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3.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(4): 416-419, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33840416

RESUMO

A boy attended the hospital at the age of 1 month due to left hand tremor for 1 week. A blood test showed a reduction in serum uric acid and a cranial MRI showed encephalomalacia, atrophy, and cystic changes. The boy had microcephalus, unusual facial features (long face, long forehead, protruded forehead, long philtrum, low nasal bridge, facial swelling, and thick lower lip), hypertonia of lower extremities, and severe global developmental delay. Whole-exome sequencing performed for the boy detected a homozygous mutation, c.217C > T(p.R73W), in the MOCS1 gene, which came from his parents and was determined as "possibly pathogenic". The boy was diagnosed with molybdenum cofactor deficiency type A based on clinical manifestations and gene test results. This disease is reported for the first time in China.


Assuntos
Erros Inatos do Metabolismo dos Metais , Ácido Úrico , Carbono-Carbono Liases , China , Humanos , Recém-Nascido , Masculino , Mutação
4.
Drugs ; 81(8): 953-956, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33909276

RESUMO

Fosdenopterin (NulibryTM) is a synthetic cyclic pyranopterin monophosphate that is being developed by Origin Biosciences (a subsidiary of BridgeBio Pharma) for the treatment of molybdenum cofactor deficiency (MoCD) type A. Fosdenopterin was recently approved by the US FDA for use in reducing the risk of mortality in paediatric and adult patients with MoCD type A. This article summarizes the milestones in the development of fosdenopterin leading to this first approval.


Assuntos
Erros Inatos do Metabolismo dos Metais/tratamento farmacológico , Compostos Organofosforados/uso terapêutico , Pterinas/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Humanos , Erros Inatos do Metabolismo dos Metais/mortalidade , Erros Inatos do Metabolismo dos Metais/fisiopatologia , Compostos Organofosforados/efeitos adversos , Compostos Organofosforados/farmacologia , Pterinas/efeitos adversos , Pterinas/farmacologia
5.
Zhonghua Er Ke Za Zhi ; 59(2): 119-124, 2021 Feb 02.
Artigo em Chinês | MEDLINE | ID: mdl-33548958

RESUMO

Objective: To explore the phenotypes and genotypes of molybdenum cofactor deficiency type B (MoCD-B) manifested as Leigh-like syndrome. Methods: The clinical data, laboratory tests, neuroimaging and gene results of one patient diagnosed as MoCD-B at Beijing Children's Hospital and Hebei Children's Hospital in December 2018 were collected. Related literature was searched and reviewed at Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure and PubMed (up to September 2020) by using terms "MOCS2" "molybdenum cofactor deficiency" "Leigh-like syndrome,MOCS2" "molybdenum cofactor deficiency, Leigh-like syndrome". The phenotypes and genotypes of MoCD-B were summarized. Results: A 7 months and 14 days old boy with the chief complaint of "cough for 6 days, abnormal posture for 4 days and fever for 2 days" was admitted to Hebei Children' Hospital on December 2018. His abnormal posture presented as opisthotonos accompanied with dysphagia, without seizures. His previous psychomotor development was described as normal. He was born at term after an uneventful pregnancy to non-consanguineous parents. Blood test showed a slightly increased lactic acid and a significantly decreased uric acid. Urine metabolism test showed an obviously increased xanthine and hypoxanthine. Brain magnetic resonance imaging showed hyperintense signal on T2 weighted image and fluid attenuated inversion recovery in bilateral globus pallidus and pedunculus cerebri. The patient was diagnosed with Leigh-like syndrome. No obvious improvement was achieved after cocktail therapy and symptomatic treatment. The whole exome sequencing showed that the patient carried a homozygous variant of MOCS2 gene, c.19G>T(p.Val7Phe), which was a previously reported pathogenic site in the literature and could cause MoCD-B. His parents carried a heterozygous variant respectively. A total of 41 MoCD-B cases with MOCS2 gene variants were collected through literature review and our study, among which 30 cases had full medical records. The onset ages of 23 (77%) cases were in neonate, manifesting with severe encephalopathy, including neonatal-onset intractable seizures, developmental delay, laboratory abnormalities included very low levels of serum and urinary uric acid, increased urinary levels of xanthine and hypoxanthine. Cranial imaging showed cerebral atrophy, cystic encephalomalacia, etc. The onset ages of 7 patients varied from 5 months to 23 years. Four cases had normal psychomotor development before disease onset. Neurological disorders appeared acutely or exacerbated after external triggers and all of them had basal ganglia involvement. Among the 30 cases, 3 cases had a relatively milder phenotype with the ability of brief communication and walking without or with support. Conclusions: Molybdenum cofactor deficiency is a rare disease. Most cases had severe phenotypes and poor outcomes, but some cases may have mild phenotype. MoCD-B caused by MOCS2 gene variants may manifest as Leigh-like syndrome with a normal psychomotor development before the trigger of infection strike. Hypouricemia, xanthinuria and hypoxanthinuria can be indicators of the disease. The presence of MOCS2 gene variants would confirm a final diagnosis.


Assuntos
Erros Inatos do Metabolismo dos Metais , Criança , Pré-Escolar , China , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo dos Metais/diagnóstico , Erros Inatos do Metabolismo dos Metais/genética , Fenótipo
6.
Genes Dev ; 35(3-4): 177-179, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526584

RESUMO

Molybdenum cofactor (Moco) is synthesized endogenously in humans and is essential for human development. Supplementation of Moco or its precursors has been explored as a therapy to treat Moco-deficient patients but with significant limitations. By using the nematode C. elegans as a model, Warnhoff and colleagues (pp. 212-217) describe the beneficial impact of protein-bound Moco supplementation to treat Moco deficiency. If such an effect is conserved, this advance from basic research in worms may have significant clinical implications as a novel therapy for molybdenum cofactor deficiency.


