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1.
Ann Endocrinol (Paris) ; 81(2-3): 110-117, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32409005

RESUMO

Hypoglycemia is defined by a low blood glucose level associated to clinical symptoms. Hypoglycemia may be related to treatment of diabetes, but also to drugs, alcohol, critical illness, cortisol insufficiency including hypopituitarism, insulinoma, bariatric or gastric surgery, pancreas transplantation or glucagon deficiency, or may be surreptitious. Some hypoglycemic episodes remain unexplained, and genetic, paraneoplastic and immune causes should be considered. Genetic causes may be related to endogenous hyperinsulinism and to inborn errors of metabolism (IEM). Endogenous hyperinsulinism is related to monogenic congenital hyperinsulinism, and especially to mutations of the glucokinase-activating gene or of insulin receptors, both characterised by postprandial hypoglycemia with major hyperinsulinism. In adulthood, IEM-related hypoglycemia can persist in a previously diagnosed childhood disease or may be a presenting sign. It is suggested by systemic involvement (rhabdomyolysis after fasting or exercising, heart disease, hepatomegaly), sometimes associated to a family history of hypoglycemia. The timing of hypoglycemic episodes with respect to the last meal also helps to orientate diagnosis. Fasting hypoglycemia may be related to type 0, I or III glycogen synthesis disorder, fatty acid oxidation or gluconeogenesis disorder. Postprandial hypoglycemia may be related to inherited fructose intolerance. Exercise-induced hyperinsulinism is mainly related to activating mutation of the SLC16A1 gene. Besides exceptional ectopic insulin secretion, paraneoplastic causes involve NICTH (Non-Islet-Cell Tumour Hypoglycemia), caused by Big-IGF2 secretion by a large tumour, with low blood levels of insulin, C-peptide and IGF1. Autoimmune causes involve antibodies against insulin (HIRATA syndrome), especially in case of Graves' disease, or against the insulin receptor. Medical history, timing, and insulin level orientate the diagnosis.


Assuntos
Hipoglicemia/epidemiologia , Hipoglicemia/etiologia , Adulto , Idade de Início , Antígenos CD/genética , Criança , Complicações do Diabetes/sangue , Complicações do Diabetes/epidemiologia , Jejum/sangue , Humanos , Hiperinsulinismo/sangue , Hiperinsulinismo/complicações , Hiperinsulinismo/epidemiologia , Insulinoma/sangue , Insulinoma/complicações , Insulinoma/epidemiologia , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo/genética , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/epidemiologia , Receptor de Insulina/genética , Fatores de Risco
2.
Rev Med Suisse ; 16(695): 1120-1122, 2020 May 27.
Artigo em Francês | MEDLINE | ID: mdl-32462842

RESUMO

Patients come in consultation with a variety of complaints, some of which are unusual. We present here the case of a patient consulting for nauseating body odors for whom a diagnosis of trimethylaminuria could be found. This pathology, not very well known, may have important psychiatric and social repercussions. Genetics play a major role in diagnosis, while treatment consists essentially of various palliative measures.


Assuntos
Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/terapia , Metilaminas/urina , Humanos , Erros Inatos do Metabolismo/genética , Odorantes/análise
3.
BMC Med Genet ; 21(1): 79, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32295532

RESUMO

BACKGROUND: Congenital chloride diarrhea (CLD; OMIM 214700) is a rare autosomal recessive disorder caused by pathogenic variations in the solute carrier family 26 member A3 (SLC26A3) gene. Without salt substitution, this chronic diarrheal disorder causes severe dehydration and electrolyte disturbances. Homozygous variants in the nearby gene SLC26A4 disrupt anion exchange in the inner ear and the thyroid, causing Pendred syndrome (PDS; OMIM 274600), which is the most frequent form of syndromic deafness. CASE PRESENTATION: We report an unusual co-occurrence of two rare homozygous mutations in both the SLC26A3 and SLC26A4 genes, causing a rare combination of both CLD and PDS in two siblings. Although the clinical pictures were typical, the combined loss of these anion transporters might modulate the risk of renal injury associated with CLD. CONCLUSIONS: Familial presentation of two rare autosomal recessive disorders with loss of function of different SLC26 anion transporters is described. Independent homozygous variants in the SLC26A3 and SLC26A4 genes cause CLD and PDS in siblings, shedding light on co-occurrence of rare recessive traits in the progeny of consanguineous couples.


