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Abstract
Background Friedreich's ataxia (FA), the most common inherited ataxia, is associated frequently with cardiac hypertrophy, and death is often cardiac related. Recently, the disease has been associated with a mutation that consists of an unstable expansion of GAA repeats in the first intron of the gene encoding frataxin on chromosome 9.
Methods and Results We studied 44 consecutive patients with FA, determined the size of GAA expansions in the frataxin gene, and examined the relation between the genotype and cardiac phenotype assessed by M-mode and two-dimensional echocardiography. All the patients were homozygous for the mutation. The size of the GAA expansion on the smaller allele varied from 270 to 1200. We found a correlation between the size of GAA expansion and the left ventricular wall thickness (r=.51, P<.001) and the left ventricular mass index (r=.45, P=.002). Left ventricular hypertrophy was observed in 81% of patients with a number of GAA repeats above the median value of 770 compared with only 14% in the other group (P=.002).
Conclusions These data demonstrate that in FA, the severity of left ventricular hypertrophy is related to the number of GAA repeats. These results suggest that abnormalities of the gene encoding frataxin, a protein of unknown function highly expressed in the normal heart, may play an important role in the modulation of cardiac hypertrophy.
Friedreich's ataxia is the most prevalent autosomal recessive ataxia and is characterized by degeneration of the posterior columns and the corticospinal and the posterior spinocerebellar tracts.1 Clinical features include ataxia of all four limbs, cerebellar dysarthria, loss of tendon reflexes, sensory loss, and skeletal deformities.1 FA is associated frequently with hypertrophic cardiomyopathy, and cardiac involvement is often the cause of death.1 2 3 4 5 6 7 In 1988, the locus of the genetic defect was found to be localized on chromosome 9.8 Recently, the gene responsible was identified and shown to encode a 210–amino acid protein, frataxin.9 Frataxin is a protein of unknown function and is highly expressed in the normal heart.9 Most of the mutations have been found to be unstable expansions of GAA trinucleotide repeat in the first intron.9 In two recent studies, the size of the GAA expansion has been associated with patient age at onset and clinical severity of the disease.10 11
The aim of the present study was to examine whether the degree of LVH is related to the genetic background.
Methods
Patients
From April 1992 to May 1996, we studied 44 patients with FA (mean age at examination, 28±9 years; 19 men and 25 women) referred to our echocardiography laboratory and 20 age-matched control subjects (mean age at examination, 30±8 years; 11 men and 9 women, NS) without prior history of cardiovascular disease and with normal cardiac examination. Patients belonged to 39 unrelated families and were classified as typical (n=38) or atypical (n=6) cases of FA on the basis of the essential diagnostic criteria of Harding as previously described.1 10 Mean age at the onset was 13±5 years (range, 3 to 28). The 5 related patients belonged to 5 unrelated families.
Echocardiographic Study
Echocardiographic examinations were performed by a senior echocardiographer on a Kontron Instruments Sigma 1 device. M-mode recordings guided by two-dimensional cross-sectional planes were carried out according to the American Society of Echocardiography.12 LVSF, LVM, and LVMi were calculated according to classic formulas.13 Abnormal LV systolic function was defined as LVSF <25%. Since most of our patients were <40 years old, we defined LVH when maximal LV wall thickness exceeded 95% prediction limits of normal according to Henry's nomograms.14
GAA-Repeat Analysis
GAA repeats were analyzed by Southern blotting of BsiHKAI-digested DNA, which yields a 2.4-kb normal fragment containing exon 1 of frataxin, as described elsewhere.10 According to the previous studies, patients were considered homozygous when a GAA expansion was present on the two alleles irrespective of the length of the expansion on these two alleles and heterozygous when a GAA expansion was found on one allele and a point mutation on the other allele.10 11
Statistical Analysis
Means are given with standard deviations. Comparisons between groups were performed with the use of Student's t test, and frequencies were compared with the use of the χ2 and Yates' corrected χ2 test when necessary. Regression coefficients were calculated between the number of GAA repeats and the echocardiographic parameters with the use of a linear model.
Results
Characteristics of the Patients
The clinical characteristics of the patients are summarized in Table 1.⇓ All the patients were homozygous for the GAA expansion; the mean number of GAA repeats on the two alleles is given in Table 1.⇓ No patients had systemic hypertension or aortic stenosis.
Echocardiographic Findings
The main results are summarized in Table 2.⇓ When compared with a normal age-matched population, VST, PWT, and LVMi were significantly higher in FA patients (VST, 11.4±3.2 versus 7.5±0.7 mm; PWT, 10.5±2 versus 7.8±0.7 mm; both P<.001; LVMi, 119±49 versus 88±11 g/m2; P<.01). Seventeen patients (39%) had LVH according to Henry's nomograms.14 Only 5 patients had an asymmetrical hypertrophy on the basis of VST/PWT ratio >1.3. All except 2 patients had normal LV systolic function.
Correlation of LVH With GAA Expansion Size
We found a significant correlation between the size of the smaller GAA expansion and VST (r=.51, P<.001) (Figure⇓), PWT (r=.45, P=.002), and LVMi (r=.45, P=.002). A weaker but significant correlation was also observed when VST and LVMi were plotted against the length of the longer allele. Five of the 44 patients were related, but all belonged to 5 unrelated families; excluding these 5 patients from the analysis did not affect the correlations between GAA expansion and VST (r=.51, P<.001), PWT (r=.46, P<.003), and LVMi (r=.45, P<.004).
