scholarly journals Hyperinsulinism/hyperammonemia (HI/HA) syndrome due to a mutation in the glutamate dehydrogenase gene

2012 ◽  
Vol 56 (8) ◽  
pp. 485-489 ◽  
Author(s):  
Maria Lúcia Corrêa-Giannella ◽  
Daniel Soares Freire ◽  
Ana Mercedes Cavaleiro ◽  
Maria Angela Zanella Fortes ◽  
Ricardo Rodrigues Giorgi ◽  
...  
Keyword(s):  
Glutamate Dehydrogenase ◽  
De Novo ◽  
Direct Sequencing ◽  
Elevated Serum ◽  
Patient Treatment ◽  
Hyperinsulinemic Hypoglycemia ◽  
Activating Mutations ◽  
Dominant Disease ◽  
Intron Boundary ◽  
Fasting Hypoglycemia

The hyperinsulinism/hyperammonemia (HI/HA) syndrome is a rare autosomal dominant disease manifested by hypoglycemic symptoms triggered by fasting or high-protein meals, and by elevated serum ammonia. HI/HA is the second most common cause of hyperinsulinemic hypoglycemia of infancy, and it is caused by activating mutations in GLUD1, the gene that encodes mitochondrial enzyme glutamate dehydrogenase (GDH). Biochemical evaluation, as well as direct sequencing of exons and exon-intron boundary regions of the GLUD1 gene, were performed in a 6-year old female patient presenting fasting hypoglycemia and hyperammonemia. The patient was found to be heterozygous for one de novo missense mutation (c.1491A>G; p.Il497Met) previously reported in a Japanese patient. Treatment with diazoxide 100 mg/day promoted complete resolution of the hypoglycemic episodes. Arq Bras Endocrinol Metab. 2012;56(8):485-9

Hyperinsulinism-hyperammonemia syndrome: a de novo mutation of the GLUD1 gene in twins and a review of the literature

2016 ◽  
Vol 29 (9) ◽  
Author(s):  
Dorotea Ninković ◽  
Vladimir Sarnavka ◽  
Anica Bašnec ◽  
Mario Ćuk ◽  
Danijela Petković Ramadža ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
De Novo ◽  
De Novo Mutation ◽  
Congenital Hyperinsulinism ◽  
Review Of The Literature ◽  
Plasma Ammonia ◽  
Activating Mutations ◽  
Dominant Disease ◽  
Recurrent Hypoglycemia ◽  
Rare Autosomal Dominant Disease

AbstractHyperinsulinism-hyperammonemia (HI/HA) syndrome is a rare autosomal dominant disease characterized by recurrent hypoglycemia and persistent mild elevation of plasma ammonia. HI/HA syndrome is one of the more common forms of congenital hyperinsulinism (CHI), caused by activating mutations within the

Hyperinsulinemic hypoglycemia: think of hyperinsulinism/hyperammonemia (HI/HA) syndrome caused by mutations in the GLUD1 gene

2015 ◽  
Vol 28 (7-8) ◽  
Author(s):  
Christel Tran ◽  
Vassiliky Konstantopoulou ◽  
Michelle Mecjia ◽  
Kusiel Perlman ◽  
Saadet Mercimek-Mahmutoglu ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Glutamate Dehydrogenase ◽  
Autosomal Dominant ◽  
Molecular Genetic ◽  
Heterozygous Mutation ◽  
Hyperinsulinemic Hypoglycemia ◽  
Molecular Genetic Testing ◽  
Autosomal Dominant Disorder ◽  
Activating Mutations ◽  
Multiple Episodes

AbstractHyperinsulinism-hyperammonemia syndrome (HI/HA) is a rare autosomal dominant disorder presenting with hypoglycemia and hyperammonemia. It is caused by activating mutations in theThree patients from two different centers, a 14-month-old female, a 28-year-old female (mother of the first patient) from Toronto and an unrelated 2.5-year-old male from Vienna, presented with multiple episodes of seizures associated with hypoglycemia.All patients had mild to moderate hypoglycemia, inappropriate insulin levels and mild hyperammonemia, thus suggesting a disorder of glutamate dehydrogenase (GDH). Molecular genetic testing of theWe present three new patients with GDH caused by heterozygous mutation in the

scholarly journals Parental mosaicism in Marfan and Ehlers–Danlos syndromes and related disorders

