Low Serum Alkaline Phosphatase Activity Research Articles

Enzyme replacement therapy for hypophosphatasia-The current paradigm.

Hypophosphatasia (HPP) is a rare, inherited, and systemic disorder characterized by impaired skeletal mineralization and low tissue nonspecific serum alkaline phosphatase (TNSALP) activity. It is caused by either autosomal recessive or dominant-negative mutations in the gene that encodes TNSALP. The phenotype of HPP is very broad including abnormal bone mineralization, disturbances of calcium and phosphate metabolism, pain, recurrent fracture, short stature, respiratory impairment, developmental delay, tooth loss, seizures, and premature death. Other than supportive care, there has been no disease-specific treatment available for those with HPP. Asfotase alfa is a fully humanized, recombinant enzyme replacement therapy for the management of HPP. It is available in several countries for the treatment of the more severe forms of HPP, namely perinatal and infantile HPP. This review will summarize the preclinical data on asfotase alfa and highlight the data from clinical trials and case reports. These data show the transformative nature of asfotase alfa when administered as part of an interdisciplinary treatment model.

ODP592 Delay in Diagnosis of Adult with Familial Hypophosphatasia

Abstract Background Familial Hypophosphatasia (HPP) is a rare genetic disorder characterized by defecitve bone and/or teeth mineralization in the presence of low alkaline phosphatase activity due to loss-of-function mutations in the Alkaline Phosphatase, Biomineralization Associated (ALPL) gene. HPP typically presents in middle age with a mild phenotype. Case Presentation A 43-year-old woman with PMH undifferentiated connective tissue disease and GERD referred to endocrinology clinic. She was previously diagnosed with schleroderma and was treated with prednisone and hydroxychloroquine without symptom improvement. Symptoms included: progressing bone, joint, and muslce pain; unsteady gait; proximal muscle weakness; fatigue; early loss of deciduous teeth; loss of teeth mineralization; history of finger and toe fractures from repetitive stress. Family History: Mother: ongoing joint/muscle pain as well as tooth loss. Daughter: failure to thrive, kyphosis, orthopedic problems, required leg casting for 1 year. Physical Exam: unrevealing (limited due to video visits). Significant Laboratory/Imaging Findings: Serum alkaline phosphatase (ALP): 16 U/L (ref. 35-140 U/L)Vitamin B6: 235.3 nmol/L (ref. 20-125 nmol/UL)Calcium: 9.3 mg/dL (ref. 8.5-10.6 mg/dL).Dual energy X-ray absorptiometry (DXA): normal bone mass for age.Genetic testing: one heterozygous pathogenic variant in ALPL, c.318G>C (p.CIn106His). Treatment Course: Genetic testing consistent with a diagnosis of familial HPP, specifically juvenile onset. Initiated on Asfotase-alfa, an alkaline phosphatase enzyme replacement therapy. Screening prior to treatment: Renal ultrasonography without ectopic calcificationOpthalmology exam without calficiations identified Discussion HPP should be suspected in patients with defective mineralization of bone and/or teeth in the setting of an unexplained low serum ALP activity and elevated Vitamin B6 level. Non-specific symptoms such as bone, joint, and muscle pain are common presenting symptoms in adults with HPP. Treatment with asfotase-alfa may be considered for adults with symptom onset in childhood, including early loss of deciduous teeth. Early diagnosis and treatment may improve overall quality of life. At this time, there are no guidelines for selecting adult patients for treatment with alfoterase-alfa. Further studies are needed to evaluate the benefits of enzyme replacement therapy among adults with HPP. Presentation: No date and time listed

Imaging patterns in pediatric hypophosphatasia.

Hypophosphatasia is a rare genetic disorder of calcium and phosphate metabolism due to ALPL gene mutations, which leads to abnormal mineralization of the bones and teeth. Hypophosphatasia is characterized by low serum alkaline phosphatase activity and a number of clinical signs, including failure to thrive, bone pain and dental issues. The diagnosis is suspected based on clinical, laboratory and imaging findings and confirmed by genetic testing. Diagnosis in children is often delayed due to a lack of disease awareness, despite specific imaging findings that are a cornerstone of the diagnosis. The recent approval of enzyme replacement therapy (bone-targeted recombinant tissue nonspecific alkaline phosphatase) has given imaging an important role in monitoring treatment efficacy. The aim of this pictorial essay is to review the imaging features of hypophosphatasia at diagnosis and during follow-up, including whole-body magnetic resonance imaging patterns.

