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Journal of Clinical Medicine Dec 2021Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase () gene. Reduced activity... (Review)
Review
Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase () gene. Reduced activity of TNAP leads to the accumulation of its substrates, mainly inorganic pyrophosphate and pyridoxal-5'-phosphate, metabolic aberrations that largely explain the musculoskeletal and systemic features of the disease. More than 400 mutations, mostly missense, are reported to date, transmitted by either autosomal dominant or recessive mode. Severe disease is rare, with incidence ranging from 1:100,000 to 1:300,000 live births, while the estimated prevalence of the less severe adult form is estimated to be between 1:3100 to 1:508, in different countries in Europe. Presentation largely varies, ranging from death in utero to asymptomatic adults. In infants and children, clinical features include skeletal, respiratory and neurologic complications, while recurrent, poorly healing fractures, muscle weakness and arthropathy are common in adults. Persistently low serum alkaline phosphatase is the cardinal biochemical feature of the disease. Management requires a dedicated multidisciplinary team. In mild cases, treatment is usually symptomatic. Severe cases, with life-threating or debilitating complications, can be successfully treated with enzyme replacement therapy with asfotase alfa.
PubMed: 34884378
DOI: 10.3390/jcm10235676 -
Endocrine Reviews May 2023Bone turnover markers (BTMs) are used widely, in both research and clinical practice. In the last 20 years, much experience has been gained in measurement and...
Bone turnover markers (BTMs) are used widely, in both research and clinical practice. In the last 20 years, much experience has been gained in measurement and interpretation of these markers, which include commonly used bone formation markers (bone alkaline phosphatase, osteocalcin, and procollagen I N-propeptide); and commonly used resorption markers (serum C-telopeptides of type I collagen, urinary N-telopeptides of type I collagen, and tartrate-resistant acid phosphatase type 5b). BTMs are usually measured by enzyme-linked immunosorbent assay or automated immunoassay. Sources contributing to BTM variability include uncontrollable factors (eg, age, gender, ethnicity) and controllable factors, particularly relating to collection conditions (eg, fasting/feeding state, and timing relative to circadian rhythms, menstrual cycling, and exercise). Pregnancy, season, drugs, and recent fracture(s) can also affect BTMs. BTMs correlate with other methods of assessing bone turnover, such as bone biopsies and radiotracer kinetics, and can usefully contribute to diagnosis and management of several diseases such as osteoporosis, osteomalacia, Paget's disease, fibrous dysplasia, hypophosphatasia, primary hyperparathyroidism, and chronic kidney disease-mineral bone disorder.
Topics: Humans; Collagen Type I; Acid Phosphatase; Alkaline Phosphatase; Bone Remodeling; Biology; Bone Resorption
PubMed: 36510335
DOI: 10.1210/endrev/bnac031 -
International Journal of Molecular... Nov 2022Among bone-material qualities, mineralization is pivotal in conferring stiffness and toughness to the bone. Osteomalacia, a disease ensuing from inadequate... (Review)
Review
Among bone-material qualities, mineralization is pivotal in conferring stiffness and toughness to the bone. Osteomalacia, a disease ensuing from inadequate mineralization of the skeleton, is caused by different processes leading to decreased available mineral (calcium and/or phosphate) or enzymatic alterations. Vitamin D deficiency, which remains the major cause of altered mineralization leading to inadequate intestinal calcium and phosphate absorption, may be also associated with other conditions primarily responsible for abnormal mineralization. Given the reality of widespread vitamin D inadequacy, a full biochemical assessment of mineral metabolism is always necessary to rule out or confirm other conditions. Both too-high or too-low serum alkaline phosphatase (ALP) levels are important for diagnosis. Osteomalacic syndrome is reversible, at least in part, by specific treatment. Osteomalacia and bone mineralization themselves constitute largely unexplored fields of research. The true prevalence of the different forms of osteomalacia and the recovery after proper therapy have yet to be determined in the real world. Although non-invasive techniques to assess bone mineralization are not available in clinical practice, the systematic assessment of bone quality could help in refining the diagnosis and guiding the treatment. This review summarizes what is known of osteomalacia recent therapeutic developments and highlights the future issues of research in this field.
Topics: Humans; Calcium; Osteomalacia; Vitamin D Deficiency; Vitamin D; Phosphates
PubMed: 36499221
DOI: 10.3390/ijms232314896 -
Journal of Clinical Periodontology May 2002Periodontal diseases are among the most frequent diseases affecting children and adolescents. These include gingivitis, localized or generalized aggressive periodontitis... (Review)
Review
BACKGROUND
Periodontal diseases are among the most frequent diseases affecting children and adolescents. These include gingivitis, localized or generalized aggressive periodontitis (a.k.a., early onset periodontitis which includes generalized or localized prepubertal periodontitis and juvenile periodontitis) and periodontal diseases associated with systemic disorders. The best approach to managing periodontal diseases is prevention, followed by early detection and treatment.
