Clinical, biochemical and genetic spectrum of low alkaline phosphatase levels in adults

Riancho‐Zarrabeitia, Leyre; García-Unzueta, Mayte; Tenorio, Jair; Gómez-Gerique, J.A.; Pérez, Víctor L.; Heath, Karen E.; Lapunzina, Pablo; Riancho, José A.

doi:10.1016/j.ejim.2015.12.019

Cited by 59 publications

(50 citation statements)

References 31 publications

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“…Furthermore, the estimated prevalence of ALPL disease-causing variants in these subjects with persistent hypophosphatasaemia was 47%. This means that one out of two subjects with persistent hypophosphatasaemia (secondary causes discarded) had HPP, which is in accordance with the study of Riancho-Zarrabeitia and coworkers [18]. More recently, the study of Mckiernan et al [19] found a higher proportion of subjects with ALPL disease-causing variants (84%), most likely because a more stringent definition of hypophosphatasaemia was used.…”

Section: Discussionsupporting

confidence: 83%

Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia?

Tornero¹,

Navarro-Compán²,

Tenorio

et al. 2020

Orphanet J Rare Dis

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Background: Hypophosphatasia (HPP) is an inborn error of metabolism characterized by low levels of serum alkaline phosphatase (ALP). Scarce evidence exists about features that should signal the potential association between hypophosphatasaemia and HPP in adults. The aim of this study is to estimate the prevalence of ALPL variants in subjects with persistent hypophosphatasaemia and determine the associated clinical and laboratory features. For this cross-sectional study, laboratory records of 386,353 subjects were screened by measurement of ALP activity. A total of 85 (0.18%) subjects with persistent hypophosphatasaemia (≥2 serum alkaline phosphatase-ALP-measurements ≤35 IU/L and none > 45 IU/L) were included (secondary causes previously discarded). ALPL genetic testing and a systematized questionnaire to retrieve demographic, clinical and laboratory data were performed. Descriptive analysis and logistic regression models were employed to identify the clinical and laboratory characteristics associated with ALPL variants. Results: Forty subjects (47%) had a variant(s) in ALPL. With regard to clinical characteristics, the presence of an ALPL variant was significantly associated only with musculoskeletal pain (OR: 7.6; 95% IC: 1.9-30.9). Nevertheless, a trend to present more dental abnormalities (OR: 3.6; 95% IC: 0.9-13.4) was observed. Metatarsal stress fractures were also more frequent (4 vs 0; p < 0.05) in this group. Regarding laboratory features, median ALP levels were lower in subjects with ALPL variants (26 vs 29 IU/L; p < 0.005). Interestingly, the threshold of ALP levels < 25 IU/L showed a specificity, positive predictive value and positive likelihood ratio of 97.8, 94.4% and 19.8 to detect a positive ALPL test, respectively. Conclusions: In subjects with persistent hypophosphatasaemia -secondary causes excluded-one out of two presented ALPL variants. Musculoskeletal pain and ALP levels < 25 IU/L are associated with this variant(s). In this scenario, ALP levels < 25 IU/L seem to be very useful to identify individuals with the presence of an ALPL variant.

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Section: Discussionsupporting

confidence: 83%

Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia?

Tornero¹,

Navarro-Compán²,

Tenorio

et al. 2020

Orphanet J Rare Dis

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“…Whatever the underlying mechanism, the data presented here support the view that p.Arg152His may be a functional variant that impairs ALP activity. Altogether, our results are consistent with previous findings of adults with persistently low levels of ALP, where 50% to 84% of individuals were found to carry coding variants in ALPL …”

Section: Discussionmentioning

confidence: 99%

“…Altogether, our results are consistent with previous findings of adults with persistently low levels of ALP, where 50% to 84% of individuals were found to carry coding variants in ALPL. (24,25) Some missense variants in ALPL have been proposed to exert dominant negative effect on enzyme function, especially those located within functional domains. (9) However, only the p. R391C variant has been tested for this in vitro with negative results.…”

Section: Discussionmentioning

confidence: 99%

Loss-of-Function Mutations in the ALPL Gene Presenting with Adult Onset Osteoporosis and Low Serum Concentrations of Total Alkaline Phosphatase

