Publications by authors named "Toshimi Michigami"

116 Publications

Genotype-phenotype analysis, and assessment of the importance of the zinc-binding site in PHEX in Japanese patients with X-linked hypophosphatemic rickets using 3D structure modeling.

Bone 2021 12 30;153:116135. Epub 2021 Jul 30.

Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan. Electronic address:

X-linked hypophosphatemic rickets (XLH) is an inheritable type of rickets caused by inactivating variants in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene, which results in the overproduction of fibroblast growth factor 23 (FGF23). The mechanism by which PHEX impairment leads to FGF23 overproduction is unknown. Because little is known regarding the genotype-phenotype correlation in Japanese XLH, we summarized the available clinical and genetic data and analyzed the genotype-phenotype relationships using 3-dimensional (3D) structure modeling to clarify the XLH pathophysiology. We retrospectively reviewed the clinical features and performed genetic analysis of 39 Japanese patients with XLH from 28 unrelated pedigrees carrying any known or novel PHEX variant. To predict changes in the 3D structure of mutant PHEX, we constructed a putative 3D model of each mutant and evaluated the effect of structural alteration by genotype-phenotype correlation analysis. Genetic analysis revealed 23 PHEX variants, including eight novel variants. They were associated with high i-FGF23 levels, hypophosphatemia, phosphaturia, high alkaline phosphatase levels, and short stature. No gene dosage effect or genotype-phenotype correlation was observed when truncating and non-truncating variants were compared. However, the conservation of the zinc-binding site and cavity in PHEX had an impact on the elevation of i-FGF23 levels. Via genotype-phenotype relationship analysis using 3D modeling, we showed that the zinc-binding site and cavity in PHEX can play a critical role in its function. These findings provide new genetic clues for investigating the function of PHEX and the pathogenesis of XLH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2021.116135DOI Listing
December 2021

Clonal osteoblastic cell lines with CRISPR/Cas9-mediated ablation of Pit1 or Pit2 show enhanced mineralization despite reduced osteogenic gene expression.

Bone 2021 10 9;151:116036. Epub 2021 Jun 9.

Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, Osaka Prefectural Hospital Organization, Izumi, Osaka 594-1101, Japan. Electronic address:

Multiple actions of extracellular Pi on the skeletal cells are likely to be partly mediated by type III sodium/phosphate (Na/Pi) cotransporters Pit1 and Pit2, although the details are not fully understood. In the current study, to determine the roles of Pit1 and Pit2 in osteoblasts, we generated Pit1-knockout (KO) and Pit2-KO osteoblastic cells by applying CRISPR/Cas9 genome editing to an osteoblastic cell line MC3T3-E1 subclone 4. The extracellular Pi level was increased in the Pit1-KO and Pit2-KO clones due to the reduced Pi uptake. Interestingly, in vitro mineralization was accelerated in the Pit1-KO and Pit2-KO clones, although the induction of the expression of osteogenic marker genes was suppressed. In the cells before mineralization, extracellular levels of pyrophosphate (PPi) and adenosine triphosphate (ATP) were increased in the Pit1-KO and Pit2-KO clones, which might be attributable to the reduced expression and activity of tissue-nonspecific alkaline phosphatase (TNSALP). A 24-h treatment with high Pi reduced the expression and activity of TNSALP, suggesting that the suppression of TNSALP in the Pit1-KO and Pit2-KO clones was caused by the increased availability of extracellular Pi. Lentiviral gene transfer of Pit1 and Pit2 restored the changes observed in Pit1-KO and Pit2-KO clones, respectively. The expressions of P2Y2 and P2X7 which encode receptors for extracellular ATP were altered in the Pit1-KO and Pit2-KO clones, suggesting an influence on purinergic signaling. In mineralized cells after long-term culture, intracellular levels of PPi and ATP were higher in the Pit1-KO and Pit2-KO clones. Taken together, ablation of Pit1 or Pit2 in this osteoblastic cell model led to accelerated mineralization, suppressed TNSALP and altered the levels of extracellular and intracellular PPi and ATP, which might be partly mediated by changes in the availability of extracellular Pi.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2021.116036DOI Listing
October 2021

Novel mutation in the ALPL gene with a dominant negative effect in a Japanese family.

J Bone Miner Metab 2021 Sep 5;39(5):804-809. Epub 2021 Apr 5.

Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15W7, Kita-Ku, Sapporo, 060-8638, Japan.

Introduction: Hypophosphatasia (HPP) is caused by mutations in the ALPL gene encoding tissue nonspecific alkaline phosphatase (TNSALP) and inherited in either an autosomal recessive or autosomal dominant manner. It is characterized clinically by defective mineralization of bone, dental problems, and low serum ALP levels. In the current report, we demonstrate a novel mutation in the ALPL gene (c.244G > A p.Gly82Arg) in a Japanese family with low serum ALP levels.

Materials And Methods: The ALPL gene analysis using hybridization capture-based next-generation sequencing was performed. The expression plasmids of the wild type and mutated TNSALP were introduced into COS-7 cells. The enzymatic activity of ALP in the cell lysates was measured using p-nitrophenylphosphate as a substrate.

Results: TNSALP with the novel ALPL mutation (c.244G > A p.Gly82Arg) completely lost its enzymatic activity and suppressed that of wild-type TNSALP, corroborating its dominant negative effect. The diagnosis of autosomal dominant HPP was confirmed in three members of the family.