Assuntos
Antiportadores de Cloreto-Bicarbonato/genética , Diarreia/congênito , Bócio Nodular/genética , Perda Auditiva Neurossensorial/genética , Erros Inatos do Metabolismo/genética , Transportadores de Sulfato/genética , Diarreia/diagnóstico , Diarreia/genética , Diarreia/patologia , Feminino , Genes Recessivos/genética , Testes Genéticos , Bócio Nodular/diagnóstico , Bócio Nodular/patologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Humanos , Lactente , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/patologia , Mutação , Linhagem , Gravidez , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/patologia , Irmãos
4.
Clin Sci (Lond) ; 134(8): 941-953, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32227118

RESUMO

The sodium-hydrogen exchanger isoform 3 (NHE3, SLC9A3) is abundantly expressed in the gastrointestinal tract and is proposed to play essential roles in Na+ and fluid absorption as well as acid-base homeostasis. Mutations in the SLC9A3 gene can cause congenital sodium diarrhea (CSD). However, understanding the precise role of intestinal NHE3 has been severely hampered due to the lack of a suitable animal model. To navigate this problem and better understand the role of intestinal NHE3, we generated a tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout mouse model (NHE3IEC-KO). Before tamoxifen administration, the phenotype and blood parameters of NHE3IEC-KO were unremarkable compared with control mice. After tamoxifen administration, NHE3IEC-KO mice have undetectable levels of NHE3 in the intestine. NHE3IEC-KO mice develop watery, alkaline diarrhea in combination with a swollen small intestine, cecum and colon. The persistent diarrhea results in higher fluid intake. After 3 weeks, NHE3IEC-KO mice show a ∼25% mortality rate. The contribution of intestinal NHE3 to acid-base and Na+ homeostasis under normal conditions becomes evident in NHE3IEC-KO mice that have metabolic acidosis, lower blood bicarbonate levels, hyponatremia and hyperkalemia associated with drastically elevated plasma aldosterone levels. These results demonstrate that intestinal NHE3 has a significant contribution to acid-base, Na+ and volume homeostasis, and lack of intestinal NHE3 has consequences on intestinal structural integrity. This mouse model mimics and explains the phenotype of individuals with CSD carrying SLC9A3 mutations.


Assuntos
Anormalidades Múltiplas/genética , Diarreia/congênito , Células Epiteliais/metabolismo , Erros Inatos do Metabolismo/genética , Trocador 3 de Sódio-Hidrogênio/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Animais , Diarreia/genética , Diarreia/metabolismo , Diarreia/mortalidade , Diarreia/patologia , Modelos Animais de Doenças , Feminino , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/mortalidade , Erros Inatos do Metabolismo/patologia , Camundongos , Camundongos Knockout , Mutação , Trocador 3 de Sódio-Hidrogênio/metabolismo
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 423-426, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219827

RESUMO

OBJECTIVE: To analyze the clinical and genetic characteristics of an infant girl featuring comprehensive developmental backwardness. METHODS: The patient was subjected to clinical examination, gas chromatography mass spectrometry and next-generation sequencing (NGS). RESULTS: The child was insensitive to sound, could not turn over, raise head, laugh or recognize his mother. Laboratory tests were all normal, but metabolic analysis suggested 3-methylglutaconic aciduria due to elevated 3-methylglutaconic acid and 3-methylglutaric acid. NGS has detected two compound heterozygous CLPB variants in the child, namely c.1085G>A and c.1700A>C, which were respectively inherited from her father and mother. Bioinformatic analysis predicted both variants to be pathogenic. The patient was diagnosed with 3-methylglutaconic aciduria type VII (MGCA7). CONCLUSION: The MGCA7 in the child was probably caused by CLPB gene variants. NGS has provided a powerful diagnostic tool for this rare disorder.


