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1.
Buenos Aires; CONETEC; nov. 2019.
Não convencional em Espanhol | BRISA/RedTESA | ID: biblio-1048252

RESUMO

INTRODUCCIÓN: La hipofosfatasia (HPP) es una enfermedad hereditaria "ultra rara" sumamente heterogénea, del metabolismo fosfo-cálcico generada por un déficit enzimático. Se presenta con múltiples formas clínicas, que van desde alteraciones dentales hasta falta de mineralización ósea generalizada, que lleva a una alta tasa de mortalidad. El pronóstico empeora cuanto más precoz es el inicio de los síntomas (formas perinatales e infantil). No se encuentran disponibles datos de prevalencia locales; se estima una incidencia de aproximadamente 2 casos nuevos de las formas severas cada año en Argentina. DESCRIPCIÓN DE LA TECNOLOGÍA: Asfotase alfa es una enzima de reemplazo diseñada para suplementar la actividad de la TN-SALP, la misma es obtenida por técnicas de ADN recombinante utilizando células de ovario de hámster chino. Se administra de forma subcutánea, la dosis recomendada por el fabricante es de 2 mg/kg tres veces por semana o 1 mg/kg seis veces por semana, aunque se ha utilizado en dosis superiores en los estudios encontrados. METODOLOGÍA: Se realizó una búsqueda en Medline, Lilacs, Cochrane, Tripdatabase, ClínicalTrials.gov, Orphanet y buscadores genéricos de internet. Se utilizaron las palabras clave "asfotase", "hypophosphatasia AND enzyme replacement", "asfotase AND hypophosphatasia", "strensiq". Se consideraron criterios de inclusión a ensayos clínicos controlados aleatorizados (ECCAs), ensayos clínicos no controlados, cohortes prospectivas, casos y controles y estudios de fase 2 o más avanzado, realizados en humanos; en idioma inglés, español, francés o portugués. RESULTADOS: Para la forma clínica perinatal severa e infantil, evidencia de muy baja calidad basada en estudios de fase 2 mostró un beneficio considerable para los desenlaces sobrevida, soporte ventilatorio y cambios radiológicos. Los costos directos anuales de la tecnología para el tratamiento de esta forma clínica se estimaron entre US$ 178.308 y US$ 217.620. En el caso de la forma clínica infanto-juvenil se incluyó un estudio de fase 2 donde se valoró un beneficio considerable para el desenlace cambios radiológicos. Sin embargo, el efecto del tratamiento fue incierto para los desenlaces sobrevida y calidad de vida. La calidad de la evidencia hallada en este caso también fue muy baja. Finalmente, para la forma clínica adulta, en el estudio de fase 2 incluido, no observó beneficio para los desenlaces mineralización ósea y dolor; y un efecto incierto del tratamiento para los desenlaces sobrevida y calidad de vida. La calidad de la evidencia hallada fue baja. CONCLUSIÓN: La información de este reporte contiene las opiniones y perspectivas de una cuidadora de un paciente pediátrico sobre la evolución de la enfermedad hasta llegar al tratamiento, y sobre la vida cotidiana. En el caso de este paciente de 6 años, con diagnostico a los 8 meses de vida, que recibe asfotase alfa hace 3 años, el tratamiento presentó buenos resultados en cuanto al dolor y al desarrollo de la marcha.


Assuntos
Humanos , DNA Recombinante/uso terapêutico , Terapia de Reposição de Enzimas , Hipofosfatasia/tratamento farmacológico , Avaliação da Tecnologia Biomédica , Análise Custo-Benefício/economia
2.
Cornea ; 38(7): 896-900, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30969260