Conclusion: Our approach would help to avoid the inappropriate use of bone resorption inhibitors for currently mis- or under-diagnosed HPP, given that the presence of further, yet undetected mutations of the ALPL gene are plausible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00774-021-01219-0DOI Listing
September 2021

Alkaline phosphatase in pediatric patients with genu varum caused by vitamin D-deficient rickets.

Endocr J 2021 Jul 24;68(7):807-815. Epub 2021 Mar 24.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

An elevated serum alkaline phosphatase (ALP) level is one of the markers for the presence of rickets in children, but it is also associated with bone formation. However, its role in diagnosing genu varum in pediatric patients with vitamin D-deficient rickets is still unknown. To clarify the role of the serum ALP level in assessing the severity of genu varum, we retrospectively investigated this issue statistically using data on rickets such as serum intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, ALP, the level of creatinine as the percentage of the median according to age (%Cr), and the metaphyseal diaphyseal angle (MDA) in the lower extremities as an index of the severity of genu varum. A multiple regression analysis revealed that log ALP and %Cr values were negatively associated with MDA values. The former association was also confirmed by a linear mixed model, while iPTH was positively associated with MDA by path model analysis. To elucidate the association of ALP with MDA in the presence of iPTH, we investigated three-dimensional figures by neural network analysis. This indicated the presence of a biphasic association of ALP with MDA: the first phase increases while the second decreases MDA. The latter phenomenon is considered to be associated with the increase in bone formation due to the mechanical stress loaded on the lower extremities. These findings are important and informative for pediatricians to understand the significance of the serum ALP level in pediatric patients with genu varum caused by vitamin D deficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1507/endocrj.EJ20-0622DOI Listing
July 2021

Lack of PTEN in osteocytes increases circulating phosphate concentrations by decreasing intact fibroblast growth factor 23 levels.

Sci Rep 2020 12 9;10(1):21501. Epub 2020 Dec 9.

Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, 840 Murodo-cho, Izumi, Osaka, 594-1101, Japan.

Fibroblast growth factor 23 (FGF23) has been centric to the regulation of phosphate (Pi) metabolism; however, the regulatory network of FGF23 in osteocytes has not yet been defined in detail. We herein investigated the role of PTEN (phosphatase and tensin homolog deleted from chromosome 10) in this regulation. We created mice lacking PTEN expression mainly in osteocytes by crossing Pten-flox mice with Dmp1-Cre mice. The lack of PTEN in the osteocytes of these mice was associated with decreased skeletal and serum intact FGF23 levels, which, in turn, resulted in reductions of urinary Pi excretion and elevations of serum Pi levels. Mechanistically, the knockdown of PTEN expression in osteoblastic UMR106 cells activated the AKT/mTORC1 (mechanistic target of rapamycin complex 1) pathway and this was associated with reductions in Fgf23 expression. Furthermore, the suppression of Fgf23 expression by PTEN knockdown or insulin simulation in UMR106 cells was partially restored by the treatment with the mTORC1 inhibitor, rapamycin. These results suggest that FGF23 expression in osteoblastic cells is in part regulated through the AKT/mTORC1 pathway and provide new insights into our understanding of the regulatory network of Pi metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-78692-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726559PMC
December 2020

Long-term outcomes for Asian patients with X-linked hypophosphataemia: rationale and design of the SUNFLOWER longitudinal, observational cohort study.

BMJ Open 2020 06 29;10(6):e036367. Epub 2020 Jun 29.

Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan.

Introduction: X-linked hypophosphataemic rickets/osteomalacia (XLH) is a chronic, debilitating genetic disease characterised by skeletal abnormalities and growth disorder. The burden of XLH begins in childhood and continues throughout life. Conventional medical therapy with phosphate, active vitamin D and surgery do not address the underlying pathophysiology of the disease. While treatment during childhood may improve bone deformity and growth retardation, a large proportion of adult patients still fail to reach normal stature. Furthermore, adult patients with XLH report comorbidities associated with unresolved childhood disease, as well as newly developed disease-related complications and significantly impaired quality of life (QOL). Despite the multiple negative aspects of XLH, Asian consensus statements for diagnosis and management are lacking.

Methods And Analysis: The Study of longitUdinal observatioN For patients with X-Linked hypOphosphataemic rickets/osteomalacia in collaboration With Asian partnERs study is a longitudinal observational cohort study of patients with XLH, designed to determine the medical characteristics and burdens (physical, emotional and financial) of this progressive disease and to evaluate the impact of treatment (including the use of burosumab) on clinical outcomes. The study was initiated in April 2018, and registration will remain open until 30 April 2022. The sample size planned for analyses is 160 patients, consisting of 100 patients in Japan and 60 patients in Korea. Up to 5 years of observation are planned per patient, from enrolment through to April 2023. Prospective and retrospective data will be collected to evaluate variables, including height/growth, rickets severity score, QOL, motor function and biomarkers for phosphate metabolism and bone turnover.

Ethics And Dissemination: Ethics approval was obtained from the Ethics Committee of Osaka University, the Ethics Committee of Kyowa Kirin Co and by the Ethics Committee of each participating medical institution. Two interim analyses and associated publications are planned using retrospective and enrolment data at year 1 and results at year 3.

