Tissue-nonspecific Isoenzyme Of Alkaline Phosphatase Research Articles

Pediatric hypophosphatasia: avoid diagnosis missteps!

Hypophosphatasia (HPP) is the dento-osseous disorder caused by deactivating mutation(s) of ALPL, the gene that encodes the "tissue-nonspecific" isoenzyme of alkaline phosphatase (TNSALP). In HPP, 3 natural substrates of cell-surface TNSALP accumulate extracellularly; phosphoethanolamine (PEA), inorganic pyrophosphate (PPi), and pyridoxal 5'-phosphate (PLP). Hypophosphatasemia together with elevated plasma levels of PEA, PPi, and PLP comprise its biochemical signature. PPi can inhibit mineralization and in extracellular excess can impair bone and tooth hardening and perhaps explain weak muscle. Autosomal dominant or autosomal recessive inheritance from among more than 400 mutations of ALPL largely accounts for HPP's broad-ranging severity, greatest among all skeletal diseases. Pediatric HPP spans life-threatening perinatal and infantile forms, childhood forms, and odonto-HPP selectively featuring premature loss of deciduous teeth. ALPL gene testing and TNSALP supplementation therapy have bolstered familiarity with HPP, but there are new considerations for diagnosis. Herein, diagnosis of a boy's mild childhood HPP was delayed by missteps involving his medical and dental history, physical examination, radiographic findings, and clinical laboratory studies. We review how pediatric HPP is now identified. Prompt diagnosis while appreciating the broad-ranging severity of HPP underlies the safe and effective management of this inborn-error-of-metabolism.

Effect of Asfotase Alfa in the Treatment of Hypophosphatasia- A Systematic Review.

Hypophosphatasia (HPP) is a life-threatening disease that occurs due to the mutation of the TNSALP (Tissue nonspecific isoenzyme of alkaline phosphatase) encoding gene. There is no approved treatment for Hypophosphatasia. Therefore, the only effective treatment for HPP is enzyme replacement therapy using the drug asfotase alfa which increases the patient's life span. The aim of the study is to evaluate the effectiveness and safety of asfotase alfa (enzyme replacement therapy) in treating HPP. A Literature search was done using PubMed, Google scholar, science direct, and Wiley LILACS utilizing MeSH keywords such as - Hypophosphatasia and asfotase alfa. A total of 411 articles were screened, of which four articles were taken for this qualitative analysis. Reporting of this systematic review is done by using PRISMA guidelines. Asfotase alfa/enzyme replacement therapy is examined on patients with different age groups and on congenital HPP patients to assess the effectiveness of HPP treatment. Enzyme replacement therapy using asfotase alfa is an effective and assured treatment for infants, children, and adults suffering from HPP.

Hypophosphatasia: Vitamin B6 status of affected children and adults.

Hypophosphatasia (HPP) is the heritable dento-osseous disease caused by loss-of-function mutation(s) of the gene ALPL that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP is a cell-surface homodimeric phosphomonoester phosphohydrolase expressed in healthy people especially in the skeleton, liver, kidneys, and developing teeth. In HPP, diminished TNSALP activity leads to extracellular accumulation of its natural substrates including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5'-phosphate (PLP), the principal circulating form of vitamin B6 (B6). Autosomal dominant and autosomal recessive inheritance involving >450 usually missense defects scattered throughout ALPL largely explains the remarkably broad-ranging severity of this inborn-error-of-metabolism. In 1985 when we identified elevated plasma PLP as a biochemical hallmark of HPP, all 14 investigated affected children and adults had markedly increased PLP levels. However, pyridoxal (PL), the dephosphorylated form of PLP that enters cells to cofactor many enzymatic reactions, was not low but often inexplicably elevated. Levels of pyridoxic acid (PA), the B6 degradation product quantified to assess B6 sufficiency, were unremarkable. Canonical signs or symptoms of B6 deficiency or toxicity were absent. B6-dependent seizures in infants with life-threatening HPP were later explained by their profound deficiency of TNSALP activity blocking PLP dephosphorylation to PL and diminishing gamma-aminobutyric acid synthesis in the brain. Now, there is speculation that altered B6 metabolism causes further clinical complications in HPP. Herein, we assessed the plasma PL and PA levels accompanying previously reported elevated plasma PLP concentrations in 150 children and adolescents with HPP. Their mean (SD) plasma PL level was nearly double the mean for our healthy pediatric controls: 66.7 (59.0) nM versus 37.1 (22.2) nM (P<0.0001), respectively. Their PA levels were broader than our pediatric control range, but their mean value was normal; 40.2 (25.1) nM versus 39.3 (9.9) nM (P=0.7793), respectively. In contrast, adults with HPP often had plasma PL and PA levels suggestive of dietary B6 insufficiency. We discuss why the B6 levels of our pediatric patients with HPP would not cause B6 toxicity or deficiency, whereas in affected adults dietary B6 insufficiency can develop.