RESUMO

PURPOSE: To assess for ectopic ocular calcification in a series of patients with hypophosphatasia (HPP) treated with asfotase alfa, a recombinant tissue-nonspecific alkaline phosphatase. METHODS: This is a retrospective analysis of subjects enrolled at Duke University Medical Center in ENB-009-10 (ClinicalTrials.gov: NCT01163149), a randomized controlled trial of asfotase alfa in adolescents and adults with HPP. Seven patients between the ages of 45 and 66 years diagnosed with HPP based on clinical features and low serum alkaline phosphatase levels were enrolled at our site. Subjects were randomized to receive either daily subcutaneous injections of asfotase alfa or no treatment. After 24 weeks, during the open-label extension phase, all subjects received treatment for at least 4 years. All subjects underwent comprehensive eye examinations at baseline and at 24-week intervals throughout the study to assess for development of ocular calcifications. RESULTS: By week 120, all 7 subjects developed asymptomatic white refractile deposits in the interpalpebral perilimbal conjunctiva. Biopsy of the conjunctival lesions in 2 subjects revealed elastosis with subepithelial calcification. The lesions were nonprogressive and in 5 subjects exhibited some degree of regression. CONCLUSIONS: Asfotase alfa was invariably associated with development of mild focal conjunctival calcification, likely through disinhibition of hydroxyapatite crystal propagation. The calcifications were not symptomatic or vision-threatening and should not preclude enzyme replacement therapy for patients with this rare and often debilitating disease.


Assuntos
Fosfatase Alcalina/efeitos adversos , Calcinose/induzido quimicamente , Doenças da Túnica Conjuntiva/induzido quimicamente , Terapia de Reposição de Enzimas/efeitos adversos , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G/efeitos adversos , Proteínas Recombinantes de Fusão/efeitos adversos , Adolescente , Adulto , Idoso , Terapia de Reposição de Enzimas/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
3.
Brain Dev ; 41(8): 721-725, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31000369

RESUMO

Hypophosphatasia (HPP) is a rare disorder caused by low serum tissue non-specific alkaline phosphatase (ALP) activity due to hypomorphic mutations in the ALPL gene. HPP is characterized by defective bone mineralization. It frequently accompanies pyridoxine-responsive seizures. Because alkaline phosphatase change pyridoxal 5' phosphate (PLP) into pyridoxal (PL), which can cross the blood brain barrier and regulates inhibitory neurotransmitter gamma-aminobutyric acid. The female patient was born at a gestational age of 37 weeks 2 days. She presented severe respiratory disorder due to extreme thoracic hypoplasia. With the extremely low serum ALP value (14 IU/L), she was clinically diagnosed as HPP. The diagnosis was confirmed with genetic testing. On day1, the subclinical seizures were detected by aEEG. Together with enzyme replacement therapy by asfotase alfa, pyridoxine hydrochloride was administered, then the seizures were rapidly controlled. While confirming that there was no seizure by aEEG monitoring, pyridoxine hydrochloride was gradually discontinued after 1 month. Before administration of pyridoxine hydrochloride, PL was extremely low (4.7 nM) and PLP was increased (1083 nM). After the withdrawal, PL was increased to 84.9 nM only by enzyme replacement. Monitoring with aEEG enabled early intervention for pyridoxine responsive seizures. Confirming increased serum PL concentration is a prudent step in determining when to reduce or discontinue pyridoxine hydrochloride during enzyme replacement therapy.


Assuntos
Terapia de Reposição de Enzimas/métodos , Hipofosfatasia/tratamento farmacológico , Fosfatase Alcalina/deficiência , Fosfatase Alcalina/genética , Fosfatase Alcalina/uso terapêutico , Eletroencefalografia , Feminino , Humanos , Hipofosfatasia/fisiopatologia , Imunoglobulina G/uso terapêutico , Recém-Nascido , Fosfato de Piridoxal/uso terapêutico , Piridoxina/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Convulsões/tratamento farmacológico , Vitamina B 6/análise , Vitamina B 6/sangue , Vitamina B 6/metabolismo
4.
BMC Musculoskelet Disord ; 20(1): 80, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764793

RESUMO

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).