Trial Registration Numbers: NCT03745521; UMIN000031605.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2019-036367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328740PMC
June 2020

Reduction in urinary angiotensinogen levels and improvement of proteinuria by renin-angiotensin system blockade in pediatric chronic kidney disease patients with very low birth weight.

Pediatr Nephrol 2020 07 11;35(7):1307-1314. Epub 2020 Mar 11.

Department of Pediatric Nephrology and Metabolism, Osaka Women's and Children's Hospital, 840 Murodo-cho, Izumi, Osaka, 594-1101, Japan.

Background: Children with low birth weight (LBW) have an increased risk of developing chronic kidney disease (CKD), and no effective strategies have been established to prevent the progression of CKD in these patients. Urinary angiotensinogen (UAGT) may represent a useful marker of intrarenal renin-angiotensin system (RAS) activation, which has been suggested to play a critical role in the development of hypertension and CKD. Herein, we conducted a prospective study to determine whether RAS blockade is beneficial for suppressing the progression of CKD in children with LBW, using UAGT as a surrogate marker of renal impairment.

Methods: Nine children with CKD (stages: 1-2) who had very low birth weight (VLBW; < 1500 g) were started on RAS blockade with candesartan. We measured blood pressure and laboratory parameters, including urinary concentrations of angiotensinogen, protein, albumin, creatinine (Cr), and estimated glomerular filtration rate (eGFR), before and after candesartan treatment.

Results: Birth weight was 712 g (range, 536-800 g). Age at evaluation was 11.6 years (range, 10.3-15.6 years). After candesartan treatment for 47.6 ± 25.0 months, the UAGT to urinary Cr ratio decreased from 61.9 ± 44.7 to 16.8 ± 14.4 μg/g (p = 0.015). The urinary protein to Cr and albumin to Cr ratios also decreased (p = 0.008 and p = 0.012, respectively), whereas there was no significant change in eGFR.

Conclusions: RAS blockade reduced UAGT levels and improved proteinuria/albuminuria in children with CKD who had VLBW. Suppression of intrarenal RAS activity may slow the progression of CKD in children with LBW.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00467-020-04520-8DOI Listing
July 2020

Clinical Practice Guidelines for Achondroplasia.

Clin Pediatr Endocrinol 2020 9;29(1):25-42. Epub 2020 Jan 9.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Achondroplasia (ACH) is a skeletal dysplasia that presents with limb shortening, short stature, and characteristic facial configuration. ACH is caused by mutations of the gene, leading to constantly activated FGFR3 and activation of its downstream intracellular signaling pathway. This results in the suppression of chondrocyte differentiation and proliferation, which in turn impairs endochondral ossification and causes short-limb short stature. ACH also causes characteristic clinical symptoms, including foramen magnum narrowing, ventricular enlargement, sleep apnea, upper airway stenosis, otitis media, a narrow thorax, spinal canal stenosis, spinal kyphosis, and deformities of the lower extremities. Although outside Japan, papers on health supervision are available, they are based on reports and questionnaire survey results. Considering the scarcity of high levels of evidence and clinical guidelines for patients with ACH, clinical practical guidelines have been developed to assist both healthcare professionals and patients in making appropriate decisions in specific clinical situations. Eleven clinical questions were established and a systematic literature search was conducted using PubMed/MEDLINE. Evidence-based recommendations were developed, and the guidelines describe the recommendations related to the clinical management of ACH. We anticipate that these clinical practice guidelines for ACH will be useful for healthcare professionals and patients alike.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1297/cpe.29.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958518PMC
January 2020

Clinical Practice Guidelines for Hypophosphatasia.

Clin Pediatr Endocrinol 2020 9;29(1):9-24. Epub 2020 Jan 9.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Hypophosphatasia (HPP) is a rare bone disease caused by inactivating mutations in the gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). Patients with HPP have varied clinical manifestations and are classified based on the age of onset and severity. Recently, enzyme replacement therapy using bone-targeted recombinant alkaline phosphatase (ALP) has been developed, leading to improvement in the prognosis of patients with life-threatening HPP. Considering these recent advances, clinical practice guidelines have been generated to provide physicians with guides for standard medical care for HPP and to support their clinical decisions. A task force was convened for this purpose, and twenty-one clinical questions (CQs) were formulated, addressing the issues of clinical manifestations and diagnosis (7 CQs) and those of management and treatment (14 CQs). A systematic literature search was conducted using PubMed/MEDLINE, and evidence-based recommendations were developed. The guidelines have been modified according to the evaluations and suggestions from the Clinical Guideline Committee of The Japanese Society for Pediatric Endocrinology (JSPE) and public comments obtained from the members of the JSPE and a Japanese HPP patient group, and then approved by the Board of Councils of the JSPE. We anticipate that the guidelines will be revised regularly and updated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1297/cpe.29.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958520PMC
January 2020

Cleidocranial dysplasia with growth hormone deficiency: a case report.

BMC Pediatr 2020 01 16;20(1):19. Epub 2020 Jan 16.

Department of Bone and Mineral Research, Research Institute, Osaka Women's Children's Hospital, Osaka Prefectural Hospital Organization, Izumi, Japan.

