Format
Sort by
Items per page

Send to

Choose Destination

Search results

Items: 1 to 20 of 809

1.
Value Health. 2018 May;21(5):508-514. doi: 10.1016/j.jval.2018.01.015. Epub 2018 Mar 15.

Clinical Outcome Assessments: Use of Normative Data in a Pediatric Rare Disease.

Author information

1
Evidera Inc., Bethesda, MD, USA; UNC Division of Physical Therapy, Chapel Hill, NC, USA. Electronic address: Dawn.Phillips@Evidera.com.
2
Physical Therapy Functional Outcomes Consultant and Private Practice Physical Therapist, Chapel Hill, NC, USA.

Abstract

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.

KEYWORDS:

asfotase alfa; clinical outcomes; hypophosphatasia; rare disease

PMID:
29753346
DOI:
10.1016/j.jval.2018.01.015
[Indexed for MEDLINE]
Icon for Elsevier Science
2.
Dent Update. 2017 Apr;44(4):317-8, 320-1.

Early Tooth Loss in Children: A Warning Sign of Childhood Hypophosphatasia.

Abstract

Premature exfoliation of primary teeth may be the first manifestation of this serious condition and the general dental practitioner plays an important role in recognizing dental anomalies and referring patients at an appropriate time. This is imperative to ensuring early diagnosis and good quality patient care. This article describes the case of a 4-year-old boy affected by childhood hypophosphatasia, who presented with premature exfoliation of his primary teeth as the first manifestation of this condition. An overview of the condition is outlined including a discussion of the likelihood of permanent dentition involvement.

CLINICAL RELEVANCE:

Oral manifestations of hypophosphatasia may be the first and the only signs of this condition and may be the basis upon which a diagnosis is made.

PMID:
29172356
DOI:
10.12968/denu.2017.44.4.317
[Indexed for MEDLINE]
3.
Am J Med Genet A. 2018 Jan;176(1):171-174. doi: 10.1002/ajmg.a.38531. Epub 2017 Nov 21.

Discordant fetal phenotype of hypophosphatasia in two siblings.

Author information

1
Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.
2
Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
3
Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, Osaka, Japan.
4
Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
5
Division of Neonatology, Perinatal Center for Maternal and Child Health, Saitama City Hospital, Saitama, Japan.

Abstract

Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype-phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31-year-old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks' gestation. Post-mortem radiographs demonstrated severely defective mineralization of the skeleton. The calvarial, spinal, and tubular bones were mostly missing. Only the occipital bones, mandible, clavicles, ribs, one thoracic vertebra, ilia, and tibia were relatively well ossified. The radiological findings suggested lethal HPP. Genetic testing for genomic DNA extracted from the umbilical cord identified compound heterozygous mutations in the ALPL gene (c.532T>C, p.Y178H; c.1559delT, p.Leu520Argfs*86). c.532T>C was a novel variant showing no residual activity of the protein by the functional analysis. The parents were heterozygous carriers. In the next pregnancy, biometric values on fetal ultrasonography at 20 and 26 weeks' gestation were normal. At 34 weeks, however, a small chest and shortening of distal long bones came to attention. The neonate delivered at 41 weeks showed serum ALP of <5U/L. Radiological examination showed only mild thoracic hypoplasia and metaphyseal mineralization defects of the long bones. ALP replacement therapy was introduced shortly after birth, and the neonate was discharged at day 22 without respiratory distress. Awareness of discordant fetal phenotypes in siblings with HPP precludes a diagnostic error, and enables early medical intervention to mildly affected neonates.

KEYWORDS:

discordant phenotype; hypophosphatasia; prenatal diagnosis; siblings; ultrasound

PMID:
29160033
DOI:
10.1002/ajmg.a.38531
[Indexed for MEDLINE]
Icon for Wiley
4.
Lakartidningen. 2017 Oct 16;114. pii: ETTH.

Tillförlitliga referensintervall krävs för värdering av P-ALP - Nya pediatriska referensintervall för alkaliskt fosfatas har klinisk betydelse för att hitta rätt till diagnosen.

[Article in Swedish]

Author information

1
Linkopings Universitet Institutionen for klinisk och experimentell medicin - Linkoping, Sweden - IKE Linköping, Sweden.

Abstract

Age- and gender-specific reference intervals are pivotal to ensure appropriate interpretation of plasma alkaline phosphatase activities in the lower range Hypophosphatasia (HPP) is an inborn error of metabolism caused by loss-of-function mutations of the ALPL gene that mainly express alkaline phosphatase (ALP) in bone and liver. The clinical expression of HPP is highly variable and is classified into six different forms mainly affecting bone and tooth mineralization. The prognosis for each of these HPP forms depends upon the severity of the skeletal disease which reflects the age at presentation. The biochemical hallmark of HPP is low plasma ALP activity (hypophosphatasemia); however, HPP is often misdiagnosed because of low awareness and sometimes absence of age- and gender-specific ALP reference intervals. Children and adolescents have higher ALP levels in comparison with adults. Reliable reference intervals are pivotal for any clinical laboratory test. Harmonized age- and gender-specific plasma ALP reference intervals ought to be used to ensure appropriate interpretation of plasma ALP activities in the lower range.

