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Hypophosphatasia (HPP) is a rare inherited bone disorder with systemic symptoms, which vary depending on the time of onset and other factors. It may be fatal or cause severe clinical symptoms in infants and children. By comparison, adult HPP generally has a more favorable prognosis, and it is usually associated with chronic pain, recurrent fractures, and impaired quality of life. However, the diagnosis of adult HPP is often delayed or it may remain undiagnosed. Additionally, treatment options for adult HPP are not well established. We report a male patient in his 50s who experienced recurrent fractures in his 40s and 50s, together with chronic pain. He was diagnosed with HPP due to low serum alkaline phosphatase levels and a heterozygous missense variant of the ALPL gene (c.529G>A). He therefore started enzyme replacement therapy with asfotase alfa. After 12 months of treatment with asfotase alfa, his motor function showed marked improvement and he experienced fewer falls and no new fragility fractures, although his chronic pain remained.

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.

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

SummaryHypophosphatasia (HPP) is a rare bone disease with limited scientific evidence on the tolerability and safety of its novel treatment, Asfotase Alfa (AA). We report 7 HPP patients’ heterogenous presentations and the significant improvement in various clinical outcomes attained with AA shedding light on this highly effective and safe therapy.IntroductionHypophosphatasia (HPP) is a rare inherited metabolic bone disorder characterized by a deficiency in the tissue non-specific alkaline phosphatase (TNSALP) due to loss of function mutation in the ALPL gene. HPP is associated with impaired skeletal mineralization due to elevations in inorganic pyrophosphate and altered phosphate : pyrophosphate ratio. Asfotase alfa (AA) “enzyme replacement” was approved for treatment of HPP in 2015. We present 7 patients with HPP, 5 with pediatric-onset, and 2 with adult-onset, who have been treated with AA and describe the efficacy and safety in these patients.Methods7 patients (4 females, 3 males) aged 19–68 years with HPP were included in this study. Diagnosis of HPP was confirmed by DNA analysis. AA was administered in doses of 6mg/kg/week with a mean follow-up of 6 months (SD= 5).ResultsSubjective improvement in muscle strength, muscle pain, walking ability, and walking distance with a reduction in the use of gait aids was seen “with AA in HPP patients.” Muscle strength and pain improved by up to 70% from baseline as quantified subjectively by patients. Walking distance improved by up to 100%. Patients also reported improved cognition, mood, and energy levels, with up to 90% improvement in mood and 75% improvement in energy levels. 4 out of 6 patients first noted clinical signs of improvement after 3 months of being on therapy. 1 out of the 7 patients sustained a toe fracture 10 months from being on AA. AA was well-tolerated with injection site reactions being the most reported adverse effect.ConclusionHPP treatment with AA in individuals with both pediatric and adult-onset forms resulted in significant subjective improvement in musculoskeletal and cognitive manifestations in addition to patients’ quality of life. The drug was well tolerated in 6 patients. 1 patient discontinued therapy because of minor adverse effects with myalgias.

SummaryHypophosphatasia (HPP) is a rare inherited disorder of bone and mineral metabolism caused by loss of function mutations in the ALPL gene. The presentation in children and adults can be extremely variable and natural history is poorly understood particularly in adults. Careful patient evaluation is required with consideration of pharmacologic intervention in individuals meeting criteria for therapy.IntroductionThe purposes of this review are to present current evidence regarding the diagnosis and management of hypophosphatasia in children and adults and provide evidence-based recommendations for management.MethodA MEDLINE, EMBASE, and Cochrane database search and literature review was completed. The following consensus recommendations were developed based on the highest level of evidence as well as expert opinion.ResultsHypophosphatasia is a rare inherited disorder of bone and mineral metabolism due to loss of function mutations in the tissue non-specific alkaline phosphatase (ALPL) gene causing reductions in the activity of the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP). Deficient levels of alkaline phosphatase result in elevation of inhibitors of mineralization of the skeleton and teeth, principally inorganic pyrophosphate. The impaired skeletal mineralization may result in elevations in serum calcium and phosphate. Clinical features include premature loss of teeth, metatarsal and subtrochanteric fractures as well as fragility fractures. Poor bone healing post fracture has been observed. Myalgias and muscle weakness may also be present. In infancy and childhood, respiratory and neurologic complications can occur.ConclusionsHPP is associated with significant morbidity and mortality. Pharmacologic intervention can result in significant clinical improvement. This Canadian position paper provides an overview of the musculoskeletal, renal, dental, respiratory, and neurologic manifestations of hypophosphatasia. The current state of the art in the diagnosis and management of hypophosphatasia is presented.

ABSTRACT 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.

