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Keywords:

  • Hypophosphatasia;
  • prevalence;
  • mutation database;
  • dominant inheritance

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest
  9. References

The prevalence of hypophosphatasia (HP), a rare metabolic disorder due to loss-of-function mutations in the ALPL gene, has never been estimated in the European population. Only one published study evaluated the incidence of severe HP at 1/100,000 in Canada 53 years ago. Moderate forms of hypophosphatasia (mHP), including HP with moderate bone features and the mildest form odontohypophosphatasia, reflect both recessive and dominant inheritance, and are therefore expected to be more frequent than severe forms of HP. Here we estimated both the prevalences of severe and mHP in European populations. The prevalence of severe HP was estimated at 1/300,000 on the basis of the number of cases tested in our laboratory and originating from France during the period 2000–2009. The prevalence of mHP was then estimated by using the proportion of dominant mutations among severe alleles and by estimating the penetrance of the disease in heterozygotes for dominant mutations. According to a genetic model with four alleles resulting in 10 distinct genotypes, the prevalence of dominant mHP in the European population was estimated to be 1/6370, pointing out that mHP is much more frequent than severe HP.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest
  9. References

Hypophosphatasia (HP) is a heritable disorder characterized by defective bone and teeth mineralization and a deficiency of tissue-nonspecific alkaline phosphatase activity (TNAP). Despite a continuum of severity, six clinical forms are currently recognized, depending on the age at diagnosis and the severity of the symptoms: perinatal, prenatal benign, infantile, childhood, adult, and odontohypophosphatasia, this latter form occurring in either childhood or adulthood (see for review (Whyte, 1994, Mornet, 2008)). The disease is due to more than 200 mutations in the ALPL gene (OMIM 171760) (Mornet, 2010).

Autosomal dominant transmission of HP has been shown on the basis of pedigree and laboratory data (Whyte et al., 1979; Whyte et al., 1982; Eastman & Bixler, 1983; Eberic et al., 1984; Moore et al., 1999), and mutations responsible for this condition were identified (Hu et al., 2000; Muller et al., 2000; Lia-Baldini et al., 2001; Lia-Baldini et al., 2008). Severe forms of HP, primarily perinatal and infantile, are inherited in an autosomal recessive manner. Moderate forms (mHP), primarily prenatal benign, childhood, adult, and odontohypophosphatasia, mostly result from heterozygosity for dominant severe alleles or from compound heterozygosity for severe and moderate alleles, and more rarely from two moderate alleles (Fauvert et al., 2009). These moderate alleles were defined on the basis of clinical status and/or transfection studies. When tested in vitro, moderate alleles produce significant residual alkaline phosphatase activity, while severe alleles do not usually have enzymatic activity (Fukushi et al., 1998; Zurutuza et al., 1999; Orimo et al., 2001; Watanabe et al., 2002; Ishida et al., 2003; Brun-Heath et al., 2005; Watanabe et al., 2005; Collmann et al., 2009; Reibel et al., 2009). We previously reported that in odontohypophosphatasia, a mild form when compared to other moderate forms, 74% of the patients were heterozygous for an ALPL gene mutation, and only 26% carried two mutations (Fauvert et al., 2009).

Only few previous studies dealt with HP prevalence. In 1957, the birth prevalence of severe HP was estimated to be 1/100,000 on the basis of pediatric records of the Hospital for Sick Children in Toronto (Fraser, 1957). This value is usually cited in the literature. However, the population studied originated from Toronto, Canada, a population presumably of British ancestry, and therefore probably not reflecting the European population. The prevalence of HP in the Mennonite Canadian population was shown to be high because of a founder effect (Greenberg et al., 1993; Orton et al., 2008), perhaps up to 1/2500 (Greenberg et al., 1990). In Japan, the prevalence of HP due to the homozygous mutation c.1559delT that represents 41% of HP alleles (Michigami et al., 2005), was estimated at 1/900,000 (Watanabe et al., 2010). In Americans with African ancestry HP seems to be extremely rare (Whyte et al., 2006).