Assuntos
Diagnóstico Tardio , Hipofosfatasia/diagnóstico , Adolescente , Adulto , Fatores Etários , Idoso , Fosfatase Alcalina/genética , Criança , Pré-Escolar , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Hipofosfatasia/tratamento farmacológico , Hipofosfatasia/epidemiologia , Hipofosfatasia/genética , Lactente , Japão/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação , América do Norte/epidemiologia , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Sistema de Registros , Fatores de Tempo , Adulto Jovem
5.
Medicine (Baltimore) ; 97(48): e13210, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30508901

RESUMO

RATIONALE: Hypophosphatasia is an inborn error of metabolism that can appear any time in life, mainly with bone manifestations due to low alkaline phosphatase activity. Asfotase alfa is a specific enzyme reposition treatment that has shown promising results in children; however, there are few reports about the outcomes in adult patients. PATIENT CONCERNS: A 36-year-old male presented with an early history of craniosynostosis, short stature, and multiple fractures since the age of 13 years-which needed numerous surgical corrections. He was admitted with a previous diagnosis of osteogenesis imperfecta, taking alendronate, calcium carbonate, cholecalciferol, and calcitriol. Bone mineral density was low (lumbar spine Z-score = -3.0 SD), with impairment of all parameters of high-resolution peripheral quantitative computed tomography (HR-pQCT). Kidney impairment was also observed with reduced creatinine clearance, nephrolithiasis, and nephrocalcinosis. DIAGNOSIS: Alkaline phosphatase was unexpectedly low (6 U/L, reference value: 30-120 U/L), with high serum vitamin B6 (260 mcg/L, reference value: 5.2-34.1). Genetic testing showed a homozygous missense mutation in ALPL gene c.443 C>T: p.Thr148Ile. INTERVENTION: Asfotase alfa was requested due to important bone deterioration, ambulatory disability, and kidney impairment. It was given subcutaneously 2 mg/kg per dose, 3 times a week, for 12 months before reassessment. OUTCOMES: Bone mineral densities of the lumbar spine and whole body, besides almost all HR-pQCT microstructural parameters of the distal tibia, showed improvements and the patient was able to walk without assistant device. Kidney function did not further deteriorate. LESSONS: Hypophosphatasia should be considered as a differential diagnosis in young patients with multiple fractures and kidney impairment, since the use of antiresorptive drugs, calcium and vitamin D, commonly used to treat fractures, worsen its symptoms and prognosis. A 12-month asfotase alfa treatment improved bone density and structural parameters even in an adult patient with late diagnosis.


Assuntos
Fosfatase Alcalina/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Osso e Ossos/efeitos dos fármacos , Hipofosfatasia/diagnóstico , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Osso e Ossos/diagnóstico por imagem , Diagnóstico Diferencial , Terapia de Reposição de Enzimas , Humanos , Masculino
6.
Drug Des Devel Ther ; 12: 3147-3161, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30288020

RESUMO

Hypophosphatasia (HPP) is a multi-systemic metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the mineralization-associated enzyme, tissue-nonspecific alkaline phosphatase (TNSALP). HPP is characterized by defective bone and dental mineralization, leading to skeletal abnormalities with complications resulting in significant morbidity and mortality. Management of HPP has been limited to supportive care until the introduction of a recently approved enzyme replacement therapy employing bone-targeted recombinant human TNSALP, asfotase alfa (AA). This new therapy has been transformative as it improves survival in severely affected infants, and overall quality of life in children and adults with HPP. This review provides an overview of HPP, focusing on important steps in the development of AA enzyme replacement therapy, including the drug design, preclinical studies in the HPP mouse model, and outcomes from clinical trials and case report publications to date, with special attention given to response to therapy of skeletal manifestations, biochemical features, and other clinical manifestations. The limitations, adverse effects, and outcomes of AA are outlined and the place in therapy for individuals with HPP is discussed.


