Background Friedreich's ataxia, the most common inherited ataxia,is associated with a mutation that consists of an unstable expansionof GAA repeats in the first intron of the frataxin gene on chromosome9, which encodes a protein of unknown function.
Methods We studied 187 patients with autosomal recessive ataxia,determined the size of the GAA expansions, and analyzed theclinical manifestations in relation to the number of GAA repeatsand the duration of disease.
Results One hundred forty of the 187 patients, with ages atonset ranging from 2 to 51 years, were homozygous for a GAAexpansion that had 120 to 1700 repeats of the trinucleotides.About one quarter of the patients, despite being homozygous,had atypical Friedreich's ataxia; they were older at presentationand had intact tendon reflexes. Larger GAA expansions correlatedwith earlier age at onset and shorter times to loss of ambulation.The size of the GAA expansions (and particularly that of thesmaller of each pair) was associated with the frequency of cardiomyopathyand loss of reflexes in the upper limbs. The GAA repeats wereunstable during transmission.
Conclusions The clinical spectrum of Friedreich's ataxia isbroader than previously recognized, and the direct moleculartest for the GAA expansion on chromosome 9 is useful for diagnosis,determination of prognosis, and genetic counseling.
Friedreich's ataxia, an autosomal recessive neurodegenerativedisorder, is the most common hereditary ataxia. Its estimatedprevalence in European populations is 1 in 50,000. In 1988 thelocus of the genetic defect was mapped to chromosome 9.1 Thefrataxin gene, encoding a protein of unknown function, was recentlyidentified, and, surprisingly, most of the mutations appearedto be unstable expansions of a GAA repeat in the first intron.2Ninety-four percent of patients with the classic form of thedisease were found to be homozygous for the GAA expansion. Thecausal role of mutations in the frataxin gene was proved bythe identification of rare compound heterozygotes with an expansionin one allele and a point mutation in the other.2
A cardinal feature of Friedreich's ataxia is ataxia of all fourlimbs, associated with cerebellar dysarthria, absent reflexesin the lower limbs, sensory loss, and pyramidal signs. The onsetof symptoms is usually before 20 years of age, and the progressionof the disease is relentless. Skeletal deformities and cardiomyopathyare found in a majority of patients, who also have an increasedfrequency of impaired glucose tolerance and diabetes. The presenceof these signs is strongly suggestive of Friedreich's ataxia.
The diagnostic criteria were revised by Harding3 to includepatients with onset up to the age of 25 and to take into accountthe incomplete clinical presentation in patients in whom theduration of disease was less than five years. Families withat least two patients meeting these criteria revealed linkageto chromosome 9q13,1,4 although an autosomal recessive deficiencyof vitamin E may produce similar symptoms.5 The existence ofpatients with autosomal recessive cerebellar ataxia who hadintact tendon reflexes6,7,8 or disease of late onset9 but withlinkage to chromosome 9q1310,11,12,13 suggested that the clinicalspectrum is broader than previously thought.
We screened 187 patients with progressive ataxia for GAA expansionin the frataxin gene. In 140 patients who were homozygous forthe expansion, we measured the size of the repeats and examinedphenotype–genotype correlations.
Methods
Patients and Families
We screened 187 patients from 147 families, selected becausethey had progressive, unremitting cerebellar ataxia of provedor possible autosomal recessive inheritance, for GAA expansionin the frataxin gene. Consanguinity was documented in 21 families,and 75 patients had no affected relatives. All but 10 patientswere initially referred to the Fédération de Neurologieat the Salpêtrière Hospital in Paris or to theDepartment of Neurology at St. Pierre Hospital on the Frenchisland of Réunion in the Indian Ocean and were examinedbetween May 1990 and March 1996. All patients were examinedby one of the authors according to a standardized protocol,and age at onset of symptoms, disease progression, and clinicalsigns associated with cerebellar ataxia were recorded. Accordingto the essential diagnostic criteria,3 103 patients had typicalFriedreich's ataxia. Patients in this group had a disease durationof at least five years, with onset of symptoms before the ageof 25, progressive ataxia of gait and limbs, absent knee andankle jerks, and extensor plantar responses. Ten other patientswith disease duration of less than five years were also classifiedas having typical Friedreich's ataxia; all these patients presentedwith no extensor plantar reflex, and two of them had intactreflexes in the lower limbs. Among the other 74 patients, atleast one of the essential criteria was still unmet after fiveyears of disease, but all had progressive, unremitting cerebellarataxia compatible with autosomal recessive inheritance. Ninehad at least one sibling with typical Friedreich's ataxia.
