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Michael P. Whyte - One of the best experts on this subject based on the ideXlab platform.
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natural history of perinatal and infantile Hypophosphatasia a retrospective study
The Journal of Pediatrics, 2019Co-Authors: Michael P. Whyte, Edward Leung, William R Wilcox, Johannes G Liese, Jesus Argente, Gabriel A Martosmoreno, Amy Reeves, Kenji P Fujita, Scott MoseleyAbstract:Objective To report clinical characteristics and medical history data obtained retrospectively for a large cohort of pediatric patients with perinatal and infantile Hypophosphatasia. Study design Medical records from academic medical centers known to diagnose and/or treat Hypophosphatasia were reviewed. Patients born between 1970 and 2011 with Hypophosphatasia and any of the following signs/symptoms at age NCT01419028 ). Patient demographics and characteristics, respiratory support requirements, invasive ventilator–free survival, and further complications of Hypophosphatasia were followed for up to the first 5 years of life. Results Forty-eight patients represented 12 study sites in 7 countries; 13 patients were alive, and 35 were dead (including 1 stillborn). Chest deformity, respiratory distress, respiratory failure (as conditioned by the eligibility criteria), failure to thrive, and elevated calcium levels were present in >70% of patients between birth and age 5 years. Vitamin B6–dependent seizures and respiratory distress and failure were associated significantly (P Conclusions Patients with perinatal or infantile Hypophosphatasia and vitamin B6–dependent seizures, with or without significant respiratory distress or chest deformities, have high morbidity and mortality in the first 5 years of life. Trial registration ClinicalTrials.gov : NCT01419028 .
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asfotase alfa for infants and young children with Hypophosphatasia 7 year outcomes of a single arm open label phase 2 extension trial
The Lancet Diabetes & Endocrinology, 2019Co-Authors: Michael P. Whyte, Kenji P Fujita, Scott Moseley, Nada J Salman, Jill H Simmons, Nick Bishop, John W Taylor, Dawn Phillips, Mairead McginnAbstract:Summary Background Our previous phase 2, open-label study of 11 infants and young children with life-threatening perinatal or infantile Hypophosphatasia showed 1 year safety and efficacy of asfotase alfa, an enzyme replacement therapy. We aimed to report the long-term outcomes over approximately 7 years of treatment. Methods We did a prespecified, end of study, 7 year follow-up of our single-arm, open-label, phase 2 trial in which children aged 3 years or younger with life-threatening perinatal or infantile Hypophosphatasia were recruited from ten hospitals (six in the USA, two in the UK, one in Canada, and one in the United Arab Emirates). Patients received asfotase alfa (1 mg/kg three times per week subcutaneously, adjusted to 3 mg/kg three times per week if required) for up to 7 years (primary treatment period plus extension phase) or until the product became commercially available; dosage adjustments were made at each visit according to changes in the patient's weight. The primary objectives of this extension study were to assess the long-term tolerability of asfotase alfa, defined as the number of patients with one or more treatment-emergent adverse events, and skeletal manifestations associated with Hypophosphatasia, evaluated using the Radiographic Global Impression of Change (RGI-C) scale (−3 indicating severe worsening, and +3 complete or near-complete healing). Respiratory support, growth, and cognitive and motor functions were also evaluated. All efficacy and safety analyses were done in all patients who received any asfotase alfa (full-analysis population). This study and extension phase are registered with ClinicalTrials.gov , number NCT01205152 , and EudraCT, number 2009-009369-32. Findings 11 participants were recruited between Oct 6, 2008, and Dec 4, 2009. Ten patients completed a 6 month treatment period and entered the extension phase; nine received asfotase alfa for at least 6 years and completed the study, with four being treated for more than 7 years. Skeletal healing was sustained over 7 years of treatment; all evaluable patients had RGI-C scores of at least +2 at year 6 (n=9; median score +2·0 [range 2·0–3·0]) and year 7 (n=7; median score +2·3 [2·0–3·0]). No patient who completed the study required respiratory support after year 4. Weight Z scores improved to within normal range from year 3 to study end; length or height Z scores improved but remained below normal. Age-equivalent scores on gross motor, fine motor, and cognitive subscales of the Bayley Scales of Infant and Toddler Development also improved. All 11 patients had at least one treatment-emergent adverse event. The most common adverse events were pyrexia (eight [73%] of 11 patients), upper respiratory tract infection (eight [73%]), craniosynostosis (seven [64%]), and pneumonia (seven [64%]). Serious adverse events related to asfotase alfa occurred in three (27%) patients (severe chronic hepatitis; moderate immediate post-injection reaction; and severe craniosynostosis with severe conductive deafness). Interpretation Patients with perinatal or infantile Hypophosphatasia treated with asfotase alfa for up to 7 years showed early, sustained improvements in skeletal mineralisation. Respiratory function, growth, and cognitive and motor function also improved, and asfotase alfa was generally well tolerated. Funding Alexion Pharmaceuticals, Inc.