Assuntos
Fosfatase Alcalina/uso terapêutico , Desenho de Drogas , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Fosfatase Alcalina/síntese química , Fosfatase Alcalina/química , Animais , Humanos , Imunoglobulina G/química , Proteínas Recombinantes de Fusão/síntese química , Proteínas Recombinantes de Fusão/química
7.
Curr Rheumatol Rep ; 20(11): 69, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30203264

RESUMO

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


Assuntos
Fosfatase Alcalina/uso terapêutico , Hipofosfatasia/diagnóstico , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/prevenção & controle , Diagnóstico Diferencial , Terapia de Reposição de Enzimas/métodos , Humanos , Hipofosfatasia/complicações
8.
J Coll Physicians Surg Pak ; 28(9): S198-S200, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30173697

RESUMO

Hypophosphatasia (HPP) is associated with significant morbidity and mortality in pediatric patients. The disease also imposes a high disease-burden in adult-onset HPP. Asfotase alfa (AA) is the first-in-class, bone-targeted, enzyme- replacement therapy designated to reverse the skeletal mineralisation defects in HPP. A male newborn presented with extreme fontanel gap and respiratory distress. He was diagnosed with perinatal lethal HPP thus AA treatment was started. Serum alkaline phosphatase (ALP) levels increased as high as 12,700 U/L during treatment. Any side effect related to AA was not observed. AA may be a valuable emerging therapy for the treatment of HPP.


Assuntos
Fosfatase Alcalina/uso terapêutico , Terapia de Reposição de Enzimas , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Humanos , Hipofosfatasia/diagnóstico , Recém-Nascido , Masculino , Resultado do Tratamento
9.
Orphanet J Rare Dis ; 13(1): 142, 2018 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115096

RESUMO

BACKGROUND: Hypophosphatasia (HPP) is a rare, heterogeneous disease caused by low tissue-nonspecific alkaline phosphatase activity and associated with a range of signs and symptoms, including bone mineralization defects, respiratory problems, seizures, premature tooth loss, and fractures. Data from patients with HPP and their healthcare resource utilization are lacking. We evaluated healthcare utilization for 3 patients with differing severities of HPP. RESULTS: Patient 1 had perinatal HPP (received enzyme replacement therapy asfotase alfa under a compassionate use program), Patient 2 had infantile HPP, and Patient 3 had childhood HPP. Healthcare resources used in the National Health Service, England, were identified from coded activities in the hospital database and detailed medical records. These data showed that healthcare utilization was directly related to disease severity. Patient 1 had respiratory complications necessitating prolonged admission for ventilation from birth. Over 2.5 years, this patient was hospitalized 725 days, with visits from 16 specialists. Patient 2 had HPP-associated signs and symptoms starting in infancy, was treated for craniosynostosis, experienced multiple fractures, and required outpatient management for > 18 years. Patient 3 developed signs and symptoms of HPP in childhood and received outpatient and day case treatment for dental, orthopedic, and cardiovascular problems over 24 years. Healthcare utilization varied with severity and complexity of disease manifestations between these patients. CONCLUSIONS: With the recent approval of asfotase alfa for HPP, data from this analysis may help mobilize multidisciplinary healthcare resources for management of HPP by elucidating healthcare resource needs of patients who show a spectrum of clinical manifestations of HPP.


Assuntos
Fosfatase Alcalina , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G , Proteínas Recombinantes de Fusão , Fosfatase Alcalina/uso terapêutico , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Lactente , Recém-Nascido , Masculino , Aceitação pelo Paciente de Cuidados de Saúde , Gravidez , Proteínas Recombinantes de Fusão/uso terapêutico
10.
Ugeskr Laeger ; 180(35)2018 Aug 27.
Artigo em Dinamarquês | MEDLINE | ID: mdl-30152322

RESUMO

Hypophosphatasia (HPP) is a rare inborn, metabolic bone disorder caused by mutations in the tissue-nonspecific alkaline phosphatase-encoding gene: ALPL. The diagnosis is based on biochemical, clinical and genetic evaluation. Low levels of alkaline phosphatase is a hallmark in diagnosing HPP. Mild forms may present unspecific symptoms and be more frequent than previously assumed. Adults with HPP may present with low bone mass, however, bisphosphonates are contra-indicated for these patients. Finally, enzyme replacement therapy has opened new therapeutic perspectives regarding severe HPP.