Background: Cleidocranial dysplasia (CCD) is a rare skeletal disorder with autosomal dominant inheritance that is characterized by hypoplastic clavicles, delayed closure of the cranial sutures, dental abnormalities, and short stature, among other features. The responsible gene for CCD is RUNX2 located on the short arm of chromosome 6p21. In general, there are intrafamilial variations in height among CCD patients. Few studies have reported data on recombinant human growth hormone (rhGH) treatment for patients with CCD; thus, it remains to be elucidated whether rhGH treatment can improve short stature. Here, we report a case of a 6-year-old girl with CCD who has growth hormone deficiency (GHD) and a novel mutation of RUNX2.

Case Presentation: At 5 years of age, this patient was diagnosed with GHD and rhGH treatment was initiated. Thereafter, she was diagnosed with CCD due to the presence of hypoplastic clavicles and an open fontanelle, which was also observed in her mother and brother. She responded well to rhGH treatment; her height improved from - 3.2 SD to - 2.4 SD after 13 months.

Conclusion: A detailed patient history and physical examination are necessary for the early diagnosis of CCD. Similarly, to ascertain the effect of rhGH treatment, careful evaluation of the patient's final height post-therapy is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12887-020-1914-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966812PMC
January 2020

Skeletal mineralization: mechanisms and diseases.

Ann Pediatr Endocrinol Metab 2019 Dec 31;24(4):213-219. Epub 2019 Dec 31.

Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, Osaka Prefectural Hospital Organization, Izumi, Japan.

Skeletal mineralization is initiated in matrix vesicles (MVs), the small extracellular vesicles derived from osteoblasts and chondrocytes. Calcium and inorganic phosphate (Pi) taken up by MVs form hydroxyapatite crystals, which propagate on collagen fibrils to mineralize the extracellular matrix. Insufficient calcium or phosphate impairs skeletal mineralization. Because active vitamin D is necessary for intestinal calcium absorption, vitamin D deficiency is a significant cause of rickets/osteomalacia. Chronic hypophosphatemia also results in rickets/osteomalacia. Excessive action of fibroblast growth factor 23 (FGF23), a key regulator of Pi metabolism, leads to renal Pi wasting and impairs vitamin D activation. X-linked hypophosphatemic rickets (XLH) is the most common form of hereditary FGF23-related hypophosphatemia, and enhanced FGF receptor (FGFR) signaling in osteocytes may be involved in the pathogenesis of this disease. Increased extracellular Pi triggers signal transduction via FGFR to regulate gene expression, implying a close relationship between Pi metabolism and FGFR. An anti-FGF23 antibody, burosumab, has recently been developed as a new treatment for XLH. In addition to various forms of rickets/osteomalacia, hypophosphatasia (HPP) is characterized by impaired skeletal mineralization. HPP is caused by inactivating mutations in tissue-nonspecific alkaline phosphatase, an enzyme rich in MVs. The recent development of enzyme replacement therapy using bone-targeting recombinant alkaline phosphatase has improved the prognosis, motor function, and quality of life in patients with HPP. This links impaired skeletal mineralization with various conditions, and unraveling its pathogenesis will lead to more precise diagnoses and effective treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6065/apem.2019.24.4.213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944863PMC
December 2019

Hypophosphatasia in Japan: ALPL Mutation Analysis in 98 Unrelated Patients.

Calcif Tissue Int 2020 03 9;106(3):221-231. Epub 2019 Nov 9.

Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, 565-0871, Osaka, Japan.

Hypophosphatasia (HPP) is highly variable in clinical expression and is generally classified into six subtypes. Although it would be beneficial to be able to predict the clinical course from the ALPL genotype, studies on this issue are limited. Here, we aimed to clarify the features of Japanese HPP and the relationships between genotype and clinical manifestations. We analyzed 98 unrelated Japanese patients to investigate the percentage of each clinical form, frequently detected mutations, and the relationship between the genotype and phenotype. Some of the identified mutants were characterized by transfection experiments. Perinatal severe form was the most frequent (45.9%), followed by perinatal benign form (22.4%). Among the 196 alleles, p.Leu520ArgfsX86 (c.1559delT) was detected in 89 alleles, and p.Phe327Leu (c.979T>C) was identified in 23 alleles. All of the homozygotes for p.Leu520ArgfsX86 were classified into perinatal severe form, and patients carrying p.Phe327Leu in one of the alleles were classified into perinatal benign or odonto HPP. Twenty of the 22 patients with perinatal benign HPP were compound heterozygous for p.Phe327Leu and another mutation. Most patients with odonto HPP were found to be monoallelic heterozygotes for dominant-negative mutations or compound heterozygotes with mutants having residual activity. The high prevalence of p.Leu520ArgfsX86 and p.Phe327Leu mutations might underlie the high rate of perinatal severe and perinatal benign forms, respectively, in Japanese HPP. Although ALPL genotyping would be beneficial for predicting the clinical course to an extent, the observed phenotypical variability among patients sharing the same genotypes suggests the presence of modifiers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00223-019-00626-wDOI Listing
March 2020

Bisphosphonate Use and Fractures in Adults with Hypophosphatasia.

JBMR Plus 2019 Oct 26;3(10):e10223. Epub 2019 Aug 26.

Department of Endocrinology Greenlane Clinical Centre Auckland New Zealand.

