Hypophosphatasia: from birth to adulthood.

Hypophosphatasia (HPP) is an inherited disease caused by a low activity of tissue-nonspecific alkaline phosphatase, a hydrolase that removes phosphate groups from many molecules. Decreased alkaline phosphatase activity leads to the accumulation of three main metabolites, i.e., pyridoxal 5´-phosphate (PLP), inorganic pyrophosphate (PPi), and phosphoethanolamine. Impairment in PLP dephosphorylation induces seizures, while PPi accumulation inhibits bone mineralization. Clinically, HPP has a wide spectrum of presentations, ranging from neonatal death to an apparent lack of symptoms. This disease is classified into six subtypes according to the age at onset of first signs or symptoms. The clinical manifestations of the disease include rickets-like bone changes, bone demineralization, fragility fractures, reduced muscular strength, chest deformity, pulmonary hypoplasia, nephrolithiasis, nephrocalcinosis, and chondrocalcinosis. Treatment of HPP consists of enzyme replacement therapy. Before this therapy was approved, treatment was palliative and associated with high morbidity and mortality. Asfotase alfa has changed the prognosis of the disease by reducing bone deformity and improving bone mineralization, lung function, and muscle weakness, among other benefits. In adults, teriparatide and anti-sclerostin antibody have been used off-label in selected cases, demonstrating benefit in accelerating fracture healing and in concomitant treatment of osteoporosis. This review summarizes the main aspects of HPP and identifies the particularities of the disease in adult patients.

Evaluation of alveolar bone hypomineralization in pediatric hypophosphatasia using orthopantomography.

Hypophosphatasia (HPP) is a metabolic disease characterized by impaired bone mineralization and early exfoliation of primary teeth. This study was performed to develop a method for quantitatively evaluating alveolar bone hypomineralization using orthopantomographic images. Alveolar bone density was defined according to the pixel values and corrected by brightness shown by an indicator applied to the orthopantomographic device. Images of 200 healthy subjects (aged 2-15 years) were classified into five age groups. The corrected pixel values were significantly lower in the younger group than in those aged 14-15 years (2-4, 5-7, and 8-10 years versus 14-15 years: P < 0.0001, 11-13 years versus 14-15 years: P < 0.01). Orthopantomographic images of 17 patients with HPP were evaluated. The corrected pixel values of three-fourths of the patients with odonto type HPP were lower than the mean values of the healthy group. One-third of patients treated with enzyme replacement therapy showed higher corrected pixel values than the healthy group. Our results suggest that odonto type HPP without skeletal problems is occasionally accompanied by hypomineralization of alveolar bone and that alveolar bone hypomineralization in patients with severe HPP is possibly improved by enzyme replacement therapy.

Gene Therapy Using Adeno-Associated Virus Serotype 8 Encoding TNAP-D10 Improves the Skeletal and Dentoalveolar Phenotypes in Alpl-/- Mice.

Hypophosphatasia (HPP) is caused by loss-of-function mutations in the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP), whose deficiency results in the accumulation of extracellular inorganic pyrophosphate (PPi ), a potent mineralization inhibitor. Skeletal and dental hypomineralization characterizes HPP, with disease severity varying from life-threatening perinatal or infantile forms to milder forms that manifest in adulthood or only affect the dentition. Enzyme replacement therapy (ERT) using mineral-targeted recombinant TNAP (Strensiq/asfotase alfa) markedly improves the life span, skeletal phenotype, motor function, and quality of life of patients with HPP, though limitations of ERT include frequent injections due to a short elimination half-life of 2.28 days and injection site reactions. We tested the efficacy of a single intramuscular administration of adeno-associated virus 8 (AAV8) encoding TNAP-D10 to increase the life span and improve the skeletal and dentoalveolar phenotypes in TNAP knockout (Alpl-/- ) mice, a murine model for severe infantile HPP. Alpl-/- mice received 3 × 1011 vector genomes/body of AAV8-TNAP-D10 within 5 days postnatal (dpn). AAV8-TNAP-D10 elevated serum ALP activity and suppressed plasma PPi . Treatment extended life span of Alpl-/- mice, and no ectopic calcifications were observed in the kidneys, aorta, coronary arteries, or brain in the 70 dpn observational window. Treated Alpl-/- mice did not show signs of rickets, including bowing of long bones, enlargement of epiphyses, or fractures. Bone microstructure of treated Alpl-/- mice was similar to wild type, with a few persistent small cortical and trabecular defects. Histology showed no measurable osteoid accumulation but reduced bone volume fraction in treated Alpl-/- mice versus controls. Treated Alpl-/- mice featured normal molar and incisor dentoalveolar tissues, with the exceptions of slightly reduced molar enamel and alveolar bone density. Histology showed the presence of cementum and normal periodontal ligament attachment. These results support gene therapy as a promising alternative to ERT for the treatment of HPP. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Hypophosphatasia.