METHODS
This paper reviews the current literature concerning the most common periodontal diseases affecting children: chronic gingivitis (or dental plaque-induced gingival diseases) and early onset periodontitis (or aggressive periodontitis), including prepubertal and juvenile periodontitis. In addition, systemic diseases that affect the periodontium and oral lesions commonly found in young children are addressed. The prevalence, diagnostic characteristics, microbiology, host-related factors, and therapeutic management of each of these disease entities are thoroughly discussed.
Topics: Adolescent; Age Factors; Aggressive Periodontitis; Candidiasis, Oral; Cheilitis; Child; Child, Preschool; Chronic Disease; Dental Plaque; Diabetes Mellitus, Type 1; Disease; Gingival Overgrowth; Gingivitis; Glossitis, Benign Migratory; HIV Infections; Humans; Hypophosphatasia; Periodontal Diseases; Puberty; Stomatitis, Aphthous; Stomatitis, Herpetic
PubMed: 12060422
DOI: 10.1034/j.1600-051x.2002.290504.x -
Human Mutation Jul 2020Hypophosphatasia (HPP) is a rare metabolic disorder characterized by low tissue-nonspecific alkaline phosphatase (TNSALP) typically caused by ALPL gene mutations. HPP is...
Hypophosphatasia (HPP) is a rare metabolic disorder characterized by low tissue-nonspecific alkaline phosphatase (TNSALP) typically caused by ALPL gene mutations. HPP is heterogeneous, with clinical presentation correlating with residual TNSALP activity and/or dominant-negative effects (DNE). We measured residual activity and DNE for 155 ALPL variants by transient transfection and TNSALP enzymatic activity measurement. Ninety variants showed low residual activity and 24 showed DNE. These results encompass all missense variants with carrier frequencies above 1/25,000 from the Genome Aggregation Database. We used resulting data as a reference to develop a new computational algorithm that scores ALPL missense variants and predicts high/low TNSALP enzymatic activity. Our approach measures the effects of amino acid changes on TNSALP dimer stability with a physics-based implicit solvent energy model. We predict mutation deleteriousness with high specificity, achieving a true-positive rate of 0.63 with false-positive rate of 0, with an area under receiver operating curve (AUC) of 0.9, better than all in silico predictors tested. Combining this algorithm with other in silico approaches can further increase performance, reaching an AUC of 0.94. This study expands our understanding of HPP heterogeneity and genotype/phenotype relationships with the aim of improving clinical ALPL variant interpretation.
Topics: Alkaline Phosphatase; Humans; Hypophosphatasia; Mutation, Missense; Protein Structure, Tertiary
PubMed: 32160374
DOI: 10.1002/humu.24010 -
Genes Oct 2022Hereditary metabolic bone diseases are characterized by genetic abnormalities in skeletal homeostasis and encompass one of the most diverse groups among rare diseases.... (Review)
Review
Hereditary metabolic bone diseases are characterized by genetic abnormalities in skeletal homeostasis and encompass one of the most diverse groups among rare diseases. In this review, we examine 25 selected hereditary metabolic bone diseases and recognized genetic variations of 78 genes that represent each of the three groups, including sclerosing bone disorders, disorders of defective bone mineralization and disorder of bone matrix and cartilage formation. We also review pathophysiology, manifestation and treatment for each disease. Advances in molecular genetics and basic sciences has led to accurate genetic diagnosis and novel effective therapeutic strategies for some diseases. For other diseases, the genetic basis and pathophysiology remain unclear. Further researches are therefore crucial to innovate ways to overcome diagnostic challenges and develop effective treatment options for these orphan diseases.
Topics: Humans; Bone Diseases, Metabolic; Rare Diseases
PubMed: 36292765
DOI: 10.3390/genes13101880 -
Osteoporosis International : a Journal... Mar 2024This manuscript provides a summary of the current evidence to support the criteria for diagnosing a child or adult with hypophosphatasia (HPP). The diagnosis of HPP is... (Review)
Review
BACKGROUND
This manuscript provides a summary of the current evidence to support the criteria for diagnosing a child or adult with hypophosphatasia (HPP). The diagnosis of HPP is made on the basis of integrating clinical features, laboratory profile, radiographic features of the condition, and DNA analysis identifying the presence of a pathogenic variant of the tissue nonspecific alkaline phosphatase gene (ALPL). Often, the diagnosis of HPP is significantly delayed in both adults and children, and updated diagnostic criteria are required to keep pace with our evolving understanding regarding the relationship between ALPL genotype and associated HPP clinical features.