Thirty-two patients had one or more children. Eighty-one ofthe 114 families with GAA expansions were French. In 74 of thesefamilies, both parents came from France. In the remaining seven,the other parent came from Italy (three), Belgium (two), Germany(one), or Morocco (one). There were also families from Réunion(17), Algeria (5), Spain (3), Italy (3), Portugal (2), Morocco(1), Greece (1), and Argentina and Uruguay (1).
GAA-Repeat Analysis
GAA repeats were analyzed by Southern blotting. In the initialreport, the expansion mutation was detected by Southern blotanalysis of DNA digested with the EcoRI restriction enzyme.2In the present study, we used the BsiHKAI enzyme, which yieldsa smaller target DNA fragment (2.4 kb instead of 8.2 kb), allowinga more accurate estimation of the number of GAA repeats anda better resolution between the two alleles. Ten microgramsof genomic DNA was digested by BsiHKAI (New England Biolabs,Beverly, Mass.), electrophoresed in 0.9 percent agarose gel,blotted on HybondN+ membranes (Amersham, Little Chalfont, UnitedKingdom), and hybridized with a 32P-radiolabeled 463-bp genomicfragment containing exon 1. The fragment was obtained by thepolymerase chain reaction with the forward primer CAAGTTCCTCCTGTTTAGand the reverse primer CCGCGGCTGTTCCCGG and cloned in pGEM-T.A 1-kb–ladder marker (GIBCO BRL, Gaithersburg, Md.) wasrun and hybridized in parallel for size measurement. Blots werewashed in 0.2x saline sodium citrate (1x saline sodium citrateis 0.15 M sodium chloride and 0.015 M sodium citrate) and 0.1percent sodium dodecyl sulfate twice at room temperature andtwice at 60°C and exposed for autoradiography at -80°Cwith an intensifying screen.
Statistical Analysis
Means were compared with use of nonparametric tests and Student'st-test, and frequencies were compared with use of the chi-squareand Yates' corrected chi-square test, when appropriate. Meansare given with standard deviations. Regression coefficientswith the quadratic model were calculated for the correlationsbetween the number of GAA repeats and both age at onset andduration of disease until the patient became confined to a wheelchair.
Results
Frequency and Size of GAA Expansions
Expanded GAA repeats were found on both alleles of the frataxingene in 140 patients from 114 families (Table 1). Nine patientsfrom six families were heterozygous for the expansion mutationand were known or expected carriers of a point mutation on theother allele, as previously shown in five families.2 Among thepatients who fullfilled Harding's criteria for Friedreich'sataxia,3 94 percent were homozygous for the GAA expansion andthe remaining 6 percent were heterozygous. Surprisingly, 46percent of the patients who did not meet all the diagnosticcriteria for Friedreich's ataxia were also homozygous for theGAA expansion. Thirty-eight patients had two alleles with GAArepeats in the normal size range, which excludes the diagnosisof Friedreich's ataxia.
Table 1. Frequency of GAA Expansions in Patients with Typical and Atypical Friedreich's Ataxia.
In the 140 patients who were homozygous for the GAA expansion,the number of repeats ranged from 120 to 1700 (Figure 1); thenormal frataxin gene has between 8 and 22 GAA repeats.2 Mostof these patients had two expanded alleles of different sizes,and no detectable somatic instability. In 28 patients the twoexpanded alleles appeared as a single band on Southern blotting.The mean numbers of GAA repeats on the smaller and the largeralleles were 630±230 and 890±230, respectively.In a few instances two major expanded alleles were detected,along with less intense bands in the expanded range, probablyreflecting somatic mosaicism. Only the bands corresponding tothe stronger signals were taken into account. The expansionwas unstable during transmission, accounting for the variablenumber of GAA repeats among siblings (Figure 2).
Figure 2. Southern Blot Analysis of a Bsi HKAI Digestion That Demonstrates GAA Expansion in the First Intron of the frataxin Gene.
A kindred is shown in which the parents (lanes 1 and 2) are heterozygous for expansion of GAA repeats. The parents have both a 2.4-kb wild-type band and a 6-kb band, which is the result of expansion of GAA repeats. The three offspring (lanes 3, 4, and 5) have variation in the size of the abnormal band, indicating variable transmission of the GAA expansion. The patients shown in lanes 6, 7, and 8 are unrelated.
