scholarly journals Genetics of Refractory Rickets: Identification of Novel PHEX Mutations in Indian Patients and a Literature Update

2018 ◽  
Vol 07 (02) ◽  
pp. 047-059 ◽  
Author(s):  
Binata Marik ◽  
Arvind Bagga ◽  
Aditi Sinha ◽  
Pankaj Hari ◽  
Arundhati Sharma
Keyword(s):  
Direct Sequencing ◽  
Genetic Disorder ◽  
Vitamin D Supplementation ◽  
Hypophosphatemic Rickets ◽  
Missense Mutations ◽  
Indian Children ◽  
Indian Patients ◽  
Number Of Patients ◽  
Precise Diagnosis ◽  
Phex Gene

AbstractRefractory rickets is a genetic disorder that cannot be treated by vitamin D supplementation and adequate dietary calcium and phosphorus. Hereditary hypophosphatemic rickets is one of the major forms of refractory rickets in Indian children and caused due to mutations in the PHEX, FGF23, DMP1, ENPP1, and SLC34A3 genes. This is the first study in India on a large number of patients reporting on mutational screening of the PHEX gene. Direct sequencing in 37 patients with refractory rickets revealed eight mutations in 13 patients of which 1 was nonsense, 2 were deletions, 1 was a deletion–insertion, and 4 were missense mutations. Of these mutations, four (c.566_567 delAG, c.651_654delACAT, c.1337delinsAATAA, and c.2048T > A) were novel mutations. This article discusses the mutations in Indian patients, collates information on the genetic causes of refractory rickets, and emphasizes the significance of genetic testing for precise diagnosis, timely treatment, and management of the condition, especially in developing countries.

scholarly journals Mutational Analysis and Genotype-Phenotype Correlation of the PHEX Gene in X-Linked Hypophosphatemic Rickets

2001 ◽  
Vol 86 (8) ◽  
pp. 3889-3899 ◽  
Author(s):  
Ingrid A. Holm ◽  
Anne E. Nelson ◽  
Bruce G. Robinson ◽  
Rebecca S. Mason ◽  
Deborah J. Marsh ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Family Members ◽  
Hypophosphatemic Rickets ◽  
Missense Mutations ◽  
Phenotype Correlation ◽  
Severity Of Disease ◽  
Skeletal Disease ◽  
Phenotype Analysis ◽  
Phex Gene ◽  
History Of

PHEX is the gene defective in X-linked hypophosphatemic rickets. In this study, analysis of PHEX revealed mutations in 22 hypophosphatemic rickets patients, including 16 of 28 patients in whom all 22 PHEX exons were studied. In 13 patients, in whom no PHEX mutation had been previously detected in 17 exons, the remaining 5 PHEX exons were analyzed and mutations found in 6 patients. Twenty different mutations were identified, including 16 mutations predicted to truncate PHEX and 4 missense mutations. Phenotype analysis was performed on 31 hypophosphatemic rickets patients with PHEX mutations, including the 22 patients identified in this study, 9 patients previously identified, and affected family members. No correlation was found between the severity of disease and the type or location of the mutation. However, among patients with a family history of hypophosphatemic rickets, there was a trend toward more severe skeletal disease in patients with truncating mutations. Family members in more recent generations had a milder phenotype. Postpubertal males had a more severe dental phenotype. In conclusion, although identifying mutations in PHEX may have limited prognostic value, genetic testing may be useful for the early identification and treatment of affected individuals. Furthermore, this study suggests that other genes and environmental factors affect the severity of hypophosphatemic rickets.

scholarly journals Mutational analysis of patients with FGF23-related hypophosphatemic rickets

2012 ◽  
Vol 167 (2) ◽  
pp. 165-172 ◽  
Author(s):  
Yuka Kinoshita ◽  
Tasuku Saito ◽  
Yuichiro Shimizu ◽  
Michiko Hori ◽  
Manabu Taguchi ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Genomic Dna ◽  
Mutational Analysis ◽  
Direct Sequencing ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Screening Methods ◽  
Number Of Patients ◽  
Clinical Diagnoses ◽  
Design And Methods