METHODS
An International Working Group (IWG) on HPP was formed, comprised of a multidisciplinary team of experts from Europe and North America with expertise in the diagnosis and management of patients with HPP. Methodologists (Romina Brignardello-Petersen and Gordon Guyatt) and their team supported the IWG and conducted systematic reviews following the GRADE methodology, and this provided the basis for the recommendations.
RESULTS
The IWG completed systematic reviews of the literature, including case reports and expert opinion papers describing the phenotype of patients with HPP. The published data are largely retrospective and include a relatively small number of patients with this rare condition. It is anticipated that further knowledge will lead to improvement in the quality of genotype-phenotype reporting in this condition.
CONCLUSION
Following consensus meetings, agreement was reached regarding the major and minor criteria that can assist in establishing a clinical diagnosis of HPP in adults and children.
Topics: Adult; Child; Humans; Hypophosphatasia; Mutation; Retrospective Studies; Alkaline Phosphatase; Genotype; Phenotype
PubMed: 37982857
DOI: 10.1007/s00198-023-06844-1 -
European Journal of Human Genetics :... Feb 2021Hypophosphatasia (HPP) is caused by pathogenic variants in the ALPL gene. There is a large continuum in the severity, ranging from a lethal perinatal form to dental...
Hypophosphatasia (HPP) is caused by pathogenic variants in the ALPL gene. There is a large continuum in the severity, ranging from a lethal perinatal form to dental issues. We analyzed a cohort of 424 HPP patients from European geographic origin or ancestry. Using 3D modeling and results of functional tests we classified ALPL pathogenic variants according to their dominant negative effect (DNE) and their severity. The cohort was described by the genotypes resulting from alleles s (severe recessive), Sd (severe dominant), and m (moderate). Many recurrent variants showed a regional anchor pointing out founder effects rather than multiple mutational events. Homozygosity was an aggravating factor of the severity and moderate alleles were rare both in number and frequency. Pathogenic variants with DNE were found in both recessive and dominant HPP. Sixty percent of the adults tested were heterozygous for a variant showing no DNE, suggesting another mechanism of dominance like haploinsufficiency. Adults with dominant HPP without DNE were found statistically less severely affected than adults with DNE variants. Adults with dominant HPP without DNE represent a new clinical entity mostly diagnosed from 2010s, characterized by nonspecific signs of HPP and low alkaline phosphatase, and for which a high prevalence is expected. In conclusion, the genetic composition of our cohort suggests a nosology with 3 clinical forms: severe HPP is recessive and rare, moderate HPP is recessive or dominant and more common, and mild HPP, characterized by low alkaline phosphatase and unspecific clinical signs, is dominantly inherited and very common.
Topics: Adolescent; Alkaline Phosphatase; Alleles; Child; Child, Preschool; Cohort Studies; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Genotype; Heterozygote; Humans; Hypophosphatasia; Infant; Mutation; Phenotype; Pregnancy
PubMed: 32973344
DOI: 10.1038/s41431-020-00732-6 -
Journal of Bone and Mineral Research :... Feb 2018Alkaline phosphatase can be considered "our favorite enzyme" for reasons apparent to those who diagnose and treat metabolic bone diseases or who study skeletal biology....
Alkaline phosphatase can be considered "our favorite enzyme" for reasons apparent to those who diagnose and treat metabolic bone diseases or who study skeletal biology. Few might know, however, that alkaline phosphatase likely represents the most frequently assayed enzyme in all of medicine. Elevated activity in the circulation is universally recognized as a marker for skeletal or hepatobiliary disease. Nevertheless, the assay conditions in many ways are nonphysiological. The term alkaline phosphatase emerged when it became necessary to distinguish "bone phosphatase" from the phosphatase in the prostate that features an acidic pH optimum. Beginning in 1948, studies of the inborn-error-of-metabolism hypophosphatasia would identify the natural substrates and establish the physiological role of alkaline phosphatase, including in biomineralization. Here, we recount the discovery in 1923 and then eventual naming of this enzyme that remains paramount in our field. © 2017 American Society for Bone and Mineral Research.
Topics: Alkaline Phosphatase; Enzyme Assays; History, 20th Century; Humans; Terminology as Topic
PubMed: 28727174
DOI: 10.1002/jbmr.3225