Burden of Illness in Adults With Hypophosphatasia: Data From the Global Hypophosphatasia Patient Registry.

Hypophosphatasia (HPP) is a rare, inherited, metabolic disease caused by deficient tissue non-specific alkaline phosphatase activity. This study aims to assess patient-reported pain, disability and health-related quality of life (HRQoL) in a real-world cohort of adults with HPP who were not receiving asfotase alfa during the analysis. Adults (≥18 years old) with HPP (confirmed by ALPL gene mutation and/or low serum alkaline phosphatase activity for age/sex) were identified from the Global HPP Registry (NCT02306720). Demographics, clinical characteristics, and data on patient-reported pain, disability, and HRQoL (assessed by Brief Pain Inventory Short Form [BPI-SF], Health Assessment Questionnaire Disability Index [HAQ-DI], and 36-Item Short-Form Health Survey version 2 [SF-36v2], respectively) were stratified by pediatric- and adult-onset HPP and summarized descriptively. Of the 304 adults included (median [min, max] age 48.6 [18.8, 79.8] years; 74% women), 45% had adult-onset HPP and 33% had pediatric-onset HPP (unknown age of onset, 22%). Of those with data, 38% had experienced ≥5 HPP manifestations and 62% had a history of ≥1 fracture/pseudofracture. Median (Q1, Q3) BPI-SF scores were 3.5 (1.5, 5.3) for pain severity and 3.3 (0.9, 6.2) for pain interference. Median (Q1, Q3) disability on the HAQ-DI was 0.3 (0.0, 0.7). Median (Q1, Q3) physical and mental component summary scores on the SF-36v2 were 42.4 (32.7, 49.9) and 45.3 (36.3, 54.8), respectively. Greater numbers of HPP manifestations experienced/body systems affected correlated significantly with poorer scores on the BPI-SF, HAQ-DI, and SF-36v2 (all p < 0.05). No significant differences between adults with pediatric- and adult-onset HPP were observed for patient-reported outcomes, except for disability and the BPI-SF question "pain at its worst," which were significantly higher among adults with pediatric- versus adult-onset HPP (p = 0.03 and 0.04, respectively). These data from the Global HPP Registry show that adults with HPP have a substantial burden of illness that is associated with reduced patient-reported HRQoL, regardless of age of disease onset. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Phenotypic Profiling in Subjects Heterozygous for 1 of 2 Rare Variants in the Hypophosphatasia Gene (ALPL).

ContextHypophosphatasia (HPP) is a syndrome marked by low serum alkaline phosphatase (AlkP) activity as well as musculoskeletal and/or dental disease. While the majority of subjects with HPP carry a pathogenic variant in the ALPL gene or its regulatory regions, individual pathogenic variants are often not tightly correlated with clinical symptomatology. We sought to better understand the genotype/phenotype correlation in HPP by examining the clinical and biochemical data of 37 subjects with 2 rare variants in ALPL.MethodsThrough BioVU, a DNA biobank that pairs individuals’ genetic information with their de-identified medical records, we identified subjects with 2 rare variants with distinct reported clinical phenotypes (p.D294A and p.T273M). We then performed a manual review of these subjects’ de-identified medical records along with computational modeling of protein structure to construct a genetic, biochemical and clinical phenotype for each subject and variant.ResultsTwenty subjects with the p.D294A variant and 17 with the p.T273M variant had sufficient data for analysis. Among subjects in our cohort with the p.D294A variant, 6 (30.0%) had both clinical bone disease and serum AlkP activity below 40 IU/L while 4 subjects (23.5%) with the p.T273M variant met the same criteria despite the distinct clinical phenotypes of these variants.ConclusionsGiven the loose genotype/phenotype correlation in HPP seen in our cohort, clinical context is crucial for the interpretation of genetic test results to guide clinical care in this population. Otherwise, over- or under-diagnosis may occur, resulting in misidentification of those who may benefit from additional screening and perhaps pharmacologic intervention.