2021 ◽  
Author(s):  
Bertrand Chesneau ◽  
Aurélie Plancke ◽  
Guillaume Rolland ◽  
Nicolas Chassaing ◽  
Christine Coubes ◽  
...  
Keyword(s):  
High Resolution ◽  
Marfan Syndrome ◽  
High Resolution Melting ◽  
De Novo ◽  
Direct Sequencing ◽  
Causal Variant ◽  
Connective Tissue Disorder ◽  
High Resolution Melting Analysis ◽  
Aortic Diseases ◽  
Melting Analysis

AbstractMarfan syndrome (MFS) is a heritable connective tissue disorder (HCTD) caused by pathogenic variants in FBN1 that frequently occur de novo. Although individuals with somatogonadal mosaicisms have been reported with respect to MFS and other HCTD, the overall frequency of parental mosaicism in this pathology is unknown. In an attempt to estimate this frequency, we reviewed all the 333 patients with a disease-causing variant in FBN1. We then used direct sequencing, combined with High Resolution Melting Analysis, to detect mosaicism in their parents, complemented by NGS when a mosaicism was objectivized. We found that (1) the number of apparently de novo events is much higher than the classically admitted number (around 50% of patients and not 25% as expected for FBN1) and (2) around 5% of the FBN1 disease-causing variants were not actually de novo as anticipated, but inherited in a context of somatogonadal mosaicisms revealed in parents from three families. High Resolution Melting Analysis and NGS were more efficient at detecting and evaluating the level of mosaicism compared to direct Sanger sequencing. We also investigated individuals with a causal variant in another gene identified through our “aortic diseases genes” NGS panel and report, for the first time, on an individual with a somatogonadal mosaicism in COL5A1. Our study shows that parental mosaicism is not that rare in Marfan syndrome and should be investigated with appropriate methods given its implications in patient’s management.

scholarly journals A novel TSC1 variant associated with tuberous sclerosis and sacrococcygeal teratoma

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Saba Ahmad ◽  
Luis Manon ◽  
Gifty Bhat ◽  
Jerry Machado ◽  
Alice Zalan ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Cellular Differentiation ◽  
Autosomal Dominant ◽  
De Novo ◽  
Autosomal Dominant Disease ◽  
Sacrococcygeal Teratoma ◽  
Dominant Disease ◽  
The Brain

AbstractTuberous sclerosis complex (TSC) is an autosomal dominant disease associated with tumors and malformed tissues in the brain and other vital organs. We report a novel de novo frameshift variant of the TSC1 gene (c.434dup;p. Ser146Valfs*8) in a child with TSC who initially presented with a sacral teratoma. This previously unreported association between TSC and teratoma has broad implications for the pathophysiology of embryonic tumors and mechanisms underlying cellular differentiation.

scholarly journals A Mutation in the KCNE3 Potassium Channel Gene Is Associated with Susceptibility to Thyrotoxic Hypokalemic Periodic Paralysis

2002 ◽  
Vol 87 (11) ◽  
pp. 4881-4884 ◽  
Author(s):  
Magnus R. Dias Da Silva ◽  
Janete M. Cerutti ◽  
Liliane A. T. Arnaldi ◽  
Rui M. B. Maciel
Keyword(s):  
Direct Sequencing ◽  
Genetic Defect ◽  
Sporadic Case ◽  
Ionic Channel ◽  
Periodic Paralysis ◽  
Resting Membrane Potential ◽  
Hypokalemic Periodic Paralysis ◽  
Dominant Disease ◽  
Periodic Paralyses ◽  
Thyrotoxic Hypokalemic Periodic Paralysis