O14 An atypical femoral fracture without a history of bisphosphonate use

Case report - IntroductionA 60-year-old female presented with an insufficiency fracture of the midshaft of the left femur and a persistently low serum alkaline phosphatase. A diagnosis of adult hypophosphatasia was made. We present this case alongside a series of other cases that we have identified locally and discuss the importance of identifying this condition in clinical practice.Case report - Case descriptionA 60-year-old female presented with left thigh pain and an 8-year history of polyarthralgia involving the medium-large sized joints. She had a traumatic fracture of the humerus 4 years previously. She had no history or examination findings suggestive of an inflammatory arthritis, connective tissue disease or systemic illness.An X-ray of left femur revealed a cortical-based lucency at the lateral cortex of midshaft. An MRI identified a focal area of cortical thickening but no evidence of bone marrow oedema suggestive of an osteoid osteoma. Finally, a CT scan confirmed the diagnosis of a healed stress fracture. The patient had never received any form of bisphosphonate treatment, no previous history of a non-traumatic fracture and no history of dental problems.Laboratory evaluation revealed persistently low levels of serum alkaline phosphatase (∼23 IU/L) with a normal vitamin D and PTH level. Bone density scan showed a T-score of -1.1 at the femoral neck and -2.6 at the lumbar spine. Serum pyridoxal phosphate level was elevated at 457 nmol/L (35-100). A diagnosis of adult hypophosphatasia was suspected and genetic study for ALPL gene confirmed the diagnosis.The following table summarises a number of other cases of adult hypophosphatasia, which we have identified locally. CaseAge / GenderPresentationAlkaline phospha tase (IU/L)Pyridoxal phosphate (nmol/L)Notes1 (Index case)62 / FWidespread pain, Atypical femoral fracture23457Genetic study confirmed278 / FWidespread pain, Osteomalacia22201Genetic study confirmed356 / MSon of Case 2, Osteoporosis, Diabetes mellitus22 – 29awaited Bisphosphonate stoppedGenetic study awaited 440 / FRecurrent metatarsal fractures, Low BMD24NormalBisphosphonate stopped548 / FPremature loss of teeth, fatigue, Widespread pain, Diabetes mellitus, hyperlipidaemia13-23327Genetic study confirmed675 / FSeronegative polyarthritis21-26120Genetic study awaitedCase report - DiscussionHypophosphatasia (HPP) is a rare inherited metabolic disease caused by mutations in the alkaline phosphatase liver type (ALPL) gene, localized on the chromosome region 1p36.1–34, encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). The disease is related to a decrease in both level and activity of alkaline phosphatase enzyme (ALP). The clinical expression is highly variable, ranging from lethal forms to mild forms diagnosed in adults. Fractures, chondrocalcinosis, calcific periarthritis, and chronic muscle and bone pain are key features for the diagnosis of HPP in adults. Teriparatide has been used for treatment in some case reports with inconsistent results. Antiresorptive drugs are contraindicated as they can worsen underlying osteomalacia.Case report - Key learning pointsCheck for persistent low serum alkaline phosphatase levels in adults presenting with fragility fractures, crystal-related arthropathies and nonspecific generalised aches.Avoid bisphosphonates in patients with low alkaline phosphatase.