Hypophosphatasia (HPP) is a group of inherited disorders characterised by the impaired mineralisation of bones and/or teeth and low serum alkaline phosphatase (ALP) activity. It is caused by a mutation in the ALPL gene encoding the tissue-non-specific isoenzyme of ALP (TNSALP) resulting in a loss of function. The disease is highly heterogenous in its clinical expression ranging from stillbirth without mineralised bone to the mild form of late adult onset with symptoms and signs such as musculoskeletal pain, arthropathy, lower-extremity fractures, premature loss of teeth or an incidental finding of reduced serum ALP activity. A classification based on the age at diagnosis and the presence or absence of bone symptoms was historically used: perinatal, prenatal benign, infantile, childhood, adult and odontohypophosphatasia. These subtypes are known to have overlapping signs and complications. Three forms of HPP distinguishable by their genetic characteristics have been described: severe, moderate and mild. Severe forms of HPP (perinatal and infantile severe) are recessively inherited, whereas moderate HPP may be dominantly or recessively inherited. The biochemical hallmark of HPP is persistently low serum ALP for age and increase in natural substrates of TNSALP, pyridoxal 5'-phosphate and phosphoethanolamine supported by radiological findings. The diagnosis is confirmed by ALPL sequencing. A multidisciplinary team of experts is essential for the effective management. Calcium restriction is recommended in infants/children to manage hypercalcaemia. A targeted enzyme replacement therapy for HPP has become available and correct diagnosis is crucial to allow early treatment.

Hypophosphatasia: A Unique Disorder of Bone Mineralization.

Hypophosphatasia (HPP) is a rare genetic disease characterized by a decrease in the activity of tissue non-specific alkaline phosphatase (TNSALP). TNSALP is encoded by the ALPL gene, which is abundantly expressed in the skeleton, liver, kidney, and developing teeth. HPP exhibits high clinical variability largely due to the high allelic heterogeneity of the ALPL gene. HPP is characterized by multisystemic complications, although the most common clinical manifestations are those that occur in the skeleton, muscles, and teeth. These complications are mainly due to the accumulation of inorganic pyrophosphate (PPi) and pyridoxal-5'-phosphate (PLP). It has been observed that the prevalence of mild forms of the disease is more than 40 times the prevalence of severe forms. Patients with HPP present at least one mutation in the ALPL gene. However, it is known that there are other causes that lead to decreased alkaline phosphatase (ALP) levels without mutations in the ALPL gene. Although the phenotype can be correlated with the genotype in HPP, the prediction of the phenotype from the genotype cannot be made with complete certainty. The availability of a specific enzyme replacement therapy for HPP undoubtedly represents an advance in therapeutic strategy, especially in severe forms of the disease in pediatric patients.

[Rare bone disorders and respective treatments]. / Seltene osteologische Erkrankungen und ihre Therapie.

Delineating the genetic background and the underlying pathophysiology of rare skeletal dysplasias enables a broader understanding of these disorders as well as novel perspectives regarding differential diagnosis and targeted development of therapeutic approaches. Hypophosphatasia (HPP) due to genetically determined Alkaline Phosphatase deficiency exemplifies this development. While an enzyme replacement therapy could be established for severe HPP with the prevailing bone manifestation, the clinical impact of not immediately bone-related manifestations just being successively understood. Correspondingly, the elucidation of the pathophysiology underlying renal phosphate wasting expanded our knowledge regarding phosphate metabolism and bone health and facilitated the development of an anti-FGF-23 Antibody for targeted treatment of X­linked Hypophosphatemia (XLH). Evolutions regarding the nosology of osteogenesis imperfecta (OI) along with the identification of further causative genes also detected in the context of genetically determined osteoporosis illustrate the pathophysiologic interrelation between monogenetic bone dysplasias and multifactorial osteoporosis. While current therapeutic strategies for OI follow osteoporosis treatment, the expanding knowledge about OI forms the fundament for establishing improved treatment strategies-for both OI and osteoporosis. Similar developments are emerging regarding rare skeletal disorders like Achondroplasia, Fibrodysplasia ossificans progressive and Morbus Morquio (Mukopolysaccharidosis Type IV).