PMID:
29039873
[Indexed for MEDLINE]
Free full text
Icon for Swedish Medical Association
5.
Mol Genet Metab. 2017 Sep;122(1-2):4-17. doi: 10.1016/j.ymgme.2017.07.010. Epub 2017 Jul 25.

Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa.

Author information

1
Division of Medical Genetics, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: priya.kishnani@duke.edu.
2
Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE 68198, USA(2).
3
Metabolic Bone Team, Sheffield Children's NHS Foundation Trust, Sheffield S10 2TH, UK.
4
Academic Unit of Child Health, University of Sheffield and Sheffield Children's Hospital, Sheffield S10 2TH, UK.
5
Division of Diabetes and Endocrinology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
6
Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich NR4 7UY, UK.
7
Pediatric Gastroenterology and Nutrition, UCSF Benioff Children's Hospital Oakland, Oakland, CA 94609, USA.
8
Service d'Endocrinologie Pédiatrique, Hôpital Bicêtre Paris-Sud, APHP, 94270 Le Kremlin Bicêtre, France.
9
Paediatrics & Child Health, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
10
Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA.
11
Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.
12
Orthopedic Department, University of Würzburg, Würzburg, Bavaria 97074, Germany.
13
Department of Pediatrics, Osaka University, Suita, Osaka 565-0871, Japan.

Abstract

Hypophosphatasia (HPP) is a rare, inherited, systemic, metabolic disorder caused by autosomal recessive mutations or a single dominant-negative mutation in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). The disease is associated with a broad range of signs, symptoms, and complications, including impaired skeletal mineralization, altered calcium and phosphate metabolism, recurrent fractures, pain, respiratory problems, impaired growth and mobility, premature tooth loss, developmental delay, and seizures. Asfotase alfa is a human, recombinant enzyme replacement therapy that is approved in many countries for the treatment of patients with HPP. To address the unmet need for guidance in the monitoring of patients receiving asfotase alfa, an international panel of physicians with experience in diagnosing and managing HPP convened in May 2016 to discuss treatment monitoring parameters. The panel discussions focused on recommendations for assessing and monitoring patients after the decision to treat with asfotase alfa had been made and did not include recommendations for whom to treat. Based on the consensus of panel members, this review provides guidance on the monitoring of patients with HPP during treatment with asfotase alfa, including recommendations for laboratory, efficacy, and safety assessments and the frequency with which these should be performed during the course of treatment. Recommended assessments are based on patient age and include regular monitoring of biochemistry, skeletal radiographs, respiratory function, growth, pain, mobility and motor function, and quality of life. Because of the systemic presentation of HPP, a coordinated, multidisciplinary, team-based, patient-focused approach is recommended in the management of patients receiving asfotase alfa. Monitoring of efficacy and safety outcomes must be tailored to the individual patient, depending on medical history, clinical manifestations, availability of resources in the clinical setting, and the clinician's professional judgment.

KEYWORDS:

Alkaline phosphatase; Asfotase alfa; Enzyme replacement therapy; Hypophosphatasia; Metabolic bone diseases; Therapeutic drug monitoring; Tissue-nonspecific alkaline phosphatase

PMID:
28888853
DOI:
10.1016/j.ymgme.2017.07.010
[Indexed for MEDLINE]
Free full text
Icon for Elsevier Science
6.
Am J Med Genet A. 2017 Oct;173(10):2747-2752. doi: 10.1002/ajmg.a.38370. Epub 2017 Aug 1.

Monoallelic FGFR3 and Biallelic ALPL mutations in a Thai girl with hypochondroplasia and hypophosphatasia.

Author information

1
Craniofacial Genetics and Stem Cells Research Group, Faculty of Dentistry, Department of Physiology, Chulalongkorn University, Bangkok, Thailand.
2
Center of Excellence for Medical Genetics, Faculty of Medicine, Department of Pediatrics, Chulalongkorn University, Bangkok, Thailand.
3
Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand.

Abstract

Skeletal dysplasias are a complex group of more than 350 disorders with phenotypic and genotypic heterogeneity affecting bone and cartilage growth. We studied a 2-year-old girl and her 21-year-old mother with disproportionate short stature. In addition to typical features of hypochondroplasia found in both patients, the child had deformities of the extremity bones, metaphyseal flares, and bilateral transverse (Bowdler) fibular spurs with overlying skin dimples detected at birth. Intravenous pamidronate was started in the child since the age of 17 days, and then every two months. Exome sequencing revealed that the girl was heterozygous for a missense mutation (c.1651A>G, p.Ile538Val) in exon 13 of FGFR3, a known mutation for hypochondroplasia, inherited from her mother. Interestingly, the child also harbored compound heterozygous missense mutations in exon 12 of ALPL, c.1460C>T (p.Ala487Val) inherited from her mother and c.1479C>A (p.Asn493Lys) inherited from her healthy father. The former mutation was previously reported in perinatal hypophosphatasia while the latter was novel. Constantly reduced serum alkaline phosphatase levels including the one before the pamidronate administration and a substantially elevated level of plasma pyridoxal 5'-phosphate detected at age 28 months supported the diagnosis of hypophosphatasia. After a definite diagnosis was achieved, pamidronate was withdrawn at the age of 28 months. No adverse events were observed during pamidronate therapy. In conclusion, we describe a unique case with monoallelic FGFR3 and biallelic ALPL mutations leading to features of both hypochondroplasia and hypophosphatasia.