The prevalence of mHP has never been estimated. Its estimation is challenging because the symptoms may escape notice and the disease may therefore remain undiagnosed. However, the prevalence of mHP is expected to be higher than the prevalence of severe HP due to the number of patients with dominant forms (and therefore heterozygous), and because moderate alleles are expected to be subject to low selective pressure.

We provide here both an estimation of the birth prevalence of severe HP and a minimum estimation of the birth prevalence of mHP in European populations. We found that the prevalence of severe HP is less common than previously reported in Canada and that the prevalence of mHP is nearly 50 times higher than severe HP.

Material and Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest
  9. References

Informed consent was obtained from each tested patient before the study.

Prevalence of Severe HP

The prevalence of severe HP was estimated on the basis of the number of cases originating from France tested in our laboratory during the last 10 years (2000–2009), and on the basis of the number of cases originating from 20 other European countries, during the same period, namely Austria, Belgium, Croatia, Czech Republic, Denmark, Finland, Germany, Greece, Hungary, Ireland, Italy, Lithuania, Netherlands, Norway, Poland, Portugal, Spain, Sweden, Switzerland, and United Kingdom. Our laboratory is the only one in France to perform molecular testing of HP and we may assume that, during this period, most of the severe cases were diagnosed and sent to us for molecular testing. For other European Union countries, some patients may have been tested elsewhere. Prenatal tests were not included in the study.

Severity of Mutations

All the ALPL mutations studied here were discovered in European patients. Their severity was determined by using different approaches. In homozygotes, the clinical form was directly deduced from the clinical symptoms and the age at diagnosis. In compound heterozygotes affected with severe forms, we assumed that each mutation composing the genotype was severe because the presence of a moderate allele was expected to provide enough residual enzymatic activity to rescue the severe phenotype (Zurutuza et al., 1999). Some mutations were confirmed by site-directed mutagenesis. In a few cases, however, patients with alleles classified as moderate exhibited a severe phenotype, probably because in vitro studies did not reflect the effect of these mutations, or perhaps because of the effect of polymorphisms in ALPL (Sogabe et al., 2008) or in other genes contributing to the regulation of bone metabolism. In some compound heterozygotes affected with moderate forms, the mutations were studied by site-directed mutagenesis in order to determine both their capacity to product residual enzymatic activity and their possible dominant effect (Fauvert et al., 2009). For all the missense mutations, we also used a metasearch engine developed in our laboratory that takes into account the results provided by three of the main predictive tools available online, SIFT (Ng & Henikoff, 2003), Pmut (Ferrer-Costa et al., 2005), Polyphen (Ramensky et al., 2002), and the experimental data provided by our laboratory or by the literature. This tool is available at the web address http://www.sesep.uvsq.fr/03_hypo_00_hpred_form.php

Dominant Effect of Mutations

The dominant-negative effect of 26 missense mutations resulting in severe alleles was previously shown in vitro by site-directed mutagenesis (Lia-Baldini et al., 2008; Fauvert et al., 2009). These mutations were selected because they were found to be heterozygous in patients affected with mHP.

Recurrence of Severe Alleles

Because the recurrence of mutations necessarily affects the relative proportions of recessive severe alleles and dominant severe alleles, respectively, we took into account the recurrence rate of each mutation. The recurrence rate was calculated by using the number of times a mutation was found in our sample of 101 European patients affected with severe HP and studied during the period of 2000–2009.

Penetrance in Dominant Forms of HP

The mean penetrance was calculated in a sample of 66 parents and relatives of heterozygous patients affected with mHP and for whom the presence of the mutation was shown by sequencing. Affected/non affected status in parents was reported by either the referring clinician or the geneticist, but in most cases a careful clinical survey was not performed.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest
  9. References

Prevalence of Severe HP in France

During the last 10 years (2000–2009) we diagnosed 65 cases of HP of French origin, of which 26 were affected with severe HP (16 with perinatal and 10 with infantile forms). Assuming 770,000 births a year in France (Sardon, 2006), the prevalence of severe HP may be estimated to 26/(10 × 770,000) = 3.4 10−6= 1/297,000.

So the prevalence of severe HP in France was estimated to be lower than the value of 1/100,000 reported by Fraser (1957) in the Canadian population. The founder effect in the Canadian Mennonite population (Greenberg et al., 1993; Orton et al., 2008) probably explains the higher prevalence reported in Fraser's study.