Assuntos
Endopeptidase Clp/genética , Erros Inatos do Metabolismo/genética , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente
6.
Endocr Pract ; 26(6): 651-659, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32045292

RESUMO

Objective: Primary generalized glucocorticoid resistance (PGGR) is a rare hereditary disease characterized by generalized partial target-tissue insensitivity to glucocorticoids. To date, few cases have been reported, and more cases, especially involving other races, are needed to fully understand this disease. Methods: This study presented a novel glucocorticoid receptor mutation in a PGGR pedigree. The index patient was a 14-year-old male with fatigue, hypokalemia, hypertension, and polyuria. Eleven family members were available for the genetic screen. Next-generation sequencing and Sanger sequencing were used to identify the mutation. We systematically investigated the molecular mechanism through which the mutation impaired glucocorticoid signal transduction in COS-7 cells. Results: The index patient carried a de novo homo-zygous mutation within exon 6 (c.1652C>A, p.551S>Y), whereas eight family members carrying a heterozygous mutation were all phenotypically silent. The affinity of the human glucocorticoid receptor (hGR) for the ligand was 1.97-fold lower in the patient than in the family members. Mutant hGRα (551Y) displayed a 3.2-fold reduction in its ability to transactivate glucocorticoid-responsive genes. When exposed to the same concentration of dexamethasone, hGRα (551Y) displayed a reduced ability to trans-locate into the nucleus and decreased levels of hGR dimer formation and could not effectively induce the glucocorticoid response element to regulate the transcription of related genes. After 2 years of dexamethasone treatment, the volume of the left and right adrenal glands of the index subject decreased by 55.6% and 32.4%, respectively. The pituitary volume decreased by 18.9%. During the 2-year follow-up, none of the heterozygous carriers developed hypertension or hypokalemia. Conclusion: We described a novel homozygous glucocorticoid receptor mutation causing PGGR. This homozygous mutation leads to hypertension and hypokalemia, but its heterozygous mutation has no relevant clinical symptoms. Abbreviations: ACTH = adrenocorticotropic hormone; DBD = DNA-binding domain; GR = glucocorticoid receptor; GRE = glucocorticoid response element; hGR = human glucocorticoid receptor; LBD = ligand-binding domain; PGGR = primary generalized glucocorticoid resistance.


Assuntos
Erros Inatos do Metabolismo , Receptores de Glucocorticoides/genética , Adolescente , Animais , Chlorocebus aethiops , Dexametasona , Glucocorticoides , Humanos , Masculino , Erros Inatos do Metabolismo/genética , Mutação
7.
Nat Commun ; 11(1): 970, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080200

RESUMO

Deregulation of mitochondrial network in terminally differentiated cells contributes to a broad spectrum of disorders. Methylmalonic acidemia (MMA) is one of the most common inherited metabolic disorders, due to deficiency of the mitochondrial methylmalonyl-coenzyme A mutase (MMUT). How MMUT deficiency triggers cell damage remains unknown, preventing the development of disease-modifying therapies. Here we combine genetic and pharmacological approaches to demonstrate that MMUT deficiency induces metabolic and mitochondrial alterations that are exacerbated by anomalies in PINK1/Parkin-mediated mitophagy, causing the accumulation of dysfunctional mitochondria that trigger epithelial stress and ultimately cell damage. Using drug-disease network perturbation modelling, we predict targetable pathways, whose modulation repairs mitochondrial dysfunctions in patient-derived cells and alleviate phenotype changes in mmut-deficient zebrafish. These results suggest a link between primary MMUT deficiency, diseased mitochondria, mitophagy dysfunction and epithelial stress, and provide potential therapeutic perspectives for MMA.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/patologia , Metilmalonil-CoA Mutase/deficiência , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Mitofagia/fisiologia , Alquil e Aril Transferases/deficiência , Alquil e Aril Transferases/genética , Erros Inatos do Metabolismo dos Aminoácidos/genética , Animais , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Técnicas de Inativação de Genes , Humanos , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Erros Inatos do Metabolismo/genética , Metilmalonil-CoA Mutase/genética , Metilmalonil-CoA Mutase/metabolismo , Camundongos , Camundongos Knockout , Doenças Mitocondriais/genética , Mitofagia/genética , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Estresse Fisiológico , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Peixe-Zebra
9.
Eur J Endocrinol ; 182(2): R15-R27, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31995340