KEYWORDS:

dento-osseous; dual diagnosis; exome sequencing; metabolic bone disease; two mendelian diseases

PMID:
28763161
DOI:
10.1002/ajmg.a.38370
[Indexed for MEDLINE]
Icon for Wiley
7.
J Bone Miner Res. 2017 Oct;32(10):1977-1980. doi: 10.1002/jbmr.3226. Epub 2017 Aug 16.

Hypophosphatasia in Adults: Clinical Assessment and Treatment Considerations.

Author information

1
Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
2
New Mexico Clinical Research and Osteoporosis Center, Albuquerque, NM, USA.

Abstract

Hypophosphatasia (HPP) is a rare inherited disorder of bone affecting approximately 500 to 600 known individuals in the United States. HPP is the result of mutations involving the gene for tissue nonspecific alkaline phosphatase. Five clinical types of HPP are recognized. The clinical presentation of HPP varies from devastating prenatal intrauterine disease to mild manifestations in adulthood. In adults, main clinical involvement includes early loss of primary or secondary teeth, osteoporosis, bone pain, chondrocalcinosis, and fractures. Treatment for HPP is limited. Asfotase alfa is a subcutaneously administered synthetic human alkaline phosphatase that is approved for treatment of patients, including adults, with perinatal/infantile- and juvenile-onset HPP. However, guidelines for the treatment of adults with HPP are not available. This discussion addresses diagnostic and treatment considerations for adults with HPP.

KEYWORDS:

ALKALINE PHOSPHATASE; ASFOTASE ALFA; HYPOPHOSPHATASIA; OSTEOMALACIA; OSTEOPOROSIS

PMID:
28731215
DOI:
10.1002/jbmr.3226
[Indexed for MEDLINE]
Icon for Wiley
8.
Rev Med Suisse. 2017 Apr 19;13(559):855-858.

[Hypophosphatasia].

[Article in French; Abstract available in French from the publisher]

Author information

1
Service des maladies osseuses, Département des spécialités de médecine, Faculté de médecine et HUG, 1211 Genève 14.

Abstract

Hypophosphatasia (HPP) is an inborn metabolic bone disorder caused by loss-of-function mutations in the gene encoding tissue nonspecific alkaline phosphatase (TNSALP). The adult form can be mistaken with common osteoporosis and/or present recurrent metatarsal fractures, skeletal and muscular pain. Subtrochanteric femoral pseudofractures resembling bisphosphonate-associated atypical femoral fractures can also be present, and Bps are therefore contraindicated in HPP. Early tooth loss and renal calcifications can orient towards the diagnosis. The diagnosis is based on low serum ALP levels (< 40 U/L) and high ALP substrate levels, such as vitamin B6 (pyridoxin), eventually on genetic testing. Recent development of an enzyme replacement therapy offers new therapeutic perspectives in severe cases.

PMID:
28727343
[Indexed for MEDLINE]
9.
J Clin Res Pediatr Endocrinol. 2017 Sep 1;9(3):229-236. doi: 10.4274/jcrpe.4549. Epub 2017 Jun 30.

Clinical and Genetic Findings of Turkish Hypophosphatasia Cases.

Author information

1
Uludağ University Faculty of Medicine, Department of Pediatrics, Division of Metabolism, Bursa, Turkey.

Abstract

OBJECTIVE:

Hypophosphatasia (HPP) is a rare, commonly unrecognized hereditary mineralization defect with a dramatically poor prognosis in severe cases. This study is the first to examine the detailed clinical and laboratory characteristics of patients with HPP and healthy carriers in Turkey.

METHODS:

The study data were obtained retrospectively from the files of 10 healthy carriers and of 16 cases with HPP (12 children and 4 adults) who were followed in our center from 2012 to 2016.

RESULTS:

The annual incidence of perinatal lethal hypophosphatasia (PLH) was estimated to be approximately 1 case per 435,517 live births,, which is the first report from Turkey. The clinical courses of the cases differed depending on the type of HPP. All of the seven cases (58.3% of all cases) with perinatal lethal form of HPP died. A need for respiratory support (p=0.001), a history of pyridoxine-dependent seizures (p=0.001), a low chest circumference measurement (p=0.017), younger age at diagnosis (p=0.029), a small head circumference at the time of presentation (p=0.042), a low arm span to height ratio (p=0.048), and a low serum alkaline phosphatase (ALP) level (p=0.042) seemed to be predicting factors for mortality. The mean height standard deviation score of the patients and those of the healthy carriers did not differ significantly (p=0.173). Different mutations were detected in nine of 14 cases (64.2%) in whom an ALPL gene mutation analysis could be performed, and five of these cases (35.7%) had novel mutations. The most common mutations were c746G>T (five alleles), c346G>A (three alleles), and c.140C>T (three alleles). In addition, the most frequently observed genotype in Turkish HPP cases was autosomal-dominant c.346G>A (p.A116T) mutations which were detected in three cases in two different families.