Adults with hypophosphatasia (HPP) may suffer femoral fractures resembling the atypical femoral fractures that can occur with long-term bisphosphonate treatment, and there is an emerging consensus that bisphosphonates should not be used in adults with HPP and low bone mass. However, the spectrum of HPP in adults is wide: ranging from the severely affected-who commonly have osteomalacia-through to the minimally affected. The former typically have biallelic and the latter, heterozygous mutations. We have reviewed reports of fractures in adults with genetically proven HPP which suggest that the risk of fracture is at least 200-fold greater in those with biallelic mutations. We also discuss two cases of postmenopausal women with heterozygous mutations. One had fractures and severe osteoporosis, but histology revealed no evidence of osteomalacia. The second had taken alendronate for 8 years, but despite profound suppression of bone turnover, histology again revealed no evidence of osteomalacia. The management of adults with HPP who have coexisting osteoporosis is challenging. More data are clearly needed, but we suggest that the risks of bisphosphonate therapy may be relatively low in patients who have heterozygous mutations and no histological evidence of osteomalacia. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbm4.10223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820463PMC
October 2019

Japanese nationwide survey of hypophosphatasia reveals prominent differences in genetic and dental findings between odonto and non-odonto types.

PLoS One 2019 10;14(10):e0222931. Epub 2019 Oct 10.

Department of Pediatric Dentistry, Osaka University Graduate School of Dentistry, Osaka, Japan.

Hypophosphatasia (HPP) is a rare and intractable metabolic bone disease caused by mutations in the ALPL gene. Here, we undertook a nationwide survey of HPP in Japan, specifically regarding the prominent genetic and dental manifestations of odonto (n = 16 cases) and other (termed "non-odonto") (n = 36 cases) types. Mean serum alkaline phosphatase (ALP) values in odonto-type patients were significantly greater than those of non-odonto-type patients (P<0.05). Autosomal dominant and autosomal recessive inheritance patterns were detected, respectively, in 89% of odonto-type and 96% of non-odonto-type patients. The ALPL "c.1559delT" mutation, associated with extremely low ALP activity, was found in approximately 70% of cases. Regarding dental manifestations, all patients classified as odonto-type showed early exfoliation of the primary teeth significantly more frequently than patients classified as non-odonto-type (100% vs. 56%; P<0.05). Tooth hypomineralisation was detected in 42% of non-odonto-type patients, but not in any odonto-type patients (0%; P<0.05). Collectively, these results suggest that genetic and dental manifestations of patients with odonto-type and non-odonto-type HPP are significantly different, and these differences should be considered during clinical treatment of patients with HPP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222931PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786601PMC
March 2020

Findings of amplitude-integrated electroencephalogram recordings and serum vitamin B6 metabolites in perinatal lethal hypophosphatasia during enzyme replacement therapy.

Brain Dev 2019 Sep 15;41(8):721-725. Epub 2019 Apr 15.

Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Japan.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.braindev.2019.03.015DOI Listing
September 2019

Roles of Phosphate in Skeleton.

Front Endocrinol (Lausanne) 2019 26;10:180. Epub 2019 Mar 26.

Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.

Phosphate is essential for skeletal mineralization, and its chronic deficiency leads to rickets and osteomalacia. Skeletal mineralization starts in matrix vesicles (MVs) derived from the plasma membrane of osteoblasts and chondrocytes. MVs contain high activity of tissue non-specific alkaline phosphatase (TNSALP), which hydrolyzes phosphoric esters such as pyrophosphates (PPi) to produce inorganic orthophosphates (Pi). Extracellular Pi in the skeleton is taken up by MVs through type III sodium/phosphate (Na/Pi) cotransporters and forms hydroxyapatite. In addition to its roles in MV-mediated skeletal mineralization, accumulating evidence has revealed that extracellular Pi evokes signal transduction and regulates cellular function. Pi induces apoptosis of hypertrophic chondrocytes, which is a critical step for endochondral ossification. Extracellular Pi also regulates the expression of various genes including those related to proliferation, differentiation, and mineralization. cell studies have demonstrated that an elevation in extracellular Pi level leads to the activation of fibroblast growth factor receptor (FGFR), Raf/MEK (mitogen-activated protein kinase/ERK kinase)/ERK (extracellular signal-regulated kinase) pathway, where the type III Na/Pi cotransporter PiT-1 may be involved. Responsiveness of skeletal cells to extracellular Pi suggests their ability to sense and adapt to an alteration in Pi availability in their environment. Involvement of FGFR in the Pi-evoked signal transduction is interesting because enhanced FGFR signaling in osteoblasts/osteocytes might be responsible for the overproduction of FGF23, a key molecule in phosphate homeostasis, in a mouse model for human X-linked hypophosphatemic rickets (XLH). Impaired Pi sensing may be a pathogenesis of XLH, which needs to be clarified in future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2019.00180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443631PMC
March 2019

[Wnt Signaling and Skeletal Dysplasias.]

Clin Calcium 2019;29(3):323-328

Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, Osaka Prefectural Hospital Organization, Izumi, Osaka, Japan.

Identification of responsible genes for skeletal dysplasias evidences their critical roles in the skeletal development and maintenance. Mutations in the genes encoding the components of Wnt canonical pathway, which include , , , and , cause the disorders characterized by abnormal in bone mass. On the other hand, mutations in the genes for the components of Wnt non-canonical pathway such as , , and are associated with dysmorphic skeletal disorders which manifest short limbs and facial anomalies. Thus, both canonical and non-canonical pathways of Wnt signaling play substantial roles in the human skeletons, and it is suggested that the former mainly controls bone mass while the latter regulates skeletal morphogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.20837/4201903323DOI Listing
September 2019

Intestinal clock system regulates skeletal homeostasis.