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Hypophosphatasia and how alkaline phosphatase promotes mineralization
Genetics of Bone Biology and Skeletal Disease (Second Edition), 2018Co-Authors: Michael P. WhyteAbstract:Abstract Hypophosphatasia (HPP) is the remarkably informative inborn error of metabolism and metabolic bone disease that features low serum alkaline phosphatase (ALP) activity (hypophosphat asemia ) due to loss-of-function mutation(s) of TNSALP ( ALPL ), the gene that encodes the “tissue nonspecific” (bone/liver) isoenzyme of ALP (TNSALP). Lessons from HPP revealed that TNSALP is a cell-surface phosphohydrolase and showed how it functions. Several phosphocompounds that are TNSALP natural substrates accumulate extracellularly in HPP, including inorganic pyrophosphate (PP i ), an inhibitor of hydroxyapatite (HA) crystal growth, and pyridoxal 5′-phosphate (PLP), the major circulating form of vitamin B 6 . The superabundance of extracellular PP i blocks mineralization of the skeleton after matrix vesicles (MVs) rupture and release their nascent HA crystals. This causes rickets or osteomalacia despite normal or sometimes elevated circulating levels of calcium and phosphorus and adequate vitamin D. Failure of the cementumcovering tooth roots to mineralize leads to premature exfoliation of deciduous teeth. However, HPP spans the greatest range of severity of all skeletal diseases. This is largely explained by autosomal dominant (AD) and autosomal recessive (AR) inheritance from among several hundred, typically missense, mutations of TNSALP . Unless treated, perinatal HPP kills rapidly due to profound skeletal hypomineralization. Infantile HPP presents postnatally, but before age 6 months with rickets, failure-to-thrive, and sometimes hypercalcemia or vitamin B 6 -dependent seizures. Progressive chest deformity often causes lethal pulmonary problems. When severe, childhood HPP features symptomatic rickets, premature loss of deciduous teeth, and chronic muscle weakness. Adult HPP typically presents in middle age with osteomalacia and pseudofractures and sometimes arthropathies involving PP i deposition. Odonto-HPP, likely the most prevalent HPP, features tooth loss without skeletal disease. AR inheritance accounts for the most severely affected patients, whereas AD and rarely AR transmission explain the mild forms. In 2015, substantially effective bone-targeted TNSALP replacement therapy (asfotase alfa) received regulatory approval multinationally, typically for pediatric-onset HPP—the last rickets/osteomalacia to await a medical treatment. Now, for a variety of disorders, excessive ALP activity in diseased tissues is implicated in ectopic mineralization.
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Hypophosphatasia an overview for 2017
Bone, 2017Co-Authors: Michael P. WhyteAbstract: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.
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asfotase alfa therapy for children with Hypophosphatasia
JCI insight, 2016Co-Authors: Michael P. Whyte, Amy Reeves, William H Mcalister, Dawn Phillips, Katherine L Madson, Amy Yakimoski, Karen E Mack, Kim Hamilton, Kori Kagan, Kenji P FujitaAbstract:Background. Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Consequently, cell-surface deficiency of TNSALP phosphohydrolase activity leads to extracellular accumulation of inorganic pyrophosphate, a natural substrate of TNSALP and inhibitor of mineralization. Children with HPP can manifest rickets, skeletal pain, deformity, fracture, muscle weakness, and premature deciduous tooth loss. Asfotase alfa is a recombinant, bone-targeted, human TNSALP injected s.c. to treat HPP. In 2012, we detailed the 1-year efficacy of asfotase alfa therapy for the life-threatening perinatal and infantile forms of HPP. Methods. Here, we evaluated the efficacy and safety of asfotase alfa treatment administered to children 6-12 years of age at baseline who were substantially impaired by HPP. Two radiographic scales quantitated HPP skeletal disease, including comparisons to serial radiographs from similarly affected historical control patients. Results. Twelve children receiving treatment were studied for 5 years. The 6-month primary endpoint was met, showing significant radiographic improvement. Additional significant improvements included patient growth, strength, motor function, agility, and quality of life, which for most patients meant achieving normal values for age- and sex-matched peers that were sustained at 5 years of treatment. For most, pain and disability resolved. Mild to moderate injection-site reactions were common and were sometimes associated with lipohypertrophy. Low anti-asfotase alfa antibody titers were noted in all patients. No evidence emerged for clinically important ectopic calcification or treatment resistance. Conclusions. Asfotase alfa enzyme replacement therapy has substantial and sustained efficacy with a good safety profile for children suffering from HPP. Trial Registration. ClinicalTrials.gov NCT00952484 (https://clinicaltrials.gov/ct2/show/NCT00952484) and NCT01203826 (https://clinicaltrials.gov/ct2/show/NCT01203826). Funding. Alexion Pharmaceuticals Inc. and Shriners Hospitals for Children.