MON-361 Late Diagnosis in Adult Form of Hypophosphatasia

INTRODUCTION/BACKGROUND:Hypophosphatasia is a rare inborn error of metabolism that presents with important foot and thigh pain due to stress fractures. The diagnose of the adult form is routinely neglected, even though it presents symptomatic and with persistent low serum alkaline phosphatase (ALP).CLINICAL CASE (DIAGNOSTIC EVALUATION, TRATMANET AND FUP):A 43-year-old amateur athlete woman presented with pain in the right femur without any local trauma. Physical examination evidenced prolonged right tight pain and no other findings. Bone mineral density evaluated by dual-energy x-ray absorptiometry was unremarkable. Biochemical investigations showed normal inorganic phosphate, calcium, zinc, and magnesium, but low ALP. The patient had six previous ALP measurements and all of them were below the lower limit of normality (46 a 116 U/L). These measurements were done in regular ob-gyn checkups with no further investigation or follow-up. In light of the hypophosphatasemia and pathologic fracture, the serum pyridoxal 5’-phosphate concentration was measured and found to be elevated 35,8 mcg/L (normal 5,0 a 30,0 mcg/L).CLINICAL LESSONS/CONCLUSION:Hypophosphatasia occurs due to a deactivating mutation (or mutations) of the gene encoding Tissue-Nonspecific Alkaline Phosphatase (TNSALP), leading to a global deficiency of TNSALP activity and inadequate skeletal mineralization and fractures. The adult form presents during middle age with stress fractures. The first complaints maybe foot pain, which is due to stress fractures of the metatarsals, and thigh pain, due to pseudo fractures of the femur. Our patient illustrates the importance of low serum ALP activity in the assessment of these patients. The correct diagnosis should help to avoid the use of traditional therapies for osteoporosis or osteomalacia, which would be ineffective or potentially harmful.

Perinatal severe hypophosphatasia: a case report

Abstract Objectives Hypophosphatasia is a rare, inherited metabolic disorder characterized by low serum alkaline phosphatase activity. It is caused by mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP) [1], [2], [3]. The degree of skeletal malformation varies, but the severe form carries a very poor prognosis. Case presentation This study reports a male neonate diagnosed with infantile hypophosphatasia (HPP). Genetic analysis showed two heterozygous missense variants at nucleotides c.977G&gt;T (protein Gly326Val) and c.862+4A&gt;G (IVS8+4A&gt;G) (protein NA). The two mutations originated separately from the parents, consistent with autosomal recessive infantile HPP. The pathogenic variant was ALPL exon-9-heterozygous, and the other allele was ALPL IVS8-heterozygous, a variant of uncertain significance. Conclusions This case of infantile HPP was caused by two heterozygous mutations. One of those is a novel genetic mutation needed for further study. Genetic consultation is recommended for future offspring of affected parents.

Adult hypophosphatasia with compound heterozygous p.Phe327Leu missense and c.1559delT frameshift mutations in tissue-nonspecific alkaline phosphatase gene: a case report

BackgroundHypophosphatasia is an inherited bone disease characterized by low alkaline phosphatase activity encoded by ALPL. Clinically, hypophosphatasia can be categorized as perinatal, infantile, childhood, and adult forms, as well as odonto-hypophosphatasia, according to the age at first sign or dental manifestations. Adult hypophosphatasia typically presents in middle-aged patients who appear to be in good health in early adulthood and manifests as painful feet caused by recurrent, slow-healing stress fractures of the lower limb. Because the symptoms of adult hypophosphatasia vary and are common, many patients with hypophosphatasia might be not diagnosed accurately and thus may receive inappropriate treatment.Case presentationWe report a case of a 35-year-old Japanese woman with low serum alkaline phosphatase detected at a routine medical checkup. She had mild muscle/bone pain but no history of rickets, fractures, or dental problems. Measurement of bone mineral density of the lumbar spine and the femoral neck revealed osteopenia below the expected range for age in a young adult. Abdominal ultrasonography revealed numerous microcalcifications in both kidneys. Analysis of amino acids in urine revealed that phosphoethanolamine was elevated. Low serum alkaline phosphatase activity, elevation of phosphoethanolamine, and low bone mineral density supported the diagnosis of hypophosphatasia. ALPL mutation analysis revealed two mutations: p.Phe327Leu and c.1559delT. These genetic abnormalities were previously reported in perinatal, infantile, and childhood but not adult hypophosphatasia. On the basis of the clinical presentation, laboratory and imaging findings, and genetic analyses, the patient was definitively diagnosed with adult hypophosphatasia. To the best of our knowledge, this is the first case report of adult hypophosphatasia with the compound heterozygous mutations p.Phe327Leu and c.1559delT.ConclusionsAlthough the risk of bone fracture was high in this case, treatment approaches differ between osteoporosis and hypophosphatasia. Because adult hypophosphatasia diagnosis is often difficult because of their varied symptoms, hypophosphatasia should be considered in the differential diagnosis of low serum alkaline phosphatase. Early diagnosis is important so that appropriate treatment can be initiated.