JCI Insight 2019 03 7;4(5). Epub 2019 Mar 7.

Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, Izumi, Osaka, Japan.

The circadian clock network is an evolutionarily conserved system involved in the regulation of metabolic homeostasis; however, its impacts on skeletal metabolism remain largely unknown. We herein demonstrated that the circadian clock network in the intestines plays pivotal roles in skeletal metabolism such that the lack of the Bmal1 gene in the intestines (Bmal1Int-/- mice) caused bone loss, with bone resorption being activated and bone formation suppressed. Mechanistically, Clock protein interaction with the vitamin D receptor (VDR) accelerated its binding to the VDR response element by enhancing histone acetylation in a circadian-dependent manner, and this was lost in Bmal1Int-/- mice because nuclear translocation of Clock required the presence of Bmal1. Accordingly, the rhythmic expression of VDR target genes involved in transcellular calcium (Ca) absorption was created, and this was not observed in Bmal1Int-/- mice. As a result, transcellular Ca absorption was impaired and bone resorption was activated in Bmal1Int-/- mice. Additionally, sympathetic tone, the activation of which suppresses bone formation, was elevated through afferent vagal nerves in Bmal1Int-/- mice, the blockade of which partially recovered bone loss by increasing bone formation and suppressing bone resorption in Bmal1Int-/- mice. These results demonstrate that the intestinal circadian system regulates skeletal bone homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.121798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483519PMC
March 2019

CREB activation in hypertrophic chondrocytes is involved in the skeletal overgrowth in epiphyseal chondrodysplasia Miura type caused by activating mutations of natriuretic peptide receptor B.

Hum Mol Genet 2019 04;28(7):1183-1198

Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, Osaka Prefectural Hospital Organization, Izumi, Osaka, Japan.

Natriuretic peptide receptor B (NPRB) produces cyclic guanosine monophosphate (cGMP) when bound by C-type natriuretic peptide (CNP). Activating mutations in NPRB cause a skeletal overgrowth disorder, which has been named epiphyseal chondrodysplasia, Miura type (ECDM; OMIM #615923). Here we explored the cellular and molecular mechanisms for the skeletal overgrowth in ECDM using a mouse model in which an activating mutant NPRB is specifically expressed in chondrocytes. The mutant mice (NPRB[p.V883M]-Tg) exhibited postnatal skeletal overgrowth and increased cGMP in cartilage. Both endogenous and transgene-derived NPRB proteins were localized at the plasma membrane of hypertrophic chondrocytes. The hypertrophic zone of growth plate was thickened in NPRB[p.V883M]-Tg. An in vivo BrdU-labeling assay suggested that some of the hypertrophic chondrocytes in NPRB[p.V883M]-Tg mice continued to proliferate, although wild-type (WT) chondrocytes stopped proliferating after they became hypertrophic. In vitro cell studies revealed that NPRB activation increased the phosphorylation of cyclic AMP-responsive element binding protein (CREB) and expression of cyclin D1 in matured chondrocytes. Treatment with cell-permeable cGMP also enhanced the CREB phosphorylation. Inhibition of cyclic adenosine monophosphate (cAMP)/protein kinase A pathway had no effects on the CREB phosphorylation induced by NPRB activation. In immunostaining of the growth plates for the proliferation marker Ki67, phosphorylated CREB and cyclin D1, most signals were similarly observed in the proliferating zone in both genotypes, but some cells in the hypertrophic zone of NPRB[p.V883M]-Tg were also positively stained. These results suggest that NPRB activation evokes its signal in hypertrophic chondrocytes to induce CREB phosphorylation and make them continue to proliferate, leading to the skeletal overgrowth in ECDM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddy428DOI Listing
April 2019

[Secondary osteoporosis. Disease-Related Osteoporosis in Children.]

Clin Calcium 2018;28(12):1591-1598

Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, Osaka Prefectural Hospital Organization, Osaka, Japan.

Similarly to adult osteoporosis, childhood osteoporosis also is usually divided into primary and secondary causes. Primary osteoporosis includes genetic disorders represented by osteogenesis imperfecta. Secondary pediatric osteoporosis is associated with various diseases and glucocorticoid treatment, and malnutrition, impaired mobility, chronic inflammation and endocrine disorders can be risk factors. In growing children, mild osteoporosis can be spontaneously recovered by elimination of risk factors. However, initiation of treatment using drugs such as bisphosphonate should be considered in primary osteoporosis including osteogenesis imperfecta and severe secondary osteoporosis which cannot be spontaneously improved. Administration of bisphosphonate increased bone mineral density in pediatric patients, but long-term safety and efficacy need further investigation. Development of new drugs to treat osteogenesis imperfecta is underway, which include the antibodies against sclerostin and TGF-β.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/CliCa181215911598DOI Listing
May 2019

[Rickets/Osteomalacia. Consensus on Vitamin D Deficiency and Insufficiency in Children.]

Clin Calcium 2018;28(10):1307-1311

Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, Osaka Prefectural Hospital Organization, Japan.