Etienne Mornet - One of the best experts on this subject based on the ideXlab platform.
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genetics of Hypophosphatasia
Archives De Pediatrie, 2017Co-Authors: Etienne MornetAbstract:Hypophosphatasia (HPP) is a rare inherited disorder primarily affecting bone and dental mineralization. Although there is a continuum in the severity of the disease, clinical forms may be arbitrarily distinguished on the basis of age at onset and the presence or absence of bone symptoms: perinatal, infantile, juvenile, adult, prenatal benign, and odontological. Severe forms (perinatal and infantile) are autosomally recessively inherited while less severe forms may be autosomally recessively or dominantly inherited. Genetic counseling is complicated by the coexistence of the two modes of inheritance, the incomplete penetrance of the dominant forms, the markedly variable expression of the disease, including intra-familial expression, and the existence of a benign prenatal form that may sometimes be difficult to distinguish from the severe prenatal form. The disease is due to loss-of-function mutations in the Alkaline Phosphatase-Liver (ALPL) gene encoding the tissue nonspecific alkaline phosphatase (TNSALP). The great variety of missence mutations and the dominant negative effect of some mutations largely explain the clinical heterogeneity. Directed mutagenesis studies allowed further elucidation of the cellular pathophysiology of HPP, classification of the alleles in terms of their severity and dominant negative effect, and molecular explanations of the dominant inheritance mode. Genetics significantly contributed to show that there are in fact two HPPs, rare, severe and recessive HPP, and mild recessive or mild dominant HPP, which is markedly more frequent and probably under-diagnosed. The prevalence of the severe forms of HPP has been estimated to be 1/300,000 in France and Northern Europe while the prevalence of the moderate forms of HPP may reach 1/6,370.
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molecular genetics of Hypophosphatasia and phenotype genotype correlations
Sub-cellular biochemistry, 2015Co-Authors: Etienne MornetAbstract:Hypophosphatasia (HPP) is due to deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNAP). This enzyme cleaves extracellular substrates inorganic pyrophosphates (PPi) , pyridoxal-5′-phosphate (PLP), phosphoethanolamine (PEA) and nucleotides , and probably other substrates not yet identified. During the last 15 years the role of TNAP in mineralization, and to a less degree in brain, has been investigated, providing hypotheses and explanations for both bone and neuronal HPP phenotypes. ALPL, the gene encoding TNAP, is subject to many mutations, mostly missense mutations . A few number of mutations are recurrently found and may be quite frequent in particular populations. This reflects founder effects. The great variety of mutations results in a great number of compound heterozygous genotypes and in highly variable clinical expressivity. A good correlation was observed between the severity of the disease and in vitro enzymatic activity of the mutant protein measured after site-directed mutagenesis. Many missense mutations found in severe Hypophosphatasia produced a mutant protein that failed to reach the cell membrane , was accumulated in the cis-Golgi and was subsequently degraded in the proteasome. Missense mutations located in the catalytic site or in the homodimer interface were often shown by site-directed mutagenesis to have a dominant negative effect. Currently molecular diagnosis of HPP is based on the sequencing of the coding sequence of ALPL that allows detection of approximately 95 % of mutations in severe cases. In addition, other genes, especially genes encoding proteins involved in the regulation of extracellular PPi concentration, could modify the phenotype (modifier genes).
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Unexpected high intrafamilial phenotypic variability observed in Hypophosphatasia
European Journal of Human Genetics, 2014Co-Authors: Christine Hofmann, Etienne Mornet, Hermann Girschick, Doris Schneider, Franz Jakob, Birgit MentrupAbstract:Hypophosphatasia (HPP) is a clinically heterogeneous rare, inherited disorder of bone and mineral metabolism with extensive allelic heterogeneity in the ALPL gene. In this report, we present a family with heterozygous parents (maternal p.(Glu191Lys), paternal p.(Gly334Asp) mutations in the ALPL gene) and four children (one genotypically normal, one heterozygous carrier and two compound heterozygous) showing an unexpected high phenotypic variability. One of the compound heterozygous showed clinical symptoms of the mild childhood form mainly affecting the teeth. The other one was more seriously affected with severe failure to thrive, delayed motor development, need for oxygen supply and profound mineralization deficit compatible with an infantile form of HPP. Functional in vitro studies identified p.(Glu191Lys) as mild (68%, no dominant-negative effect) and p.(Gly334Asp) as severely affected allele (1.2%, dominant-negative effect). In vitro simulation of the children’s genetic status showed a residual AP activity of 29%, while the biochemical AP activity in the serum was comparably reduced in both children (22 and 36 U/l). This family report indicates that mapping ALPL mutations within the gene does not necessarily help to predict the clinical severity of the phenotype. Therefore, results of prenatal diagnostics have to be interpreted with caution and prenatal genetic diagnosis and counseling for HPP should be provided within an experienced multidisciplinary team. Research about other confounding factors is urgently needed.
