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Archives de pédiatrie
Volume 24, n° 5S2
pages 549-550 (mai 2017)
Doi : 10.1016/S0929-693X(18)30013-7
Hypophosphatasia: better knowledge for better care…
Hypophosphatasie : mieux comprendre pour mieux soigner…
 

J.-P. Salles 1, 2, , A. Linglart 3, 4
1 Centre de référence pour les maladies rares du métabolisme du calcium et du phosphate, filière OSCAR, unité d’endocrinologie, maladies osseuses, génétique et gynécologie, hôpital des enfants, CHU de Toulouse, TSA 70034, 31059 Toulouse Cedex 09, France 
2 INSERM UMR 1043, centre de physiopathologie de Toulouse-Purpan, CPTP, université de Toulouse Paul-Sabatier, 31059 Toulouse, France 
3 AP-HP, Centre de référence pour les maladies rares du métabolisme du calcium et du phosphate, filière OSCAR, Plateforme d’Expertise Maladies Rares Paris-Sud, and service d’endocrinologie pédiatrique hôpital Bicêtre Paris-Sud, Le Kremlin-Bicêtre, France 
4 INSERM U1169, hôpital Bicêtre, Le Kremlin-Bicêtre, université Paris-Saclay 

*Corresponding author.

In biology and medicine nothing would exist without biochemistry. This was stressed in 1997 by Arthur Kornberg, who won a Nobel prize in 1959 for his contribution to the elucidation of nucleic acid synthesis pathways [1]. He also highlighted the fact that enzymatic activity is one of the most active functions of biochemistry. However it is striking to observe that for many enzymes numerous mysteries still persist with regard to their activities in various tissues and their substrates.

The activity of alkaline phosphatase, a hydrolase that cleaves a phosphoester bond releasing a hydroxyl group and phosphate at optimum alkaline pH, is ubiquitous in the animal kingdom. In man, four genes contribute to that activity. The gene responsible for nontissue specific activity (Alkaline Phosphatase-Liver [ALPL], also known as Tissue-Nonspecific Alkaline Phosphatase [TNSALP]) produces an enzyme that is particularly active in the bones, liver, kidneys and developing teeth. The gene’s products constitute a series of isoforms that only differ in terms of post-translational modifications. While ALPL is strongly expressed in the liver (hence its name) its role in that organ remains unknown. The enzyme’s biological impact in mineralized tissues has been much more clearly defined.

In 1948, the Canadian physician John C. Rathbun assigned the name hypophosphatasia (HPP) to a developmental abnormality observed in a child aged 2 years who died of a disease that mimicked rickets and seizures with, paradoxically, low plasma alkaline phosphatase activity [2]. Rathbun also observed that the patient presented with high plasma calcium and phosphate levels, the opposite of what is observed in calcium and/or vitamin D deficiency-induced rickets, which is characterized by insufficient mineral binding in the skeleton due to low availability of calcium and phosphate. It was therefore suggested that a primary enzymatic deficiency in phosphate ester hydrolysis, responsible for deficient mineralization, underlies HPP. The hydrolysis function involved in mineralization had been postulated by Robert Robison in 1923 when he reported an enzymatic activity releasing inorganic phosphate [3]. Subsequently, in 1953, the genetic nature of HPP, involving the enzyme TNSALP, and the early loss of deciduous teeth as a cardinal sign of the disease, were established [4].

Numerous biochemical and structural studies, together with murine knockout models, have since enabled further elucidation of the role of TNSALP. The latter is an ectoenzyme found on the plasma membrane of cells involved in the mineralization process. The hydrolysis of inorganic pyrophosphate by TNSALP associated with collagen fibrils, is essential for the availability of the phosphate necessary for mineralization in the environment of the osteoblasts and chondrocytes of the growth plate and acellular cement. The enzyme is also involved in the metabolism of vitamin B6, with pyridoxal phosphate as substrate [4]. However, the importance of other substrates and the role of TNSALP in non-mineralized tissues remains largely unknown.

HPP provides an example of a human enzyme-genetic deficiency that has long been known and for which gradual progress in our understanding of its pathophysiology has enabled development of a promising biotherapy. HPP also provides an example of a particularly short translation lag (interval between the proof of concept of a new therapy and its clinical application in man). Alkaline phosphatase infusions derived from the plasma of patients presenting with Paget’s disease of bone had previously been shown to be ineffective [5]. In 2008, the proof of concept of the efficacy of a recombinant enzyme pre-modified to target bone tissue (addition of a fragment Fc of immunoglobulin G1 [IgG1] and a decaaspartate motif enabling bonding to hydroxyapatite) was demonstrated in a murine model in which the gene for TNSALP had been knocked out [6]. In 2012, the results of an initial clinical trial demonstrating clinical and radiological efficacy in infants and young children presenting with fatal forms of HPP were published [7].