RESUMO

Glucocorticoids (GC) such as cortisol regulate multiple physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene in humans). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, and recruitment of functional transcriptional machinery. Generalized glucocorticoid resistance syndrome, due to GR loss-of-function mutations, may be related to the impairment of one of the GC signaling steps. To date, 31 NR3C1 loss-of-function mutations have been reported in patients presenting with various clinical signs such as hypertension, adrenal hyperplasia, hirsutism or metabolic disorders associated with biological hypercortisolism but without Cushing syndrome signs and no negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Functional characterization of GR loss-of-function mutations often demonstrates GR haploinsufficiency and a decrease of GR target gene induction in relevant cell types. The main signs at presentation are very variable from resistant hypertension, bilateral adrenal hyperplasia likely related to increased ACTH levels but not exclusively, hirsutism to isolated renin-angiotensin-aldosterone system abnormalities in a context of 11ßHSD2 deficiency. Some mutated GR patients are obese or overweight together with a healthier metabolic profile that remains to be further explored in future studies. Deciphering the molecular mechanisms altered by GR mutations should enhance our knowledge on GR signaling and ultimately facilitate management of GC-resistant patients. This review also focuses on the criteria facilitating identification of novel NR3C1 mutations in selected patients.


Assuntos
Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Receptores de Glucocorticoides/deficiência , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/genética , Glucocorticoides/sangue , Glucocorticoides/genética , Humanos , Hidrocortisona/sangue , Hidrocortisona/genética , Erros Inatos do Metabolismo/sangue , Receptores de Glucocorticoides/sangue , Receptores de Glucocorticoides/genética
10.
Adv Clin Chem ; 94: 85-153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31952575

RESUMO

Metabolomics is an intriguing field of study providing a new readout of the biochemical activities taking place at the moment of sampling within a subject's biofluid or tissue. Metabolite concentrations are influenced by several factors including disease, environment, drugs, diet and, importantly, genetics. Metabolomics signatures, which describe a subject's phenotype, are useful for disease diagnosis and prognosis, as well as for predicting and monitoring the effectiveness of treatments. Metabolomics is conventionally divided into targeted (i.e., the quantitative analysis of a predetermined group of metabolites) and untargeted studies (i.e., analysis of the complete set of small-molecule metabolites contained in a biofluid without a pre-imposed metabolites-selection). Both approaches have demonstrated high value in the investigation and understanding of several monogenic and multigenic conditions. Due to low costs per sample and relatively short analysis times, metabolomics can be a useful and robust complement to genetic sequencing.


Assuntos
Testes Genéticos , Metabolômica , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Fenótipo
11.
Nat Commun ; 11(1): 322, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949167

RESUMO

We previously observed an unexpected fivefold (35 vs. 200 days) difference in the survival of respiratory chain complex III (CIII) deficient Bcs1lp.S78G mice between two congenic backgrounds. Here, we identify a spontaneous homoplasmic mtDNA variant (m.G14904A, mt-Cybp.D254N), affecting the CIII subunit cytochrome b (MT-CYB), in the background with short survival. We utilize maternal inheritance of mtDNA to confirm this as the causative variant and show that it further decreases the low CIII activity in Bcs1lp.S78G tissues to below survival threshold by 35 days of age. Molecular dynamics simulations predict D254N to restrict the flexibility of MT-CYB ef loop, potentially affecting RISP dynamics. In Rhodobacter cytochrome bc1 complex the equivalent substitution causes a kinetics defect with longer occupancy of RISP head domain towards the quinol oxidation site. These findings represent a unique case of spontaneous mitonuclear epistasis and highlight the role of mtDNA variation as modifier of mitochondrial disease phenotypes.