Abstract Hypokalemic Periodic Paralyses comprise diverse diseases characterized by acute and reversible attacks of severe muscle weakness, associated with low serum potassium. The most common causes are Familial Hypokalemic Periodic Paralysis (FHypoKPP), an autosomal dominant disease, and Thyrotoxic Hypokalemic Periodic Paralysis (THypoKPP), secondary to thyrotoxicosis. Symptoms of paralysis are similar in both diseases, distinguished by thyrotoxicosis present in THypoKPP. FHypoKPP is caused by mutations in ionic channel genes calcium (CACN1AS), sodium (SCN4A) and potassium (KCNE3). Since both diseases are similar, we tested the hypothesis that THypoKPP could carry the same mutations described in FHypoKPP, being the paralysis a genetically conditioned complication of thyrotoxicosis. In 15 patients with THypoKPP, using target-exon PCR, CSGE screening, and direct sequencing, we excluded known mutations in CACN1AS and SCN4A genes. On the other hand, we were able to identify the R83H mutation in the KCNE3 gene in one sporadic case of THypoKPP, a man who had been asymptomatic until developing thyrotoxicosis caused by Graves’ disease; we confirmed the disease-causing mutation in 2 of 3 descendants. R83H was recently found in two FHypoKPP unrelated families, in which the mutant decreased outward potassium flux, resulting in a more positive resting membrane potential. We, therefore, identified the first genetic defect in THypoKPP, a mutation in the KCNE3 gene.

scholarly journals The Ret proto-oncogene in the WAG/Rij rat strain: an animal model for inherited C-cell carcinoma?

2003 ◽  
Vol 37 (3) ◽  
pp. 215-221 ◽  
Author(s):  
M. De Miguel ◽  
J. M. Fernández-Santos ◽  
I. Trigo-Sánchez ◽  
I. Matera ◽  
I. Ceccherini ◽  
...  
Keyword(s):  
Animal Model ◽  
Direct Sequencing ◽  
Sequence Difference ◽  
Single Strand Conformational Polymorphism ◽  
Medullary Thyroid ◽  
Activating Mutations ◽  
C Cell ◽  
High Incidence ◽  
Rat Strain

WAG/Rij rat strain has been suggested as an animal model for the study of inherited human medullary thyroid carcinoma (MTC), due to its high incidence of spontaneous C-cell thyroid tumours. Although the role of the Ret proto-oncogene mutations, as responsible for human MTC, is well established, nothing has been published concerning this putative animal model. Based upon the previously reported rat Ret sequence, exons 10, 11, 13, 14, 15, and 16, known to carry activating mutations in humans, have been analysed in the WAG/Rij rat by PCR, single strand conformational polymorphism (SSCP) and direct sequencing. Neither the germline nor MTC samples showed any Ret sequence difference in the exons when analysed in comparison to a non-MTC-susceptible rat strain. Our results indicate that Ret exons relevant in humans are not involved in WAG/Rij rat MTC, as expected, and this questions the validity of this strain as a model for the human disease, and suggests there must be additional mechanisms for the genesis and progression of rat MTC.

scholarly journals Importance of Extraintestinal Manifestations in Early Diagnosis of Gardner Syndrome

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Bruno Besteiro ◽  
Filipa Gomes ◽  
Cláudia Costa ◽  
Raquel Portugal ◽  
Isabel Garrido ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
De Novo ◽  
Hypochromic Anemia ◽  
Extraintestinal Manifestations ◽  
Gastrointestinal Involvement ◽  
Gardner Syndrome ◽  
Clinical Challenge ◽  
Endoscopic Study ◽  
Dominant Disease ◽  
Etiological Study

Gardner’s syndrome is an autosomal dominant disease caused by a mutation in the APC gene with 20–30% of cases presenting de novo. This entity is a variant of familial adenomatous polyposis, with a prevalence of 3/100,000 habitants. It may present as early as 2 months of age with a variety of both colonic and extracolonic symptoms. We report a case of a 21-year-old man, without any known family history, presenting with microcytic hypochromic anemia and constitutional symptoms for two months. Ultimately, after the etiological study, Gardner syndrome diagnosis was established as an index primary familiar case. Gardner syndrome is a clinical challenge which requires a prompt suspicion in order to reach its diagnosis. Given the malignant evolution of adenomas in 100% of untreated patients, early identification of extraintestinal manifestations (identifiable prior to colonic symptoms) is of the essence. A consequent endoscopic study to confirm gastrointestinal involvement is essential for a more favorable prognosis.