Assuntos
Hipofosfatasia , Adulto , Criança , Pré-Escolar , Diagnóstico Diferencial , Humanos , Hipofosfatasia/classificação , Hipofosfatasia/diagnóstico , Hipofosfatasia/tratamento farmacológico , Hipofosfatasia/terapia , Lactente , Perda de Dente/etiologia
11.
Br Dent J ; 224(12): 937-943, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29999027

RESUMO

Hypophosphatasia (HPP) is an inherited metabolic disorder that results in poorly mineralised bones and teeth. Clinical symptoms vary widely from mild dental anomalies to fatal fetal defects. The most common dental symptoms include exfoliation of the primary incisors before the age of three with little or no root resorption, large pulp chambers, alveolar bone loss and thin dentinal walls. There is generally minimal periodontal inflammation associated with the bony destruction and tooth loss. The general dental practitioner is usually the first clinician to spot signs of the milder forms of HPP. Patients diagnosed with dental symptoms in childhood can go on to develop significant morbidity in middle age with chronic bone pain and stress fractures of the long bones. The primary dental care clinician is the key to early diagnosis of such cases, whether they present in childhood or adulthood. Emerging enzyme replacement therapy has considerably changed the landscape of the disease, resulting in astonishing improvements in bone mineralisation and a significant reduction in mortality and morbidity. It is increasingly likely that primary and secondary care clinicians will treat patients with the severe forms of HPP, who would previously not have survived infancy.


Assuntos
Assistência Odontológica , Hipofosfatasia/complicações , Hipofosfatasia/diagnóstico , Adulto , Perda do Osso Alveolar/etiologia , Densidade Óssea , Criança , Pré-Escolar , Dentina/patologia , Diagnóstico Diferencial , Terapia de Reposição de Enzimas , Feminino , Humanos , Hipofosfatasia/tratamento farmacológico , Lactente , Masculino , Reabsorção da Raiz/etiologia , Esfoliação de Dente/etiologia , Perda de Dente/etiologia
12.
Orphanet J Rare Dis ; 13(1): 116, 2018 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-30012160

RESUMO

BACKGROUND: Hypophosphatasia (HPP) is a rare inborn error of metabolism that results from dysfunction of the tissue non-specific alkaline phosphatase enzyme. Its manifestations are extremely variable, ranging from early lethality to disease limited to the dentition. The disease is life-threatening when manifesting within the first six months of life, excepting the extremely rare benign perinatal hypophosphatasia. Childhood hypophosphatasia, defined as onset of symptoms between six months and eighteen years, can manifest as rickets, pain, decreased mobility, deficits of growth, and fractures. Historical treatment has generally involved a combination of dietary and rehabilitative interventions. MAIN DOCUMENT: Asfotase alfa (Strensiq™), is a first-in-class bone-targeted recombinant tissue nonspecific alkaline phosphatase which has shown significant improvements in morbidity and mortality in patients with perinatal and infantile hypophosphatasia. Subsequent research has also shown improvements in morbidity for patients with childhood hypophosphatasia as measured by improvement in rickets, growth, strength, mobility, and quality of life. This enzyme replacement therapy has generally been well-tolerated, with most adverse reactions being mild-to-moderate in nature. The author shares their approach to decisions on commencement of ERT based from experience of managing approximately fifteen patients across the age spectrum. This approach focuses on assessing the severity of five key manifestations of childhood HPP: decreased mobility, pain, rickets, deficits of growth, and fractures.


Assuntos
Hipofosfatasia/tratamento farmacológico , Fosfatase Alcalina/metabolismo , Fosfatase Alcalina/uso terapêutico , Doenças Ósseas/tratamento farmacológico , Doenças Ósseas/enzimologia , Terapia de Reposição de Enzimas/métodos , Feminino , Humanos , Hipofosfatasia/enzimologia , Imunoglobulina G/metabolismo , Imunoglobulina G/uso terapêutico , Masculino , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/uso terapêutico
14.
Mol Genet Metab ; 125(1-2): 174-180, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30049651