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molecular evolution of the tissue nonspecific alkaline phosphatase allows prediction and validation of missense mutations responsible for Hypophosphatasia
Journal of Biological Chemistry, 2014Co-Authors: Jeremie Silvent, Etienne Mornet, Barbara Gasse, Jeanyves SireAbstract:ALPL encodes the tissue nonspecific alkaline phosphatase (TNSALP), which removes phosphate groups from various substrates. Its function is essential for bone and tooth mineralization. In humans, ALPL mutations lead to Hypophosphatasia, a genetic disorder characterized by defective bone and/or tooth mineralization. To date, 275 ALPL mutations have been reported to cause Hypophosphatasia, of which 204 were simple missense mutations. Molecular evolutionary analysis has proved to be an efficient method to highlight residues important for the protein function and to predict or validate sensitive positions for genetic disease. Here we analyzed 58 mammalian TNSALP to identify amino acids unchanged, or only substituted by residues sharing similar properties, through 220 millions years of mammalian evolution. We found 469 sensitive positions of the 524 residues of human TNSALP, which indicates a highly constrained protein. Any substitution occurring at one of these positions is predicted to lead to Hypophosphatasia. We tested the 204 missense mutations resulting in Hypophosphatasia against our predictive chart, and validated 99% of them. Most sensitive positions were located in functionally important regions of TNSALP (active site, homodimeric interface, crown domain, calcium site, …). However, some important positions are located in regions, the structure and/or biological function of which are still unknown. Our chart of sensitive positions in human TNSALP (i) enables to validate or invalidate at low cost any ALPL mutation, which would be suspected to be responsible for Hypophosphatasia, by contrast with time consuming and expensive functional tests, and (ii) displays higher predictive power than in silico models of prediction.
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genetics of Hypophosphatasia
Clinical Reviews in Bone and Mineral Metabolism, 2013Co-Authors: Etienne MornetAbstract:Hypophosphatasia (HPP) results from mutations in the ALPL gene, mostly missense mutations. The gene is subject to a very high allelic heterogeneity, and some of these mutations have a dominant negative effect, two features that explain the most part of the clinical heterogeneity. Severe forms of the disease (perinatal and infantile) are inherited as an autosomal recessive trait. In the milder forms, autosomal recessive and autosomal dominant inheritance coexist. Experimental data show that there is a good correlation between the severity of the disease and in vitro alkaline phosphatase activity of the mutant protein. As a consequence of the existence of dominant mutations, moderate forms may be recessively or dominantly inherited and are expected more frequent than severe forms. The incidence of severe forms, inherited as a recessive trait, has been estimated at 1/300,000 in Europe. Genetic counseling is difficult in families where the mode of inheritance is unclear, or in prenatal context because of the prenatal benign form that may mimic severe perinatal HPP. During the ten last years, the mechanism of mineralization has been greatly deciphered, pointing out others gene that could modulate the HPP phenotype and explain particular cases where the phenotype does not correlate with the phenotype.
Jose Luis Millan - One of the best experts on this subject based on the ideXlab platform.
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Alkaline Phosphatase and Hypophosphatasia
Calcified Tissue International, 2016Co-Authors: Jose Luis Millan, Michael P. WhyteAbstract:Hypophosphatasia (HPP) results from ALPL mutations leading to deficient activity of the tissue-non-specific alkaline phosphatase isozyme (TNAP) and thereby extracellular accumulation of inorganic pyrophosphate (PP_i), a natural substrate of TNAP and potent inhibitor of mineralization. Thus, HPP features rickets or osteomalacia and hypomineralization of teeth. Enzyme replacement using mineral-targeted TNAP from birth prevented severe HPP in TNAP-knockout mice and was then shown to rescue and substantially treat infants and young children with life-threatening HPP. Clinical trials are revealing aspects of HPP pathophysiology not yet fully understood, such as craniosynostosis and muscle weakness when HPP is severe. New treatment approaches are under development to improve patient care.