SUN-529 Burden of Illness in Adults with Hypophosphatasia: Data From the Global Hypophosphatasia Patient Registry

Background: Hypophosphatasia (HPP) is a rare, systemic, metabolic disease caused by tissue-nonspecific alkaline phosphatase deficiency, characterized by poor skeletal mineralization, muscle weakness and ambulatory difficulties. Limited data are available on the burden of illness in adults with HPP. Methods: Data from the Global HPP Patient Registry were used to identify adults (≥ 18 years old) who had a diagnosis of HPP (confirmed by low serum alkaline phosphatase activity for age and sex and/or an ALPL pathogenic variant) and who had never been treated with asfotase alfa (AA). The following components of disease burden were assessed in these patients: occurrence of clinical HPP manifestations, number of body systems affected by HPP manifestations, number of fractures/pseudofractures and use of pain medication. Patient-reported pain (assessed by the Brief Pain Inventory Short Form [BPI-SF]; scale 0 to 10; higher scores represent higher levels of pain), disability (assessed by the Health Assessment Questionnaire Disability Index [HAQ-DI]; scale 0 to 3; higher scores represent more severe disability) and quality of life (QoL; assessed by the 36-item Short-Form Health Survey version 2 [SF-36v2]; scale 0 to 100; higher scores indicate better QoL) were analyzed in relation to the number of HPP manifestations experienced. Results: Of the 218 adult patients (74% female) included in this analysis, mean (standard deviation [SD]) age at HPP diagnosis was 41.0 (18.8) years. Most patients had adult-onset (50%) or pediatric-onset (38%) HPP (33% and 5% of patients had juvenile- or infantile-onset HPP, respectively); age of onset was unknown for 12% of patients. The most common clinical HPP manifestations were chronic bone pain (60% of patients), generalized body pain (41%), and recurrent and poorly healing fractures (33%); 58% of patients had at least one fracture/pseudofracture (mean [SD] = 2.8 [2.6] per patient). Most patients (52%) had at least five clinical HPP manifestations, and 34% had manifestations in at least five body systems. Use of pain medication was reported in 41% of patients, 48% of whom were receiving opioids. Median self-reported pain scores on the BPI-SF were 3.6 (0-9.5) for pain severity and 3.1 (0-9.4) for pain interference in daily activities. Mean (SD) disability measured on the HAQ-DI was 0.5 (0.6). The mean (SD) physical component summary score of the SF-36v2 was 41.8 (10.8) and the mean (SD) mental component summary score was 45.6 (10.1); both scores were lower than the mean among the general population (50.0). There were significant correlations between greater numbers of HPP manifestations experienced and poorer scores on the BPI-SF, HAQ-DI and SF-36v2 (all p < 0.05). Conclusion: Adults with HPP who have never been treated with AA often experience pain and have a substantial burden of illness which can impact patient-reported QoL.

SUN-528 The Clinical Utility of Gene Sequencing in Hypophosphatasia: Lessons from Patients with Two Rare Variants

