Hypophosphatasia: diagnostic application of linked DNA markers in the dominantly inherited adult form

1999 ◽  
Vol 97 (1) ◽  
pp. 73-78 ◽  
Author(s):  
S. J. IQBAL ◽  
D. S. PLAHA ◽  
G. H. LINFORTH ◽  
R. DALGLEISH
Keyword(s):  
Alkaline Phosphatase ◽  
Dna Analysis ◽  
Serum Alkaline Phosphatase ◽  
Chorionic Villus ◽  
Rflp Analysis ◽  
Serum Levels ◽  
Clinical Findings ◽  
Screening Methods ◽  
Inorganic Pyrophosphate ◽  
Low Serum

Hypophosphatasia is a rare disease characterized by low serum levels of tissue non-specific alkaline phosphatase (TNSALP) and a spectrum of skeletal disease varying from the severest form with death in utero to mild with no clinical abnormality in adults. Currently, the diagnosis of hypophosphatasia is made on the basis of clinical findings, radiography, low serum alkaline phosphatase levels and raised abnormal phosphorylated metabolites; there are elevations in serum pyridoxal 5′-phosphate, urinary phosphoethanolamine and inorganic pyrophosphate. In borderline cases the biochemical diagnosis remains uncertain. Prenatally, diagnosis is made using radiography and ultrasonography together with chorionic villus tissue biopsy, in which TNSALP levels are measured using an antibody-based assay. Since hypophosphatasia results from mutations in the TNSALP gene we have, for the first time in two U.K. families, undertaken restriction fragment length polymorphism (RFLP) analysis using three intragenic RFLPs for BclI and MspI at the ALPL locus. One family was informative, and a mutant-allele-specific haplotype with respect to three RFLPs was defined. In the other family the disease was shown to segregate with one allele of the BclI RFLP, but the MspI RFLPs were not informative. The disease segregated in the two families with different alleles of the BclI RFLP, suggesting that the mutations are likely to be different. We confirm that DNA analysis is likely to be the way ahead for diagnosing hypophosphatasia, and that standardized screening methods need to be developed for detecting mutations in these and other families.

scholarly journals Case of Juvenile Onset Hypophosphatasia Diagnosed in an Adult Patient

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A187-A188
Author(s):  
Nirmal Nair
Keyword(s):  
Alkaline Phosphatase ◽  
Dental Caries ◽  
Ankle Fracture ◽  
Vitamin B6 ◽  
Serum Alkaline Phosphatase ◽  
Bone Mineralization ◽  
Multiple Fractures ◽  
History Of ◽  
Tissue Nonspecific Alkaline Phosphatase ◽  
Low Serum

Abstract Background: Hypophosphatasia is a rare multisystem disease caused by mutations in genes encoding tissue nonspecific alkaline phosphatase, a key player in promoting bone mineralization1. Here we present a case of hypophosphatasia in a patient with history of recurrent fractures and dental caries since childhood. Case Report: Patient is a 52-year-old woman with history of multiple fractures who initially presented for follow up of osteoporosis following an atraumatic ankle fracture. Further questioning revealed a history of 16 atraumatic fractures since the age of 4, involving ankles, toes, and fingers. Several adult teeth had never developed requiring braces to fill in gaps at age 13, dental caries and tooth fractures involving the majority of her adult teeth. DEXA scan in 2019 revealed T score of -2.4 in the left femoral neck. Suspicion for hypophosphatasia in February 2019 following an ankle fracture and patient’s prior history prompted further workup, revealing low serum alkaline phosphatase levels of 29 and 32 (bone fraction 62 percent, liver fraction 38 percent), and Vitamin B6 levels elevated to 66.2. Remainder of workup, with Vitamin D, PTH, Magnesium, and Calcium was normal. A childhood history of multiple atraumatic fractures, various dental issues, with elevated Vitamin B6 and low serum alkaline phosphatase suggested Hypophosphatasia. As bisphosphonates are contraindicated in these patients due to their potential to reduce ALP, teriparatide was initiated. Discussion: Hypophosphatasia involves mutations in tissue nonspecific alkaline phosphatase, a key player in bone mineralization. In normal individuals, this enzyme dephosphorylates inorganic pyrophosphate (PPi), which otherwise inhibits bone mineralization. The mutated TNSALP leads to accumulation of PPi, and thereby unmineralized osteoid.1 Although individual presentations can vary, developmental abnormalities, such as delayed growth, early loss of primary or secondary teeth, or history of multiple fractures are characteristic. Due to the rarity of the disease, and its potential to be confused for more common bone and rheumatologic diseases, diagnosis is often delayed1. Patients in whom suspicion for hypophosphatasia is present, should undergo further testing with bone specific Alkaline phosphatase and Vitamin B6 which would be low and elevated, respectively and may be candidates for enzyme replacement therapy with bone-targeting recombinant alkaline phosphatase1. Traditional treatments such as bisphosphonates potentially decrease ALP and worsen disease, making accurate diagnosis all the more crucial. References1 Bishop N. Clinical management of hypophosphatasia. Clin Cases Miner Bone Metab. 2015;12(2):170–173.