CONCLUSION:

Because of the respiratory problems, especially the lung hypoplasia, the clinical course is poor in cases with the perinatal lethal form of HPP. Some minor abnormalities such as mild short stature and osteopenia could be observed in asymptomatic heterozygote carriers. Laboratory findings were normal in these cases.

KEYWORDS:

Turkish children hypophosphatasia.

PMID:
28663156
PMCID:
PMC5596804
DOI:
10.4274/jcrpe.4549
[Indexed for MEDLINE]
Free PMC Article
Icon for Galenos Yayinevi Icon for PubMed Central
10.
Orv Hetil. 2017 Jul;158(26):1003-1007. doi: 10.1556/650.2017.30785.

[Differencial diagnosis of the low alkaline phosphatase activities].

[Article in Hungarian]

Author information

1
I. Gyermekgyógyászati Klinika, Semmelweis Egyetem, Általános Orvostudományi Kar Budapest, Bókay János u. 53-54., 1083.

Abstract

Laboratory diagnostics is especially important in the diagnosis of certain diseases. We compared manual measurements results to laboratory normal values. In some cases, these values depend on the gender and age as well. In the case of alkaline phosphatase, it is rarely considered that reference values change over life periods. Unfortunately, during the daily practice we do not always take into account of the changes with aging. This is especially true if the laboratory does not specify the age related normal values. Another problem that we mostly focus on the results exceeding the normal values, and do not pay enough attention to the low values. Of course, these results should be put in the context of the clinical picture and other diagnostic test results. We would like to draw attention to the measuring of alkaline phosphatase and the differential diagnosis for low serum activity. Orv Hetil. 2017; 158(26): 1003-1007.

KEYWORDS:

alkalikus foszfatáz; alkaline phosphatase; hypophosphataemia; hypophosphatasia

PMID:
28651458
DOI:
10.1556/650.2017.30785
[Indexed for MEDLINE]
Icon for Atypon
11.
Zhongguo Dang Dai Er Ke Za Zhi. 2017 May;19(5):539-544.

[Infantile hypophosphatasia caused by a novel compound heterozygous mutation: a case report and pedigree analysis].

[Article in Chinese]

Author information

1
Department of Pediatrics, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China. land6785@163.com.

Abstract

This article reported the clinical features of one child with infantile hypophosphatasia (HPP) and his pedigree information. The proband was a 5-month-old boy with multiple skeletal dysplasia (koilosternia, bending deformity of both radii, and knock-knee deformity of both knees), feeding difficulty, reduction in body weight, developmental delay, recurrent pneumonia and respiratory failure, and a significant reduction in blood alkaline phosphatase. Among his parents, sister, uncle, and aunt (other family members did not cooperate with us in the examination), his parents and aunt had a slight reduction in alkaline phosphatase and his aunt had scoliosis; there were no other clinical phenotypes or abnormal laboratory testing results. His ALPL gene mutation came from c.228delG mutation in his mother and c.407G>A compound heterozygous mutation in his father. His aunt carried c.228delG mutation. The c.407G>A mutation had been reported as the pathogenic mutation of HPP, and c.228delG mutation was a novel pathogenic mutation. Hypophosphatasia is caused by ALPL gene mutation, and ALPL gene detection is an effective diagnostic method. This study expands the mutation spectrum of ALPL gene and provides a theoretical basis for genetic diagnosis of this disease.

PMID:
28506345
[Indexed for MEDLINE]
12.
J Clin Invest. 2017 Jun 1;127(6):2148-2158. doi: 10.1172/JCI83731. Epub 2017 Apr 24.

Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia.

Author information

1
Orthopedic Center of Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany.
2
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
3
Children's Hospital and.
4
Institute for Human Genetics, University of Würzburg, Würzburg, Germany.
5
Novartis Pharma AG, Basel, Switzerland.
6
Novartis Institutes for BioMedical Research Inc., Cambridge, Massachusetts, USA.

Abstract

BACKGROUND:

Hypophosphatasia (HPP) is a rare genetic disorder resulting in variable alterations of bone formation and mineralization that are caused by mutations in the ALPL gene, encoding the tissue-nonspecific alkaline phosphatase (ALP) enzyme.

METHODS:

In this phase IIA open-label, single-center, intra-patient, dose-escalating study, adult patients with HPP received 3 ascending intravenous doses of 5, 10, and 20 mg/kg BPS804, a fully human anti-sclerostin monoclonal antibody, on days 1, 15, and 29, respectively. Patients were followed for 16 weeks after the last dose. We assessed the pharmacodynamics, pharmacokinetics, preliminary efficacy, and safety of BPS804 administrations at specified intervals during treatment and follow-up.

RESULTS:

Eight patients (mean age 47.8 years) were enrolled in the study (6 females, 2 males). BPS804 treatment increased mean ALP and bone-specific ALP enzymatic activity between days 2 and 29. Transient increases in the bone formation markers procollagen type-I N-terminal propeptide (PINP), osteocalcin, and parathyroid hormone as well as a transient decrease in the bone resorption marker C-telopeptide of type I collagen (CTX-1) were observed. Lumbar spine bone mineral density showed a mean increase by day 85 and at end of study. Treatment-associated adverse events were mild and transient.