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Hypophosphatasia pathophysiology and treatment
Actualizaciones en osteologia, 2012Co-Authors: Jose Luis Millan, Horacio PlotkinAbstract:Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) in the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNAP). The disease has been classified according to patient age when the first signs and symptoms manifest; i.e., perinatal, infantile, childhood, adult HPP. Other types include odonto HPP and perinatal benign. Babies with the perinatal/infantile forms of HPP often die with severe rickets and respiratory insufficiency and sometimes hypercalcemia and vitamin B6-responsive seizures. The primary biochemical defect in HPP is a deficiency of TNAP activity that leads to elevated circulating levels of substrates, in particular inorganic pyrophosphate (PPi), a potent calcification inhibitor. To-date, the management of HPP has been essentially symptomatic or orthopedic. However, enzyme replacement therapy with mineral-targeting TNAP (sALP-FcD10, also known as ENB-0040 or asfotase alfa) has shown promising results in a mouse model of HPP (Alpl-/- mice). Administration of mineral-targeting TNAP from birth increased survival and prevented the seizures, rickets, as well as all the tooth abnormalities, including dentin, acellular cementum, and enamel defects in this model of severe HPP. Clinical trials using mineral-targeting TNAP in children 3 years of age or younger with life-threatening HPP was associated with healing of the skeletal manifestations of HPP as well as improved respiratory and motor function. Improvement is still being observed in the patients receiving continued asfotase alfa therapy, with more than 3 years of treatment in some children. Enzyme replacement therapy with asfotase alfa has to-date been successful in patients with life-threatening HPP.
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enzyme replacement therapy prevents dental defects in a model of Hypophosphatasia
Journal of Dental Research, 2011Co-Authors: Marc D Mckee, Michael P. Whyte, Yukiko Nakano, David L Masica, Jeffrey J Gray, Isabelle Lemire, R Heft, Philippe Crine, Jose Luis MillanAbstract:Hypophosphatasia (HPP) occurs from loss-of-function mutation in the tissue-non-specific alkaline phosphatase (TNALP) gene, resulting in extracellular pyrophosphate accumulation that inhibits skeletal and dental mineralization. TNALP-null mice (Akp2-/-) phenocopy human infantile Hypophosphatasia; they develop rickets at 1 week of age, and die before being weaned, having severe skeletal and dental hypomineralization and episodes of apnea and vitamin B6-responsive seizures. Delay and defects in dentin mineralization, together with a deficiency in acellular cementum, are characteristic. We report the prevention of these dental abnormalities in Akp2-/- mice receiving treatment from birth with daily injections of a mineral-targeting, human TNALP (sALP-FcD10). sALP-FcD10 prevented hypomineralization of alveolar bone, dentin, and cementum as assessed by micro-computed tomography and histology. Osteopontin – a marker of acellular cementum – was immuno-localized along root surfaces, confirming that acellular cementum, typically missing or reduced in Akp2-/- mice, formed normally. Our findings provide insight concerning how acellular cementum is formed on tooth surfaces to effect periodontal ligament attachment to retain teeth in their osseous alveolar sockets. Furthermore, they provide evidence that this enzyme-replacement therapy, applied early in post-natal life – where the majority of tooth root development occurs, including acellular cementum formation – could prevent the accelerated tooth loss seen in individuals with HPP.
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enzyme replacement therapy for murine Hypophosphatasia
Journal of Bone and Mineral Research, 2007Co-Authors: Jose Luis Millan, Sonoko Narisawa, Isabelle Lemire, Thomas P Loisel, Guy Boileau, Pierre Leonard, Svetlana Gramatikova, Robert Terkeltaub, Nancy P Camacho, Marc D MckeeAbstract:Introduction Hypophosphatasia (HPP) is the inborn error of metabolism that features rickets or osteomalacia caused by loss-of-function mutation(s) within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNALP). Consequently, natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5`-phosphate (PLP), a co-factor form of vitamin B6. Babies with the infantile form of HPP often die with severe rickets and sometimes hypercalcemia and vitamin B6-dependent seizures. There is no established medical treatment.
