Hypophosphatasia: An overview For 2017

Whyte, Michael P.

doi:10.1016/j.bone.2017.02.011

Cited by 178 publications

(199 citation statements)

References 102 publications

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“…This results in variants in ALPL, located on chromosome 1p36.1-p34, which encodes the tissue-nonspecific alkaline phosphatase [1,2]. Impaired ALP activity can lead to the extracellular accumulation of ALP-specific substrates, such as inorganic pyrophosphate (PPi), a potent inhibitor of bone and dental mineralization [3].…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…H ypophosphatasia (HPP), also known as Rathbun disease, is a rare, heritable inborn error of metabolism that has both autosomal dominant and recessive inheritance patterns due to loss-of-function mutations in the alkaline phosphatase gene (ALPL) located on the short arm of chromosome 1, which encodes the tissue nonspecific isozyme of alkaline phosphatase (TNSALP). (1)(2)(3)(4) Clinical features of HPP include low serum alkaline phosphatase (ALP) activity, defective mineralization of bone, and elevated levels of ALP substrates such as pyridoxal-5-phosphate (vitamin B6). Skeletal manifestations include bone pain, pathologic fractures, poor fracture healing, and poor dentition.…”

Section: Introductionmentioning

confidence: 99%

Fracture Healing in Two Adult Patients With Hypophosphatasia After Asfotase Alfa Therapy

Klidaras

Severt

Aggers³

et al. 2018

JBMR Plus

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Infants and children with hypophosphatasia (HPP) treated with asfotase alfa show improvement in bone mineralization and motor function, but it is unclear whether the medication can affect fracture healing in adult HPP patients. We present the course of fracture healing in two adults with HPP on enzyme replacement. Case 1 is a 41‐year‐old female with infantile‐onset HPP who was wheelchair‐bound due to a nonhealing tibial fragility fracture sustained 3 years before and also had nonhealing femoral pseudofracture sustained 17 years before starting asfotase alfa therapy in December 2015. One month after medication initiation, she underwent elective osteotomy of tibia and fibula with intramedullary nail fixation. After 3 months of enzyme replacement, she was full weight‐bearing and radiographs demonstrated callus formation at osteotomy sites, and at 11 months of therapy, radiographs showed union of the osteotomies. By 11 months of asfotase alfa therapy, there was near resolution of the femoral pseudofracture without interval surgery at this site. Case 2 is a 61‐year‐old male who showed nonunion of a fragility fracture of the right femur 8 years prior, intramedullary nail fixation 6 years prior, and stress fracture of the left femoral diaphysis sustained 1 year before starting asfotase alfa in October 2015. A trial of teriparatide was unsuccessful in healing of these fractures. On asfotase alfa, radiographs revealed interval healing of the left femur fracture after 12 months and complete healing of the right femur fracture and near resolution of the left femur fracture after 16 months of medical therapy. These two adult patients with HPP showed significant clinical and radiographic improvements in a total of four recalcitrant fractures on enzyme replacement therapy with asfotase alfa. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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“…Инфантильная гипофосфатазия -аутосомно-рецес-сивное заболевание, которое манифестирует в младен-ческом возрасте с дефектов костеобразования, характе-ризующихся выраженным остеопорозом, микромелией, деформацией конечностей и переломами костей [64]. Гипофосфатазия вызвана мутациями в гене ALPL , коди-рующем тканевую неспецифическую щелочную фосфа-тазу, катализирующую отщепление фосфатной группы от неорганического пирофосфата и его связывание с каль-цием с образованием гидроксиапатита.…”

Section: дифференциальная диагностикаunclassified

“…Низкая актив-ность или отсутствие фермента обусловливают наруше-ние минерализации кости. Накапливающийся при этом неорганический пирофосфат связывается с аморфным фосфатом кальция, образует кристаллы пирофосфата кальция, который может откладываться в почечной тка-ни с формированием нефрокальциноза или суставах, вызывая артрит или псевдоподагру [64]. Своевременная диагностика инфантильной гипофосфатазии принципи-ально важна, т.к.…”

Section: дифференциальная диагностикаunclassified