Objective Hypophosphatasia (HPP) is a rare inherited disorder caused by ALPL gene mutations, with fracture nonunion being a serious complication. This study investigated the effects of teriparatide and asfotase alfa (AA) on femoral fracture healing of an adult patient with HPP, accompanied with a literature review. Methods A 37-year-old woman wheelchair-bound was diagnosed with HPP due to an extremely low serum alkaline phosphatase (ALP) level (4–10 U/L), who suffered from bilateral femur pain and non-union of femoral shaft fractures on both sides. Compound heterozygous missense mutations (c.382G > A and c.461C > T) were identified in exon5 of ALPL gene. The patient received teriparatide sequential AA therapy. Serum levels of ALP, β-isomerized carboxy-telopeptide of type I collagen (β-CTX) and procollagen type 1 amino-terminal peptide (P1NP), bone mineral density (BMD) and skeletal X-ray were measured during the treatment. Literature was searched by keywords of “Hypophosphatasia”, “HPP”, “ALPL”, “TNSALP”, “ALP” combined with “Asfotase alfa”, “AA”, “enzyme replacement therapy”, and “ERT”. Results After unsuccessful 6-month teriparatide treatment for femoral fracture, AA treatment was initiated, at a dose of 2 mg/kg, 3 times a week. After the first month of AA treatment, serum ALP level increased from 4 to 9206 U/L, and serum calcium and phosphate levels decreased, with increase in PTH, β-CTX, and P1NP levels. After 4 months of AA treatment, her bone pain significantly alleviated, accompanied by significant shortening of the fracture line. After 10 months of AA therapy, the fracture demonstrated complete healing and the patient could walk independently. BMD at lumbar spine and hips was significantly increased. Among 295 adult patients with HPP reported in the literature, 213 (72.2%) exhibited skeletal-related symptoms and 91 (30.8%) presented with bone fractures. In addition to skeletal manifestations, the patients presented with early tooth loss, muscle weakness and ectopic calcification. AA treatment, spanning 9 weeks to 3 years, has been shown to increase ALP levels, promote fracture healing, improve mobility, and alleviate bone pain. Conclusion Adult HPP patients mainly present with recurrent or poorly healing fractures, bone pain, and early loss of teeth. AA replacement therapy can effectively promote fracture healing, relieve bone pain, and enhance mobility.

Background Hypophosphatasia (HPP) is a rare, inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the tissue-nonspecific alkaline phosphatase TNAP (ORPHA 436). Its clinical presentation is highly heterogeneous with a remarkably wide-ranging severity. HPP affects patients of all ages. In children HPP-related musculoskeletal symptoms may mimic rheumatologic conditions and diagnosis is often difficult and delayed. To improve the understanding of HPP in children and in order to shorten the diagnostic time span in the future we studied the natural history of the disease in our large cohort of pediatric patients. This single centre retrospective chart review included longitudinal data from 50 patients with HPP diagnosed and followed at the University Children’s Hospital Wuerzburg, Germany over the last 25 years. Results The cohort comprises 4 (8%) perinatal, 17 (34%) infantile and 29 (58%) childhood onset HPP patients. Two patients were deceased at the time of data collection. Diagnosis was based on available characteristic clinical symptoms (in 88%), low alkaline phosphatase (AP) activity (in 96%), accumulating substrates of AP (in 58%) and X-ray findings (in 48%). Genetic analysis was performed in 48 patients (31 compound heterozygous, 15 heterozygous, 2 homozygous mutations per patient), allowing investigations on genotype-phenotype correlations. Based on anamnestic data, median age at first clinical symptoms was 3.5 months (min. 0, max. 107), while median time to diagnosis was 13 months (min. 0, max. 103). Common symptoms included: impairment of motor skills (78%), impairment of mineralization (72%), premature loss of teeth (64%), musculoskeletal pain and craniosynostosis (each 64%) and failure to thrive (62%). Up to now 20 patients started medical treatment with Asfotase alfa. Conclusions Reported findings support the clinical perception of HPP being a chronic multi-systemic disease with often delayed diagnosis. Our natural history information provides detailed insights into the prevalence of different symptoms, which can help to improve and shorten diagnostics and thereby lead to an optimised medical care, especially with promising therapeutic options such as enzyme-replacement-therapy with Asfotase alfa in mind.

Background Hypophosphatasia (HPP; OMIM 241510, 241500, and 146300) is a progressive metabolic, genetic disease with wide clinical heterogeneity, ranging from perinatal lethality to mild or moderate localized symptoms. This study aims to analyze the perception of pain, quality of life, and access barriers to healthcare among patients diagnosed with hypophosphatasia in Colombia. In this document we present pain and quality of life results. Methods This study is an observational cohort of 18 HPP patients registered in the Colombian Association of Patients with Lysosomal Storage Diseases and Other Orphan Diseases (ACOPEL) database. We conducted a descriptive analysis using data from three questionnaires (SF-36, Brief Pain Questionnaire (BPQ), and Hypophosphatasia Impact Patient Survey (HIPS); the latter was translated into Spanish and validated for this study. Results The most affected features, according to the SF-36 questionnaire, were overall health, vitality, and pain, with a median score above 67%. Patients' perception of their health status (HIPS questionnaire) was favorable, with 38.9% of cases reporting excellent health. On average, results from the BPQ indicated mild to moderate intensity of current pain experienced by patients. Consistency was observed in the reports of either the absence of pain or the presence of mild to moderate intensity when analyzing the results of the three questionnaires. Conclusions Colombian patients with HPP experience mild to moderate impairment in quality of life and pain that interfere with their daily activities. However, there is wide variability in the results obtained.