Vitamin B6 deficiency with normal plasma levels of pyridoxal 5'-phosphate in perinatal hypophosphatasia.

Pyridoxal 5'-phosphate (PLP), the principal circulating form of vitamin B6 (B6), is elevated in the plasma of individuals with hypophosphatasia (HPP). HPP is the inborn-error-of-metabolism caused by loss-of-function mutation(s) of ALPL, the gene that encodes the "tissue-nonspecific" isoenzyme of alkaline phosphatase (TNSALP). PLP accumulates extracellularly in HPP because it is a natural substrate of this cell-surface phosphomonoester phosphohydrolase. Even individuals mildly affected by HPP manifest this biochemical hallmark, which is used for diagnosis. Herein, an exclusively breast-fed newborn boy with life-threatening perinatal HPP had uniquely normal instead of markedly elevated plasma PLP levels before beginning asfotase alfa (AA) TNSALP-replacement therapy. These abnormal PLP levels were explained by B6 deficiency, confirmed by his low plasma level of 4-pyridoxic acid (PA), the B6 degradation product. His mother, a presumed carrier of one of his two ALPL missense mutations, had serum ALP activity of 50U/L (Nl 40-130) while her plasma PLP level was 9 μg/L (Nl 5-50) and PA was 3 μg/L (Nl 3-30). Her dietary history and breast milk pyridoxal (PL) level indicated she too was B6 deficient. With B6 supplementation using a breast milk fortifier, the patient's plasma PA level corrected, while his PLP level remained in the normal range but now in keeping with AA treatment. Our experience reveals that elevated levels of PLP in the circulation in HPP require some degree of B6 sufficiency, and that anticipated increases in HPP can be negated by hypovitaminosis B6.

Hypophosphatasia Misdiagnosed as Osteoporosis in a Young Girl

Introduction: Hypophosphatasia (HPP) is a rare inherited disease of mineral metabolism characterized by low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNALP), which causes an inability to liberate inorganic phosphate for hydroxyapatite crystal propagation as well as toxic accumulation of inorganic pyrophosphate, pyridoxal-5’-phosphate and urinary phosphoethanolamine. It has a prevalence of 1/100,000 to 1/900,000, although milder forms have an estimated prevalence of 1/6,370. Variable mutations in TNALP cause clinical expressions ranging from a severe perinatal form, which is often fatal after birth from pulmonary complications, to an infantile form, which can cause vitamin B6-responsive seizures, to an asymptomatic adult form. Case: A 27-year-old, ventilator-dependent female with osteoporosis, hypothyroidism, cerebral palsy with previous spinal fusion, seizure disorder and nephrocalcinosis presented with surgical site infection from a right femur ORIF she underwent a month ago. She had a history of microfractures and low-impact fractures of both femurs requiring several surgeries. Osteoporosis was diagnosed at age 5 and she had been on Fosamax ever since. She did not meet any developmental milestones as a baby and never reached menarche. Various diagnoses by multiple specialists did not fully explain her clinical presentation. Her medications included alendronate 5 mg, calcium carbonate 600 mg, ergocalciferol 400 U and levothyroxine 50 mcg. Physical exam showed poor dentition, a misshapen skull and bowed legs with contractures of her extremities. Her labs revealed Ca 9.1 mg/dL (8.4–10.2 mg/dL), albumin 3.2 gm/dL (3.5–5.2 gm/dL), phosphorus 5.1 mg/dL (2.5–4.5 mg/dL), alkaline phosphatase 32 U/L (35–105 U/L), PTH 28 pg/mL (15–65 pg/mL), vitamin D 33.5 ng/mL (30–100 ng/mL), C-telopeptide 509 pg/mL (34–635 pg/mL). A right knee X-Ray reported diffusely gracile and demineralized bones with muscular atrophy. She recently transitioned care from a pediatric endocrinologist to an adult endocrinologist, who tested her positive for heterozygous ALPL pathogenic variant hypophosphatasia and was considering her for asfotase alfa enzyme replacement therapy. Discussion: Our patient had infantile HPP, but due to misdiagnosis as osteoporosis, she was inappropriately treated with a bisphosphate for over 20 years. Treatment of HPP had been supportive until the approval of asfotase alfa (Strensiq) in October 2015. It is a bone-targeted human recombinant enzyme replacement therapy approved for infantile- and juvenile-onset HPP and has been shown to decrease mortality from 73% to 16% at age 5. With improvement in life-sustaining technology, more HPP patients are able to survive into adulthood. Awareness of the complex and polymorphic presentation of HPP by adult endocrinologists is paramount for accurate diagnosis, thus avoiding inappropriate treatments.