Vitamin D deficiency is usually manifested as rickets in children. Since vitamin D deficiency/insufficiency is common worldwide, global consensus has been formulated on prevention, diagnosis and treatment of nutritional rickets represented by vitamin D-deficient rickets. This consensus has defined vitamin D insufficiency as the status with serum 25-hydroxyvitamin D(25OHD)level between 12 and 20 ng/mL and vitamin D deficiency as the status with serum 25OHD level below 12 ng/mL. Generally low dietary calcium(Ca)intake coexists with vitamin D deficiency/insufficiency in patients with rickets, and it is important to ensure sufficient Ca intake ensure in the management of nutritional rickets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/CliCa181013071311DOI Listing
June 2019

CYP7A1 expression in hepatocytes is retained with upregulated fibroblast growth factor 19 in pediatric biliary atresia.

Hepatol Res 2019 Mar 3;49(3):314-323. Epub 2018 Oct 3.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Aim: Bile acid biosynthesis is strictly regulated under physiological conditions. The expression of fibroblast growth factor (FGF) 19 is induced when bile acids bind to the farnesoid X receptor in the intestinal epithelium. Fibroblast growth factor 19 is then transported by the portal flow, causing transcriptional inhibition of cytochrome P450, family 7, subfamily A, polypeptide 1 (CYP7A1), a key enzyme in bile acid biosynthesis, through the extracellular signal-regulated kinase (ERK) pathway. However, the regulatory mechanisms of these signaling pathways in hepatocytes under chronic cholestasis remain unclear. We investigated the regulation of these signaling pathways in patients with biliary atresia (BA).

Methods: We analyzed the regulation of molecules in these signaling pathways using liver and serum samples from eight BA children and four non-cholestatic disease controls.

Results: CYP7A1 mRNA expression was not inhibited in BA microdissected hepatocyte-enriched tissue (HET) despite high serum bile acid concentrations. The FGF19 protein was synthesized in BA HET, and its serum concentration was elevated. Fibroblast growth factor receptor 4 was phosphorylated in BA livers. However, ERK phosphorylation was significantly reduced. We examined SPRY2 expression to determine how the ERK pathway was inactivated downstream of the FGF receptor; the expression was significantly increased in BA HET.

Conclusions: This is the first study to measure the CYP7A1 mRNA levels in human BA HET. Fibroblast growth factor 19 was increased in BA hepatocytes. By focusing on its regulation in hepatocytes, we showed that the FGF19 pathway did not suppress bile acid synthesis, probably due to an altered mechanism involving upregulated SPRY2 in BA patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hepr.13245DOI Listing
March 2019

Phosphate as a Signaling Molecule and Its Sensing Mechanism.

Physiol Rev 2018 10;98(4):2317-2348

Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, Osaka Prefectural Hospital Organization, Izumi, Osaka , Japan ; and Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka , Japan.

In mammals, phosphate balance is maintained by influx and efflux via the intestines, kidneys, bone, and soft tissue, which involves multiple sodium/phosphate (Na/P) cotransporters, as well as regulation by several hormones. Alterations in the levels of extracellular phosphate exert effects on both skeletal and extra-skeletal tissues, and accumulating evidence has suggested that phosphate itself evokes signal transduction to regulate gene expression and cell behavior. Several in vitro studies have demonstrated that an elevation in extracellular P activates fibroblast growth factor receptor, Raf/MEK (mitogen-activated protein kinase/ERK kinase)/ERK (extracellular signal-regulated kinase) pathway and Akt pathway, which might involve the type III Na/P cotransporter PiT-1. Excessive phosphate loading can lead to various harmful effects by accelerating ectopic calcification, enhancing oxidative stress, and dysregulating signal transduction. The responsiveness of mammalian cells to altered extracellular phosphate levels suggests that they may sense and adapt to phosphate availability, although the precise mechanism for phosphate sensing in mammals remains unclear. Unicellular organisms, such as bacteria and yeast, use some types of P transporters and other molecules, such as kinases, to sense the environmental P availability. Multicellular animals may need to integrate signals from various organs to sense the phosphate levels as a whole organism, similarly to higher plants. Clarification of the phosphate-sensing mechanism in humans may lead to the development of new therapeutic strategies to prevent and treat diseases caused by phosphate imbalance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/physrev.00022.2017DOI Listing
October 2018

A case of perinatal hypophosphatasia with a novel mutation in the gene: clinical course and review of the literature.

Clin Pediatr Endocrinol 2018 31;27(3):179-186. Epub 2018 Jul 31.

Department of Pediatrics, Osaka Hospital, Japan Community Healthcare Organization (JCHO), Osaka, Japan.

Hypophosphatasia (HPP) is a metabolic bone disease characterized by failure of bone calcification and vitamin B6 dependent seizures. It is caused by loss-of-function mutations in the gene. A newborn girl required respiratory support by nasal-directional positive airway pressure at birth, and pyridoxine hydrochloride administration for vitamin B6-dependent seizures observed from day two. Umbilical cord blood showed low alkaline phosphatase (ALP) activity and high pyridoxal phosphate levels. Radiographs showed severe rickets-like appearance of the bones. Genetic analysis of the gene revealed compound heterozygous mutations, c.1559delT/p.Ser188Pro. We diagnosed her with perinatal severe HPP, and started the patient on asfotase alfa from day six. Following enzyme replacement therapy (ERT), skeletal mineralization and respiratory insufficiency improved with no remarkable side-effects. Crying vital capacity (CVC) was used to evaluate respiratory status, which continuously improved from 13.3 mL/kg (day 22) to 20.6 mL/kg (day 113). Since no seizures occurred, pyridoxine hydrochloride was tapered off at one year of age. Strategies to manage perinatal severe HPP cases following ERT have not been established till date. A review of the literature shows that CVC may be a good indicator for weaning from ventilatory support. In addition, ERT will most likely enable withdrawal of pyridoxine treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1297/cpe.27.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073057PMC
July 2018

Pyridoxal 5'-phosphate and related metabolites in hypophosphatasia: Effects of enzyme replacement therapy.