Features of Patients Homozygous for the GAA Expansion
Clinical Characteristics
Of the 140 patients homozygous for the GAA expansion, 72 werewomen and 68 were men. The mean age at onset of the diseasewas 15.5±8 years (range, 2 to 51), and the mean age atexamination was 31±13 years (range, 7 to 77). The meantime until the patient became confined to a wheelchair was 10.8±6years (range, 1 to 25). The presenting symptom was gait ataxiain all patients except for seven in whom scoliosis was diagnosedbefore the ataxia. The overall clinical picture is detailedin Table 2. In addition, the following signs and symptoms wereobserved: facial dysmorphia (five patients in three families),seizures (two patients), dystonic postures (two patients), myoclonus(five patients), postural tremor (two patients), limited eyegaze with preserved vestibulo-ocular movements (five patients),and mental retardation (five patients). These features mightbe associated with, but not caused by, the mutation.
Table 2. Frequency of Clinical Signs in 140 Patients Homozygous for the GAA Expansion and in Patients Studied by Harding.
Thirty-four of the 140 homozygous patients had an atypical clinicalpresentation for one or more of the following reasons: an ageof more than 25 years at onset (19 patients); retained tendonreflexes in lower limbs, including 4 patients with brisk reflexes(13 patients); and absence of extensor plantar response (21patients). In addition, 10 patients who had had the diseasefor less than five years had an incomplete clinical picturebut were homozygous for the expansion, confirming the diagnosisof Friedreich's ataxia.
Correlation of Age at Onset and Rate of Disease Progression with GAA-Expansion Size
We determined the correlations between the size of the smallerand the larger expansions for each pair of alleles and bothage at onset and duration of disease before the patient becameconfined to a wheelchair. An inverse relation was found betweenthe size of the smaller GAA expansion and both age at onset(n = 140, r = -0.75, P<0.001) (Figure 3) and time until confinementto a wheelchair (n = 48, r = -0.49, P<0.005). The correlationwas less strong between the size of the larger allele and ageat onset (n = 140, r = -0.5, P<0.001). However, the sizesof the two alleles were not independent (r = 0.5, P<0.001),possibly because of consanguinity or a founder effect in a substantialproportion of the families. This observation may explain inpart the correlation between the size of the larger allele andage at onset. Only the number of GAA repeats in the smallerexpansion was used in subsequent calculations.
Figure 3. Correlation between Age at Onset and the Number of GAA Repeats in the Smaller Allele in the 140 Study Patients.
The best fit was obtained with the quadratic model for the regression coefficient (r = -0.75, P<0.001). The patient with 1000 GAA repeats and onset at 23 years of age had mosaicism for a third expanded fragment of 670 repeats, which might in part explain his late age at the onset of disease.
Correlation of Phenotype with GAA-Expansion Size and Duration of Disease
The frequency of some clinical signs increased with the sizeof the GAA expansion (Table 3), whereas the following appearedto be linked mostly to duration of disease at examination: dysarthria(P<0.001), decreased vibration sense (P<0.001), decreasedvisual acuity (P = 0.01), hearing loss (P<0.001), sphincterdisturbances (P<0.005), and swallowing difficulties (P =0.01). The frequency of the extensor plantar response, muscleweakness in the lower limbs, and amyotrophy of the lower limbswas dependent on both the number of GAA repeats and the durationof disease. Cardiomyopathy on echocardiography was present inmost patients with large expansions on the smaller allele. Themean number of GAA repeats in patients with normal echocardiographicresults was 575±210, as compared with 740±180in patients with cardiomyopathy (P<0.005). The presence ofcardiomyopathy was not dependent on duration of disease. Thefrequency of scoliosis and pes cavus was strongly correlatedwith increasing expansion size. Symptoms such as lower-limbareflexia, diabetes, and abnormal evoked visual or brain-stemauditory potentials were not correlated with the size of theGAA expansion or with the duration of disease.
Table 3. Clinical Features as a Function of the Number of GAA Repeats in the Smaller Allele.
