Asfotase alfa

Hypophosphatasia (HPP) is an inherited, systemic disorder, caused by loss-of-function variants of the ALPL gene encoding the enzyme tissue non-specific alkaline phosphatase (TNSALP). HPP is characterized by low serum TNSALP concentrations associated with defective bone mineralization and increased fracture risk. Dental manifestations have been reported as the exclusive feature (odontohypophosphatasia) and in combination with skeletal complications. Enzyme replacement therapy (asfotase alfa) has been shown to improve respiratory insufficiency and skeletal complications in HPP patients, while its effects on dental status have been understudied to date...

BACKGROUND: Hypophosphatasia (HPP) is a rare congenital disease caused by a mutation affecting tissue non-specific alkaline phosphatase, an enzyme involved in phosphate metabolism. The clinical manifestation usually includes bone-mineralization disorders, neurological symptoms, and persistent muscle pain. CASE REPORT: This case involves a woman in her sixties of Central European descent who suffers from life-long chronic pain and muscle weakness due to hypophosphatasia and concomitant degenerative changes of the lumbar spine...

In recent years, new therapies for the treatment of rare pediatric bone disorders have emerged, guided by an increasing understanding of the genetic and molecular etiology of these diseases. Herein, we review three such disorders, impacted by debilitating deficits in bone mineralization or cartilage ossification, as well as the novel disease-modifying drugs that are now available to treat these conditions. Specifically, we discuss asfotase alfa, burosumab-twza, and vosoritide, for the treatment of hypophosphatasia, X-linked hypophosphatemia and achondroplasia, respectively...

Hypophosphatasia (HPP), a genetic disorder characterized by decreased tissue-nonspecific alkaline phosphatase (TNSALP) activity, is caused by loss-of-function mutations in the ALPL gene, which encodes TNSALP. The most frequent pathogenic variant in Japanese patients with HPP is a frameshift mutation in the ALPL gene, c.1559delT, and its carrier frequency is reported to be one in 480 in the Japanese population. We report the cases of two Japanese children with HPP who had a heterozygous c.1559delT variant in the ALPL gene...

Hypophosphatasia (HPP) is a genetic condition with broad clinical manifestations caused by alkaline phosphatase (ALP) deficiency. Adults with HPP exhibit a wide spectrum of signs and symptoms. Dental manifestations including premature tooth loss are common. Much of the published literature reporting dental manifestations consists of case reports and series of symptomatic patients, likely biased towards more severe dental manifestations. The objective of this study was to systematically explore the dental manifestations among adults with HPP by conducting a comprehensive dental evaluation...

Asfotase alfa is a human recombinant enzyme replacement therapy for hypophosphatasia. We describe 6 adults who were treated with asfotase alfa for 61-68 months in a clinical trial (NCT01163149), after which asfotase alfa was discontinued for 15-48 months. The patients experienced clinical deterioration and, when treatment was restarted, showed improvement. Patients with hypophosphatasia should be closely monitored if asfotase alfa is stopped as clinical decline is likely. Clinical practice guidelines are needed...

The last decade has been revolutionary regarding the management of rare bone diseases caused by impaired calcium and phosphate metabolism. Elucidation of the underlying genetic basis and pathophysiologic alterations has been the determinant factor for the development of new, disease-specific treatment agents. The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) possesses a critical role in the pathogenesis of various hypophosphatemic disorders. Among them, the genetic disorder of X-linked hypophosphatemia and the acquired syndrome of tumor-induced osteomalacia, although very rare, have attracted the scientific community's attention towards designing an FGF23-inhibitor as a potential specific therapy...

OBJECTIVES: We investigated the utility of urine phosphoethanolamine (PEA) as a marker to aid in diagnosing and/or confirming hypophosphatasia (HPP) in adults and for monitoring patients on enzyme replacement therapy (ERT). METHODS: Data was collected from seventy-eight adults who were referred to the Vanderbilt Program for Metabolic Bone Disease for evaluation of a possible or confirmatory HPP diagnosis between July 2014 through December 2019. Fifty-nine patients were diagnosed with HPP and nineteen were excluded from a diagnosis of HPP...

BACKGROUND: The clinical signs and symptoms of hypophosphatasia (HPP) can manifest during any stage of life. The age at which a patient's symptoms are reported can impact access to targeted treatment with enzyme replacement therapy (asfotase alfa), as this treatment is indicated for patients with pediatric-onset HPP in most countries. As such, many patients reported to have adult-onset HPP typically do not receive treatment. Comparison of the disease in treated and untreated adult patients is confounded by the approved indication...