Assuntos
Complexo III da Cadeia de Transporte de Elétrons/genética , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Epistasia Genética/genética , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Mitocôndrias/genética , Doenças Mitocondriais/genética , ATPases Associadas a Diversas Atividades Celulares/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Animais , Grupo dos Citocromos b/química , Grupo dos Citocromos b/genética , Citocromos b , DNA Mitocondrial , Complexo III da Cadeia de Transporte de Elétrons/química , Metabolismo Energético , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Simulação de Dinâmica Molecular , Oxirredução
12.
Clin Chim Acta ; 502: 133-138, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31893530

RESUMO

Inborn errors of metabolism (IEMs) can cause intellectual disability or even death in children. To evaluate the disease spectrum and genetic characteristics of IEMs in Jining City of Shandong Province in East China, we used tandem mass spectrometry (MS/MS) technology for IEMs screening combined with genetic analysis. Newborns were screened from July 14, 2014, to December 31, 2018. Amino acid and carnitine contents were detected by MS/MS. According to the results for normal newborns, the reference range of our laboratory was established with the percentile method. The suspected positive newborns were further diagnosed using next-generation sequencing. A total of 514,234 newborns were screened, and 265 were diagnosed with IEMs, with a detection rate of 1:1941. Of the 265 patients, 130 (49.06%) had organic acid disorders, 83 (31.32%) had amino acid disorders, 34 (12.83%) had fatty acid oxidation disorders, and 18 (6.79%) had urea circulatory disorders. PAHD and MMA were the two most common disorders. IEMs-associated genes were identified in 233 patients. Our data indicated that IEMs are never uncommon in Jining, and the disease spectrum and genetic background were clearly elucidated, contributing to the treatment and prenatal genetic counseling of these disorders in the region.


Assuntos
Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Triagem Neonatal , Grupo com Ancestrais do Continente Asiático , China , Feminino , Testes Genéticos , Humanos , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/sangue , Espectrometria de Massas em Tandem
13.
Int J Mol Sci ; 21(1)2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31878022

RESUMO

Amino acid transporters play very important roles in nutrient uptake, neurotransmitter recycling, protein synthesis, gene expression, cell redox balance, cell signaling, and regulation of cell volume. With regard to transporters that are closely connected to metabolism, amino acid transporter-associated diseases are linked to metabolic disorders, particularly when they involve different organs, cell types, or cell compartments. To date, 65 different human solute carrier (SLC) families and more than 400 transporter genes have been identified, including 11 that are known to include amino acid transporters. This review intends to summarize and update all the conditions in which a strong association has been found between an amino acid transporter and an inherited metabolic disorder. Many of these inherited disorders have been identified in recent years. In this work, the physiological functions of amino acid transporters will be described by the inherited diseases that arise from transporter impairment. The pathogenesis, clinical phenotype, laboratory findings, diagnosis, genetics, and treatment of these disorders are also briefly described. Appropriate clinical and diagnostic characterization of the underlying molecular defect may give patients the opportunity to avail themselves of appropriate therapeutic options in the future.