ObjectiveX-linked hypophosphatemic rickets (XLHR) caused by mutations in the PHEX gene is considered to be the most frequent cause of fibroblast growth factor 23 (FGF23)-related congenital hypophosphatemic rickets. In previous studies, mutations in the PHEX gene were detected in 60–70% of patients with clinical diagnoses of XLHR. This leads to the question whether current screening methods for mutations in the PHEX gene are inadequate or whether there is a substantial number of patients with other genetic causes of hypophosphatemic rickets. We conducted a genetic analysis of patients with FGF23-related hypophosphatemic rickets to clarify their etiology and evaluate the prevalence of XLHR among this group.Design and methodsWe studied 27 patients with familial and sporadic congenital hypophosphatemic rickets in whom serum FGF23 was above 30 pg/ml using an assay for the full-length protein. Exons and exon–intron junctions of genomic DNA of causative genes for FGF23-related hypophosphatemic rickets were sequenced. PHEX mRNA from peripheral blood was analyzed in some patients.ResultsDirect sequencing of genomic DNA identified 11 novel and four known mutations in the PHEX gene. Additionally, there was a large PHEX gene deletion in one case and abnormal PHEX mRNA splicing in another. In summary, 26 patients (96%) had XLHR and one patient had autosomal recessive hypophosphatemic rickets 2.ConclusionsXLHR is by far the most prevalent cause of FGF23-related hypophosphatemic rickets. We propose that analysis of PHEX mRNA from peripheral blood would be appropriate for the first screening step in determining the etiology of FGF23-related hypophosphatemic rickets.

scholarly journals Novel PHEX Variants and Splicing Mutations in Patients with X-Linked Hypophosphatemia

2021 ◽  
Author(s):  
Xuesha Xing ◽  
Jinlan Gao ◽  
Hongwei Ma ◽  
Lina Zhang ◽  
Fang Li ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Genetic Disorder ◽  
Exon Skipping ◽  
Hypophosphatemic Rickets ◽  
Missense Mutations ◽  
Splice Sites ◽  
Nonsense Mutations ◽  
Reading Frame ◽  
Splicing Mutations ◽  
Mutation Database

Abstract Background: X-linked hypophosphatemia rickets (XLH) is a genetic disorder of phosphate wasting that causes the majority of inherited hypophosphatemic rickets. The disease is caused by mutations in the phosphate-regulating endopeptidase gene (PHEX). All types of mutations have been detected in the PHEX gene. There is no clear preference for the position and the type of mutation.Methods: In this study, we performed DNA sequencing and ex vivo splicing analysis to study the PHEX gene in ten sporadic patients and six core families with XLH. Results: A total of 25 patients were studied. Fifteen different mutations were detected in these patients, including five missense mutations, five splicing mutations, two nonsense mutations, two small deletions, and one small insertion. Five mutations were not previously reported. We also characterized the splicing mutations identified in our study, which consisted of exon skipping and activation of new splice sites in an exon or intron. Most of the observed changes resulted in a frameshift of the PHEX open reading frame.Conclusions: The genetic etiology in patients with XLH were successfully identified. This study expands the mutation database of the PHEX gene. We also explored the pathogenesis of XLH caused by splice site mutations. These results will contribute to the diagnosis of XLH and the pathogenicity analysis of mutations in patients.

Ayurvedic management of Ducchen’s Muscular Dystrophy - A Case report

2017 ◽  
Vol 2 (4) ◽  
Author(s):  
Jayaraj R. ◽  
Veena G. Rao ◽  
Jyothi Nagalikar
Keyword(s):  
Muscular Dystrophy ◽  
Cardiac Dysfunction ◽  
Muscle Wasting ◽  
Progressive Disease ◽  
Genetic Disorder ◽  
Dystrophin Gene ◽  
Wasting Disease ◽  
Number Of Patients ◽  
Choice Of Treatment ◽  
Muscle Wasting Disease

Ducchen’s muscular dystrophy is most common X-linked recessive disorder affecting 30 in 100,000 live male births. The primary cause of this disease is mutations in Dystrophin gene which is essential for the structural and functional integrity of muscle. It is a progressive muscle wasting disease in which patients frequently develop contractures and lose the ability to walk between 6 and 12 years of age. With progressive disease most patients succumb to death from respiratory failure and cardiac dysfunction in their twenties. As this is a genetic disorder we can consider it as Adibala Pravritta Vyadhi. As Mamsa Kshaya is seen at some muscles and Mamsa Vriddhi at other this is an Avarana Vata Vyadhi. In both Upsthambha and Nirupasthmbha Vatavyadhi, Basthi is considered as prime choice of treatment. A Variety of Ksheerabasti in the form of Kalabasti is studied in this condition by taking subjective and objective parameters. As this has given better improvement with no adverse effects in the patient, it can be tried in large number of patients.

