Mild hypophosphatasia may be twice as prevalent as previously estimated: an effective clinical algorithm to detect undiagnosed cases

Abstract

Objectives Since the prevalence of hypophosphatasia (HPP), a rare genetic disease, seems to be underestimated in clinical practice, in this study, a new diagnostic algorithm to identify missed cases of HPP was developed and implemented. Methods Analytical determinations recorded in the Clinical Analysis Unit of the Hospital Universitario Clínico San Cecilio in the period June 2018 – December 2020 were reviewed. A new clinical algorithm to detect HPP-misdiagnosed cases was used including the following steps: confirmation of persistent hypophosphatasemia, exclusion of secondary causes of hypophosphatasemia, determination of serum pyridoxal-5′-phosphate (PLP) and genetic study of ALPL gene. Results Twenty-four subjects were selected to participate in the study and genetic testing was carried out in 20 of them following clinical algorithm criteria. Eighty percent of patients was misdiagnosed with HPP following the current standard clinical practice. Extrapolating these results to the current Spanish population means that there could be up to 27,177 cases of undiagnosed HPP in Spain. In addition, we found a substantial proportion of HPP patients affected by other comorbidities, such as autoimmune diseases (∼40 %). Conclusions This new algorithm was effective in detecting previously undiagnosed cases of HPP, which appears to be twice as prevalent as previously estimated for the European population. In the near future, our algorithm could be globally applied routinely in clinical practice to minimize the underdiagnosis of HPP. Additionally, some relevant findings, such as the high prevalence of autoimmune diseases in HPP-affected patients, should be investigated to better characterize this disorder.

Systemic effects of hypophosphatasia characterization of two novel variants in the ALPL gene

“…reevaluated the prevalence of mild HPP in Europe (1/2,430), which aligned with the prevalence we observed in Spain ( 5 ). Nevertheless, our most recent study, published in 2023, has revealed a new estimate for mild HPP prevalence in Spain, nearly double the earlier figure (1/1,692 vs. 1/3,100) ( 6 ). During the last 20 years, the perception of this disease has evolved significantly from a rare, recessive, bone disease to a systemic disease with higher incidence than previously reported and dominant inheritance in the mild forms ( 7 ).…”

“…This prevalence represents an incidence of autoimmune diseases 4-10 times higher than that described for the general population (3-8%). Autoimmune diseases found in the patients participants in this study mainly affect bones, skin and circulatory system ( 6 ).…”

Hypophosphatasia: A rare disease with an easy diagnosis and available therapy

“…(2) Novější studie z Evropy nicméně ukazují na značnou poddiagnostikovanost mírnějších forem HPP. (3,4) Nedávná studie ze Španělska ukazuje geneticky potvrzený výskyt HPP u jednoho z 2500 testovaných jedinců. (3) genetiKa Gen ALPL kódující ALP se nachází na 1. chromozomu (lokus 1p36.12) a obsahuje 12 exonů.…”

“…(3,4) Nedávná studie ze Španělska ukazuje geneticky potvrzený výskyt HPP u jednoho z 2500 testovaných jedinců. (3) genetiKa Gen ALPL kódující ALP se nachází na 1. chromozomu (lokus 1p36.12) a obsahuje 12 exonů. (5,6) Dosud bylo popsáno více než 400 patogenních variant genu ALPL, povětšinou jde o missense mutace.…”

Compromised Muscle Properties in a Severe Hypophosphatasia Murine Model

“…There are more than 300 known mutations in the ALPL gene, and HPP has a range of symptoms and pathologies, with more severe forms of the disease presenting earlier in life [2]. HPP is a rare disease, with an estimated prevalence of severe cases ranging from 1/100,000 [3] to 1/300,000 [4], moderate cases at 1/6370 [4] in Europe, and recent estimates of mild case prevalence ranging from 1/3100 [5] throughout Europe to 1/1692 in Spain [6]. A mutated ALPL gene leads to the accumulation of pyridoxal-5 -phosphate and inorganic pyrophosphate, both of which are natural substrates for TNAP.…”