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tissue nonspecific alkaline phosphatase and plasma cell membrane glycoprotein 1 are central antagonistic regulators of bone mineralization
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Lovisa Hessle, Sonoko Narisawa, Robert Terkeltaub, Kristen Johnson, Clarke H Anderson, Adnan Sali, James W Goding, Jose Luis MillanAbstract:Osteoblasts mineralize bone matrix by promoting hydroxyapatite crystal formation and growth in the interior of membrane-limited matrix vesicles (MVs) and by propagating the crystals onto the collagenous extracellular matrix. Two osteoblast proteins, tissue-nonspecific alkaline phosphatase (TNAP) and plasma cell membrane glycoprotein-1 (PC-1) are involved in this process. Mutations in the TNAP gene result in the inborn error of metabolism known as Hypophosphatasia, characterized by poorly mineralized bones, spontaneous fractures, and elevated extracellular concentrations of inorganic pyrophosphate (PPi). PPi suppresses the formation and growth of hydroxyapatite crystals. PPi is produced by the nucleoside triphosphate pyrophosphohydrolase activity of a family of isozymes, with PC-1 being the only member present in MVs. Mice with spontaneous mutations in the PC-1 gene have hypermineralization abnormalities that include osteoarthritis and ossification of the posterior longitudinal ligament of the spine. Here, we show the respective correction of bone mineralization abnormalities in knockout mice null for both the TNAP (Akp2) and PC-1 (Enpp1) genes. Each allele of Akp2 and Enpp1 has a measurable influence on mineralization status in vivo. Ex vivo experiments using cultured double-knockout osteoblasts and their MVs demonstrate normalization of PPi content and mineral deposition. Our data provide evidence that TNAP and PC-1 are key regulators of the extracellular PPi concentrations required for controlled bone mineralization. Our results suggest that inhibiting PC-1 function may be a viable therapeutic strategy for Hypophosphatasia. Conversely, interfering with TNAP activity may correct pathological hyperossification because of PPi insufficiency.
Steven Mumm - One of the best experts on this subject based on the ideXlab platform.
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adult Hypophosphatasia treated with teriparatide
The Journal of Clinical Endocrinology and Metabolism, 2007Co-Authors: Michael P. Whyte, Steven Mumm, Chad DealAbstract:Introduction: Hypophosphatasia (HPP) features low serum alkaline phosphatase (ALP) activity (hypophosphatasemia) due to loss-of-function mutation within TNSALP, the gene that encodes “tissue-nonspecific” ALP (TNSALP). Consequently, inorganic pyrophosphate accumulates extracellularly and impairs skeletal mineralization. Affected adults manifest osteomalacia, often with slowly healing metatarsal stress fractures (MTSFs) and proximal femur pseudofractures. Pharmacotherapy remains elusive. Patient and Methods: A middle-aged woman sustained a slowly healing MTSF and then two enlarging MTSFs and a spontaneous proximal femur fracture. Pain persisted at all fracture sites. HPP was diagnosed as a result of low ALP activity (10–24 IU/liter; normal, 40–150 IU/liter) and elevated inorganic phosphate and pyridoxal 5′-phosphate concentrations in serum. Teriparatide (TPTD) (recombinant human PTH 1–34), 20 μg, was injected sc daily in an attempt to enhance osteoblast synthesis of TNSALP. Results: Six weeks later, all fra...
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low serum alkaline phosphatase activity and pathologic fracture case report and brief review of Hypophosphatasia diagnosed in adulthood
Endocrine Practice, 2006Co-Authors: Hasnain M Khandwala, Michael P. Whyte, Steven MummAbstract:Objective: To describe an elderly patient with low serum alkaline phosphatase (ALP) activity detected after a pathologic fracture and to characterize Hypophosphatasia in adult patients.Methods: We present a case report of a 64-year-old woman, who was referred after sustaining an atraumatic femoral fracture treated successfully with intramedullary nailing. Clinical, biochemical, radiologic, and molecular studies explore the differential diagnosis of her hypophosphatasemia, and the features, diagnosis, and management of the adult form of Hypophosphatasia are reviewed.Results: Physical examination of our patient was revealing only for short stature. Bone mineral density evaluated by dual-energy x-ray absorptiometry was unremarkable. Biochemical investigations showed normal calcium, elevated inorganic phosphate, and low ALP levels in serum. In light of the hypophosphatasemia and pathologic fracture, the serum pyridoxal 5'-phosphate concentration was measured and found to be considerably elevated, a substantia...
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marrow cell transplantation for infantile Hypophosphatasia
Journal of Bone and Mineral Research, 2003Co-Authors: Michael P. Whyte, Steven Mumm, Michelle N Podgornik, William H Mcalister, Stephen P Coburn, Lawrence M Ryan, Joanne Kurtzberg, Cindy R Miller, Gary S GottesmanAbstract:An 8-month-old girl who seemed certain to die from the infantile form of Hypophosphatasia, an inborn error of metabolism characterized by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP), underwent the first trial of bone marrow cell transplantation for this heritable type of rickets. After cytoreduction, she was given T-cell-depleted, haplo-identical marrow from her healthy sister. Chimerism in peripheral blood and bone marrow became 100% donor. Three months later, she was clinically improved, with considerable healing of rickets and generalized skeletal remineralization. However, 6 months post-transplantation, worsening skeletal disease recurred, with partial return of host hematopoiesis. At the age of 21 months, without additional chemotherapy or immunosuppressive treatment, she received a boost of donor marrow cells expanded ex vivo to enrich for stromal cells. Significant, prolonged clinical and radiographic improvement followed soon after. Nevertheless, biochemical features of Hypophosphatasia have remained unchanged to date. Skeletal biopsy specimens were not performed. Now, at 6 years of age, she is intelligent and ambulatory but remains small. Among several hypotheses for our patient's survival and progress, the most plausible seems to be the transient and long-term engraftment of sufficient numbers of donor marrow mesenchymal cells, forming functional osteoblasts and perhaps chondrocytes, to ameliorate her skeletal disease.