scholarly journals X-linked hypophosphatemic rickets: Case report

2014 ◽  
Vol 142 (1-2) ◽  
pp. 75-78 ◽  
Author(s):  
Vladimir Radlovic ◽  
Zeljko Smoljanic ◽  
Nedeljko Radlovic ◽  
Zoran Lekovic ◽  
Dragana Ristic ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
De Novo ◽  
Serum Levels ◽  
High Serum ◽  
Hypophosphatemic Rickets ◽  
De Novo Mutation ◽  
Inherited Disease ◽  
X Ray ◽  
Phex Gene ◽  
Renal Tubular

Introduction. X-linked hypophosphatemic rickets (XLHR) is a dominant inherited disease caused by isolated renal phosphate wasting and impairment of vitamin D activation. We present a girl with X-linked hypophosphatemic rickets (XLHR) as a consequence of de novo mutation in the PHEX gene. Case Outline. A 2.2-year-old girl presented with prominent lower limb rachitic deformity, waddling gait and disproportionate short stature (79 cm, <P5; -1,85 SD). On the basis of hypophosphatemia, hyperphosphaturia, high serum level of alkaline phosphatase, normal calcemia, 25(OH)D and PTH, as well as characteristic clinical and X-ray findings, diagnosis of hypophosphatemic rickets (HR) was made. Normal calciuria and absence of other renal tubular disorders indicated HR as a consequence of isolated hyperphosphaturia. The treatment (phosphate 55 mg/kg and calcitriol 35 ng/kg per day), introduced 15 month ago, resulted in a stable normalization of alkaline phosphatase and phosphorus serum levels (with intact calcemia and calciuria), disappearance of X-ray signs of the active rickets and improvement of the child?s longitudinal growth (0.6 cm per month). Subsequently, by detection of already known mutation in the PHEX gene: c.1735G>A (p.G579R) (exon 17), XLHR was diagnosed. Analysis of the parental PHEX gene did not show the abnormality, which indicated that the child?s XLHR was caused by de novo mutation of this gene. Conclusion. Identification of genetic defects is exceptionally significant for diagnosis and differential diagnosis of hereditary HR.

Monogenic Epilepsies: Disease Mechanisms, Clinical Phenotypes, and Targeted Therapies

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012744
Author(s):  
Renzo Guerrini ◽  
Simona Balestrini ◽  
Elaine C. Wirrell ◽  
Matthew C. Walker
Keyword(s):  
Observational Studies ◽  
Current Knowledge ◽  
Functional Characterization ◽  
Treatment Strategies ◽  
Controlled Trials ◽  
Epileptogenic Zone ◽  
Missense Mutations ◽  
Number Of Patients ◽  
Functional Consequences ◽  
Genetic Epilepsies

A monogenic aetiology can be identified in up to 40% of people with severe epilepsy. To address earlier and more appropriate treatment strategies, clinicians are required to know the implications that specific genetic causes might have on pathophysiology, natural history, comorbidities and treatment choices. In this narrative review, we summarise concepts on the genetic epilepsies based on the underlying pathophysiological mechanisms and present the current knowledge on treatment options based on evidence provided by controlled trials or studies with lower classification of evidence. Overall, evidence robust enough to guide antiseizure medication (ASM) choices in genetic epilepsies remains limited to the more frequent conditions for which controlled trials and observational studies have been possible. Most monogenic disorders are very rare and ASM choices for them are still based on inferences drawn from observational studies and early, often anecdotal, experiences with precision therapies. Precision medicine remains applicable to only a narrow number of patients with monogenic epilepsies and may target only part of the actual functional defects. Phenotypic heterogeneity is remarkable, and some genetic mutations activate epileptogenesis through their developmental effects, which may not be reversed postnatally. Other genes seem to have pure functional consequences on excitability, acting through either loss- or gain-of-function effects, and these may have opposite treatment implications. In addition, the functional consequences of missense mutations may be difficult to predict, making precision treatment approaches considerably more complex than estimated by deterministic interpretations. Knowledge of genetic aetiologies can influence the approach to surgical treatment of focal epilepsies. Identification of germline mutations in specific genes contraindicates surgery while mutations in other genes do not. Identification, quantification and functional characterization of specific somatic mutations before surgery using cerebrospinal fluid liquid biopsy or after surgery in brain specimens, will likely be integrated in planning surgical strategies and re-intervention after a first unsuccessful surgery as initial evidence suggests that mutational load may correlate with the epileptogenic zone. Promising future directions include gene manipulation by DNA or mRNA targeting; although most are still far from clinical use, some are in early phase clinical development.