Assuntos
Sistemas de Transporte de Aminoácidos , Aminoácidos , Erros Inatos do Metabolismo , Transdução de Sinais/genética , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Aminoácidos/genética , Aminoácidos/metabolismo , Animais , Transporte Biológico Ativo/genética , Humanos , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/patologia
14.
Medicine (Baltimore) ; 98(48): e18143, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770251

RESUMO

INTRODUCTION: The occurrence of repeated and progressive rhabdomyolysis is rare in clinical settings, particularly in adults. The pathogenesis of rhabdomyolysis is often overlooked due to its rapid recovery. Carnitine palmitoyltransferase (CPT) II deficiency could be a rare etiology of repetitive nontraumatic rhabdomyolysis, and several mutations of CPT II have been reported. PATIENT CONCERNS: A 41-year-old man presented with high fever, general malaise, myalgia, dyspnea, and dark-colored urine, and then progressed to anuria. In the past 15 years, he experienced dark-colored urine twice due to exercise and high fever. Physical examination revealed oliguria, suppurated tonsils, poor hemoglobin saturation, alert consciousness, normal neurological signs and reflexes, hypertension, and tachypnea. Laboratory investigations showed positive test results for inflammation, high serum myogenic enzyme levels, and evidence of acute kidney injury (AKI). DIAGNOSES: Investigations revealed an extremely high serum myogenic enzyme levels and impaired renal function with serum creatinine level of 510 µmol/L, consistent with the diagnosis of rhabdomyolysis, AKI stage 3, and acute respiratory distress syndrome. High levels of acylcarnitine in the serum confirmed the diagnosis of CPT II deficiency. In addition, whole exome sequencing (WES) was conducted in the patient and his mother. INTERVENTIONS: Intubation, ventilator support, and hemodialysis were the major therapeutic interventions at the peak of disease progression. He was then administered valsartan tablets at a dosage of 80 mg per day and L-carnitine supplements. OUTCOMES: WES conducted in the patient and his mother revealed 2 novel mutations of CPT II (c.482G>A and c.1493G>T) in this patient. The patient recovered from the severe AKI but the renal function remained impaired at chronic kidney disease stage 3a. CONCLUSION: Thus, gene examination can help to understand the etiology of repetitive nontraumatic rhabdomyolysis. Accurate diagnosis can be beneficial for providing an individualized treatment for patients with repeated and progressive rhabdomyolysis.


Assuntos
Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Erros Inatos do Metabolismo/genética , Rabdomiólise/genética , Adulto , Carnitina O-Palmitoiltransferase/sangue , Humanos , Masculino , Erros Inatos do Metabolismo/complicações , Mutação , Recidiva , Rabdomiólise/sangue
15.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(11): 1131-1137, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31753097

RESUMO

OBJECTIVE: To establish a congenital chloride diarrhea (CCD)-associated SLC26A3 c.392C>G (p.P131R) polymorphism-expressing cell model, and to investigate its biological function. METHODS: The sequence of the SLC26A3 gene in GenBank was used to design the upstream and downstream single-guide RNA (sgRNA) that could specifically recognize the 392 locus of the SLC26A3 gene, and the sgRNA was mixed with the pSpCas9-puro vector after enzyme digestion to construct an eukaryotic recombinant expression plasmid (pSpCas9-SLC26A3). Caco-2 cells were transfected with the recombinant plasmid and synthesized single-stranded DNA oligonucleotides (ssODNs), and Taqman genotyping assay and Sanger sequencing were used to identify the expression of SLC26A3 c.392C>G (p.P131R) in Caco-2 cells. Wild-type Caco-2 cells were selected as normal control group and the Caco-2 cells with successful expression of SLC26A3 c.392C>G (p.P131R) was selected as P131R group. Both groups were treated with 100 ng/mL tumor necrosis factor-α (TNF-α), and then the normal control group was named as TNF-α group, and the P131R group was named as TNF-α+P131R group. Electric cell-substrate impedance sensing (ECIS) assay was used to evaluate the change in the monolayer barrier function of intestinal epithelial cells in the above four groups, and Western blot was used to measure the change in the expression of SLC26A3 protein in the normal control group and the P131R group. RESULTS: The eukaryotic recombinant expression plasmid (pSpCas9-SLC26A3) was successfully constructed. Both Taqman genotyping assay and Sanger sequencing confirmed the successful establishment of the Caco-2 cell model of SLC26A3 c.392C>G (p.P131R) expression. ECIS assay showed that compared with the normal control group, the P131R group had a significant increase in the monolayer permeability of intestinal epithelial cells (P<0.05), and at the same time, the P131R group had a significantly greater increase in cell membrane permeability after the induction with 100 ng/mL TNF-α (P<0.05). Western blot showed that compared with the normal control group, the P131R group had a significant reduction in the expression of SLC26A3 protein (P=0.001). CONCLUSIONS: SLC26A3 c.392C>G (p.P131R) can reduce the expression of SLC26A3 protein, increase the monolayer permeability of intestinal epithelial cells, and thus lead to diarrhea.