CONCLUSION:

BPS804 treatment was well tolerated and resulted in increases in bone formation biomarkers and bone mineral density, suggesting that sclerostin inhibition could be applied to enhance bone mineral density, stability, and regeneration in non-life-threatening clinical situations in adults with HPP.

TRIAL REGISTRATION:

Clinicaltrials.gov NCT01406977.

FUNDING:

Novartis Institutes for BioMedical Research, Basel, Switzerland.

PMID:
28436937
PMCID:
PMC5451251
DOI:
10.1172/JCI83731
[Indexed for MEDLINE]
Free PMC Article
Icon for American Society for Clinical Investigation Icon for PubMed Central
13.
Clin Endocrinol (Oxf). 2017 Jul;87(1):10-19. doi: 10.1111/cen.13343. Epub 2017 May 2.

Safety and efficacy of treatment with asfotase alfa in patients with hypophosphatasia: Results from a Japanese clinical trial.

Author information

1
Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
2
Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
3
Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
4
Department of Pediatric Nephrology and Metabolism, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
5
Department of Bone and Mineral Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
6
Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
7
Department of Pediatrics, Tohoku University School of Medicine, Miyagi, Japan.
8
Department of Pediatrics, Showa General Hospital, Tokyo, Japan.
9
Division of Endocrinology and Metabolism, Saitama Children's Medical Center, Saitama, Japan.
10
Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
11
Department of Pediatrics, Nagara Medical Center, Gifu, Japan.
12
Division of Clinical Genetics, Nippon Medical School Hospital, Tokyo, Japan.
13
Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan.

Abstract

OBJECTIVE:

Hypophosphatasia (HPP) is a rare skeletal disease characterized by hypomineralization and low alkaline phosphatase activity. Asfotase alfa (AA) has been recently developed to treat HPP complications. This study evaluated its safety and efficacy in Japan.

DESIGN:

Open-label, multicentre, prospective trial. Patients were enrolled in 11 hospitals from June 2014 to July 2015.

PATIENTS:

Thirteen patients (9 females, 4 males) ages 0 days to 34 years at baseline were enrolled and treated with AA (2 mg/kg three times weekly subcutaneously in all but one patient). All had ALPL gene mutations. HPP forms were perinatal (n=6), infantile (n=5), childhood (n=1) and adult (n=1).

MEASUREMENTS:

Safety determined from adverse events (AEs) and laboratory data was the primary outcome measure. Efficacy was assessed as a secondary outcome measure from overall survival, respiratory status, rickets severity and gross motor development.

RESULTS:

Injection site reactions were the most frequent AEs. Serious AEs possibly related to treatment were convulsion and hypocalcaemia observed in a patient with the perinatal form. In addition, hypercalcaemia and/or hyperphosphatemia was observed in three patients with the infantile form and a low-calcium and/or low-phosphate formula was given to these patients. With respect to efficacy, all patients survived and the radiographic findings, developmental milestones and respiratory function improved.

CONCLUSION:

Asfotase alfa therapy improved skeletal, respiratory and physical symptoms with a few serious AEs in patients with HPP. Our results add support to the safety and efficacy of AA therapy for HPP patients.

KEYWORDS:

alkaline phosphatase; asfotase alfa; convulsion; enzyme replacement therapy; hypocalcaemia; hypophosphatasia

PMID:
28374482
DOI:
10.1111/cen.13343
[Indexed for MEDLINE]
Icon for Wiley
14.
Prenat Diagn. 2017 May;37(5):491-496. doi: 10.1002/pd.5040. Epub 2017 Apr 17.

Parental serum alkaline phosphatase activity as an auxiliary tool for prenatal diagnosis of hypophosphatasia.

Author information

1
Department of Fetal-Maternal Medicine, Nagara Medical Center, Gifu, Japan.
2
Department of Obstetrics and Gynecology, Hyogo College of Medicine, Nishinomiya, Japan.
3
Department of Obstetrics, Miyagi Children's Hospital, Sendai, Japan.
4
Department of Obstetrics and Gynecology, Elm Josei Clinic, Aomori, Japan.
5
Department of Obstetrics and Gynecology, Hokkaido University, Sapporo, Japan.
6
Department of Obstetrics and Gynecology, Aichi Children's Health and Medical Center, Aichi, Japan.
7
Department of Obstetrics and Gynecology, Kurume University School of Medicine, Fukuoka, Japan.
8
Department of Obstetrics and Gynecology, Yamaguchi Grand Medical Center, Yamaguchi, Japan.
9
Division of Clinical Genetics, Nippon Medical School Hospital, Tokyo, Japan.
10
Department of Radiology, National Center for Child Health and Development, Tokyo, Japan.
11
Department of Radiology, Tokyo Metropolitan Kiyose Children's Hospital, Tokyo, Japan.

Abstract

OBJECTIVE:

The objective of this study is to clarify the usefulness of parental alkaline phosphatase (ALP) for prenatal diagnosis of hypophosphatasia (HPP).

METHODS:

Maternal (m) and paternal (p) ALP values were measured in 77 cases from a multicenter cohort (fetal skeletal dysplasia forum in Japan) of cases with short limbs on ultrasonography during pregnancy. After birth, X-rays, cord blood ALP, and gene analysis were evaluated to achieve an exact diagnosis. The screening usefulness of ALP was examined retrospectively.