Non-Inversion Factor VIII Mutations in 80 Hemophilia A Families Including 24 with Alloimmune Responses

2002 ◽  
Vol 87 (02) ◽  
pp. 273-276 ◽  
Author(s):  
Miao-Liang Liu ◽  
Shelley Nakaya ◽  
Arthur Thompson
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
De Novo ◽  
High Titer ◽  
Direct Sequencing ◽  
Normal Variant ◽  
Missense Mutations ◽  
Gene Deletions ◽  
Intron Splice ◽  
Splice Junctions

SummaryHeteroduplex screening identified 74 small mutations in the factor VIII genes of 72 families with hemophilia A. In addition, patients from 3 families with high titer inhibitors had partial gene deletions and 5 unrelated families that were negative for heteroduplex formation had a mutation on direct sequencing. The latter had mild hemophilia A with an inhibitor, and sequencing their exon 23 fragments found a transition predicting a recurrent Arg2150 to His. Of 69 distinct mutations (including the 3 partial gene deletions), 47 are novel. Of small mutations, 51 were missense (one possibly a normal variant and two that could also alter splicing) at 39 sites, 13 were small deletions or insertions (3 inframe and one a normal variant in an intron), 13 were nonsense at 12 sites and 2 altered intron splice junctions. In 24 families, at least one affected member had evidence for an alloimmune response to factor VIII; of these, 11 were associated with missense mutations. In 14 families, de novo origin was demonstrated.

Phenotypic and Genotypic Characteristics of Mastocytosis Differ According to the Age of Disease’s Onset.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3091-3091
Author(s):  
Fanny Lanternier ◽  
Annick Cohen-Akenine ◽  
Fabienne Palmerini ◽  
Frederic Feger ◽  
Laurent Nasca ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Systemic Disease ◽  
Systemic Involvement ◽  
Activating Mutations ◽  
Genotypic Analysis ◽  
Anaphylactoid Reactions ◽  
Group 2 ◽  
Cutaneous Mastocytosis ◽  
Genotypic Characteristics ◽  
Group 1

Abstract Mastocytosis is a heterogeneous group of disease with respect to clinical, biological and genotypic features, which may either occur during childhood or at the adult’s age. Adult’s mastocytosis is usually associated with persistent systemic involvement and c-kit 816 mutations, while pediatric’s disease is mostly limited to the skin and often resolves spontaneously during adolescence. No study has attended to compare characteristics of adult’s mastocytosis according to the age of disease’s onset. Among 155 adult patients with histologically proven cutaneous mastocytosis and complete phenotypic and genotypic data available recruited through the French mastocytosis network (AFIRMM), disease started before 15 years in 23 patients (15%) and later than 18 years in 132 patients (85%). We compared phenotypic and genotypic features of patients whose disease started during childhood (Group 1, n = 23) with those of 31 randomly allocated patients whose disease started at adult’s age (Group 2). Genotypic analysis was performed on skin biopsy by direct sequencing of c-kit exons 17 and 8 to 13 in which most of activating mutations are found. According to the WHO classification, the percentage of systemic disease was similar in both groups (61 vs. 79%) in groups 1 and 2, respectively. Bone pain (57% vs. 23%) and flush (83% vs. 39%) differ between groups (p < 0.01). Bullous lesions were only observed in group 1 (14%) while telangiectasia macularis eruptiva perstans was only observed in group 2 (16%). Major asthenia, syncope, mood disturbances, anaphylactoid reactions, gastrointestinal and respiratory disturbances and blood cell count, serum tryptase and liver enzymes levels did not differ between groups. C-kit 816 mutations was found in 33% and 77% of patients in groups 1 and 2, respectively (p < 0.001). 45% of patients whose disease’s onset occurred before the age of 2 years vs. 7% of those whose disease’s onset occurred later during childhood presented with C-kit 816 mutation (p < 0.001). Other c-kit activating mutations were found in 29% and 3% (p < 0.001) and lack of c-kit activating mutation in 38% and 20% (p < 0.001) in groups 1 and 2, respectively. In conclusion, pathogenesis of mastocytosis significantly differs according to the age of disease’s onset. Our data may have major therapeutic relevance when considering c-kit-targeted therapy.

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