Seasonal variations of serum 1,25-dihydroxyvitamin D3 and alkaline phosphatase in relation to the antler formation in the fallow deer (Dama dama L.)

1984 ◽  
Vol 107 (1) ◽  
pp. 141-144 ◽  
Author(s):  
B. Eiben ◽  
St. Scharla ◽  
K. Fischer ◽  
H. Schmidt-Gayk
Keyword(s):  
Alkaline Phosphatase ◽  
Seasonal Variation ◽  
Serum Alkaline Phosphatase ◽  
Serum Levels ◽  
Fallow Deer ◽  
Dama Dama ◽  
Dihydroxyvitamin D3 ◽  
Hydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D3 ◽  
25 Hydroxyvitamin D

Abstract. Serum 1,25-dihydroxyvitamin D3 and serum alkaline phosphatase increased several fold during the antler formation period in July. Both maxima were observed in the second half of the antler formation period, where the mineralization of the antler takes place. In contrast serum levels of calcium and 25-hydroxyvitamin D3 showed no alternation or seasonal variation.

scholarly journals Hypophosphatasia

2021 ◽  
Vol 10 (23) ◽  
pp. 5676
Author(s):  
Symeon Tournis ◽  
Maria P. Yavropoulou ◽  
Stergios A. Polyzos ◽  
Artemis Doulgeraki
Keyword(s):  
Alkaline Phosphatase ◽  
Autosomal Dominant ◽  
Serum Alkaline Phosphatase ◽  
Severe Disease ◽  
Loss Of Function ◽  
Inorganic Pyrophosphate ◽  
Live Births ◽  
Enzyme Replacement ◽  
Asfotase Alfa ◽  
Reduced Activity

Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNAP) gene. Reduced activity of TNAP leads to the accumulation of its substrates, mainly inorganic pyrophosphate and pyridoxal-5΄-phosphate, metabolic aberrations that largely explain the musculoskeletal and systemic features of the disease. More than 400 ALPL mutations, mostly missense, are reported to date, transmitted by either autosomal dominant or recessive mode. Severe disease is rare, with incidence ranging from 1:100,000 to 1:300,000 live births, while the estimated prevalence of the less severe adult form is estimated to be between 1:3100 to 1:508, in different countries in Europe. Presentation largely varies, ranging from death in utero to asymptomatic adults. In infants and children, clinical features include skeletal, respiratory and neurologic complications, while recurrent, poorly healing fractures, muscle weakness and arthropathy are common in adults. Persistently low serum alkaline phosphatase is the cardinal biochemical feature of the disease. Management requires a dedicated multidisciplinary team. In mild cases, treatment is usually symptomatic. Severe cases, with life-threating or debilitating complications, can be successfully treated with enzyme replacement therapy with asfotase alfa.

scholarly journals Bilateral atypical femoral fractures during denosumab therapy in a patient with adult-onset hypophosphatasia

2021 ◽  
Vol 2021 ◽  
Author(s):  
Annabelle M Warren ◽  
Peter R Ebeling ◽  
Vivian Grill ◽  
Ego Seeman ◽  
Shoshana Sztal-Mazer
Keyword(s):  
Alkaline Phosphatase ◽  
Vitamin B6 ◽  
Serum Alkaline Phosphatase ◽  
Serum Vitamin ◽  
Femoral Fractures ◽  
Adult Onset ◽  
Antiresorptive Therapy ◽  
Atypical Femoral Fractures ◽  
Asfotase Alfa ◽  
Low Serum

Summary Hypophosphatasia (HPP) is a rare and under-recognised genetic defect in bone mineralisation. Patients presenting with fragility fractures may be mistakenly diagnosed as having osteoporosis and prescribed antiresorptive therapy, a treatment which may increase fracture risk. Adult-onset HPPhypophosphatasia was identified in a 40-year-old woman who presented with bilateral atypical femoral fractures after 4 years of denosumab therapy. A low serum alkaline phosphatase (ALP) and increased serum vitamin B6 level signalled the diagnosis, which was later confirmed by identification of two recessive mutations of the ALPL gene. The patient was treated with teriparatide given the unavailability of ALP enzyme-replacement therapy (asfotase alfa). Fracture healing occurred, but impaired mobility persisted. HPP predisposes to atypical femoral fracture (AFF) during antiresorptive therapy; hence, bisphosphonates and denosumab are contraindicated in this condition. Screening patients with fracture or ‘osteoporosis’ to identify a low ALP level is recommended. Learning points Hypophosphatasia (HPP) is a rare and under-recognised cause of bone fragility produced by impaired matrix mineralisation that can be misdiagnosed as a fragility fracture due to age-related bone loss. Antiresorptive therapy is contraindicated in HPP. Low serum alkaline phosphatase (ALP) provides a clue to the diagnosis. Elevated serum vitamin B6 (an ALP substrate) is indicative of HPP, while identification of a mutation in the ALPL gene is confirmatory. Enzyme therapy with recombinant ALP (asfotase alfa) is currently prohibitively costly. Treatment with anabolic bone agents such as teriparatide has been reported, but whether normally mineralized bone is formed requires further study.

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