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denaturing gradient gel electrophoresis analysis of the tissue nonspecific alkaline phosphatase isoenzyme gene in Hypophosphatasia
Molecular Genetics and Metabolism, 2002Co-Authors: Paula S. Henthorn, Michael P. Whyte, Steven Mumm, Jonathan Jones, Patrick M Finnegan, Michelle N PodgornikAbstract:Hypophosphatasia, a heritable form of rickets/osteomalacia, was first described in 1948. The biochemical hallmark, subnormal alkaline phosphatase (ALP) activity in serum, reflects a generalized disturbance involving the tissue-nonspecific isoenzyme of ALP (TNSALP). Deactivating mutations in the gene that encodes TNSALP have been reported in patients worldwide. Nevertheless, Hypophosphatasia manifests an extraordinary range of clinical severity spanning death in utero to merely premature loss of adult teeth. There is no known medical treatment. To delineate the molecular pathology which explains the disease variability and to clarify the pattern(s) of inheritance for mild cases of Hypophosphatasia, we developed comprehensive mutational analysis of TNSALP. High efficiency of mutation detection was possible by denaturing gradient gel electrophoresis (DGGE). Primers and conditions were established for all TNSALP coding exons (2-12) and adjacent splice sites so that the amplicons incorporated a GC clamp on one end. For each amplicon, the optimum percentage denaturant was determined by perpendicular DGGE. In 19 severely affected pediatric subjects (having perinatal or infantile Hypophosphatasia or early presentation during childhood) from among our large patient population, we detected 2 TNSALP mutations each in 16 patients (84%) as expected for autosomal recessive disease. For 2 patients (11%), only 1 TNSALP mutation was detected by DGGE. However, one subject (who died from perinatal Hypophosphatasia) had a large deletion as the second mutation. In the other (with infantile Hypophosphatasia), no additional mutation was detected by DNA sequencing of all protein-coding exons. Possibly, she too has a deletion. For the final patient, with unclassifiable Hypophosphatasia (5%), we detected only a single mutation which has been reported to cause relatively mild autosomal dominant disease; the other allele appeared to be intact. Hence, DGGE analysis was 100% efficient in detecting mutations in the coding exons and adjacent splice sites of TNSALP in this group of severely affected patients but, as expected, failed to detect a large deletion. To date, at least 78 different TNSALP mutations (in about 70 Hypophosphatasia patients) have been reported globally. In our large subset of severely affected patients, we identified 8 novel TNSALP mutations (Ala34Ser, Val111Met, Delta G392, Thr117His, Arg206Gln, Gly322Arg, Leu397Met, and Gly409Asp) and 1 new TNSALP polymorphism (Arg135His) furthering the considerable genotypic variability of Hypophosphatasia.
Toshimi Michigami - One of the best experts on this subject based on the ideXlab platform.
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clinical practice guidelines for Hypophosphatasia
Clinical Pediatric Endocrinology, 2020Co-Authors: Toshimi Michigami, Makoto Fujiwara, Takuo Kubota, Hideaki Sawai, Yasuhisa Ohata, Hiroshi Mochizuki, Masanori Adachi, Taichi Kitaoka, Noriyuki Namba, Kosei HasegawaAbstract:Hypophosphatasia (HPP) is a rare bone disease caused by inactivating mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). Patients with HPP have varied clinical manifestations and are classified based on the age of onset and severity. Recently, enzyme replacement therapy using bone-targeted recombinant alkaline phosphatase (ALP) has been developed, leading to improvement in the prognosis of patients with life-threatening HPP. Considering these recent advances, clinical practice guidelines have been generated to provide physicians with guides for standard medical care for HPP and to support their clinical decisions. A task force was convened for this purpose, and twenty-one clinical questions (CQs) were formulated, addressing the issues of clinical manifestations and diagnosis (7 CQs) and those of management and treatment (14 CQs). A systematic literature search was conducted using PubMed/MEDLINE, and evidence-based recommendations were developed. The guidelines have been modified according to the evaluations and suggestions from the Clinical Guideline Committee of The Japanese Society for Pediatric Endocrinology (JSPE) and public comments obtained from the members of the JSPE and a Japanese HPP patient group, and then approved by the Board of Councils of the JSPE. We anticipate that the guidelines will be revised regularly and updated.