During the same period (2000–2009), we diagnosed 119 cases of HP in the 20 other EU countries from which we received samples to test; among them 75 were affected with severe HP (47 with perinatal and 28 with infantile forms). Assuming 4,030,000 births a year in these countries (Sardon, 2006), the prevalence of severe HP may be estimated to 75/ (10 × 4,030,000) = 1.9 10−6= 1/538,000. However, there is a discrepancy between North and West Europe where the prevalence was similar to France (62/(10 × 2,264,000) = 2.7 10−6= 1/366,000), and South and East Europe where the prevalence was somewhat lower (13/[10 × 1,766,000]= 7.4 10−7= 1/1,358,000) (Table 1). It is not clear whether the difference is due to variable distribution of allelic frequencies or to the possibility that the countries of South and East Europe did not systematically request mutation testing of their patients (see discussion).

Table 1.  Estimated prevalences of severe HP in European countries on the basis of molecular tests between 2000 and 2009 in our laboratory.
AreaSevere HP cases over 10 yearsNumber of births (Sardon, 2006)aEstimated prevalence
  1. aRounded numbers of births in 2004 were considered.

France26770,0001/297,000
North Europe391,487,0001/337,000
West Europe (UK and Irland)23777,0001/339,000
South and East Europe131,766,0001/1,358,000
Total1014,800,0001/476,000

Because we had the completeness of the molecular test during this period in France, we finally considered that the best estimation of the prevalence in Europe was based on the French patients.

Classification of ALPL Alleles

We classified the ALPL gene mutations into three groups: severe alleles without dominant effect (a1), moderate alleles (a2), and severe alleles with dominant effect (a3). We may therefore consider that there are four distinct alleles of the ALPL gene in the population: A (normal), a1, a2, and a3. These four alleles may result in 10 genotypes and three phenotypes (Table 2). Assuming that the population matches Hardy–Weinberg equilibrium, we may ascribe to each of the genotypes a frequency equal to the product of allelic frequencies p (allele A), q1 (allele a1), q2 (allele a2), and q3 (allele a3) (Table 2), with the following equation:

  • image
Table 2.  Genotypes, phenotypes and genotype frequencies in the population according to our allele classification. A: normal allele; a1 severe allele without evidence of dominant-negative effect; a2: moderate allele; a3: severe allele with dominant-negative effect.
GenotypeGenotype frequencyPhenotype
A/Ap2Normal
A/a12pq1 
A/a22pq2 
A/a32pq3Moderate
a1/a22q1q2 
a2/a2q22 
a2/a32q2q3 
a1/a1q12Severe
a1/a32q1q3 
a3/a3q32 

Estimation of Prevalence in mHP

According to our estimation of the prevalence of severe forms in France (1/297,000), we may assume that (q12+ 2q1q3+ q32) = (q1+ q3)2= 1/297,000, where q1 and q3 are the allele frequencies of severe recessive and severe dominant mutations, respectively. Thus, q1+ q3= 1.83 10−3= 1/546.

Among the 26 missense mutations shown to have a dominant-negative effect, 16 were detected in Europe and represent 16.3% of the 98 severe recessive and severe dominant alleles in the ALPL gene. Taking recurrence into account, the total number of severe recessive and severe dominant alleles in the sample was 202, and the proportion of dominant severe alleles was 27/202 = 0.134. Thus we can estimate that 13.4% of severe alleles in HP chromosomes in the European population have a dominant-negative effect.