Assuntos
Antiportadores de Cloreto-Bicarbonato/genética , Diarreia/congênito , Erros Inatos do Metabolismo , Transportadores de Sulfato/genética , Células CACO-2 , Diarreia/genética , Humanos , Mucosa Intestinal , Erros Inatos do Metabolismo/genética , Polimorfismo de Nucleotídeo Único , Junções Íntimas , Fator de Necrose Tumoral alfa
16.
BMJ Case Rep ; 12(10)2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666257

RESUMO

Transcobalamin (TC) deficiency is a rare autosomal recessive inborn error of cobalamin transport which clinically manifests in early infancy. We describe a child with TC deficiency who presented with classical clinical and lab stigmata of inborn error of vitamin B12 metabolism except normal serum B12 levels. He was started on empirical parenteral cobalamin supplements at 2 months of age; however, the definitive diagnosis could only be established at 6 years of age when a genetic evaluation revealed homozygous nonsense variation in exon 8 of the TCN2 gene (chr22:g.31019043C>T).


Assuntos
Erros Inatos do Metabolismo/diagnóstico , Transcobalaminas/deficiência , Deficiência de Vitamina B 12/diagnóstico , Vitamina B 12/sangue , Criança , Éxons , Testes Genéticos/métodos , Homozigoto , Humanos , Injeções Intramusculares , Masculino , Erros Inatos do Metabolismo/genética , Transcobalaminas/genética , Vitamina B 12/uso terapêutico , Complexo Vitamínico B/uso terapêutico
17.
Mol Med Rep ; 20(6): 4915-4924, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31661128

RESUMO

Sodium taurocholate cotransporting polypeptide (NTCP), a carrier protein encoded by solute carrier family 10 member 1 (SLC10A1), is expressed in the basolateral membrane of hepatocytes, where it is responsible for the uptake of bile acids from plasma into hepatocytes. The first patient with NTCP deficiency was described in 2015. A limited number of such patients have been reported in the literature and their genotypic and phenotypic features require further investigation. The current study investigated 4 patients with NTCP deficiency from two unrelated families. The patients were subjected to SLC10A1 genetic analysis and it was revealed that all patients were compound heterozygous for the c.800C>T (p.Ser267Phe) and c.595A>C (p.Ser199Arg) SLC10A1 variants. To the best of the authors' knowledge, the latter variant had not been previously reported. Further analysis in 50 healthy individuals did not identify carriers. The c.595A>C (p.Ser199Arg) variant exhibited co­segregation with hypercholanemia and exhibited a relatively conserved amino acid when compared with homologous peptides. Moreover, SWISS­MODEL prediction revealed that the mutation affected the conformation of the NTCP molecule. The 4 patients demonstrated varying degrees of hypercholanemia while a downward trend in the plasma levels of total bile acids (TBA) in 2 pediatric patients and occasionally normal TBA level in an adult case were observed. The results indicated an autosomal recessive trait for NTCP deficiency, supported the primary role of NTCP in the uptake of bile acids from plasma and suggested that hepatic uptake of bile acids may occur by means other than NTCP uptake. Moreover, the novel missense variant c.595A>C(p.Ser199Arg) enriched the SLC10A1 mutation spectrum and may serve as a new genetic marker for the molecular diagnosis and genetic counseling of NTCP deficiency.