Looking for new anabolic treatment from rare diseases of bone formation.

Bone remodelling is a complex mechanism regulated by osteoclasts and osteoblasts and perturbation of this process leads to the onset of diseases, which may be characterised by altered bone erosion or formation. In this review, we will describe some bone formation-related disorders as sclerosteosis, van Buchem disease, hypophosphatasia and Camurati-Engelmann disease. In the past decades, the research focused on these rare disorders offered the opportunity to understand important pathways regulating bone formation. Thus, the identification of the molecular defects behind the etiopathology of these diseases will open the way for new therapeutic approaches applicable also to the management of more common bone diseases including osteoporosis.

Adult hypophosphatasia manifests in a marathon runner.

A 49-year-old woman, previously healthy, presented with recurrent fractures provoked by minimal trauma. She had sustained seven fractures over the previous 2 years. While she was an avid runner, her injuries were determined to be out of proportion to the degree of trauma. Initial evaluation, exploring the more common causes such as low bone density and abnormal vitamin D metabolism, was unremarkable. On repeat of the some of the tests, a low alkaline phosphatase (AP) was noted, which raised suspicion for hypophosphatasia (HPP), a rare cause of recurrent fractures. Subsequent workup revealed a low bone-specific AP and elevated vitamin B6 Subsequently, genetic testing confirmed the diagnosis of adult-onset HPP caused by a heterozygous mutation c.407G>A in the ALPL gene. Asfotase alfa was started; however, the patient developed an allergic reaction leading to the discontinuation of the drug.

Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment.

This article provides an overview of the current knowledge on hypophosphatasia-a rare genetic disease of very variable presentation and severity-with a special focus on adolescents and adults. It summarizes the available information on the many known mutations of tissue-nonspecific alkaline phosphatase (TNSALP), the epidemiology and clinical presentation of the disease in adolescents and adults, and the essential diagnostic clues. The last section reviews the therapeutic approaches, including recent reports on enzyme replacement therapy (EnzRT).

Treatment of hypophosphatasia.

Hypophosphatasia (HPP) is a rare disorder with perinatal, infantile, childhood, and adult presentations. Severe forms are autosomal recessive with an early onset, whereas milder forms have a later onset. The underlying cause of the disease is a mutation based on a genetic disorder of the tissue non-specific alkaline phosphatase (TNSALP) gene, leading on the one hand to decreased activity of the TNSALP enzyme, and on the other hand to accumulation of TNSALP substrates. Symptoms like non-traumatic and non-healing fractures, musculoskeletal pain, chondrocalcinosis, seizures, premature loss of fully rooted teeth or delayed development of milk teeth, respiratory insufficiency, and calcinosis in muscles, kidneys, and joints occur. Supportive treatment is important for HPP patients, including mechanical ventilation, accurate fracture treatment, physical therapy, dental monitoring, and follow-up care to avoid subsequent problems. A causal enzyme therapy replacement with asfotase-alfa was approved by the Food and Drug Administration (FDA) in 2015. Asfotase-alfa improves respiratory insufficiency, bone mineralization, and long-term survival, and has a very good safety profile.

High-Level Expression of Alkaline Phosphatase by Adeno-Associated Virus Vector Ameliorates Pathological Bone Structure in a Hypophosphatasia Mouse Model.

Hypophosphatasia (HPP) is a systemic skeletal disease caused by mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP). We recently reported that survival of HPP model mice can be prolonged using an adeno-associated virus (AAV) vector expressing bone-targeted TNALP with deca-aspartate at the C terminus (TNALP-D10); however, abnormal bone structure and hypomineralization remained in the treated mice. Here, to develop a more effective and clinically applicable approach, we assessed whether transfection with TNALP-D10 expressing virus vector at a higher dose than previously used would ameliorate bone structure defects. We constructed a self-complementary AAV8 vector expressing TNALP driven by the chicken beta-actin (CBA) promoter (scAAV8-CB-TNALP-D10). The vector was injected into both quadriceps femoris muscles of newborn HPP mice at a dose of 4.5 × 1012 vector genome (v.g.)/body, resulting in 20 U/mL of serum ALP activity. The 4.5 × 1012 v.g./body-treated HPP mice grew normally and displayed improved bone structure at the knee joints in X-ray images. Micro-CT analysis showed normal trabecular bone structure and mineralization. The mechanical properties of the femur were also recovered. Histological analysis of the femurs demonstrated that ALP replacement levels were sufficient to promote normal, growth plate cartilage arrangement. These results suggest that AAV vector-mediated high-dose TNALP-D10 therapy is a promising option for improving the quality of life (QOL) of patients with the infantile form of HPP.