RESUMO

OBJECTIVE: To investigate the utility of serum pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) as a diagnostic marker of hypophosphatasia (HPP) and an indicator of the effect of, and patient compliance with, enzyme replacement therapy (ERT), we measured PLP, PL, and PA concentrations in serum samples from HPP patients with and without ERT. METHODS: Blood samples were collected from HPP patients and serum was frozen as soon as possible (mostly within one hour). PLP, PL, and PA concentrations were analyzed using high-performance liquid chromatography with fluorescence detection after pre-column derivatization by semicarbazide. We investigated which metabolites are associated with clinical phenotypes and how these metabolites change with ERT. RESULTS: Serum samples from 20 HPP patients were analyzed. The PLP-to-PL ratio and PLP concentration were elevated in all HPP patients. They correlated negatively with serum alkaline phosphatase (ALP) activity and showed higher values in more severe phenotypes (perinatal severe and infantile HPP) compared with other phenotypes. PL concentration was reduced only in perinatal severe HPP. ERT reduced the PLP-to-PL ratio to mildly reduced or low-normal levels and the PLP concentration was reduced to normal or mildly elevated levels. Urine phosphoethanolamine (PEA) concentration did not return to normal levels with ERT in most patients. CONCLUSIONS: The serum PLP-to-PL ratio is a better indicator of the effect of ERT for HPP than serum PLP and urine PEA concentrations, and a PLP-to-PL ratio of <4.0 is a good indicator of the effect of, and patient compliance with, ERT.


Assuntos
Fosfatase Alcalina/genética , Terapia de Reposição de Enzimas , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G/genética , Fosfato de Piridoxal/sangue , Proteínas Recombinantes de Fusão/genética , Adolescente , Adulto , Fosfatase Alcalina/sangue , Fosfatase Alcalina/uso terapêutico , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Etanolaminas/urina , Feminino , Humanos , Hipofosfatasia/sangue , Hipofosfatasia/patologia , Hipofosfatasia/urina , Imunoglobulina G/uso terapêutico , Lactente , Recém-Nascido , Masculino , Piridoxal/sangue , Ácido Piridóxico/sangue , Proteínas Recombinantes de Fusão/uso terapêutico , Vitamina B 6/metabolismo , Adulto Jovem
15.
Value Health ; 21(5): 508-514, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29753346

RESUMO

Pediatric rare diseases present unique challenges in clinical trial design and in selection of clinical outcome assessments (COAs) used to support claims in medical product labeling. COAs that discriminate level of function relative to a normative sample are particularly important in the pediatric rare disease setting because the literature is often void of natural history data. Pediatric rare disease clinical trials will often include a wide age distribution. Gross and fine motor skills, communication, cognition, and independence in activities of daily living vary by age, and it may be difficult to distinguish between treatment effect and change due to developmental maturation. Asfotase alfa was granted breakthrough therapy designation and subsequently approved for the treatment of hypophosphatasia (HPP; a genetic metabolic musculoskeletal disorder) and is used in this discussion to illustrate COA selection in a pediatric rare disease. Multiple COAs with normative data in HPP clinical trials for asfotase alfa are presented. The assessment instruments included the Bayley Scales of Infant and Toddler Development-Third Edition, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, the Childhood Health Assessment Questionnaire, the Pediatric Outcomes Data Collection Instrument, handheld dynamometry, the 6-minute walk test, and the Modified Performance-Oriented Mobility Assessment-Gait scale. Multiple end points were required to adequately capture the impact of asfotase alfa treatment on the multiple systems affected in HPP. These data illustrate the importance of using multiple COAs that provide normative data and to use COAs early in the drug development process for rare pediatric disease.