Alonso

Larraz-Prieto

Berg

et al. 2019

Journal of Bone and Mineral Research

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Hypophosphatasia (HPP) is a rare inherited disorder characterized by rickets and low circulating concentrations of total alkaline phosphatase (ALP) caused by mutations in ALPL. Severe HPP presents in childhood but milder forms can present in adulthood. The prevalence and clinical features of adult HPP are poorly defined. The aim of this study was to evaluate the prevalence and clinical significance of low serum total alkaline phosphatase (ALP) levels in a clinic‐based population of adult osteoporotic patients. We searched for patients with low ALP in a cohort of 3285 patients referred to an osteoporosis clinic over a 10‐year period and performed mutation screening of ALPL in those with low ALP (≤40 U/L) on two or more occasions. These individuals were matched with four clinic controls with a normal ALP. We also evaluated the prevalence of low ALP and ALPL mutations in 639 individuals from the general population from the same region. We identified 16/3285 (0.49%) clinic patients with low ALP and 14 (87.5%) had potentially pathogenic variants in ALPL. Eight of these individuals were heterozygous for mutations previously described in HPP and 2 were heterozygous for novel mutations (p.Arg301Trp and p.Tyr101X). These mutations were not found in clinic controls or in the general population. Eight patients with low ALP, including 4 with ALPL mutations, were treated with bisphosphonates for an average of 6.5 years. In these individuals, the rate of fractures during treatment was comparable to that in normal ALP clinic controls who were treated with bisphosphonates. We conclude that heterozygous loss‐of‐function mutations in ALPL are common in osteoporosis patients with low ALP. Further studies are required to determine how best these individuals should be treated. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

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“…The cohort included a total of 83 patients [age: 36 ± 22 years], 28 males and 55 females, and 28 family members, referred from 11 different hospitals from six countries: Spain (n = 45), Italy (n = 1), Russia (n = 24), Egypt (n = 4), United Arab Emirates (n = 7), and Denmark (n = 1) En tabla I aparece Portugal y Emiratos Arabes. Preliminary results of 39 of the adult patients were recently described [Riancho‐Zarrabeitia et al, ]. This project was approved by the local ethical research board and all patients or parents gave informed consent to participate in this study.…”

Section: Methodsmentioning

confidence: 99%

Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia

Tenorio

Álvarez²,

Riancho‐Zarrabeitia

et al. 2017

American J of Med Genetics Pt A

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Hypophosphatasia (HPP) is a rare autosomal dominant or recessive metabolic disorder caused by mutations in the tissue nonspecific alkaline phosphatase gene (ALPL). To date, over 300 different mutations in ALPL have been identified. Disease severity is widely variable with severe forms usually manifesting during perinatal and/or infantile periods while mild forms are sometimes only diagnosed in adulthood or remain undiagnosed. Common clinical features of HPP are defects in bone and tooth mineralization along with the biochemical hallmark of decreased serum alkaline phosphatase activity. The incidence of severe HPP is approximately 1 in 300,000 in Europe and 1 in 100,000 in Canada. We present the clinical and molecular findings of 83 probands and 28 family members, referred for genetic analysis due to a clinical and biochemical suspicion of HPP. Patient referrals included those with isolated low alkaline phosphatase levels and without any additional clinical features, to those with a severe skeletal dysplasia. Thirty-six (43.3%) probands were found to have pathogenic ALPL mutations. Eleven previously unreported mutations were identified, thus adding to the ever increasing list of ALPL mutations. Seven of these eleven were inherited in an autosomal dominant manner while the remaining four were observed in the homozygous state. Thus, this study includes a large number of well-characterized patients with hypophosphatasemia which has permitted us to study the genotype:phenotype correlation. Accurate diagnosis of patients with a clinical suspicion of HPP is crucial as not only is the disease life-threatening but the patients may be offered bone targeted enzymatic replacement therapy. © 2017 Wiley Periodicals, Inc.

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Clinical, biochemical and genetic spectrum of low alkaline phosphatase levels in adults

Cited by 59 publications

References 31 publications

Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia?

Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia?

Loss-of-Function Mutations in the ALPL Gene Presenting with Adult Onset Osteoporosis and Low Serum Concentrations of Total Alkaline Phosphatase

Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia

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