This means that

  • • 
    q1= 0.866 × 1/546
  • • 
    q3= 0.134 × 1/546

The frequency of heterozygotes carrying a severe dominant allele is therefore

  • image

Penetrance

Among the 38 parents heterozygous for the dominant allele inherited by the index cases, 26 were reported as unaffected and 12 as affected. They mostly suffered from premature loss of teeth in childhood or adulthood, or from slight features such as fractures without obvious cause or sagittal suture synostosis at birth. On the basis of these data, the penetrance for mHP could be estimated at 12/38 = 0.32. When we considered all the 66 relatives of index cases (i.e., parents and other relatives), 38 were unaffected while 28 were affected, resulting in a penetrance value of 28/66 = 0.42. The difference is likely due to a bias of ascertainment in favor of genetic testing of affected siblings versus unaffected siblings. We therefore adopted the value of 0.32 as the best estimation of the penetrance. Thus, the prevalence of patients affected with mHP due to dominant heterozygous mutations may be estimated to 1/2036 × 0.32 ≈ 1/6370 which is 47 times higher than the frequency of patients affected with severe HP (1/297,000).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest
  9. References

Only few studies addressed the prevalence of HP (Fraser, 1957; Greenberg et al., 1990; Whyte et al., 2006; Watanabe et al., 2010) and none comprehensively investigated the European population. In two studies attempting to estimate the prevalence of skeletal dysplasias in France and in Italy, no case of HP was detected among 105,374 births in France (Stoll et al., 1989) and among 217,061 births in Italy (Camera & Mastroiacovo, 1982), which is consistent with our estimation (1/297,000). The observed discrepancy between North-West and South-East Europe may be due to several factors among which are included no suspicion of HP, no request of mutation analysis, and molecular testing in other laboratories than ours, but which may also be due to particular recurrent mutations in North and West Europe reflecting founder effects. Also, it is noticeable that HP is extremely rare in Americans of African ancestry (Whyte et al., 2006), suggesting a strong variability of HP allele frequencies in the world. Identifying the cause of the discrepancy will require additional data from South and East Europe, and detailed breakdown of the ethnic background of the tested patients.

In this study, we estimated the prevalence of mHP on the basis of the estimation of the prevalence of severe HP in Europe and on a genetic model with four alleles A, a1, a2, a3, (respectively the so-called normal allele, severe recessive allele, moderate allele, and severe dominant-negative allele), their frequencies being p, q1, q2, and q3. Within this model, mHP is expected to be more frequent than severe HP because heterozygotes for a severe dominant allele may express the disease.

The part of mHP due to dominant mutations alone represents 47 times the frequency of severe HP with a prevalence of 1/6370, suggesting that, as previously conjectured (Taillard et al., 1984; Mornet, 2007; Moulin et al., 2009), many cases of mHP may be undiagnosed. This part, however, mostly includes the less severely affected patients, especially those with odontohypophosphatasia. In our experience 75% of patients with odontohypophosphatasia are heterozygous (Fauvert et al., 2009). It is possible that many adult patients with ondontohypophosphatasia were diagnosed with periodontitis, a common disease that shares with HP similar symptoms such as compromised attachment and early loss of teeth. According to the literature, loss of attachment affects up to 19% of the adult population between 35 and 64 years, 2.6% of males and 1.5% of females between 35 and 45 years (Bouchard et al., 2006) and periodontitis is the most frequent cause of tooth extraction for people over 40 years of age (Reich & Hiller, 1993). In addition the association between HP and periodontitis is documented (Baab et al., 1986; Watanabe et al., 1993; Plagmann et al., 1994; Watanabe et al., 1999) although still controversial (Machtei et al., 1994; Valenza et al., 2006; Reibel et al., 2009).

However, it remains also possible that we overestimated the prevalence of dominant mHP because its calculation is based on multiple estimated parameters (prevalence of severe HP, proportion of dominant mutations, penetrance), thereby introducing multiple possible inaccuracies. Notably, our estimation of the penetrance is based on reports including specific signs such as premature loss of teeth during childhood, but also nonspecific signs such as loss of teeth during adulthood, fractures or sagittal suture synostosis at birth. We may therefore overestimate the penetrance by assigning the affected status to parents with another condition, especially periondontitis. In addition, parents with more severely affected children are more likely to be tested than parents with less severely affected children, which may also artificially increase the penetrance value.