Assuntos
Pediatria , Doenças Raras , Projetos de Pesquisa , Resultado do Tratamento , Atividades Cotidianas/classificação , Fosfatase Alcalina/uso terapêutico , Humanos , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Lactente , Modalidades de Fisioterapia , Proteínas Recombinantes de Fusão/uso terapêutico , Inquéritos e Questionários
16.
Clin Biochem ; 58: 118-121, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29709501

RESUMO

OBJECTIVES: We report a case of discordant total and free testosterone values in a patient with hypogonadism and juvenile hypophosphatasia after he initiated treatment with asfotase alfa, recombinant tissue non-specific alkaline phosphatase. METHODS: Total testosterone was evaluated using immunoassay pre and post initiation of therapy with asfotase alfa, and free testosterone was evaluated using radioimmunoassay and LC-MS/MS while on asfotase alfa therapy. RESULTS: Total testosterone measured by immunoassay was normal prior to therapy with asfotase alfa, and was low post initiation of therapy. During the same time frame, free testosterone measured using RAI and total testosterone measured using LC-MS/MS were normal on asfotase alfa therapy. This suggests assay interference with the total testosterone immunoassay. CONCLUSION: When laboratory results are discordant or do not match the clinical impression, the possibility of assay interference should be considered. Alternative laboratory methods free of the interference should be selected to evaluate these patients. HUMAN GENES DISCUSSED IN THE PAPER: ALPL gene, Approved name: Alkaline phosphatase, liver/bone/kidney, Synonym: Tissue non-specific alkaline phosphatase (TNSAP).


Assuntos
Fosfatase Alcalina/administração & dosagem , Fosfatase Alcalina/efeitos adversos , Hipofosfatasia/sangue , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G/administração & dosagem , Imunoglobulina G/efeitos adversos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Testosterona/sangue , Adulto , Cromatografia Líquida/métodos , Humanos , Masculino , Espectrometria de Massas/métodos , Radioimunoensaio/métodos
17.
J Bone Miner Res ; 33(5): 868-874, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29297597

RESUMO

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


Assuntos
Fosfatase Alcalina/uso terapêutico , Osso e Ossos , Terapia de Reposição de Enzimas , Hipofosfatasia , Imunoglobulina G/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Tomografia Computadorizada por Raios X , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Hipofosfatasia/diagnóstico por imagem , Hipofosfatasia/tratamento farmacológico , Hipofosfatasia/metabolismo , Lactente , Recém-Nascido , Masculino
18.
Osteoporos Int ; 29(2): 511-515, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29046930

RESUMO

We describe the clinical outcome of asfotase alfa therapy in a 16-year-old boy with severe childhood hypophosphatasia (HPP), who began therapy at age 15 years. The patient was diagnosed with HPP at age 2 years when he presented with genu varum and premature loss of primary teeth. He had a history of multiple fractures requiring 16 orthopedic surgeries with rod and pin placement in his lower extremities. He had chronic skeletal pain and used cane to ambulate with great difficulty. His height Z score at age 15 years was - 5. He had severe scoliosis and deformity of both legs. Bone radiograph showed hypomineralization and characteristic "tongues" of radiolucency in the distal radius and ulna. His serum alkaline phosphatase level was stable, with elevated serum pyridoxal 5'-phosphate and urine phosphoethanolamine, consistent with HPP. He was started on asfotase alfa 2 mg/kg given subcutaneously thrice weekly. He had marked clinical improvement in mobility with no report of pain after 3 months of treatment. At 6 month, he walked without cane and participated in outdoor activities with peers. Bone radiograph at 6 months showed striking improvement in previous radiolucent areas. At 9 months, his annualized growth velocity was 9.5 cm/year, while growth velocity of arm span was 12 cm/year. However, at 12 months, he was noted to have worsening scoliosis from 60 degrees before therapy to 110 degrees, with a slight decrease in height, necessitating a spinal fusion surgery. In conclusion, treatment with asfotase alfa significantly improved physical function, pain, overall quality of life, and skeletal radiographic findings in this patient. Close monitoring for progression of scoliosis in adolescents with HPP treated with asfotase alfa is recommended.