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Benign prenatal Hypophosphatasia: a treatable disease not to be missed
Pediatric Radiology, 2014Co-Authors: Masaki Matsushita, Toshimi Michigami, Kanako Tachikawa, Hiroshi Kitoh, Naoki IshiguroAbstract:Prenatal bowing of the long bones is often associated with severe bone dysplasias. We report a child who presented marked bowing of the long bones at birth but showed a relatively benign postnatal course with spontaneous improvement of bowing. The fetal imaging showed normal skeletal mineralization and normal chest and abdominal circumferences despite the limb bowing and shortening. Decreased serum alkaline phosphatase activity and elevated urine phosphoethanolamine was biochemically evident, and compound heterozygous mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene were identified, which confirmed the diagnosis of a benign form of prenatal Hypophosphatasia. Benign prenatal Hypophosphatasia should be considered in the differential diagnosis of congenital bowing of the long bones.
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Hypophosphatasia now draws more attention of both clinicians and researchers a commentary on prevalence of c 1559delt in alpl a common mutation resulting in the perinatal lethal form of Hypophosphatasias in japanese and effects of the mutation on heterozygous carriers
Journal of Human Genetics, 2011Co-Authors: Keiichi Ozono, Toshimi MichigamiAbstract:Hypophosphatasia now draws more attention of both clinicians and researchers: A Commentary on prevelance of c. 1559delT in ALPL , a common mutation resulting in the perinatal (lethal) form of Hypophosphatasias in Japanese and effects of the mutation on heterozygous carriers
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clinical characteristics of perinatal lethal Hypophosphatasia a report of 6 cases
Clinical Pediatric Endocrinology, 2010Co-Authors: Akari Nakamurautsunomiya, Kanako Tachikawa, Satoshi Okada, Keiichi Hara, Shinichiro Miyagawa, Kanae Takeda, Rie Fukuhara, Yusei Nakata, Michiko Hayashidani, Toshimi MichigamiAbstract:Hypophosphatasia is a rare inherited disorder caused by deficient tissue-nonspecific alkaline phosphatase activity. It is classified into 6 subtypes, and the perinatal lethal form of Hypophosphatasia is the most severe. Patients with this form suffer from various symptoms, including respiratory failure, premature craniosynostosis, rachitic changes in the metaphyses, convulsions and hypercalcemia. This report presents 6 cases of the perinatal lethal form of Hypophosphatasia. All of the patients showed shortening of the long bones in utero in ultrasonographic examinations. Two of the six patients died at birth because they could not establish spontaneous breathing. Three of the remaining four patients also died before 1 yr of age. The major cause of death was respiratory failure due to hypoplastic lung. All of the patients, except for the two who died at birth, experienced convulsions in their clinical courses. Vitamin B6 therapy effectively reduced the frequency and severity of convulsions. However, it could not always make the patients convulsion free. Three patients underwent a genetic analysis. The 1559delT mutation, which abolishes Alkaline Phosphatase (ALP) activity, was a hot spot. A homozygous 1559delT mutation was observed in two patients. However, they differed in severity of symptoms. Although a good genotype-phenotype correlation has been reported in Hypophosphatasia, the genotype alone does not always predict the life span of the patients. These cases therefore suggested the importance of genetic counseling.
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Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with Hypophosphatasia
European Journal of Pediatrics, 2005Co-Authors: Toshimi Michigami, Takayuki Uchihashi, Akira Suzuki, Kanako Tachikawa, Shigeo Nakajima, Keiichi OzonoAbstract:A total of 22 Japanese patients with Hypophosphatasia were included in a study analysing the relationship between mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene and the severity of the phenotype in Japanese patients with Hypophosphatasia. The enzymatic activity of some of the identified mutant TNSALP proteins was also examined using corresponding expression vectors. Eighteen mutations, including 6 novel ones, were identified in the patients. Among them, the common mutations were F310L and T1559del. Of note, five patients with F310L mutation in one of the alleles exhibited a relatively mild phenotype without respiratory complications despite its perinatal onset. In contrast, the T1559del mutation is associated with perinatal lethal and infantile forms when not found in patients with the F310L mutation. The genotype-phenotype relationship was, to some extent, consistent with the enzymatic activity of the mutant ALP proteins; mutations K207E and G409C found in a surviving case of infantile Hypophosphatasia, as well as F310L, retained some residual activities, whereas T1559del caused a complete loss of activity. Conclusion: In Japanese patients, the common mutations F310L and T1559del are associated with the relatively mild and lethal forms of Hypophosphatasia, respectively. Our results may enhance the importance of genotyping patients with Hypophosphatasia to predict their prognosis.