Hypophosphatasia: is it an underdiagnosed disease even by expert physicians?

Hypophosphatasia (HPP) is caused by mutations in the ALPL that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (ALP). Clinical manifestations range from extreme life-threatening lethal forms to no signs or symptoms at all. Consecutive 30,000 outpatients and inpatients with ALP data were screened retrospectively, out of which 1000 patients were found to have low levels of ALP more than once. Then, patients were evaluated for the symptoms and signs of HPP with further biochemical and genetic analyses. Thirty-seven patients who had severe musculoskeletal pain, recurrent fractures, and tooth anomalies were then screened with substrate and DNA sequencing analyses for HPP. It was determined that eight patients had variants in the ALPL gene. A total of eight different ALPL variants were identified in eight patients. The variants, namely c.244G > C (p.Gly82Arg), c.1444C > T (p.His482Tyr), c.1487A > G (p.Asn493Ser), and c.675_676insCA (p.Met226GlnfsTer52), had not been previously reported. Considering the wide spectrum of clinical signs and symptoms, HPP should be among the differential lists of bone, muscle, and tooth abnormalities at any age.

Hypophosphatasia: Current Literature for Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment.

Hypophosphatasia (HPP) is a rare inherited bone disorder identified by impaired bone mineralization. There are seven subtypes of HPP mainly characterized by their age of onset. These subtypes consist of perinatal (prenatal) benign, perinatal lethal, infantile, childhood, adult, odontohypophosphatasia, and pseudohypophosphatasia. Due to limited awareness of the condition, either misdiagnosis or delayed diagnosis is common. Furthermore, the condition is frequently treated with contraindicated drugs. This literature illustrates the most recent findings on the etiology, pathophysiology, clinical manifestations, diagnosing, and treatment for HPP and its subtypes. The etiology of the disease consists of loss-of-function mutations of the ALPL gene on chromosome one, which encodes for tissue nonspecific isoenzyme of alkaline phosphatase (TNAP).A decrease of TNAP reduces inorganic phosphate (Pi) for bone mineralization and allows for an increase in inorganic pyrophosphate (PPi) and phosphorylated osteopontin (p-OPN), which further reduces bone mineralization. The combination of these processes softens bone and mediates a clinical presentation similar to rickets/osteomalacia. HPP has an additional wide range of clinical features depending on its subtype.Although a concrete diagnostic guideline has not yet been established, many studies have supported a similar method of identifying HPP. Clinical features, radiological findings, and/or biomarker levels of the disorder should raise suspicion and encourage the inclusion of HPP as a differential diagnosis. Biomarkers, especially alkaline phosphatase (ALP), are major contributors to diagnosis. However, genetic testing is done for definitive diagnosis.The primary treatment for HPP is the reintroduction of TNAP as a recombinant enzyme called asfotase alfa. There are additional pharmaceutical treatments and in some cases, surgical intervention may be indicated. Pharmaceutical therapies such as bisphosphonates, denosumab, potent antiresorptive agents, and vitamin D are contraindicated in adults with HPP.We hope to raise awareness for HPP in order to prevent delayed diagnosis or misdiagnosis. We plan to encourage appropriate care and avoid treatments that may be contraindicating. We also encourage the development of a diagnostic guideline that will promote a consistently favorable patient prognosis.

Healing of vitamin D deficiency rickets complicating hypophosphatasia suggests a role beyond circulating mineral sufficiency for vitamin D in musculoskeletal health.