The part of mHP due to recessive HP is dependent on q2, (Fig. 1) which could not be easily estimated. However, the selective pressure against moderate alleles is expected to be low and therefore q2 may be higher than q1 and q3. Corroborating this hypothesis, recessive mHP patients represent 58% of mHP patients tested in our laboratory, a proportion attributable to both the high frequency of q2 and the better detection of patients generally more affected than in dominant forms.

image

Figure 1. Frequency of mHP as a function of q2, the frequency of moderate alleles. When q2= 0, the frequency of mHP is only due to heterozygotes for dominant alleles (1/6370 = 1.57 10−4). When q2≠ 0, the frequency of mHP is inline image

Download figure to PowerPoint

In the absence of any prior epidemiologic study, our present work provides an estimation of the prevalence of both severe HP and mHP in European populations, and shows that the prevalence of mHP is much higher than that of severe HP. The results are of importance for the management of patients with premature and spontaneous loss of teeth alone without any history of trauma, for whom the diagnosis of HP should be considered (Mornet et al., 2010). In terms of genetic counseling, our estimate of the prevalence of severe HP in the European population should improve the accuracy of risk assessments in pedigrees.

Acknowledgments

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest
  9. References

We thank Dr Pierre Darlu (INSERM U545, Epidémiologie génétique et structure des populations, Villejuif, France) and Pr. Agnès Bloch-Zupan (Centre de référence des manifestations odontologiques de maladies rares, Strasbourg, France) for helpful discussion.

The authors would like to thank the many clinicians and geneticists who gave us the opportunity to test the patients: Y. Alembik, S. Amarri, D.J. Aughton, M. Badura-Stronka, Z. Ban, A. Baroncini, C. Baumann, C. Beck, J. Berger, P. Berlettani, J. Bergoffen, E. Bieth, E.K. Bijlsma, P. Blanchet, O. Blankenstein, G. Calcagno, G. Cambonie, F. Carvalho, M. Cazzato, B. Casey, K. Chandler, C. Chombart, J. Claesson, J. Clayton-Smith, A. Collins, J.A. Cook, MP Cordier, V. Cormier-Daire, J.C. Cuvellier, A.M. Das, R. Day, F. Debiais, S. Delanote, H. Dollfus, T. Duelund, R. Ensenauer, F. Fourches, P. Freisinger, A. Fryer, JP. Fryns, L. Garavelli, J. Gastier-Foster, M. Gerard-Blanluet, B. Gilbert-Dussardier, Y. Gillerot, H. Girschick, A. Goldenberg, C. Gonzalez Armengod, C.A. Graham, I. Grochova, K. Hämmerle, J. Hersh, U. Hladnik, H. Hoey, K. Horton, B. Isidor, M. Irving, A. Jackson, R.M. Javier, C. Jern, C. Johansson, M. Kabus, M. Kassem, K. Keppler, M. Klehr-Martinelli, S. Körtge-Jung, D. Kotzot, W. Kreß, V.K.A. Kumar, H. Laivuori, A. Larget-Piet, J. Lastuvkova, V. Layet, D.J. Lefeber, B. Leheup, M. Le Merrer, S.A.J. Lesnik Oberstein, M. Lund, I. Liebaers, H. Malmgren, C. Marcelis, M. Mathieu, G. Matthijs, R. McGowan, S. McKee, C. McKeown, C. King, A. Meldgaard Lund, S. Mehta, K. Metcalfe, J. Morton, P. Moulin, H. Mulder, G. Muller, S. de Munnik, M. Nunes, C. Oley, A. Pearn, D. Petkovic, T. Prescott, F. Prieur, N. Quercia, Reibel A., W. Reardon, S. Robertson, E. Roche, S-L Sallinen, P. Sarda, G. Scarano, H. Schmidt, M. M. Schmidt, D. Schnabel, S. Sharif, S. Smithson, B. Steinmann, M. Stuhrmann-Spangenberg, A. Superti-Furga, S. Taffinder, C. Taylor, V. Tokic, S. Tomkins, V. Tsikrika, S. Unger, A. Utkus, I. van der Burgt, P.C. Vasudevan, V. Ventura, A. Verloes, S. Vignola, T. Voigtländer, B.B.A. de Vries, O. Wagner, R. Wallerstein, J.L. Whittaker, M. Willing, R. Winder, I. Witters, L. Zelante.

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  1. Top of page
  2. Summary
  3. Introduction
  4. Material and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Conflict of Interest
  9. References
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