Assuntos
Fosfatase Alcalina/uso terapêutico , Terapia de Reposição de Enzimas/métodos , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Adolescente , Desmineralização Patológica Óssea/diagnóstico por imagem , Desmineralização Patológica Óssea/tratamento farmacológico , Desmineralização Patológica Óssea/etiologia , Humanos , Hipofosfatasia/complicações , Hipofosfatasia/fisiopatologia , Masculino , Qualidade de Vida , Radiografia , Escoliose/etiologia
19.
Joint Bone Spine ; 85(3): 365-367, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29246529

RESUMO

Atypical femoral fractures are defined as atraumatic fractures located in the subtrochanteric region or femoral shaft. They have been mainly reported in patients taking bisphosphonates. We report the case of a 67-year-old female with osteoporosis treated by alendronate during ten years. Radiographies showed atypical femoral fractures. Serum levels of total and bone-specific alkaline phosphatase were low. In order to accelerate bone healing, teriparatide was introduced. After one year of teriparatide treatment, pain and functional difficulty have decreased, and alkaline phosphatase levels were normalized. In view of this history of recurrent fractures, of atypical femoral fractures, of early spontaneous loss of teeth, and of low serum total and bone-specific alkaline phosphatase levels, the diagnosis of hypophosphatasia has been considered and confirmed by genetic research. Other conditions than exposure to anti-resorptive therapies may promote atypical femoral fractures, such as in conditions associated with abnormal bone structures, as hypophosphatasia, a rare inherited bone metabolism disorder. A few case reports have reported adult hypophosphatasia treated by teriparatide with a good efficacy on bone pain and consolidation but with mixed results on biological markers. Teriparatide may be therefore a treatment option in adult hypophosphatasia. ALP levels should be carefully checked among osteoporotic patients and specially before introducing a bone resorption inhibitor. Low alkaline phosphatase levels have to be taken into account and an evocative history of hypophosphatasia has to be sought because this condition may expose patients to develop atypical femoral fractures during bisphosphonate treatment.


Assuntos
Difosfonatos/efeitos adversos , Fraturas do Fêmur/induzido quimicamente , Fraturas Espontâneas/induzido quimicamente , Hipofosfatasia/diagnóstico por imagem , Hipofosfatasia/tratamento farmacológico , Teriparatida/efeitos adversos , Idoso , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fraturas do Fêmur/diagnóstico por imagem , Seguimentos , Fraturas Espontâneas/diagnóstico por imagem , Humanos , Hipofosfatasia/sangue , Osteoporose Pós-Menopausa/diagnóstico por imagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Medição de Risco , Índice de Gravidade de Doença , Teriparatida/uso terapêutico , Fatores de Tempo , Resultado do Tratamento
20.
Brain Dev ; 40(2): 140-144, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28802630

RESUMO

BACKGROUND: Hypophosphatasia (HPP) is a rare genetic disorder characterized by rachitic bone manifestations and a low serum alkaline phosphatase (ALP) level. It is caused by mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene, which encodes the tissue non-specific isozyme of ALP. HPP patients exhibit various presentations depending on their age at onset, such as infantile HPP combined with vitamin B6-responsive seizures. CASE PRESENTATION: A newborn with infantile HPP presented with tonic convulsions from day 5 after birth and received intravenous vitamin B6 (10mg/kg/day pyridoxal phosphate). Eleven days later, frequent apneic episodes occurred, and head magnetic resonance imaging (MRI) showed bilateral reticular formation lesions in the brain stem, including the medulla oblongata. After the pyridoxal phosphate dose was increased (to 40mg/kg/day), the patient's seizures and apnea resolved, and her MRI findings also improved. Genetic testing revealed that she was homozygous for the 1559delT mutation of TNSALP. CONCLUSIONS: High-dose pyridoxal phosphate is a useful treatment for HPP-induced seizures and might improve reticular formation lesions.


Assuntos
Anticonvulsivantes/uso terapêutico , Hipofosfatasia/tratamento farmacológico , Fosfato de Piridoxal/uso terapêutico , Formação Reticular/diagnóstico por imagem , Convulsões/tratamento farmacológico , Diagnóstico Diferencial , Feminino , Humanos , Hipofosfatasia/diagnóstico por imagem , Hipofosfatasia/genética , Hipofosfatasia/fisiopatologia , Recém-Nascido , Convulsões/diagnóstico por imagem , Convulsões/genética , Convulsões/fisiopatologia
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