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Diagnosing Friedreich’s ataxia
  1. Department of Clinical Neurology, Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG

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    The condition that now bears his name was first described by Nicolaus Friedreich in a series of papers between 1863 and 1877. He noted the onset at around puberty of ataxia and dysarthria; sensory loss and weakness developed later. The skeletal deformities of pes cavus and scoliosis were also reported. Over the following generations there was a tendency to lump the inherited ataxias together, and the essential features of Friedreich’s ataxia became diluted. Clinical studies in the 1970s and 1980s1 2 and subsequent genetic studies have helped clarify these features, and Friedreich’s ataxia is now known to be the commonest of the inherited ataxias, accounting for at least 50% in most large series and affecting approximately one in 50 000 individuals.3 Although at present it is an incurable and progressive disease, recent identification of the affected gene has not only provided a highly sensitive and specific diagnostic test, but has also given useful insight into the cellular pathology which may lead to the development of effective treatment.

    Key messages

    • Friedreich’s ataxia is the commonest inherited ataxia (1:50 000)

    • Over 97% will have a homozygous GAA unstable repeat in intron 1 of the frataxin gene on chromosome 9q; a direct test is now available

    • There is a correlation between repeat length and age at onset

    • The frataxin protein may be an iron transporter within the mitochondria

    Clinical diagnosis

    Despite the relatively homogeneous clinical picture of an early onset of progressive ataxia involving the trunk and the limbs, it was necessary to formulate strict clinical criteria in order to perform genetic linkage analyses, and two notable studies,1 2provided these. Harding’s criteria (table 1) were widely adopted and are still useful today, although of course we are now able to reinterpret “atypical” cases in the light of available genetic data.

    Table 1

    Strict diagnostic criteria (after Harding, 19812)

    In addition to ataxia, there are several variable features, including pyramidal tract involvement. Initially this may be mild, with only extensor plantar responses, but after five or more years a pyramidal type of weakness in the legs invariably occurs and this can eventually lead to paralysis. The association of extensor plantar responses, absence of ankle reflexes, and a progressive course provide the core features.

    Skeletal abnormalities are also commonly found. These include scoliosis (85%), and foot deformities; although pes cavus is the best known of these, pes planus and equinovarus are also often found. Amyotrophy of the lower leg and rarely of the hands may also be found. When all these features are present in a case of early onset (before 20 years of age) autosomal recessive ataxia, genetic analysis will prove that Friedreich’s ataxia is the correct diagnosis in the vast majority.4 Additional clinical support for a suspected diagnosis includes optic atrophy, which occurs in 25% of cases; however, it is rare for there to be major visual impairment in Friedreich’s ataxia (less than 5%).2 Deafness is found in less than 10% of cases.

    The most important non-neurological feature of Friedreich’s ataxia is cardiomyopathy. The exact proportion of patients with cardiomyopathy is still debated. However, in a study where hearts were examined in detail, over 90% were found to have abnormalities, though the clinical significance of some of the lesser changes is unclear.5About 65% of patients have an abnormal electrocardiogram (ECG), with widespread T wave inversion in the inferolateral chest leads. The most frequent echocardiographic abnormality is concentric ventricular hypertrophy.6 Although heart failure is a late event, referral to a cardiologist may be necessary as arrhythmias are an important cause of premature death. Review of the patient should therefore always include an ECG. It should also include an estimation of blood sugar, since diabetes is seen in approximately 10% of cases.

    Before identification of the gene, additional investigations were done to screen for the associations listed above and to rule out other diseases with a similar presentation. Nerve conduction studies reveal a predominantly sensory neuronopathy with absent sensory action potentials. This differentiates Friedreich’s from the Roussy-Levy variant of hereditary motor sensory neuropathy type 1, which was at one time thought to be a “forme-fruste” of Friedreich’s ataxia as it produces a sensory ataxia with absent tendon reflexes. The neurophysiological findings in this condition are those of a severe demyelinating process rather than an axonopathy.