Discussion
The first report on the frataxin gene in Friedreich's ataxiashowed that all patients with the classic form of the disease,as defined by Harding's diagnostic criteria,3 carried the GAAexpansion, and 94 percent were homozygotes.2 In the presentstudy, we analyzed a broader sample of patients with progressiveataxia, 40 percent of whom did not meet all of Harding's criteria,3to determine the range of phenotypes associated with mutationsin the frataxin gene. Furthermore, we measured the number ofGAA repeats by a more accurate technique than that used in theinitial report, to see whether the size of the GAA expansioncorrelated with disease severity or clinical presentation, asin other trinucleotide-expansion diseases such as myotonic dystrophyand Huntington's disease, or whether instead there was an all-or-noneeffect on clinical manifestations once a threshold in the sizeof the mutation was reached, as in the fragile X mental retardationsyndrome.14
Eighty percent of the patients studied had at least one GAAexpansion in the frataxin gene; this result was expected becauseFriedreich's ataxia is the chief cause of progressive autosomalrecessive ataxia. The diagnostic criteria for Friedreich's ataxiahad been defined with precision,3 and it was thought that Friedreich'sataxia was a homogeneous clinical entity. The criteria includedautosomal recessive inheritance, onset before the age of 25,the absence of lower-limb reflexes, and the presence of pyramidalsigns. Indeed, all the patients who met these criteria had aGAA expansion. The expansion was present on both alleles in94 percent of these patients and on one allele in 6 percent.The latter patients are presumed to carry a point mutation ontheir nonexpanded allele, as previously demonstrated in severalfamilies.2
Although very specific, these diagnostic criteria do not appearto be sensitive enough, since about one quarter of our patientswho were homozygous for the expansion lacked at least one ofthem. There is a wider clinical spectrum in Friedreich's ataxiathan has been previously appreciated. Late onset is not uncommonamong patients with homozygous expansions; 19 of our patients(14 percent) had onset between 26 and 51 years of age. Reflexesmay be retained in the lower limbs, as observed in 13 patients,and in 4 they were brisk. Linkage analyses in a few families10,11,12,13had suggested that such variant clinical presentations mightbe allelic with Friedreich's ataxia.
A clinical analysis of patients with early-onset cerebellarataxia and retained reflexes suggested that they differed frompatients with Friedreich's ataxia by the absence of cardiomyopathyand optic atrophy,6 the presence of cerebellar atrophy on magneticresonance imaging (11 of 14 patients),9 and longer times beforebecoming confined to a wheelchair (33 ± 19 years6 or21 ± 11 years,9 as compared with 6 ± 0.4 yearsin Friedreich's ataxia9). Among our patients, the 10 who presentedwith clinical and electrophysiologic features of early-onsetcerebellar ataxia and with retained reflexes had, in fact, Friedreich'sataxia with small GAA expansions. Unusual signs (such as mentalretardation) were rarely observed and are probably not partof the phenotype of Friedreich's ataxia.
The size of the expansion varied greatly among patients andwithin and among families. The wide range of GAA repeats, from120 to 1700, reflects the instability of the expansion duringtransmission, which is characteristic of all mutations withlarge trinucleotide-repeat expansions.14 The size of the expansionin Friedreich's ataxia is similar to those found in fragileX syndrome and myotonic dystrophy, in which the expansion liesin the untranslated region of the corresponding transcript.14However, it is larger than those found in neurodegenerativedisorders such as autosomal dominant cerebellar ataxias resultingfrom translated CAG expansions15,16 that lead to a toxic abnormalprotein.17
Correlation between the size of the GAA expansion and age atonset of the disease is evidence that the expansion is the causeof the disease rather than being associated by linkage disequilibriumwith another, unidentified mutation located elsewhere in thenoncoding part of the frataxin gene. The size of the smallerGAA expansion is strongly correlated with age at onset and withthe rate of disease progression. The number of repeats on theallele with the smaller expansion accounts for approximately50 percent of the variability in age at onset, as compared withless than 20 percent for the allele with the larger expansion.Individual variations are large, however, and more than 30 percentof the variance results from unknown factors, so that the predictivevalue of expansion size is limited.
Autosomal recessive inheritance suggests that the mutation resultsin a loss of function. This view is supported by the observationof greatly decreased levels of the frataxin transcript in lymphoblastsfrom patients2 and by the fact that in some patients who areheterozygous for the expansion, the other allele carries mutationsthat result in clear loss of function by interfering with thematuration or translation of frataxin messenger RNA (mRNA).The consequence of the expansion in Friedreich's ataxia is similarto that in fragile X syndrome, where absence of the FMR1 mRNA,protein, or both has been demonstrated.18,19 In myotonic dystrophythe expansion is unlikely to create a simple loss of function.If there were a loss of function, one would expect to find pointmutations with similar effects in some patients. In Friedreich'sataxia, the correlation observed between clinical severity andthe size of the expansion in the smaller allele suggests thatsmall expansions do not totally inhibit transcription or maturationof frataxin mRNA and allow substantial residual expression ofthe frataxin protein. Above a certain threshold, probably above700 GAA repeats, the residual expression is too low to influencethe clinical presentation. Consequently, the amount of frataxinis driven mostly by the smaller allele.