scholarly journals Missense mutations in SARS-CoV2 genomes from Indian patients

Genomics ◽  
2020 ◽  
Vol 112 (6) ◽  
pp. 4622-4627 ◽  
Author(s):  
Sk. Sarif Hassan ◽  
Pabitra Pal Choudhury ◽  
Bidyut Roy ◽  
Siddhartha Sankar Jana
Keyword(s):  
Missense Mutations ◽  
Indian Patients

scholarly journals ANGPT2 and NOS3 Polymorphisms and Clinical Outcome in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1023 ◽  
Author(s):  
Giorgia Marisi ◽  
Elisabetta Petracci ◽  
Francesco Raimondi ◽  
Luca Faloppi ◽  
Francesco Giuseppe Foschi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Direct Sequencing ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Advanced Hepatocellular Carcinoma ◽  
Nucleotide Polymorphisms ◽  
Number Of Patients ◽  
Angiopoietin 2 ◽  
Oxide Synthase

Sorafenib represents the standard of care for advanced hepatocellular carcinoma (HCC), even though a large number of patients have reported limited efficacy. The aim of the present study was to evaluate the prognostic value of single-nucleotide polymorphisms on angiopoietin-2 (ANGPT2) and endothelial-derived nitric oxide synthase (NOS3) genes in 135 patients with advanced HCC receiving sorafenib. Eight ANGPT2 polymorphisms were analyzed by direct sequencing in relation to overall survival (OS) and progression-free survival (PFS). In univariate analysis, ANGPT2rs55633437 and NOS3 rs2070744 were associated with OS and PFS. In particular, patients with ANGPT2rs55633437 TT/GT genotypes had significantly lower median OS (4.66 vs. 15.5 months, hazard ratio (HR) 4.86, 95% CI 2.73–8.67, p < 0.001) and PFS (1.58 vs. 6.27 months, HR 4.79, 95% CI 2.73–8.35, p < 0.001) than those homozygous for the G allele. Moreover, patients with NOS3 rs2070744 TC/CC genotypes had significantly higher median OS (15.6 vs. 9.1 months, HR 0.65, 95% CI 0.44–0.97; p = 0.036) and PFS (7.03 vs. 3.5 months, HR 0.43, 95% CI 0.30–0.63; p < 0.001) than patients homozygous for the T allele. Multivariate analysis confirmed these polymorphisms as independent prognostic factors. Our results suggest that ANGPT2rs55633437 and NOS3 rs2070744 polymorphisms could identify a subset of HCC patients more resistant to sorafenib.

scholarly journals Frequency of AIP Gene Mutations in Young Patients With Acromegaly: A Registry-Based Study

2014 ◽  
Vol 99 (12) ◽  
pp. E2789-E2793 ◽  
Author(s):  
Christof Schöfl ◽  
Jürgen Honegger ◽  
Michael Droste ◽  
Martin Grussendorf ◽  
Reinhard Finke ◽  
...  
Keyword(s):  
Family History ◽  
Direct Sequencing ◽  
Positive Family History ◽  
Young Patients ◽  
Gene Mutations ◽  
Interacting Protein ◽  
Aryl Hydrocarbon ◽  
Number Of Patients ◽  
The Individual ◽  
Aip Gene

Context: Familial and sporadic GH-secreting pituitary adenomas are associated with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. Patients with an AIP mutation (AIPmut) tend to have more aggressive tumors occurring at a younger age. Objective: The objective of the study was to investigate the frequency of AIPmut in patients diagnosed at 30 years of age or younger. Design: The German Acromegaly Registry database (1795 patients in 58 centers) was screened for patients diagnosed with acromegaly at 30 years of age or younger (329 patients). Sixteen centers participated and 91 patients consented to AIPmut analysis. Intervention: DNA was analyzed by direct sequencing and multiplex ligation dependent probe amplification Main outcome Measures: The number of patients with AIPmut was measured. Results: Five patients had either a mutation (c.490C&gt;T, c.844C&gt;T, and c.911G&gt;A, three males) or gross deletions of exons 1 and 2 of the AIP gene (n = 2, one female). The overall frequency of an AIPmut was 5.5%, and 2.3% or 2.4% in patients with an apparently sporadic adenoma or macroadenoma, respectively. By contrast, three of four patients (75%) with a positive family history were tested positive for an AIPmut. Except for a positive family history, there were no significant differences between patients with and without an AIPmut. Conclusions: The frequency of AIPmut in this registry-based cohort of young patients with acromegaly is lower than previously reported. Patients with a positive family history should be tested for an AIPmut, whereas young patients without an apparent family history should be screened, depending on the individual cost to benefit ratio.

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