    It was noted in the early 1980s that patients with vitamin E malabsorption associated with various disorders including abetalipoproteinaemia, chronic liver disease, and cystic fibrosis7-12 could develop a spinocerebellar syndrome which resembled Friedreich’s ataxia but could be distinguished by those additional features. In 1985 Harding et al described a patient in whom vitamin E deficiency was seen in the absence of malabsorption or other identified problem.13 Although this disorder has undergone various name changes, including several acronyms, most people have now settled for AVED (ataxia with isolated vitamin E deficiency). The gene responsible for this illness was linked to 8q14 and identified by Ouahchi et al.15 The gene encodes a protein called α tocopherol transporter protein, and abnormalities which ensue from mutations of this gene result in impaired incorporation of vitamin E into very low density lipoprotein. Therefore, although vitamin E is absorbed adequately, it is soon lost from the system as the circulating reservoir is dysfunctional. Although clinically there are similarities with Friedreich’s ataxia, the neuronopathy is more central and therefore conduction studies are often normal. The clinical clue to the presence of this disease is a characteristic titubation which is rarely seen in classical Friedreich’s ataxia. However, despite the rarity of this illness, supplementation with vitamin E can result in either modest improvement of the clinical syndrome, or at least in cessation of its progression, and therefore it is always worthwhile measuring vitamin E in such patients. Since absorption is normal, a direct inquiry should be made about the use of supplementary vitamins—it is possible to be misled by a normal vitamin E level if vitamin E supplements are being taken.

    If the spinocerebellar syndrome is complicated by other neurological problems, for example dementia, then other illnesses should be considered, including hexoseaminidase A deficiency, abetalipoproteinaemia, adrenoleucodystrophy, and related conditions.

    The natural history of this disease unfortunately remains one of relentless progression, with dysarthria and pyramidal weakness presenting within a few years of onset, followed by jerky eye movements giving way to nystagmus. The patient usually becomes wheelchair bound within 10 to 15 years of onset.2 It is worth noting that patients may present to cardiologists with cardiomyopathy as the sole initial feature. We have recently seen two cases who presented with a choreiform movement disorder with no signs of ataxia. The clue that Friedreich’s ataxia was the underlying condition was given by the absence of reflexes in both, scoliosis in one, and cardiomyopathy in the other.16

    Genetic diagnosis

    The gene for Friedreich’s ataxia was mapped to chromosome 9q13 in 1988 by Chamberlain and colleagues.17 There then followed a competitive hunt for the gene and a refinement of the genetic locus. This allowed a re-evaluation of the strict clinical criteria described above and it became apparent that the onset of Friedreich’s ataxia could be seen after the age of 20 years, and retention of the tendon reflexes did not completely exclude it. It was also shown that the milder variant of the disease described in the Acadian population was mapped to the same locus. Following international collaboration, an anonymous transcript called X25 in which three point mutations were found was identified in 1996.18 Further work showed that the predominant mutation was a trinucleotide repeat (GAA) in intron 1 of this gene. Expansion of both alleles was found in over 70 patients. In three patients point mutations were found on one allele and an expansion on the other. This is clear evidence that X25 is directly involved in Friedreich’s ataxia, although there is still some debate as to the exact construction of the gene itself.19 Moreover, initial mRNA studies have reported a decrease in frataxin protein. Interestingly, the tissue specific distribution seen in this disease—including expression in the pancreas, the heart, and the dorsal spinal cord—mirrors that of the pathology of the disease.

    This was the first autosomal recessive condition found to be due to a dynamic repeat, and it permitted the introduction of a specific and sensitive diagnostic test as it is a relatively simple matter to measure the repeat size. On normal chromosomes the number of GAA repeats varies from seven to 22 units, whereas on disease chromosomes the range varies from around 100 to 2000 repeats. This is in sharp contrast to the modest exonic repeat expansions seen in the dominant genetic ataxias (SCA 1, 2, and 3), where an expansion of somewhere over 40 repeats is sufficient to cause a degenerative ataxia.

