuals were found to carry 65 tandem repeats of the GAAGGA hexanucleotide sequence in place of the normal GAA triplet repeat. This sequence is non-pathogenic.
Immediately upstream of the Alu repeat element within which the GAA triplet repeat maps is a mononucleotide tract of adenines (poly A tract) that is polymorphic. Interallelic variation showed either 14 or 17 adenines [Monticelli et al 2004].
Monticelli et al (2004) identified a C/T polymorphism 212-bp downstream of the GAA repeat.
The (TAA)2/(TAA)4 biallelic polymorphism is situated 0.15 kb 3' of the GAA repeat in intron 1 [Montermini, Richter et al 1997; Bidichandani et al 1998]. The (TAA)2 allele is seen in approximately 10% of normal alleles but very rarely in expanded alleles.
Intron 3 contains two polymorphisms. ITR3 is a C/T dimorphism and F5225 is a (TCTA)n(TCCA)n microsatellite marker [Cossee, Schmitt et al 1997].
Intron 4 contains another C/T single-nucleotide polymorphism (ITR4) [Cossee, Schmitt et al 1997].
Mutable normal (premutation) alleles: Pure (uninterrupted) GAA repeat alleles ranging in size from 34 to 65 triplets have been found to expand into the disease range [Cossee, Schmitt et al 1997; Epplen et al 1997; Montermini, Andermann et al 1997] and are called "premutations" (also see Molecular Genetic Testing, Mutable normal alleles). These alleles are rare and account for fewer than 1% of the non-disease associated alleles.
Pathologic allelic variants:
Pathogenic GAA repeat expansions. Most individuals with FRDA are homozygous for large GAA trinucleotide repeat expansions of the polymorphic (GAA)n sequence in intron 1 [Campuzano et al 1996]. The size range associated with disease is 66-1700 triplets [Campuzano et al 1996, Durr et al 1996, Epplen et al 1997], but the majority of alleles contain 600-1200 repeats. This mutation is seen in 1% of alleles in Indo-European populations and accounts for 96% of all FXN mutant alleles.
The expanded alleles display somatic length variability among cells of the same tissue and among various different tissues [Campuzano et al 1996; Montermini, Kish et al 1997; Pianese et al 1997; Machkhas et al 1998; Bidichandani et al 1999, Sharma et al 2002]. The GAA repeat is unstable during germline transmission [Monros et al 1997, Pianese et al 1997, De Michele et al 1998]. Contractions outnumber expansions and a clear differential parental effect is seen. While maternal transmissions result in both expansions and contractions, paternal transmissions predominantly result in contractions. The magnitude of repeat length variation is typically 10-20% of the initial allele length. Although intergenerational variation can exceed 50% in some individuals, complete reversion to the normal size has never been seen in the FXN gene. Pianese et al (1997) and De Michele et al (1998) found that GAA expansion size in sperm was almost always shorter than blood, providing a biological explanation for the contractions seen following paternal transmission. Delatycki et al (1998) showed that a premutation allele with 100 GAA repeats had expanded to contain 320 repeats in a sperm sample, indicating that premutation alleles and short expansions may behave differently in germ cells compared to larger expansions.
The GAA trinucleotide repeat expansion interferes with transcription and is associated with a severe deficiency of normally spliced FXN mRNA in individuals homozygous for the GAA expansion [Cossee, Campuzano et al 1997; Bidichandani et al 1998]. The reduction in the amount of FXN mRNA, and consequently frataxin protein, directly correlates with the size of the GAA expansion [Campuzano et al 1997]. Given the severe deficiency associated with very long repeats, the total residual FXN mRNA in those homozygous for the GAA expansion is determined as a function of the shorter of the two repeats. This is thought to be the reason for the remarkable correlation between the clinical features in FRDA and the size of the shorter of the two repeats [Durr et al 1996; Filla et al 1996; Montermini, Richter et al 1997].
In vitro and in vivo transcription experiments indicate that the GAA triplet repeat itself presents a length- and orientation-dependent hindrance to transcription [Bidichandani et al 1998, Ohshima et al 1998, Grabczyk & Usdin 2000]. Sequences with more than 59 GAA triplet repeats form a novel DNA structure called "sticky DNA," formed by the intermolecular association of two triplexes [Sakamoto et al 1999]. Sticky DNA results in dramatic interference with transcription in vitro, and interruption in the purity of the GAA sequence (e.g., with GGA) results in destabilization of sticky DNA with lack of transcriptional inhibition [Ohshima et al 1999, Sakamoto, Larson et al 2001, Sakamoto, Ohshima et al 2001]. Saveliev et al (2003) showed that expanded GAA repeats introduced into the mouse genome induced position-effect variegation of an adjacent reporter gene, suggesting that frataxin deficiency associated with expanded GAA repeats may also be mediated by abnormal chromatin organization.