Case Report: Efficacy of Reduced Doses of Asfotase Alfa Replacement Therapy in an Infant With Hypophosphatasia Who Lacked Severe Clinical Symptoms.

Background: Hypophosphatasia is a rare bone disease characterized by impaired bone mineralization and low alkaline phosphatase activity. Here, we describe the course of bone-targeted enzyme replacement therapy with asfotase alpha for a female infant patient with hypophosphatasia who lacked apparent severe clinical symptoms. Case presentation: The patient exhibited low serum alkaline phosphatase (60 U/L; age-matched reference range, 520-1,580) in a routine laboratory test at birth. Further examinations revealed skeletal demineralization and rachitic changes, as well as elevated levels of serum calcium (2.80 mmol/L; reference range, 2.25-2.75 mmol/L) and ionic phosphate (3.17 mmol/L; reference range, 1.62-2.48 mmol/L), which are typical features in patients with hypophosphatasia. Sequencing analysis of the tissue-nonspecific alkaline phosphatase (TNSALP) gene identified two pathogenic mutations: c.406C>T, p.Arg136Cys and c.979T>C, p.Phe327Leu. Thus, the patient was diagnosed with hypophosphatasia. At the age of 37 days, she began enzyme replacement therapy using asfotase alpha at the standard dose of 6 mg/kg/week. Initial therapy from the age of 37 days to the age of 58 days substantially improved rickets signs in the patient; it also provided immediate normalization of serum calcium and ionic phosphate levels. However, serum ionic phosphate returned to a high level (2.72 mmol/L), which was presumed to be a side effect of asfotase alpha. Thus, the patient's asfotase alfa treatment was reduced to 2 mg/kg/week, which allowed her to maintain normal or near normal skeletal features thereafter, along with lowered serum ionic phosphate levels. Because the patient exhibited slight distal metaphyseal demineralization in the knee at the age of 2 years and 6 months, her asfotase alfa treatment was increased to 2.4 mg/kg/week. No signs of deterioration in bone mineralization were observed thereafter. At the age of 3 years, the patient's motor and psychological development both appeared normal, compared with children of similar age. Conclusion: This is the first report in which reduced doses of asfotase alfa were administered to an infant patient with hypophosphatasia who lacked apparent severe clinical symptoms. The results demonstrate the potential feasibility of a tailored therapeutic option based on clinical severity in patients with hypophosphatasia.

Alkaline Phosphatase Replacement Therapy.

Hypophosphatasia (HPP) is a rare genetic disease, characterized by the defective production of tissue-non-specific alkaline phosphatase (TNSALP). Six subtypes of the disease - affecting neonates (beginning in utero), infants, children, or adults - are recognized: perinatal lethal, prenatal benign, infantile, childhood, adult, and odontohypophosphatasia. The clinical presentation of these subtypes is very different and the severity ranges from mild to lethal. This chapter, after an overview of the genetics, epidemiology, classification, and clinical presentation of the different forms of HPP, will review the current experience with enzyme replacement therapy (ERT).

Alkaline Phosphatase Replacement Therapy for Hypophosphatasia in Development and Practice.

Hypophosphatasia (HPP) is an inherited disorder that affects bone and tooth mineralization characterized by low serum alkaline phosphatase. HPP is caused by loss-of-function mutations in the ALPL gene encoding the protein, tissue-nonspecific alkaline phosphatase (TNSALP). TNSALP is expressed by mineralizing cells of the skeleton and dentition and is associated with the mineralization process. Generalized reduction of activity of the TNSALP leads to accumulation of its substrates, including inorganic pyrophosphate (PPi) that inhibits physiological mineralization. This leads to defective skeletal mineralization, with manifestations including rickets, osteomalacia, fractures, and bone pain, all of which can result in multi-systemic complications with significant morbidity, as well as mortality in severe cases. Dental manifestations are nearly universal among affected individuals and feature most prominently premature loss of deciduous teeth. Management of HPP has been limited to supportive care until the introduction of a TNSALP enzyme replacement therapy (ERT), asfotase alfa (AA). AA ERT has proven to be transformative, improving survival in severely affected infants and increasing overall quality of life in children and adults with HPP. This chapter provides an overview of TNSALP expression and functions, summarizes HPP clinical types and pathologies, discusses early attempts at therapies for HPP, summarizes development of HPP mouse models, reviews design and validation of AA ERT, and provides up-to-date accounts of AA ERT efficacy in clinical trials and case reports, including therapeutic response, adverse effects, limitations, and potential future directions in therapy.