    The polymerase chain reaction (PCR) with nucleotide primers spanning the repeated region is used to amplify the DNA in intron 1, and the products are then fractionated on an agarose or polyacrylamide gel (fig1). The rarity of point mutations means that it is extremely unlikely that a case of Friedreich’s will have two point mutations, and therefore a normal sized repeat length on both chromosomes is strongly against a diagnosis of Friedreich’s ataxia. To put this into some sort of perspective, there is approximately a one in 2500 chance that a patient with typical Friedreich’s ataxia will have a double point mutation. However, the phenotype of atypical cases is still unresolved.

    Figure 1

    Agarose gel of long range PCR products of the repeated region of intron 1. Lane 1 shows the marker. Lanes 2 and 4 represent carriers of the expansion. Lane 3 is a normal “heterozygote” with two normal sized (but polymorphic) repeat alleles. Lane 5 shows an affected patient with two expanded alleles (approximate 900 and 1100 repeats respectively). Lane 6 is a second affected patient with two more closely sized alleles (∼1000 +/− repeats). Lane 7 is a “homozygote” positive control.

    The exact mechanism of action of this repeat in intron 1 is not known, but it is likely that this huge expansion disrupts normal splicesome binding and therefore exon 1 is not spliced correctly to exon 2. This is reflected in a reduction in mRNA and protein levels.

    There has been progress in our understanding of the protein.20 A very recent report21 has investigated a yeast analogue of the protein and shown it to be a mitochondrial iron transporter. There is preliminary evidence in human studies that frataxin is also mitochondrially placed (M Pandolfo, personal communication). If this is indeed the function of frataxin in humans, the corollary of this is that iron will build up inside the mitochondria with relative diminution in the cytosol. The free iron may cause a number of problems but most interest concerns free radical regulation and oxidative phosphorylation. Clinically this fits—a syndrome of ataxia and neuropathy, in association with diabetes, cardiomyopathy, deafness and optic atrophy, has all the hallmarks of a mitochondrial disease, so perhaps Friedreich’s ataxia will turn out to be the commonest mitochondrial disease of all!

    Genotype-phenotype correlations

    The identification of a diagnostic test has allowed the clinical phenotype to be re-evaluated. It is now confirmed that retained tendon reflexes are present in a small proportion of patients with Friedreich’s ataxia. Although most patients present below the age of 25, onset can be later than this and the oldest reported case was 51 years.22 Studies of large numbers of patients4 22 23 are in broad agreement that the length of repeat size is a determinant of the age of onset and therefore to some degree influences the severity of the disease, in that cases with early onset tend to progress more rapidly. However, this correlation applies to populations of patients and is not useful in guiding an individual patient or family. The presence of cardiomyopathy is also linked to the length of the repeat, but further studies are needed to disentangle the exact relation between the two.23

    We have also identified three families in whom inheritance initially appeared to be dominant, as in all three cases the parent had an ataxic syndrome. In one of these families, pseudodominance has been proved by identification of two abnormal alleles in the parental generation as well as two in the affected offspring, that is, it was a case of a patient marrying a carrier. In the other two families, the children have both clinical and genetic Friedreich’s ataxia. However, the fathers have a more complicated ataxia and a later onset. They are heterozygotes for the expansion, and the possibility arises that either they both have point mutations which are modifying the phenotype, or they have ataxia from some other cause.


    Clinical diagnosis is still of the utmost importance and following our review of cases diagnosed using the strict criteria, 100% were homozygous for the expansion.4 However, now that there is a relatively simple direct genetic test, the diagnosis can be considered in more unusual cases. Genetic testing has been shown to be of value in establishing the correct diagnosis and in directing the appropriate screening tests, including cardiological assessment and blood sugar estimation.

    Perhaps the most interesting development following identification of the gene is the rapid progress in our understanding of the protein. If, as seems likely, it turns out to be a mitochondrial protein involved in iron transport, it gives cause for hope of effective treatment.