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Correlation between the number of GAA repeats on the smaller allele on the x-axis and the VST on the y-axis in 44 patients with FA who are homozygous for the GAA expansion (r=.51, y=5.67+0.0078x, P<.001).
VST, PWT, and LVMi were higher in patients with a number of GAA repeats above 770 (median value of our population) than in the other patients (Table 3).⇓ Consequently, the frequency of LVH was higher in the former than in the latter group (81% versus 14%, P=.002). However, even patients with a number of GAA repeats below 770 had higher LV wall thickness and LVMi than age-matched control subjects (VST, 10.3±2.4 versus 7.5±0.7 mm; PWT, 9.8±1.4 versus 7.8±0.7 mm; both P<.001; LVMi, 105±55 versus 88±30 g/m2; P=.031). No differences were observed in LVSF between the two groups, although the two patients with a decrease of LVSF had a number of GAA repeats of 970 and 1030 on the smaller allele.
Discussion
Cardiac involvement in FA is a common finding and is characterized by an increased thickness of the ventricular wall, a normal or small LV cavity, and usually a normal systolic function.1 2 3 4 5 6 7 LVH varies from 28% to 100%1 2 3 4 5 6 7 and is usually symmetrical and concentric. However, during the evolution, an increase of LV diameter and a decrease of LV wall thickness and LV systolic function may occur, especially in patients with prior LVH3 7 ; these may lead to heart failure and death.1 2 3 4 5 6 7 The increased thickness of the ventricular wall is due primarily to myocyte hypertrophy (≈40% greater than normal) and increased fibrosis, which replaces cardiac muscle as the disease progresses.4 Although most of the symptoms in FA are secondary to neuronal degeneration, the heart is usually considered an independent site of primary degeneration. In fact, in our study, no patient had hypertension or aortic stenosis, which could have explained the LVH.
The gene involved in FA has been identified recently.9 It encodes a 210–amino acid protein of unknown function named frataxin. Northern blot analysis reveals that a prominent site of expression of frataxin mRNA is the heart and that the mRNA is also expressed in the other primary sites of degeneration in FA (spinal cord and pancreas).9 Furthermore, patients with FA exhibit a decreased level of frataxin mRNA in lymphoblasts when compared with carriers or unrelated control subjects.9 These observations suggest that the intronic GAA expansion results in a defect in RNA synthesis or processing, which is expected to lead to a decreased expression of frataxin protein. This finding suggests that FA cardiomyopathy results from intrinsic degeneration. However, demonstration of decreased cardiac tissue levels of the frataxin protein and/or the corresponding mRNA is required to confirm this hypothesis.
Recently, a relation has been reported between the size of the GAA expansion and the clinical severity of the disease assessed by patient age at onset, disease progression, frequency of cardiac involvement,10 11 and frequency of diabetes.11 In the present study, we showed that LV wall thickness and LVM are related to the number of GAA repeats on the smaller allele. However, the number of GAA repeats accounts for ≈25% of wall thickness variability. Individual variations were large, and other unknown factors may interfere, making the predictive value of GAA expansion size limited. Furthermore, even patients with a number of GAA repeats below the median value of our population had a greater wall thickness than age-matched control subjects. These data taken together suggest that there is no all-or-none effect related to a threshold expansion size, as is the case in the fragile X mental retardation syndrome.15 Rather, our findings would favor a continuous relationship between GAA repeat length and LVM, as, for instance, the relation observed between the number of CTG trinucleotide repeats and the severity of cardiac conduction abnormalities in myotonic dystrophy.16
Since the function of frataxin is unknown, the mechanism by which the hypothesized decrease in frataxin amounts within the heart may result in LVH remains unclear. However, important biochemical abnormalities have been found in patients with FA, including abnormalities in the pyruvate metabolism and deficiency in the mitochondrial malic enzyme.17 18 Since phylogenetic conservation of frataxin down to yeast and gram negative bacteria suggests that frataxin is a mitochondrial protein,19 a working hypothesis is that LVH may be related to a compensatory phenomenon secondary to a defect in energy supply, as observed in mitochondrial myopathy.20
Conclusions
The cardiac phenotype-genotype correlation established in this work might provide new insights regarding the pathophysiology and the prognosis of the disease. Obviously, further functional studies are needed to elucidate the precise mechanisms underlying the relationship between LVH and the loss of frataxin within the myocardium in FA.
Selected Abbreviations and Acronyms
| FA | = | Friedreich's ataxia |
| LV | = | left ventricular |
| LVH | = | LV hypertrophy |
| LVM | = | LV mass |
| LVMi | = | LVM index |
| LVSF | = | LV shortening fraction |
| PWT | = | posterior wall thickness |
| VST | = | ventricular septal thickness |
Acknowledgments
We are indebted to Marc Fiszman and Anne Lombes for fruitful discussions and to Mrs Vachon and the Association Française de l'Ataxie de Friedreich (AFAF) for technical help and financial support.
- Received December 11, 1996.
- Revision received March 10, 1997.
- Accepted March 11, 1997.
- Copyright © 1997 by American Heart Association
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