RESULTS:

Seventeen cases were eventually diagnosed as HPP and 60 as not HPP; the overall mean m-ALP and p-ALP (standard deviation) values were 133.4 (53) versus 197 (69) IU/L and 149.6 (71.8) versus 231 (61.4) IU/L (p < 0.001). Receiver operating characteristic curve analysis showed that the optimal m-ALP and p-ALP cutoff values were 123 and 165 IU/L, respectively. Presence of at least one of the m-ALP or p-ALP values abnormally low had a sensitivity, specificity, and positive predictive values of 82% (14/17), 93%, and 78%, respectively, for the diagnosis of HPP.

CONCLUSION:

Parental ALP measurement might be an auxiliary tool to hone in the prenatal diagnosis of fetal HPP. © 2017 John Wiley & Sons, Ltd.

PMID:
28326564
DOI:
10.1002/pd.5040
[Indexed for MEDLINE]
Icon for Wiley
15.
Am J Med Genet A. 2017 Mar;173(3):601-610. doi: 10.1002/ajmg.a.37991. Epub 2017 Jan 27.

Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia.

Author information

1
Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.
2
CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
3
Medical Division, Alexion Pharmaceuticals, Madrid, Spain.
4
Department of Rheumatology, Hospital Universitario Marqués Valdecilla, IDIVAL, Santander, Spain.
5
Department of Endocrinology, Hospital Universitario Niño Jesús, IIS La Princesa, Madrid, Spain.
6
Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain.
7
CIBEROBN, Centro de Investigación Biomédica en Red sobre Fisiopatología de la obesidad y nutrición, Instituto de Salud Carlos III, Madrid, Spain.
8
Department of Medical Genetics, San Luigi University Hospital, Orbassano, Italy.
9
Department Clinical and Biological Sciences, University of Torino, Torino, Italy.
10
Department of Pediatrics, Hospital de la Moraleja, Madrid, Spain.
11
Diagnostic Specialist, Alexion Pharmaceuticals, Moscow, Russia.
12
Medical Division, Alexion Pharma Middle East, Dubai Media City, United Arab Emirates.
13
Department of Pediatrics, Privat Hospitalet Denmark, Charlottenlund, Denmark.
14
Department of Genetics, Hospital Universitario de Móstoles, Madrid, Spain.
15
Department of Biochemistry, Hospital Universitario La Paz, IdiPaz, Madrid, Spain.
16
Division of Human Genetics and Genome Research, Department of Clinical Genetics, National Research Centre, Cairo, Egypt.
17
Centre of Excellence for Human Genetics, National Research Centre, Cairo, Egypt.
18
Department of Clinical Biochemistry, Hospital Universitario Marqués Valdecilla, IDIVAL, Santander, Spain.
19
Bone Metabolism Unit, San Raffaele Scientific Institute, Milano, Italy.
20
Department of Internal Medicine, Hospital Universitario Marqués Valdecilla, IDIVAL, University of Cantabria, RETICEF, Santander, Spain.
21
Division of Human Genetics and Genome Research, Department of Medical Molecular Genetics, National Research Centre, El Cairo, Egypt.
22
Skeletal Dysplasia Multidisciplinary Unit (UMDE), Hospital Universitario La Paz, Madrid, Spain.
23
Instituto de Investigaciones Biológicas (IB), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid, Madrid, Spain.

Abstract

Hypophosphatasia (HPP) is a rare autosomal dominant or recessive metabolic disorder caused by mutations in the tissue nonspecific alkaline phosphatase gene (ALPL). To date, over 300 different mutations in ALPL have been identified. Disease severity is widely variable with severe forms usually manifesting during perinatal and/or infantile periods while mild forms are sometimes only diagnosed in adulthood or remain undiagnosed. Common clinical features of HPP are defects in bone and tooth mineralization along with the biochemical hallmark of decreased serum alkaline phosphatase activity. The incidence of severe HPP is approximately 1 in 300,000 in Europe and 1 in 100,000 in Canada. We present the clinical and molecular findings of 83 probands and 28 family members, referred for genetic analysis due to a clinical and biochemical suspicion of HPP. Patient referrals included those with isolated low alkaline phosphatase levels and without any additional clinical features, to those with a severe skeletal dysplasia. Thirty-six (43.3%) probands were found to have pathogenic ALPL mutations. Eleven previously unreported mutations were identified, thus adding to the ever increasing list of ALPL mutations. Seven of these eleven were inherited in an autosomal dominant manner while the remaining four were observed in the homozygous state. Thus, this study includes a large number of well-characterized patients with hypophosphatasemia which has permitted us to study the genotype:phenotype correlation. Accurate diagnosis of patients with a clinical suspicion of HPP is crucial as not only is the disease life-threatening but the patients may be offered bone targeted enzymatic replacement therapy.

KEYWORDS:

ALPL; TNSALP; alkaline phosphatase; bone mineralization; hypophosphatasia; odontohypophosphatasia; skeletal dysplasia

PMID:
28127875
DOI:
10.1002/ajmg.a.37991
[Indexed for MEDLINE]
Icon for Wiley
16.
J Bone Miner Res. 2017 Apr;32(4):667-675. doi: 10.1002/jbmr.3075. Epub 2017 Jan 31.