Hypophosphatasia (HPP) is the metabolic bone disease caused by loss-of-function mutation(s) of the ALPL gene that encodes the cell-surface tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). In HPP, extracellular accumulation of inorganic pyrophosphate (PPi), a TNSALP natural substrate and inhibitor of biomineralization, often leads to rickets or osteomalacia despite normal or sometimes elevated circulating levels of calcium (Ca) and inorganic phosphate (Pi). We report an infant girl with vitamin D deficiency rickets subsequently healed by cholecalciferol administration alone before receiving TNSALP-replacement therapy for accompanying HPP. Throughout her clinical course, circulating Ca and Pi levels were normal or elevated. At presentation with failure-to-thrive at age six months, radiographs revealed severe rickets and serum 25(OH)D was 8 ng/mL (Nl, 30-100), yet low ALP activity 55 U/L (Nl, 124-341), normal Ca 9.3 mg/dL (Nl, 8.5-10.1) and Pi 6.4 mg/dL (Nl, 3.5-7.0), and low-normal parathyroid hormone 21 pg/mL (Nl, 14-72) were instead consistent with HPP. At age nine months, after 1000 IU of cholecalciferol orally each day for six weeks, serum 25(OH)D was 86 ng/mL, strength markedly better, and radiographs documented significant improvement of rickets. At age 18 months, with fully healed vitamin D deficiency rickets, findings of underlying HPP included a waddling gait and Gower sign, metaphyseal "tongues" of radiolucency, elevated serum pyridoxal 5'-phosphate 121 ng/mL (Nl, 2-33), and bi-allelic ALPL missense mutations. Then, nearly complete restoration of strength and radiographic healing of her remaining skeletal disease from HPP occurred during asfotase alfa enzyme replacement treatment. At no time, including presentation, were circulating Ca or Pi levels compromised. Instead, and in keeping with HPP, high-normal or elevated serum Ca and Pi concentrations were consistently documented. Thus, our findings suggest some role for vitamin D in musculoskeletal health beyond assuring circulating mineral sufficiency.

Hyperphosphatemia with low FGF7 and normal FGF23 and sFRP4 levels in the circulation characterizes pediatric hypophosphatasia.

Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) of the ALPL gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP in healthy individuals is on cell surfaces richly in bone, liver, and kidney. Thus, TNSALP natural substrates accumulate extracellularly in HPP, including inorganic pyrophosphate (PPi), a potent inhibitor of hydroxyapatite crystal formation and growth. Superabundance of extracellular PPi (ePPi) in HPP impairs mineralization of bones and teeth, often leading to rickets during childhood and osteomalacia in adult life and to tooth loss at any age. HPP's remarkably broad-ranging severity is largely explained by nearly four hundred typically missense mutations throughout the ALPL gene that are transmitted as an autosomal dominant or autosomal recessive trait. In the clinical laboratory, the biochemical hallmark of HPP is low serum ALP activity (hypophosphatasemia). However, our experience indicates that hyperphosphatemia from increased renal reclamation of filtered inorganic phosphate (Pi) is also common. Herein, from our prospective single-center study, we document throughout the clinical spectrum of non-lethal pediatric HPP that hyperphosphatemia reflects increased renal tubular threshold maximum for phosphorus adjusted for the glomerular filtration rate (TmP/GFR). To explore its pathogenesis, we studied mineral metabolism and quantitated circulating levels of three phosphatonins [fibroblast growth factor 23 (FGF23), secreted frizzled-related protein 4 (sFRP4), and fibroblast growth factor 7 (FGF7)] in 41 pediatric patients with HPP, 73 with X-linked hypophosphatemia (XLH), and 15 healthy pediatric control (CTR) subjects. The HPP and XLH cohorts had normal serum total and ionized calcium and parathyroid hormone levels (Ps > 0.10) and uncompromised glomerular filtration. In XLH, serum FGF23 was characteristically elevated (P < 0.0001) and despite hypophosphatemia sFRP4 was normal (P > 0.4) while FGF7 was low (P < 0.0001). In HPP, despite hyperphosphatemia serum FGF23 and sFRP4 were normal (Ps > 0.8) while FGF7 was low (P < 0.0001). Subsequently, in rats, we confirmed that FGF7 is phosphaturic. Thus, hyperphosphatemia in non-lethal pediatric HPP is associated with phosphatonin insufficiency together with, as we discuss, ePPi excess and diminished renal TNSALP activity.