Assuntos
Erros Inatos do Metabolismo/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Polimorfismo de Nucleotídeo Único , Simportadores/genética , Adulto , Ácidos e Sais Biliares/metabolismo , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Erros Inatos do Metabolismo/metabolismo , Modelos Moleculares , Mutação de Sentido Incorreto , Transportadores de Ânions Orgânicos Dependentes de Sódio/química , Transportadores de Ânions Orgânicos Dependentes de Sódio/deficiência , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Linhagem , Mutação Puntual , Simportadores/química , Simportadores/deficiência , Simportadores/metabolismo
18.
Indian Pediatr ; 56(9): 757-766, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31638009

RESUMO

The present century is being hailed as the century for genetic therapies, and inborn errors of metabolism is leading the way. As we gear ourselves for treating children with genetic and metabolic disorders, the key is to recognize them early and accurately for best outcomes. In these changing times with advent of technology, clinicians are now more aware, exposed and well equipped with the armamentarium of diagnostic modalities. However, it is difficult to choose between the tests without a baseline knowledge about testing for genetic and metabolic disorders. The key question for a clinician when dealing with a suspected metabolic disorder case is 'what test to order' and 'how to proceed.' The current article provides a rational view on the various laboratory testing modalities available for diagnosis of inborn errors of metabolism. The article provides details of the basic and advanced metabolic tests that can be ordered in appropriate settings.


Assuntos
Erros Inatos do Metabolismo/diagnóstico , Biomarcadores/metabolismo , Criança , Pré-Escolar , Testes Genéticos/métodos , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Triagem Neonatal/métodos
19.
Genes (Basel) ; 10(10)2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658606

RESUMO

Phosphoglycerate kinase (PGK)1 deficiency is an X-linked inherited disease associated with different clinical presentations, sometimes as myopathic affectation without hemolytic anemia. We present a 40-year-old male with a mild psychomotor delay and mild mental retardation, who developed progressive exercise intolerance, cramps and sporadic episodes of rhabdomyolysis but no hematological features. A genetic study was carried out by a next-generation sequencing (NGS) panel of 32 genes associated with inherited metabolic myopathies. We identified a missense variant in the PGK1 gene c.1114G > A (p.Gly372Ser) located in the last nucleotide of exon 9. cDNA studies demonstrated abnormalities in mRNA splicing because this change abolishes the exon 9 donor site. This novel variant is the first variant associated with a myopathic form of PGK1 deficiency in the Spanish population.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Erros Inatos do Metabolismo/genética , Mutação de Sentido Incorreto , Fosfoglicerato Quinase/genética , Adulto , Células Cultivadas , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Masculino , Erros Inatos do Metabolismo/patologia , Fosfoglicerato Quinase/deficiência , Fosfoglicerato Quinase/metabolismo , Processamento de RNA , Espanha
20.
Exp Suppl ; 111: 85-102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588529

RESUMO

Primary generalized glucocorticoid resistance or Chrousos syndrome is a rare disorder, which affects all tissues expressing the human glucocorticoid receptor. It is characterized by generalized, partial tissue insensitivity to glucocorticoids caused by genetic defects in the NR3C1 gene. We and others have applied standard methods of molecular and structural biology to investigate the molecular mechanisms and conformational alterations through which the mutant glucocorticoid receptors lead to the broad spectrum of clinical manifestations of Chrousos syndrome. The ever-increasing application of novel technologies, including the next-generation sequencing, will enhance our knowledge in factors that influence the glucocorticoid signal transduction in a positive or negative fashion.


Assuntos
Erros Inatos do Metabolismo/genética , Receptores de Glucocorticoides/deficiência , Glucocorticoides , Humanos , Receptores de Glucocorticoides/genética , Transdução de Sinais
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