Hypophosphatasia: Enzyme Replacement Therapy Brings New Opportunities and New Challenges.

Author information

1
Department of Internal Medicine, Division of Bone and Mineral Diseases, Washington University School of Medicine, and Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA.

Abstract

Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Autosomal inheritance (dominant or recessive) from among more than 300 predominantly missense defects of TNSALP (ALPL) explains HPP's broad-ranging severity, the greatest of all skeletal diseases. In health, TNSALP is linked to cell surfaces and richly expressed in the skeleton and developing teeth. In HPP,TNSALP substrates accumulate extracellularly, including inorganic pyrophosphate (PPi), an inhibitor of mineralization. The PPi excess can cause tooth loss, rickets or osteomalacia, calcific arthropathies, and perhaps muscle weakness. Severely affected infants may seize from insufficient hydrolysis of pyridoxal 5'-phosphate (PLP), the major extracellular vitamin B6 . Now, significant successes are documented for newborns, infants, and children severely affected by HPP given asfotase alfa, a hydroxyapatite-targeted recombinant TNSALP. Since fall 2015, this biologic is approved by regulatory agencies multinationally typically for pediatric-onset HPP. Safe and effective treatment is now possible for this last rickets to have a medical therapy, but a number of challenges involving diagnosis, understanding prognosis, and providing this treatment are reviewed herein.

KEYWORDS:

ALKALINE PHOSPHATASE; CALCIFICATION; CHONDROCALCINOSIS; HYDROXYAPATITE; HYPERCALCEMIA; INBORN-ERROR-OF-METABOLISM; INORGANIC PYROPHOSPHATE; MATRIX VESICLE; MINERALIZATION; OSTEOMALACIA; RICKETS; VITAMIN B6

PMID:
28084648
DOI:
10.1002/jbmr.3075
[Indexed for MEDLINE]
Free full text
Icon for Wiley
17.
J Neurochem. 2017 Mar;140(6):919-940. doi: 10.1111/jnc.13950.

Identification of altered brain metabolites associated with TNAP activity in a mouse model of hypophosphatasia using untargeted NMR-based metabolomics analysis.

Author information

1
Groupe de RMN Biomédicale, Laboratoire SPCMIB (CNRS UMR 5068), Université Paul Sabatier, Université de Toulouse, Toulouse Cedex, France.
2
Centre de Recherche Cerveau et Cognition (CerCo), Université de Toulouse UPS; CNRS UMR 5549, Toulouse, France.
3
Unité de Génétique Constitutionnelle Prénatale et Postnatale, Service de Biologie, Centre Hospitalier de Versailles, Le Chesnay, France.
4
Sanford Children's Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.

Abstract

Tissue non-specific alkaline phosphatase (TNAP) is a key player of bone mineralization and TNAP gene (ALPL) mutations in human are responsible for hypophosphatasia (HPP), a rare heritable disease affecting the mineralization of bones and teeth. Moreover, TNAP is also expressed by brain cells and the severe forms of HPP are associated with neurological disorders, including epilepsy and brain morphological anomalies. However, TNAP's role in the nervous system remains poorly understood. To investigate its neuronal functions, we aimed to identify without any a priori the metabolites regulated by TNAP in the nervous tissue. For this purpose we used 1 H- and 31 P NMR to analyze the brain metabolome of Alpl (Akp2) mice null for TNAP function, a well-described model of infantile HPP. Among 39 metabolites identified in brain extracts of 1-week-old animals, eight displayed significantly different concentration in Akp2-/- compared to Akp2+/+ and Akp2+/- mice: cystathionine, adenosine, GABA, methionine, histidine, 3-methylhistidine, N-acetylaspartate (NAA), and N-acetyl-aspartyl-glutamate, with cystathionine and adenosine levels displaying the strongest alteration. These metabolites identify several biochemical processes that directly or indirectly involve TNAP function, in particular through the regulation of ecto-nucleotide levels and of pyridoxal phosphate-dependent enzymes. Some of these metabolites are involved in neurotransmission (GABA, adenosine), in myelin synthesis (NAA, NAAG), and in the methionine cycle and transsulfuration pathway (cystathionine, methionine). Their disturbances may contribute to the neurodevelopmental and neurological phenotype of HPP.

KEYWORDS:

MSCA-1; cystathionine; neuron; nucleotide; pyridoxal phosphate; tissue non-specific alkaline phosphatase

PMID:
28072448
PMCID:
PMC5339068
DOI:
10.1111/jnc.13950
[Indexed for MEDLINE]
Free PMC Article
Icon for Wiley Icon for PubMed Central
18.
Mol Cell Biochem. 2017 Mar;427(1-2):169-176. doi: 10.1007/s11010-016-2908-6. Epub 2016 Dec 20.

Molecular defect of tissue-nonspecific alkaline phosphatase bearing a substitution at position 426 associated with hypophosphatasia.

Author information

1
, 3-22 Heiman Street, Kitchener, ON, N2M 3L6, Canada.
2
Kitasato Junior College of Health and Hygienic Sciences, 500 Kurotsuchi-Shinden, Minami-Uonuma, Niigata, 949-7241, Japan. komaru.k@kitasato-u.ac.jp.
3
Division of Oral Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
4
Showa Hospital, 911-1 Tokunaga Omachi, Nishi-ku, Fukuoka, 819-0375, Japan.