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. .

L’hypophosphatasie

Hypophosphatasia is a rare inherited skeletal disorder caused by loss-of function mutations in the APLP gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). There is a great variability of clinical expression. The presentation varies from a lethal neonatal presentation to mild manifestations in adulthood. In adults clinical manifestations include fractures, with recurrent metatarsal fractures and slowly healing, atypical femoral fractures, dental anomalies, chondrocalcinosis with crystalline arthritis, muscle pain. There is poor recognition of low alkaline phosphatase values. However, this diagnosis is important in order to avoid the use of antiresorptive therapy in case of fracture. The management of hypophosphatasia is provided by a multidisciplinary team, in collaboration with reference centers for rare bone diseases; it includes symptomatic measures and enzymatic replacement therapy (asfotase alfa) is an approved treatment for pediatric-onset hypophphosphatasia now available.

Hypophosphatasia: From Diagnosis to Treatment.

Hypophosphatasia (HPP) is a rare genetic disorder caused by mutations of the ALPL gene. ALPL encodes the tissue-non-specific isoenzyme of alkaline phosphatase (TNSALP). Consequently, bone mineralization is decreased leading to fractures, arthralgia, and extra-skeletal manifestations including tissue calcification, respiratory failure, and neurological complications. This review summarizes the most important clinical findings, diagnosis, and treatment options for HPP. Asfotase alfa is a recombinant human alkaline phosphatase, used as treatment for the underlying cause of HPP. Asfotase alfa enhances the survival in life-threatening HPP and improves bone mineralization, muscle strength, and pulmonary function. However, discontinuation of asfotase alfa leads to reappearance of bone hypomineralization. Due to its varied manifestations, HPP often mimics rheumatological and other bone diseases, thereby delaying its diagnosis. Asfotase alfa, a recombinant alkaline phosphatase, is available for the long-term enzyme replacement therapy in patients with pediatric-onset HPP to treat the bone manifestations of the disease.

Validation of a Novel Scoring System for Changes in Skeletal Manifestations of Hypophosphatasia in Newborns, Infants, and Children: The Radiographic Global Impression of Change Scale.

Hypophosphatasia (HPP) is the heritable metabolic disease characterized by impaired skeletal mineralization due to low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase. Although HPP during growth often manifests with distinctive radiographic skeletal features, no validated method was available to quantify them, including changes over time. We created the Radiographic Global Impression of Change (RGI-C) scale to assess changes in the skeletal burden of pediatric HPP. Site-specific pairs of radiographs of newborns, infants, and children with HPP from three clinical studies of asfotase alfa, an enzyme replacement therapy for HPP, were obtained at baseline and during treatment. Each pair was scored by three pediatric radiologists ("raters"), with nine raters across the three studies. Intrarater and interrater agreement was determined by weighted Kappa coefficients. Interrater reliability was assessed using intraclass correlation coefficients (ICCs) and by two-way random effects analysis of variance (ANOVA) and a mixed-model repeated measures ANOVA. Pearson correlation coefficients evaluated relationships of the RGI-C to the Rickets Severity Scale (RSS), Pediatric Outcomes Data Collection Instrument Global Function Parent Normative Score, Childhood Health Assessment Questionnaire Disability Index, 6-Minute Walk Test percent predicted, and Z-score for height in patients aged 6 to 12 years at baseline. Eighty-nine percent (8/9) of raters showed substantial or almost perfect intrarater agreement of sequential RGI-C scores (weighted Kappa coefficients, 0.72 to 0.93) and moderate or substantial interrater agreement (weighted Kappa coefficients, 0.53 to 0.71) in patients aged 0 to 12 years at baseline. Moderate-to-good interrater reliability was observed (ICC, 0.57 to 0.65). RGI-C scores were significantly (p ≤ 0.0065) correlated with the RSS and with measures of global function, disability, endurance, and growth in the patients aged 6 to 12 years at baseline. Thus, the RGI-C is valid and reliable for detecting clinically important changes in skeletal manifestations of severe HPP in newborns, infants, and children, including during asfotase alfa treatment. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Genetic analysis of adults heterozygous for ALPL mutations.

Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the ALPL gene. Patients have consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain. Adult HPP may be recessively or dominantly inherited; the latter case is assumed to be due to the dominant negative effect (DNE) of missense mutations derived from the functional homodimeric structure of TNSALP. However, there is no biological argument excluding the possibility of other causes of dominant HPP. Rheumatologists and endocrinologists are increasingly solicited for patients with low AP and nonpathognomonic symptoms of HPP. Many of these patients are heterozygous for an ALPL mutation and a challenging question is to determine if these symptoms, which are also common in the general population, are attributable to their heterozygous ALPL mutation or not. In an attempt to address this question, we reviewed a cohort of 61 adult patients heterozygous for an ALPL mutation. Mutations were distinguished according to their statistical likelihood to show a DNE. One-half of the patients carried mutations predicted with no DNE and were slightly less severely affected by the age of onset, serum AP activity and history of fractures. We hypothesized that these mutations result in another mechanism of dominance or are recessive alleles. To identify other genetic factors that could trigger the disease phenotype in heterozygotes for potential recessive mutations, we examined the next-generation sequencing results of 32 of these patients for a panel of 12 genes involved in the differential diagnosis of HPP or candidate modifier genes of HPP. The heterozygous genotype G/C of the COL1A2 coding SNP rs42524 c.1645C>G (p.Pro549Ala) was associated with the severity of the phenotype in patients carrying mutations with a DNE whereas the homozygous genotype G/G was over-represented in patients carrying mutations without a DNE, suggesting a possible role of this variant in the disease phenotype. These preliminary results support COL1A2 as a modifier gene of HPP and suggest that a significant proportion of adult heterozygotes for ALPL mutations may have unspecific symptoms not attributable to their heterozygosity.

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: Enzyme Replacement Therapy Brings New Opportunities and New Challenges.

Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Autosomal inheritance (dominant or recessive) from among more than 300 predominantly missense defects of TNSALP (ALPL) explains HPP's broad-ranging severity, the greatest of all skeletal diseases. In health, TNSALP is linked to cell surfaces and richly expressed in the skeleton and developing teeth. In HPP,TNSALP substrates accumulate extracellularly, including inorganic pyrophosphate (PPi), an inhibitor of mineralization. The PPi excess can cause tooth loss, rickets or osteomalacia, calcific arthropathies, and perhaps muscle weakness. Severely affected infants may seize from insufficient hydrolysis of pyridoxal 5'-phosphate (PLP), the major extracellular vitamin B6 . Now, significant successes are documented for newborns, infants, and children severely affected by HPP given asfotase alfa, a hydroxyapatite-targeted recombinant TNSALP. Since fall 2015, this biologic is approved by regulatory agencies multinationally typically for pediatric-onset HPP. Safe and effective treatment is now possible for this last rickets to have a medical therapy, but a number of challenges involving diagnosis, understanding prognosis, and providing this treatment are reviewed herein. © 2017 American Society for Bone and Mineral Research.

Hypophosphatasia: Natural history study of 101 affected children investigated at one research center