Cossee, Schmitt et al (1997) showed by haplotype analysis that most "long normal" and expanded alleles share the same major haplotype. This haplotype was rarely seen in "short normal" alleles, indicating that most (if not all) long normal alleles may have arisen from a single founder chromosome and that expanded alleles are derived from this fraction, possibly via premutation intermediates. Similar strong linkage disequilibrium was found among expanded alleles in Spanish, French, and German families with FRDA [Monros et al 1996, Zuhlke et al 1999]. Labuda et al (2000) proposed a "two-step" process for the genesis of premutation alleles, suggesting that long normal alleles may have arisen by duplication of an ancient short normal allele; indeed, the most common short normal and long normal alleles contain 8-9 and 16-18 GAA repeats. Monticelli et al (2004) showed that long normal alleles arose from a subclass of short normal alleles with nine repeats, suggesting that a duplication from nine to 18 repeats occurred. Further, premutation alleles, with their propensity to hyperexpand, may have arisen by a second duplication event involving an ancestral long normal allele. Long normal, premutation, and expanded alleles are found predominantly in Indo-European populations (European, Middle-Eastern, Indian, and North-African). The paucity of these alleles in East and Southeast Asians (Japan, Taiwan, Indonesia, Thailand), Papua New Guineans, and Native Americans correlates with the rarity of FRDA among these populations [Labuda et al 2000, Sasaki et al 2000, Justice et al 2001, Mori et al 2001] (see also Prevalence). Gomez et al (2004) found that the lower prevalence of FRDA in Mexico was the result of low-level genetic admixture with European FXN mutable / mutant alleles. Haplotype and linkage disequilibrium studies indicate that the transition from long normal to premutation and expanded alleles may have occurred approximately 25,000 years ago [Labuda et al 2000] or 682 generations ago [Colombo & Carobene 2000]. Clark et al (2004) showed that while most GAA repeats in the human genome have arisen in the 3' poly(A) tails of Alu elements, the GAA repeat in intron 1 of the FXN gene is highly unusual because of its location at the center of an Alu element.
Borderline alleles. Sharma et al (2004) described a new class of allele containing a pure tract of 44-66 GAA triplets that are unstable in somatic cells in vivo. These alleles, by virtue of their genetic instability, are capable of conferring a risk of phenotypic expression, if the other FXN gene has a full penetrance disease-causing allele. Sensitive analysis via small pool PCR showed that 15%-75% of somatic cells in vivo contained more than 66 triplets, despite the presence of fewer than 66 triplets by conventional PCR and sequencing.
Other inactivating FXN gene mutations. Approximately 4% of individuals with FRDA are compound heterozygotes with a GAA expansion on one allele and another inactivating mutation on the homologous FXN allele; the latter are believed to be loss-of-function mutations (Table 2; pdf) of two types: a) nonsense mutations, errors of splicing or frameshift mutations that result in premature termination of translation; or b) missense mutations in the highly conserved carboxy-terminal domain (Table 2; pdf).
The I154F mutation is common in Sardinia [Campuzano et al 1996, Filla et al 1996]. The G130V mutation, seen in multiple, apparently unrelated individuals, is likely to have arisen from a common founder [Delatycki, Knight et al 1999]. Codons 1, 106, 165, and 182 are apparently mutation hot spots (Table 2; pdf).
Normal gene product: The FXN gene encodes frataxin, a 210-amino acid protein that localizes to the inner mitochondrial membrane [Campuzano et al 1996, Babcock et al 1997, Campuzano et al 1997, Koutnikova et al 1997, Priller et al 1997]. The carboxy-terminal region of frataxin is highly conserved in evolution [Campuzano et al 1996, Gibson et al 1996] and is a target for inactivating missense mutations (Table 2; pdf). Frataxin shows tissue- and developmental-specific expression. Besides being expressed in tissues that are pathologically affected in FRDA, frataxin is also expressed in tissues that have a high metabolic rate, including the liver, kidney, and brown fat [Koutnikova et al 1997]. The tissues primarily affected in Friedreich ataxia are known to express high levels of frataxin.
Abnormal gene product: The pathology in Friedreich ataxia results from frataxin deficiency or lack of function.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
Friedreich's Ataxia Research Alliance (FARA)
2001 Jefferson Davis Highway Suite 209
Arlington VA 22202
Phone: 703-413-4468
Fax: 703-413-4467
Email: fara@faresearchalliance.org
www.faresearchalliance.org
Medline Plus
Friedreich's Ataxia
National Library of Medicine Genetics Home Reference
Friedreich ataxia
NCBI Genes and Disease
Friedreich's ataxia
euro-ataxia (European Federation of Hereditary Ataxias)
Boherboy Dunlavin
Co Wicklow
Ireland
Phone: +353 45 401218
Fax: +353 45 401371
Email: mary.kearneyl@euro-ataxia.org
www.euro-ataxia.org
International Network of Ataxia Friends (INTERNAF)
www.internaf.org
Muscular Dystrophy Association (MDA)
3300 East Sunrise Drive
Tucson AZ 85718-3208
Phone: 800-FIGHT-MD (800-344-4863); 520-529-2000
Fax: 520-529-5300
Email: mda@mdausa.org
www.mdausa.org
National Ataxia Foundation
2600 Fernbrook Lane Suite 119
Minneapolis MN 55447
Phone: 763-553-0020
Fax: 763-553-0167
Email: naf@ataxia.org
www.ataxia.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
SI Bidichandani's work is supported by the National Institutes of Health, Muscular Dystrophy Association (MDA), Friedreich Ataxia Research Alliance (FARA), and Oklahoma Center for the Advancement of Science and Technology (OCAST). T Ashizawa's work is supported by the National Institutes of Health. MB Delatycki is an NHMRC Practitioner Fellow.
Tetsuo Ashizawa, MD (1998-present)
Sanjay I Bidichandani, MBBS, PhD (1998-present)
Martin Delatycki, MBBS, FRACP, PhD (2006-present
Pragna I Patel, PhD; Baylor College of Medicine (1998-2002)
25 August 2006 (me) Comprehensive update posted to live Web site
30 August 2004 (cd) Revision: addition of sequence analysis
22 June 2004 (me) Comprehensive update posted to live Web site
9 December 2002 (sb) Revisions
3 April 2002 (me) Comprehensive update posted to live Web site
18 December 1998 (pb) Review posted to live Web site
20 September 1998 (sb) Original submission