Abstract

Mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP) cause hypophosphatasia (HPP), a genetic disorder characterized by deficiency of serum ALP and hypomineralization of bone and teeth. Three missense mutations for glycine 426 (by standard nomenclature) of TNSALP have been reported: cysteine (p.G426C), serine (p.G426S), and aspartate (p.G426D). We expressed TNSALP mutants carrying each missense mutation in mammalian cells. All three TNSALP mutants appeared on the cell surface like the wild-type (WT) TNSALP, although the cells expressing each TNSALP mutant exhibited markedly reduced ALP activity. TNSALP (WT) was mainly present as a 140 kDa catalytically active dimeric form, whereas ~80 kDa monomers were the predominant molecular species in the cells expressing TNSALP (p.G426D) or TNSALP (p.G426S), suggesting that aspartate or serine at position 426 may hamper the subunit assembly essential for the enzymatic function of TNSALP. Alternatively, the subunits of TNSALP (p.G426C) were found to be aberrantly cross-linked by disulfide bonds, giving rise to a 200 kDa form lacking ALP activity. Taken together, our results reveal that the amino acid substitutions at position 426 of TNSALP differentially affect the structure and function of TNSALP, leading to understanding of the molecular and cellular basis of HPP.

KEYWORDS:

Cross-linking; Dimerization; Disulfide bond; Genetic disorder; Hypophosphatasia; Tissue-nonspecific alkaline phosphatase

PMID:
28000043
DOI:
10.1007/s11010-016-2908-6
[Indexed for MEDLINE]
Icon for Springer
19.
Zhonghua Yi Xue Za Zhi. 2016 Dec 13;96(46):3718-3723. doi: 10.3760/cma.j.issn.0376-2491.2016.46.006.

[Mutation analysis for two hypophosphatasia families with targeted next-generation sequencing].

[Article in Chinese]

Author information

1
*Prenatal Diagnosis Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.

Abstract

Objective: To detect the mutations in alkaline phosphatase (ALPL) gene of two Chinese families with perinatal hypophosphatasia (HPP), in order to explore the mechanism of this condition. Methods: Next-generation sequencing (NGS) of osteology system panel was carried out for exome sequencing in the mothers of 2 HPP fetuses, who visited Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University. Further polymerase chain reaction (PCR) and Sanger sequencing validation was performed in the parents, affected fetuses and 200 unrelated healthy individuals to verify the mutation sites. Results: The mother and father of No.1 family carried ALPL gene c. 333delC (p.Gly112AlafsX10) and c. 568_570delAAC (p.190delAsn) base deletions, respectively. The affected fetus carried compound heterozygotes of the two mutations. Two mutations in ALPL gene known to be associated with hypophosphatasia were found in No.2 family, c. 1250A>G (p.Asn417Ser) in the mother and c. 1166C>A (p.Thr389Asn) in the father, while the fetus was a compound heterozygote carrying both of the two mutations. Both families met the pattern of autosomal recessive inheritance. ALPL gene c. 333delC (p.Gly112AlafsX10) was a novel mutation, and it was not found in the 200 unrelated healthy individuals. Conclusions: The mutations in ALPL gene may be the cause of HPP in the 2 families. NGS technology combined with Sanger sequencing could be an efficient and accurate diagnostic method.

PMID:
27998428
[Indexed for MEDLINE]
Icon for Chinese Medical Association Publishing House Ltd.
20.
J Clin Pediatr Dent. 2016;40(6):496-502.

Hypophosphatasia: Evaluation of Size and Mineral Density of Exfoliated Teeth.

Abstract

OBJECTIVE:

Most cases of hypophosphatasia (HPP) exhibit early loss of primary teeth. Results of micro-computed tomography (micro-CT) analysis of teeth with HPP have not yet been reported. The purpose of the present study was to describe the size and mineral density distribution and mapping of exfoliated teeth with HPP using micro CT.

STUDY DESIGN:

Seven exfoliated teeth were obtained from a patient with HPP. Exfoliated teeth sizes were measured on micro CT images and mineral densities of the mandibular primary central incisors were determined.

RESULTS:

Partial dentures were fabricated for the patient to replace the eight primary teeth which had exfoliated. Most primary teeth sizes were within the normal range. The mean values of enamel and dentin mineral densities in teeth with HPP were 1.35 and 0.88 g/cm3, respectively, in the mandibular primary central incisors.

CONCLUSION:

Mineral density distribution and mapping revealed that the values in teeth with HPP were lower than the homonymous teeth controls in all regions from the crown to apex. Furthermore, it was demonstrated that the differences between HPP and controls were larger on the crown side and the differences tended to converge on the apex side. These results suggested that the present patient showed mild hypomineralization in the primary dentition.

KEYWORDS:

hypophosphatasia; micro-CT; mineral density

PMID:
27805893
DOI:
10.17796/1053-4628-40.6.496
[Indexed for MEDLINE]
Icon for Allen Press, Inc.

Supplemental Content

Loading ...
Support Center