Objectives: Hypophosphatasia (HPP) is a syndrome marked by low serum alkaline phosphatase (AlkP) activity along with clinical manifestations varying from seizures to frequent fractures. Diagnosis of HPP is complicated both by its variable clinical phenotype and variable age of onset - patients are often asymptomatic well into adulthood. Although caused by variants in the ALPL gene, individual mutations are not tightly correlated with disease due to variable penetrance, expressivity, and the effect of modifier genes. In this study we sought to better understand the genotype/phenotype correlation in HPP by closely examining the clinical courses of a series of 37 patients with two rare variants in ALPL. Methods: Using BioVU, a DNA biobank that pairs patient’s genetic information with their de-identified medical record, we identified all patients that had at least one variant in ALPL. Among these patients, we chose to further study those with one of two variants. One (rs121918002) has previously been associated with disease while the other (rs148405563) was previously reported as benign. Clinical phenotypes and AlkP values were then obtained through manual review of the de-identified medical records of patients with one of these variants. Results: 20 patients with the rs121918002 (disease-associated) and 17 with the rs148405563 (benign) variant had sufficient clinical data for further analysis. None of these patients carried the diagnosis of HPP. Patients with the disease-associated variant had an average serum AlkP activity of 70.67 IU/L (SD 52.22), and 16 patients (80%) had at least one serum AlkP less than the lower limit of normal (40 IU/L). Among patients with a low AlkP, only 6 (30%) had clinical phenotypes consistent with disease. Patients with the benign variant had an average serum AlkP of 53.92 IU/L (SD 16.30) and 8 (47.1%) had at least one serum AlkP less than 40 IU/L. Among those with a low AlkP, 4 patients (23%) also had clinical phenotypes consistent with disease. Conclusions: Our study highlights the importance of clinical context to guide decisions around genetic testing in this population. In particular, genetic testing is of limited utility in those who meet clinical criteria for diagnosis. However, ALPL sequencing may be useful in younger patients with low AlkP but who do not have clinical disease. In these patients it may identify those at highest risk to go on to develop disease and assist in earlier intervention with appropriate therapy.

MON-494 Infantile Hypophosphatasia Diagnosed in Adulthood: A Case Report

Background: Hypophosphatasia (HPP) is a result of loss of function mutations within ALPL gene that encodes for the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). It is characterized by low serum alkaline phosphatase (ALP) activity. To date, HPP was recognized in 500-600 individuals in the United States. Clinical presentation and severity is broad, which can be explained by variable mutations in the TNSALP gene. Elevation of serum pyridoxal-5’-phosphate (vitamin B6), elevation of urinary of phosphoethanolamine (PEA) and finding of a mutation in the ALPL gene support the diagnosis. Asfotase alfa is a recombinant human alkaline phsosphatase that was approved in 2015 for treatment of patients, including adults, with pediatric-onset HPP. Case report: A 56 year old physician presented with a long history of low serum ALP on routine laboratory testing since childhood. During infancy he was diagnosed with craniosynostosis. He had delayed motor milestones and a waddling gait. He was never able to run as a child and he attended high school in a wheelchair. He had severe periodontal disease, lost his first tooth at age 4 and continued to lose his teeth despite excellent dental hygiene care. He has an extensive bone fractures history. He had his first fracture at the elbow at age 6 after he was pulled up by his hands. He developed metatarsal fractures around that time after a fall. He had a metacarpal fracture as an adult with bumping of his hand against the wall. At age 12 he developed hip pain and uveitis. He was diagnosed with ankylosing spondylitis (AS) at age 16 year with a positive HLA B 27. His most recent fracture was at age 45 after he slipped in the shower and sustained a hip fracture. At that time he had a BMD that showed osteoporosis. A bisphosphonate was offered but the patient refused medication as he was worried of the side effects. He has a family history of musculoskeletal disorders. His late mother had a history of low ALP, dental problems, metatarsal fractures and osteopenia. His sister has low ALP and had a low impact radial fracture. His sister’s son who is 18 years old was found to have low serum ALP and was found to have a Z score of -1.5 on BMD. When the patient presented to our clinic, his serum ALP was 22 U/L (n 40-115) and vitamin B 6 was 253 ng/ml (n 2.1-21.7). Genetic testing revealed heterozygous variant in the ALPL gene c.1251T>G (p.Asn417Lys). The patient’s sister and her son were found to have similar mutation of the ALPL gene. The patient was started on treatment with Asfotase alfa. After three months of treatment, the patient reported increased strength and reduced fatigue. Conclusion: We present a rare diagnosis of a 56 year old gentleman who was diagnosed with infantile HPP as an adult. The disease manifested as craniosynostosis, recurrent fractures and periodontal disease. He was started on Asfotase alfa with improvement of symptoms. .

Diagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry

BackgroundHypophosphatasia (HPP) is a rare, systemic disease caused by mutation(s) within the ALPL gene encoding tissue-nonspecific alkaline phosphatase (ALP). HPP has a heterogeneous presentation, which coupled with its rarity, often leads to missed/delayed diagnosis and an incomplete understanding of its natural history. To better understand the epidemiology and clinical course of HPP, including timing of diagnosis after first reported manifestation, we present baseline data for patients enrolled in the Global HPP Registry.MethodsData were analyzed from patients with an HPP diagnosis confirmed by low serum ALP activity and/or an ALPL pathogenic variant, regardless of prior or current treatment, according to age at enrollment (children: < 18 y; adult: ≥18 y). All analyses were descriptive.ResultsOf 269 patients from 11 countries enrolled January 2015–September 2017, 121 (45.0%) were children and 148 (55.0%) were adults. The majority of children and adults were female (61.2 and 73.0%, respectively) and white (57.7 and 90.0%, respectively). Children had a median (min, max) age at earliest reported HPP manifestation of 7.2 months (− 2.3 mo, 16.0 y), which was > 12 months before diagnosis at age 20.4 months (− 0.2 mo, 16.0 y). In adults, the earliest reported manifestation occurred at a median (min, max) age of 37.6 years (0.2 y, 75.2 y), which preceded age at diagnosis (47.5 years [0.2 y, 75.2 y]) by ~ 10 years. Premature loss of deciduous teeth (48.2%, age ≥ 6 mo), bone deformity (32.5%), and failure to thrive (26.7%) were most commonly reported in the HPP-related disease history of children. Pain (74.5%), orthopedic procedures and therapies (44.6%), and recurrent and poorly healing fractures (36.5%) were most commonly reported in the HPP-related disease history of adults.ConclusionsThe Global HPP Registry represents the largest observational study of patients with HPP, capturing real world data. This analysis shows that diagnostic delay is common, reflecting limited awareness of HPP, and that HPP is associated with systemic manifestations across all ages. Many patients diagnosed in adulthood had HPP manifestations in childhood, highlighting the importance of taking thorough medical histories to ensure timely diagnosis.Trial registrationClinicaltrials.gov: NCT02306720, December 2014; ENCePP.eu: EUPAS13526, May 2016 (retrospectively registered).

ALPL mutations in adults with rheumatologic disorders and low serum alkaline phosphatase activity.

Tissue-nonspecific alkaline phosphatase (ALP), encoded by ALPL, is important for bone homeostasis and interacts with collagen type I. In the present study, we sequenced ALPL and a panel of collagen type I-related genes in 24 adults (age 22-80years; 20 female) with persistently low serum ALP (< 40 U/L) and a range of rheumatologic symptoms. We found heterozygous pathogenic or likely pathogenic variants in ALPL in 14 (58%) of these individuals. In addition, 7 study participants had potentially damaging heterozygous variants of uncertain significance in genes related to collagen type I. Patients who were positive for ALPL variants had similar age and serum ALP levels to patients in whom no ALPL variants were detected, but had higher serum pyridoxal-5-phosphate concentrations (median 214nmol/L vs. 64nmol/L; p = 0.02; U test). In summary, heterozygous ALPL variants are frequent in individuals with rheumatologic symptoms and low ALP serum activity. It is possible that variants in genes that are involved in collagen type I production have a modifying effect on the clinical consequences of such ALPL variants.

Low serum alkaline phosphatase activity in Kikuchi-Fujimoto disease.

Various laboratory findings are helpful in making a diagnosis of Kikuchi-Fujimoto disease (KFD); however, they are not specific. We found decreased serum alkaline phosphatase (SAP) activity in children with KFD. The levels of SAP fell in the acute phase and recovered during convalescence. We conclude that low SAP activity is a characteristic of KFD and may be an auxiliary diagnostic marker for the disease.

Hypophosphatasia: An overview For 2017

Hypophosphatasia (HPP) is the inborn-error-of-metabolism that features low serum alkaline phosphatase (ALP) activity (hypophosphatasemia) caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of ALP (TNSALP). Autosomal recessive or autosomal dominant inheritance from among >300 TNSALP (ALPL) mutations largely explains HPP's remarkably broad-ranging severity. TNSALP is a cell-surface homodimeric phosphohydrolase richly expressed in the skeleton, liver, kidney, and developing teeth. In HPP, TNSALP substrates accumulate extracellularly. Among them is inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. Superabundance of extracellular PPi explains the hard tissue complications of HPP that feature premature loss of deciduous teeth and often rickets or osteomalacia as well as calcific arthropathies in some affected adults. In infants with severe HPP, blocked entry of minerals into the skeleton can cause hypercalcemia, and insufficient hydrolysis of pyridoxal 5′-phosphate (PLP), the major circulating form of vitamin B6, can cause pyridoxine-dependent seizures. Elevated circulating PLP is a sensitive and specific biochemical marker for HPP. Also, the TNSALP substrate phosphoethanolamine (PEA) is usually elevated in serum and urine in HPP, though less reliably for diagnosis. Pathognomonic radiographic changes occur in pediatric HPP when the skeletal disease is severe. TNSALP mutation analysis is essential for recurrence risk assessment for HPP in future pregnancies and for prenatal diagnosis. HPP was the final rickets/osteomalacia to have a medical treatment. Now, significant successes using asfotase alfa, a mineral-targeted recombinant TNSALP, are published concerning severely affected newborns, infants, and children. Asfotase alfa was approved by regulatory agencies multinationally in 2015 typically for pediatric-onset HPP.

Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment.

Hypophosphatasia is the inborn error of metabolism characterized by low serum alkaline phosphatase activity (hypophosphatasaemia). This biochemical hallmark reflects loss-of-function mutations within the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP is a cell-surface homodimeric phosphohydrolase that is richly expressed in the skeleton, liver, kidney and developing teeth. In hypophosphatasia, extracellular accumulation of TNSALP natural substrates includes inorganic pyrophosphate, an inhibitor of mineralization, which explains the dento-osseous and arthritic complications featuring tooth loss, rickets or osteomalacia, and calcific arthopathies. Severely affected infants sometimes also have hypercalcaemia and hyperphosphataemia due to the blocked entry of minerals into the skeleton, and pyridoxine-dependent seizures from insufficient extracellular hydrolysis of pyridoxal 5'-phosphate, the major circulating form of vitamin B6, required for neurotransmitter synthesis. Autosomal recessive or dominant inheritance from ~300 predominantly missense ALPL (also known as TNSALP) mutations largely accounts for the remarkably broad-ranging expressivity of hypophosphatasia. High serum concentrations of pyridoxal 5'-phosphate represent a sensitive and specific biochemical marker for hypophosphatasia. Also, phosphoethanolamine levels are usually elevated in serum and urine, though less reliably for diagnosis. TNSALP mutation detection is important for recurrence risk assessment and prenatal diagnosis. Diagnosing paediatric hypophosphatasia is aided by pathognomic radiographic changes when the skeletal disease is severe. Hypophosphatasia was the last type of rickets or osteomalacia to await a medical treatment. Now, significant successes for severely affected paediatric patients are recognized using asfotase alfa, a bone-targeted recombinant TNSALP.

Calcific Periarthritis as the Only Clinical Manifestation of Hypophosphatasia in Middle-Aged Sisters

Hypophosphatasia (HPP) is the inborn error of metabolism that features low serum alkaline phosphatase (ALP) activity caused by loss-of-function mutation(s) within the gene for the tissue nonspecific isoenzyme of ALP (TNSALP). In HPP, extracellular accumulation of inorganic pyrophosphate (PPi), a TNSALP substrate and inhibitor of mineralization, leads frequently to premature tooth loss and often to rickets or osteomalacia. In affected adults, the excess PPi sometimes also causes calcium pyrophosphate dihydrate (CPPD) deposition, PPi arthropathy, or pseudogout, or seemingly paradoxical deposition of hydroxyapatite crystals in ligaments or around joints when the condition is called calcific periarthritis (CP). We report three middle-aged sisters with CP as the only clinical manifestation of HPP. Each presented during early adult life with recurrent episodes of pain principally around the shoulders, elbows, wrists, hips, or Achilles tendon. Otherwise, they were in good health, including no history of unusual dental disease, fractures, or pseudofractures. Calcific deposits were identified in symptomatic areas principally by ultrasonographic assessment but also confirmed radiographically. All three sisters had low serum levels of total and bone-specific ALP, hyperphosphatemia, and increased serum concentrations of the TNSALP substrate pyridoxal 5'-phosphate together characteristic of HPP. Mutation analysis revealed that each carried a single unique 18-bp duplication within TNSALP (c.188_205dup18, p.Gly63_Thr68dup) as did two of their healthy sons and their mother, who was without signs of CPPD deposition or CP but had knee osteoarthritis. We find that CP can be the only complication of HPP in adults. Thus, multiple juxta-articular deposits of hydroxyapatite causing CP may be a useful sign of HPP, especially when the CP is familial.

“Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia

We report a 55-year-old woman who suffered atypical subtrochanteric femoral fractures (ASFFs) after 4 years of exposure to alendronate and then zolendronate given for "osteoporosis." Before alendronate treatment, she had low bone mineral density. After several months of therapy, metatarsal stress fractures began. Bisphosphonate (BP) administration was stopped following the ASFFs, and the adult form of hypophosphatasia (HPP) was diagnosed from low serum alkaline phosphatase (ALP) activity, high endogenous levels of two natural substrates for the "tissue-nonspecific" isoenzyme of ALP (TNSALP), and a heterozygous mutation within the gene that encodes this enzyme. Experience with other HPP families showed that her mutation (Arg71His) with a second defective TNSALP allele can cause severe HPP in infancy, and when heterozygous can cause mild HPP featuring premature loss of deciduous teeth in children. Because the skeletal disease of HPP results from extracellular accumulation of the TNSALP substrate inorganic pyrophosphate (PPi) and its inhibitory effect on mineralization, perhaps HPP patients or carriers will have adverse effects from BPs. BPs are analogues of PPi and can suppress bone turnover but also deactivate TNSALP. Our report is the first of BP exposure preceding ASFFs in adult HPP. To explore a potential role for TNSALP deactivation in ASFFs, mutation analysis of TNSALP should be studied in a cohort of these patients. Meanwhile, clinicians must suspect HPP when clinical or laboratory clues include premature loss of primary dentition, pseudofractures or recurrent poorly healing metatarsal stress fractures, a family history suggestive of HPP, or low serum ALP activity. If HPP is documented, BP treatment might be avoided. To establish the diagnosis of HPP, assays for two natural substrates for TNSALP and TNSALP mutation analysis are available in commercial laboratories. With positive findings, radiological or bone biopsy evidence of acquired osteomalacia would indicate the adult form of this inborn-error-of-metabolism.

Adult hypophosphatasia with painful periarticular calcification treated with surgical resection

Hypophosphatasia is a rare inherited disorder characterized by a low serum alkaline phosphatase (ALP) activity and defective bone mineralization. Adult hypophosphatasia typically manifests in middle-age as a result of osteomalacia with recurrent stress fractures of the lower limb. However, considerable variation occurs in the clinical expression of hypophosphatasia, and no curative treatment has yet been established. We herein report a case of adult hypophosphatasia with painful calcific periarthritis, which showed improvement after surgical resection. A 32-year-old male was referred to our clinic complaining of pain in his elbows and knees. A painful subcutaneous mass was palpable on his right lateral epicondyle, where periarticular calcification was detected by plain radiography. The laboratory data showed a slight decrease in serum ALP activity and bone mineral density, and an elevation in the urinary phosphoethanolamine. Genomic DNA sequencing revealed an F310L mutation and a Y246H polymorphism in the tissue-nonspecific alkaline phosphatase gene, confirming the diagnosis of hypophosphatasia. The pain in the patient's right elbow was not responsive to nonsteroidal anti-inflammatory drugs, and triamcinolone diacetate was locally injected for treatment. His symptoms were ameliorated after the injection; however, they recurred in 3months, and he became refractory to additional steroid injection. Surgical debridement of the calcified lesion was performed, and his symptoms were successfully ameliorated after the surgery.

Restoration of cellular function of mesenchymal stem cells from a hypophosphatasia patient

Mesenchymal stem cells (MSCs) can differentiate into multiple cell lineages and are used for regenerative treatments for a variety of diseases. However, the patient's cells cannot be used to treat genetic diseases. Allogeneic cells can serve as an alternative but long-term survival is uncertain. Our experience of allo-transplantation to a patient with hypophosphatasia, which is caused by mutations of the tissue non-specific alkaline phosphatase (TNSALP) gene resulting in low serum alkaline phosphatase (ALP) activity and skeletal deformity, did not improve these clinical characteristics. Therefore, we sought to use autologous MSCs for the treatment of hypophosphatasia. MSCs derived from the patient's bone marrow had a similar profile when compared with well-reported MSCs. However, the MSCs had extremely low ALP activity and could not produce a mineralized bone matrix even under the osteogenic culture conditions. We therefore transduced a retroviral vector with TNSALP promoter-driven TNSALP gene in the MSCs. In the culture condition, the MSCs had about 7-fold higher ALP activity than did mock-transduced MSCs, and showed mineralization as well as bone-specific markers. Furthermore, the MSCs, but not mock-transduced MSCs, newly formed bone at the frequency of 50% in nude rats. Transplantation of the TNSALP-transduced autologous MSCs might become a new therapy for hypophosphatasia.