Mol Genet Metab 2018 09 17;125(1-2):174-180. Epub 2018 Jul 17.

Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2018.07.006DOI Listing
September 2018

Incidence rate and characteristics of symptomatic vitamin D deficiency in children: a nationwide survey in Japan.

Endocr J 2018 Jun 10;65(6):593-599. Epub 2018 Mar 10.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.

There is concern that vitamin D deficiency is prevalent among children in Japan as well as worldwide. We conducted a nationwide epidemiologic survey of symptomatic vitamin D deficiency to observe its incidence rate among Japanese children. A questionnaire inquiring the number of new patients with vitamin D deficiency rickets and/or hypocalcemia for 3 years was sent to 855 randomly selected hospitals with a pediatrics department in Japan. In this survey, we found that 250 children were diagnosed with symptomatic vitamin D deficiency. The estimated number of patients with symptomatic vitamin D deficiency per year was 183 (95% confidence interval (CI): 145-222). The overall annual incidence rate among children under 15 years of age was 1.1 per 100,000 population (95% CI: 0.9-1.4). The second survey has provided detailed information on 89 patients with symptomatic vitamin D deficiency under 5 years of age in hospitals in the current research group. The nationwide and second surveys estimated the overall annual incidence rate of symptomatic vitamin D deficiency in children under 5 years of age to be 3.5 (2.7-4.2) per 100,000 population. The second survey revealed 83% had bowed legs, 88% had exclusive breastfeeding, 49% had a restricted and/or unbalanced diet and 31% had insufficient sun exposure among the 89 patients. This is the first nationwide survey on definitive clinical vitamin D deficiency in children in Japan. Elucidating the frequency and characteristics of symptomatic vitamin D deficiency among children is useful to develop preventative public health strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1507/endocrj.EJ18-0008DOI Listing
June 2018

[Homeostasis and Disorder of Musculoskeletal System.Diagnosis and Treatment of Congenital Musculoskeletal Diseases.]

Clin Calcium 2018;28(3):381-388

Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, Osaka Prefectural Hospital Organization, Japan.

Congenital skeletal dysplasias have been considered to be fundamentally untreatable diseases. However, molecular diagnosis by genetic testing has become more prevalent, and efforts are being made to develop novel therapies based on the pathogenesis. As treatments for osteogenesis imperfecta, in addition to anti-resorptive agents, neutralizing antibodies against sclerostin and transforming growth factor(TGF)-β and chemical chaperones can be beneficial. Enzyme replacement therapy using bone-targeting recombinant alkaline phosphatase has been recently developed to treat hypophosphatasia and has much improved the prognosis of the patients affected with severe forms of the disease. To treat the severe short stature in achondroplasia, drugs targeting the fibroblast growth factor receptor 3(FGFR3)-mediated signal are in development for clinical use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/CliCa1803381388DOI Listing
February 2019

Cover Image, Volume 176A, Number 1, January 2018.

Am J Med Genet A 2018 01;176(1)

Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.

The cover image, by Satoru Ikenoue et al., is based on the Clinical Report Discordant fetal phenotype of hypophosphatasia in two siblings, DOI: 10.1002/ajmg.a.38531.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.38585DOI Listing
January 2018

Discordant fetal phenotype of hypophosphatasia in two siblings.

Am J Med Genet A 2018 01 21;176(1):171-174. Epub 2017 Nov 21.

Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.38531DOI Listing
January 2018

[Update on recent progress in vitamin D research. Vitamin D Metabolism and Its Regulation.]

Clin Calcium 2017;27(11):1517-1523

Department of Bone and Mineral Research, Osaka Women's and Children's Hospital, Osaka Prefectural Hospital Organization, Japan.

Vitamin D is taken up from food as D and D. Vitamin D is also synthesized from 7-dehydrocholesterol in the skin by the exposure of ultraviolet B. The D and D, which are called native vitamin D, are hydroxylated at C25 in the liver by CYP2R1 and then at C1 in the kidney by CYP27B1, to be converted to an active vitamin D metabolite, 1,25-dihydroxyvitamin D[1,25(OH)D]. CYP24A1 converts 25-hydroxyvitamin D(25OHD)and 1,25(OH)D to 24,25-dihydroxyvitamin D[24,25(OH)D]and 1,24,25-trihydroxyvitamin D[1,24,25(OH)D], respectively, to decrease the level of 1,25(OH)D. CYP27B1 and CYP24A1 are mainly expressed in the kidney but also detected in other tissues, and it is suggested that 1,25(OH)D produced in the extra-renal tissues may exert its effects locally.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/CliCa171115171523DOI Listing
February 2018
-->