Both the number of GAA repeats and the duration of disease affect,in varying proportions, the signs associated with cerebellarataxia. Hypertrophic, most commonly concentric, cardiomyopathyhas been recognized as specific for the diagnosis of Friedreich'sataxia and was present in almost all patients with classic Friedreich'sataxia studied by echocardiography.20 We showed that its frequencyincreases with the size of the GAA expansion, as does the frequencyof the extensor plantar response and skeletal deformities. Thecorrelation of pes cavus and scoliosis with GAA-expansion sizemight reflect the early onset of peripheral neuropathy. Theassociation of cardiomyopathy with large expansions is importantfor prognosis, since complications of cardiomyopathy are a frequentcause of death in Friedreich's ataxia. It also suggests thatalthough frataxin mRNA is highly expressed in the heart, thereis probably a threshold of residual active protein below whichcardiomyopathy appears.
The presence of other signs, such as the extensor plantar responseand weakness and wasting in the lower limbs, was determinedin part by both the number of GAA repeats and the duration ofthe disease, whereas the frequency of dysarthria, decreasedvibration sense, sphincter disturbances or swallowing difficulties,and hearing or visual loss was associated with increased diseaseduration alone. Some of these signs were thought to be crucialfor differential diagnosis, but our results suggest otherwise.Yet unidentified factors may also contribute to the complexphenotype observed in patients with Friedreich's ataxia.
In conclusion, we demonstrated that the spectrum of Friedreich'sataxia is broader than previously thought, with onset between26 and 51 years of age in 14 percent of the patients studiedand retained lower limb reflexes in 12 percent. Friedreich'sataxia is a progressive disease, so a full clinical presentationis observed only several years after onset, a fact that makesit difficult to diagnose the disease early. In Europe and NorthAmerica, most cases are sporadic and occur in nonconsanguineousfamilies. Autosomal recessive inheritance cannot be demonstratedin such cases. Delayed diagnosis, however, impairs genetic counselingfor future pregnancies. Direct molecular diagnosis through determinationof the size of the GAA expansion should become an essentialtool in clinical practice, differential diagnosis, and geneticcounseling for patients with recessive or sporadic cerebellarataxias.
Supported by INSERM, the Centre National de la Recherche Scientifique,the Centre Hospitalier Universitaire de Strasbourg, the AssociationFrançaise contre les Myopathies, the Ministèrede l'Enseignement Supèrieur et de la Recherche, the AssistancePublique–Hôpitaux de Paris, and the Verum Foundationfor Behavior and Environment. Dr. Cossee is the recipient ofa fellowship from the Association Française contre lesMyopathies, and Dr. Campuzano is the recipient of a fellowshipfrom the Ministerio de Educación y Ciencia, Spain.
We are indebted to the families for their participation; tothe Association Française de l'Ataxie de Friedreich andDrs. M. Abada-Bendib, N. Aboujaoude, C. Desnuelle, J.R. Feve,M. Gugenheim, J.P. Harpey, J.M. Mussini, G. Ponsot, and B. Singerfor referring patients; to L. Reutenauer, J. Bou, D. Hillaire,I. Lagroua, C. Musenger, and Y. Pothin for technical help; toProfessor M. Komajda for echocardiographic evaluations; to Dr.S. Laffont for measuring the evoked potentials; and to Dr. P.Bouche for performing the electrophysiologic examinations.
Source Information
From the Fédération de Neurologie and INSERM Unité 289, Hôpital de la Salpêtrière, Paris (A.D., Y.A., C.P., A.B.); the Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg (M.C., V.C., J.-L.M., M.K.); and the Centre Hospitalier Général de Saint-Pierre, Ile de La Réunion (C.M.) — all in France.
Address reprint requests to Dr. Brice at INSERM Unité 289, Hôpital de la Salpêtrière, 47 Blvd. de l'Hôpital, 75651 Paris CEDEX 13, France.
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Genetic Abnormalities in Friedreich's Ataxia
Dutka D. P., Nunez D. J.R., Filla A., De Michele G., Cocozza S., Madhani H. D., Dürr A., Brice A., Koenig M., Rosenberg R. N.
Extract |
Full Text
N Engl J Med 1997;
336:1021-1023, Apr 3, 1997.
Correspondence
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