Hypophosphatasia (HPP) is the inborn-error-of-metabolism that features deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Resultant extracellular accumulation of inorganic pyrophosphate, a TNSALP substrate and potent inhibitor of mineralization, typically leads to tooth loss and sometimes to rickets or osteomalacia. HPP's remarkably broad-ranging severity is largely explained by autosomal dominant versus autosomal recessive transmission from among several hundred usually missense mutations positioned throughout the gene that encodes TNSALP. In 2015, our cross-sectional investigation of 173 affected children validated and expanded the clinical nosology commonly used for pediatric HPP.Herein, for the 101 patients in that cohort with longitudinal data, we explored the natural history of pediatric HPP by assessing their z-scores for height and then for weight, grip strength, and bone mineral density (BMD) determined by dual energy X-ray absorptiometry (DXA) also after adjusting for patient height. Eighteen patients contributed to “across” puberty evaluation.According to increasing HPP severity, there were 28 odonto HPP, 28 mild childhood HPP, 37 severe childhood HPP, and 8 infantile HPP patients typically studied from early to mid-childhood. The individual values for each parameter were wide-ranging within, and overlapping between, the four successive patient groups. Final mean/median z-scores, like the published initial values, paralleled the nosology. Longitudinal findings were similar for the boys versus girls and across puberty. Mean/median height z-scores remained constant for all four patient groups. In contrast, mean/median weight z-scores increased with aging, including after height-adjustment, resembling the recent trend for American children. However, excessive weight gain was typically not observed and mean/median values became average for height. Mean/median z-scores calculated routinely for chronologic age did not change for grip strength or for lumbar spine or total hip BMD. However, height-correction of the cohort suggested some worsening of grip strength z-scores and indicated improvement in spine BMD z-scores.Overall, in affected children and adolescents, HPP represents a clinically stable but chronic disorder.

A concise review on hypophosphatasia with case report

Hypophosphatasia (HPP) is an inherited dento-osseous metabolic disease characterized by inactivating mutations in the gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) which lead to a deficiency in TNSALP enzymatic activity. Low TNSALP activity results in increased levels of 3 known phosphocompound substrates: inorganic pyrophosphate (PPi), pyridoxal 5’-phosphate (PLP; the major circulating form of vitamin B6), and phosphoethanolamine (PEA). We discussed a systematic review with novel approach and a case report in which patient had multiple jaw reconstructive surgeries and early tooth loss in his childhood age but remained undiagnosed till his 60s. It should raise awareness among health care providers regarding low TNSALP and performing thorough etiological investigations which can ensure optimal clinical care and decision making for their patients by preventing complications like chondrocalcinosis, arthritis, early tooth loss, pseudo/complete fractures and pseudogout among the patients diagnosed with HPP even later in their life.

Adult Hypophosphatasia Treated with Teriparatide: Report of 2 Patients and Review of the Literature

Hypophosphatasia (HPP) is a rare inherited metabolic bone disease from deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Reportedly, teriparatide (parathyroid hormone 1-34) can benefit the adult form of HPP, including fracture healing. We studied 2 women with adult HPP given teriparatide and reviewed the reports of 6 additional patients. A 68-year-old black woman (patient 1) described low-trauma fractures and had subnormal serum alkaline phosphatase (ALP) activity. Biochemical findings were consistent with HPP. Mutation analysis revealed a heterozygous defect in exon 10 of TNSALP (ALPL). Teriparatide was injected daily for 2 years. Four years later, she fractured her right hip. Treatment was resumed for 8 months without further fractures. A 53-year-old white woman (patient 2) reported low-trauma fractures and had subnormal serum ALP. Mutation analysis revealed a heterozygous defect in exon 8 of TNSALP. She injected teriparatide daily for 2 years. One year later, bone mineral density (BMD) declined and treatment was resumed for 3 months. When she sustained a sacral fracture, teriparatide was administered for a further 18 months. Patient 1's serum ALP increased while receiving teriparatide and returned to baseline after its discontinuation. BMD remained unchanged, but no fractures were sustained. Patient 2's serum ALP increased, but the improvement was not sustained. Femoral neck BMD increased significantly during the first cycle, declined significantly afterwards, and was regained during a second course of teriparatide. Teriparatide shows some benefit for adult HPP. ALP = alkaline phosphatase BMD = bone mineral density BSAP = bone-specific alkaline phosphatase CTX = C-telopeptide DXA = dual-energy X-ray absorptiometry FN = femoral neck HPP = hypophosphatasia LS = lumbar spine PEA = phosphoethanolamine PLP = pyridoxal 5'-phosphate PTH = parathyroid hormone SQ = subcutaneous TNSALP = tissue-nonspecific isoenzyme of alkaline phosphatase TPTD = teriparatide.