In that historical context, we devote this edition to addressing the pleomorphism of HPP, defined as an ‘ultra-rare’ disease.

We address the genetic definition of HPP and its diagnostic through the biochemistry. We also describe the major clinical forms from the antenatal period to adulthood. The clinical expression of HPP is extremely variable and we have chosen to highlight major complications, which, particularly during childhood, may lead to diagnosis (including craniosynostosis, muscular features and renal impairment. We have also invited patients to voice their opinions to illustrate the trajectories of rare diseases, including errance and diagnostic difficulties, the difficulty of making useful contacts, and the shortage of institutions able to respond adequately to patients’ needs.

The advent of a new effective therapy will doubtless revolutionize our behavior. Announcement of the diagnosis, based on genetics, will now have to be weighed up carefully. Making or rejecting a diagnosis will have consequences for symptomatic children. The patients who have been identified are doubtless the tip of the iceberg. The adult patients presenting with HPP are those who grew up with a severe infantile or juvenile form of the disease, but also, more numerous, those who were not diagnosed. How many new patients with HPP will now be recognized? But also, how many can or should be treated? The involvement of the national and international rare diseases networks is essential, with the patients’ assistance, to document the natural history of the disease and elucidate the impact of new treatments. Their involvement will enable enhanced definition of treatment modalities and the design of new studies to elucidate further and understand better the short- and long-term effects of enzyme replacement therapy.

While the enzyme has long been known, gaps in our knowledge persist. What are its substrates in the brain. Where is it expressed?

Does it contribute to neurological manifestations that, for the time being, are poorly defined? Does it contribute directly to muscular manifestations or are those manifestations the consequences of skeletal abnormalities? Will therapy targeting mineralized tissues be decisively effective with regard to those symptoms? Arthur Kornberg recommended paying special attention to the role of enzymes in neuropsychological functions, an aspect that has been little explored in the context of HPP [1].

Practitioners need to be aware of HPP, know when to suspect it and diagnose it, and refer patients to the reference centers so that those questions can be resolved in the future. The objective of this edition is thus simply to promote awareness of HPP so that it can be diagnosed better and treated better, as early and as quickly as possible.


Acknowledgments

Jean-Pierre Salles would like thank Prof. Hugues Chap for his input on the historical perspectives of biochemistry, and Dr. Pierre Moulin for his presence during the first steps into the terra incognita of HPP, and Françoise Conte-Auriol for her support in clinical trials.

Statements of interests

Jean-Pierre Salles and Agnès Linglart have received fees from Alexion Pharmaceuticals for occasional interventions and expert reviews, and have been or are principal investigators or investigators in clinical trials sponsored by the company.

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References

Kornberg A. Centenary of the birth of modern biochemistry Trends Biochem Sci 1997 ;  22 : 282-283 [cross-ref]
Rathbun J.C. Hypophosphatasia: a new developmental anomaly Am J Dis Child 1948 ;  75 : 822-831 [cross-ref]
Robison R. The possible significance of hexosephosphoric esters in ossification J Biol Chem 1923 ;  17 : 286-293 [cross-ref]
Whyte M.P. Hypophosphatasia – aetiology, nosology, pathogenesis, diagnosis and treatment Nature Rev Endocrinol 2016 ;  12 : 1-14
Whyte M.P., McAlister W.H., Patton L.S., Magill H.L., Fallon M.D., Lorentz W.B., and al. Enzyme replacement therapy for infantile hypophosphatasia attempted by intravenous infusions of alkaline phosphatase-rich Paget plasma: results in three additional patients J Pediatr 1984 ;  105 : 926-933 [cross-ref]
Millán J.L., Narisawa S., Lemire I., Loisel T.P., Boileau G., Leonard P., and al. Enzyme replacement therapy for murine hypophosphatasia J Bone Miner Res 2008 ;  23 : 777-787
Whyte M.P., Greenberg C.R., Salman N.J., Bober M.B., McAlister W.H., Wenkert D., and al. Enzyme-replacement therapy in life-threatening hypophosphatasia N Engl J Med 2012 ;  366 : 904-913 [cross-ref]


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