Hypophosphatasia (HPP) is a rare genetic condition that can manifest from the prenatal period to adulthood. Clinical presentation is characterized by six major forms. HPP can be complex and debilitating. A two-year-old male with a past medical history of HPP presented to our emergency room with a non-displaced supracondylar fracture after minor trauma. Non-accidental trauma was considered in addition to inadequate medical control of his HPP. He was referred to our multidisciplinary clinic and asfotase alfa was increased to an appropriate dose...

Bisphosphonates, first-line medications for osteoporosis, are often not tolerated or discontinued for multiple reasons. Hypophosphatasia (HPP) is a genetic deficiency with the enzyme activity of tissue-nonspecific alkaline phosphatase (TNSALP). The symptoms of adult HPP are often non-specific, and the diagnosis may be delayed for years. Low serum alkaline phosphatase, a hallmark feature of HPP, is often overlooked. Genetic testing is recommended to confirm diagnosis, and treatment with asfotase alfa, a recombinant alkaline phosphatase, is available for patients with HPP...

Hypophosphatasia (HPP) is a rare inherited disorder caused by mutations in the ALPL gene. Mineralization defect in bones and teeth, abnormal respiratory function, seizures, hypotonia, bone pain, and nephrocalcinosis can be observed. Clinical forms are usually recognized based on age at diagnosis and severity of features. We present an infant with an enlarged anterior fontanelle, soft calvarium, fractures, respiratory distress, and seizures. Biochemical analysis showed hypercalcemia, normal serum phosphate, and low serum alkaline phosphatase (ALP) levels...

Hypophosphatasia (HPP) is a congenital disorder with decreased activity of tissue-nonspecific alkaline phosphatase. Asfotase alfa is the only treatment approved for HPP and improves the impairment of bone mineralization. Although several previous studies have reported the efficacy of asfotase alfa to treat fractures and pseudofractures in patients with HPP, there are only a few reports with a detailed description of the healing process. In this case report, we present an 18-year-old female patient with benign prenatal HPP who received asfotase alfa to treat her pseudofracture...

Developing therapeutics for the treatment of rare diseases usually requires a strong understanding of the natural history of the disease. Often, it also requires the creation of novel assessment tools and clinical trial endpoints. In diseases where mobility is impacted, the use of video to capture the impact of the disease and the assessment of specific parameters, such as gait and stride length, can help design sensitive endpoints. Video as an assessment tool also allows the use of historical videos or videos filmed by non-experts outside of clinical settings...

Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase ( TNAP ) gene. Reduced activity of TNAP leads to the accumulation of its substrates, mainly inorganic pyrophosphate and pyridoxal-5'-phosphate, metabolic aberrations that largely explain the musculoskeletal and systemic features of the disease. More than 400 ALPL mutations, mostly missense, are reported to date, transmitted by either autosomal dominant or recessive mode...

We report a 41-year-old man diagnosed with the adult form of hypophosphatasia (HPP) and treated for 4 years with less frequent than conventional daily doses of teriparatide (TPTD). He presented with a history of three low-energy fractures and low bone mineral density (BMD) ineffectively treated with bisphosphonate. We identified within ALPL , the gene that encodes the homodimeric "tissue-nonspecific" isoenzyme of alkaline phosphatase (ALP) and underlies HPP, a heterozygous missense mutation (c.455 G>A→R135H)...

Background: Asfotase alfa is the only approved treatment that can normalize mineralization in patients with hypophosphatasia (HPP). Its interference in alkaline phosphatase (ALP) dependent immunoassays has been reported. Objective: To describe thyroid function tests interfered with by asfotase alfa and elucidate the underlying mechanism. Patients and Methods . Three patients with HPP treated with asfotase alfa were included. Thyroid hormone levels measured using five different immunoassays with or without ALP as a labeling enzyme during asfotase alfa treatment were evaluated...

OBJECTIVES: With the advent of asfotase alfa, the enzyme replacement therapy (ERT) approved for hypophosphatasia (HPP), health care providers need to navigate management of ERT during critical illness. CASE PRESENTATION: We present the case of a young girl, treated with ERT for severe perinatal HPP, who had cardiorespiratory arrest in the setting of influenza A. Her life-saving treatment involving extra corporeal membrane oxygenation (ECMO) required a two-week interruption of ERT leading to persistent hypercalcemia and hyperphosphatemia...

No abstract text is available yet for this article.

SUMMARY: Hypophosphatasia (HPP) is a rare and under-recognised genetic defect in bone mineralisation. Patients presenting with fragility fractures may be mistakenly diagnosed as having osteoporosis and prescribed antiresorptive therapy, a treatment which may increase fracture risk. Adult-onset HPPhypophosphatasia was identified in a 40-year-old woman who presented with bilateral atypical femoral fractures after 4 years of denosumab therapy. A low serum alkaline phosphatase (ALP) and increased serum vitamin B6 level signalled the diagnosis, which was later confirmed by identification of two recessive mutations of the ALPL gene...