Natural History of Perinatal and Infantile Hypophosphatasia: A Retrospective Study.

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 <6 months were eligible: vitamin B6-dependent seizures, respiratory compromise, or rachitic chest deformity (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 < .05) with the risk of early death. Serum alkaline phosphatase activity in all 41 patients tested (mean [SD]: 18.1 [15.4] U/L) was below the mean lower limit of normal of the reference ranges of the various laboratories (88.2 U/L). Among the 45 patients with relevant data, 29 had received respiratory support, of whom 26 had died at the time of data collection. The likelihood of invasive ventilator-free survival for this cohort decreased to 63% at 3 months, 54% at 6 months, 31% at 12 months, and 25% at 5 years. 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.

A Case of the Perinatal Form Hypophosphatasia Caused by a Novel Large Duplication of the ALPL Gene and Report of One Year Follow-up with Enzyme Replacement Therapy

Hypophosphatasia (HPP) is a rare disease caused by mutations in the ALPL gene encoding tissue-non-specific isoenzyme of alkaline phosphatase (TNSALP). Duplications of the ALPL gene account for fewer than 1% of the mutations causing HPP. It has been shown that asfotase alfa enzyme replacement treatment (ERT) mineralizes the skeleton and improves respiratory function and survival in severe forms of HPP. Our patient was a newborn infant evaluated for respiratory failure and generalized hypotonia after birth. Diagnosis of HPP was based on low-serum ALP activity, high concentrations of substrates of the TNSALP and radiologic findings. On day 21 after birth, ERT using asfotase alfa (2 mg/kg three times per week, subcutaneous injection) was started. His respiratory support was gradually reduced and skeletal mineralization improved during treatment. We were able to discharge the patient when he was seven months old. No mutation was detected in the ALPL gene by all exon sequencing, and additional analysis was done by quantitative polymerase chain reaction (qPCR). As a result, a novel homozygote duplication encompassing exons 2 to 6 was detected. Early diagnosis and rapid intervention with ERT is life-saving in the severe form of HPP. qPCR can detect duplications if a mutation cannot be detected by sequence analysis in these patients.

New diagnostic modalities and emerging treatments for neonatal bone disease.

Bone disease in the neonatal period has often been regarded as an issue affecting premature infants, or a collection of rare and ultra-rare disorders that most neonatologists will see only once or twice each year, or possibly each decade. The emergence of targeted therapies for some of these rare disorders means that neonatologists may be faced with diagnostic dilemmas that need a rapid solution in order to access management options that did not previously exist. The diagnostic modalities available to the neonatologist have not changed a great deal in recent years; blood tests and radiographs still form the mainstays with other techniques usually reserved for research studies, but rapid access to genomic testing is emergent. This paper provides an update around diagnosis and management of bone problems likely to present to the neonatologist.

Enzyme-replacement therapy in perinatal hypophosphatasia: Case report and review of the literature.

Hypophosphatasia (HPP) is a rare disease resulting from alterations of the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Perinatal HPP is mainly characterized by bone hypomineralization and severe respiratory insufficiency. We describe a full-term boy diagnosed with perinatal HPP after birth, showing dramatic improvement after treatment with Asfotase Alfa, an enzyme-replacement therapy (ERT) prescribed in HPP cases. He initially presented with respiratory insufficiency due to bone hypomineralization, and severe pulmonary hypoplasia that required tracheostomy and invasive ventilation for 8 months. He was taken off ventilation at 41 weeks of age. He also presented complications including hypercalcemia, craniosynostosis, nephrocalcinosis, hypotonia, and a severe feeding disorder. He is still alive at 30 months of age, and his respiratory status and tonus is steadily improving. This case reflects the progression of HPP patients with specific therapy added to symptomatic management. Some aspects of the disease are now well known, such as nephrocalcinosis and craniosynostosis, related to the natural course of the disease, which persisted despite the ERT. The long-term prognosis and outcome for this newborn child remain unknown.