Assuntos
Caenorhabditis elegans , Pteridinas , Animais , Coenzimas , Humanos , Erros Inatos do Metabolismo dos Metais , Metaloproteínas
7.
CEN Case Rep ; 10(3): 378-382, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33502714

RESUMO

Molybdenum cofactor is essential for the activity of multiple enzymes including xanthine dehydrogenase. Molybdenum cofactor deficiencies are rare inborn errors of metabolism. Clinically, they present with intractable seizures, axial hypotonia, and hyperekplexia. They further develop cerebral atrophy, microcephaly, global developmental delay and ectopia lentis. We report a 5-year-old female with clinically, biochemically and genetically confirmed molybdenum cofactor deficiency type B due to compound heterozygous pathogenic variants in the molybdenum cofactor synthesis 2 gene found on whole exome sequencing. The xanthine stones were a key clue towards diagnosis. No mutation was detected in XDH gene. Implementation of a low-purine diet, urine alkalization and hydration lead to a near complete decrease in stone burden. The patient received pyridoxine supplementation with improvement in energy levels and attentiveness. Despite reports of high mortality at a young age, our patient was 9 years old at the time of this writing. Molybdenum cofactor deficiencies should be considered in neonates with early-onset seizures, hypotonia, and feeding difficulties. Screening with serum uric acid levels and empiric treatment may be considered while awaiting genetic results.


Assuntos
Erros Inatos do Metabolismo dos Metais/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/etiologia , Criança , Humanos , Erros Inatos do Metabolismo dos Metais/complicações
8.
J Dermatol ; 48(4): 519-528, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33458872

RESUMO

PSTPIP1-associated myeloid-related proteinaemia inflammatory (PAMI) syndrome has been described as a rare and distinct clinical phenotype of PSTPIP1-associated inflammatory diseases. We report PSTPIP1 mutation in both father and son who have leukopenia and acne-like lesions. Through whole-exome sequencing on blood DNA, it is found a heterozygous mutation of PSTPIP1 gene c.748G>A on the father and son. The diagnosis of PAMI is made based on DNA sequencing results and clinical characteristics of typical lesions, leukopenia, and the markedly increased serum S100A8/A9 (calprotectin).


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas do Citoesqueleto/genética , Pai , Humanos , Inflamação/genética , Masculino , Erros Inatos do Metabolismo dos Metais/genética , Mutação , Mutação de Sentido Incorreto , Síndrome
9.
Genes Dev ; 35(3-4): 212-217, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33446569

RESUMO

The molybdenum cofactor (Moco) is a 520-Da prosthetic group that is synthesized in all domains of life. In animals, four oxidases (among them sulfite oxidase) use Moco as a prosthetic group. Moco is essential in animals; humans with mutations in genes that encode Moco biosynthetic enzymes display lethal neurological and developmental defects. Moco supplementation seems a logical therapy; however, the instability of Moco has precluded biochemical and cell biological studies of Moco transport and bioavailability. The nematode Caenorhabditis elegans can take up Moco from its bacterial diet and transport it to cells and tissues that express Moco-requiring enzymes, suggesting a system for Moco uptake and distribution. Here we show that protein-bound Moco is the stable, bioavailable species of Moco taken up by C. elegans from its diet and is an effective dietary supplement, rescuing a C elegans model of Moco deficiency. We demonstrate that diverse Moco:protein complexes are stable and bioavailable, suggesting a new strategy for the production and delivery of therapeutically active Moco to treat human Moco deficiency.


Assuntos
Caenorhabditis elegans/metabolismo , Coenzimas/administração & dosagem , Erros Inatos do Metabolismo dos Metais/terapia , Metaloproteínas/administração & dosagem , Pteridinas/administração & dosagem , Animais , Bactérias/metabolismo , Transporte Biológico , Coenzimas/deficiência , Coenzimas/farmacocinética , Humanos , Metaloproteínas/deficiência , Metaloproteínas/farmacocinética , Ligação Proteica , Pteridinas/farmacocinética
10.
Hematology Am Soc Hematol Educ Program ; 2020(1): 465-470, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33275715

RESUMO

Inherited microcytic anemias can be broadly classified into 3 subgroups: (1) defects in globin chains (hemoglobinopathies or thalassemias), (2) defects in heme synthesis, and (3) defects in iron availability or iron acquisition by the erythroid precursors. These conditions are characterized by a decreased availability of hemoglobin (Hb) components (globins, iron, and heme) that in turn causes a reduced Hb content in red cell precursors with subsequent delayed erythroid differentiation. Iron metabolism alterations remain central to the diagnosis of microcytic anemia, and, in general, the iron status has to be evaluated in cases of microcytosis. Besides the very common microcytic anemia due to acquired iron deficiency, a range of hereditary abnormalities that result in actual or functional iron deficiency are now being recognized. Atransferrinemia, DMT1 deficiency, ferroportin disease, and iron-refractory iron deficiency anemia are hereditary disorders due to iron metabolism abnormalities, some of which are associated with iron overload. Because causes of microcytosis other than iron deficiency should be considered, it is important to evaluate several other red blood cell and iron parameters in patients with a reduced mean corpuscular volume (MCV), including mean corpuscular hemoglobin, red blood cell distribution width, reticulocyte hemoglobin content, serum iron and serum ferritin levels, total iron-binding capacity, transferrin saturation, hemoglobin electrophoresis, and sometimes reticulocyte count. From the epidemiological perspective, hemoglobinopathies/thalassemias are the most common forms of hereditary microcytic anemia, ranging from inconsequential changes in MCV to severe anemia syndromes.


Assuntos
Anemia , Ferro/metabolismo , Erros Inatos do Metabolismo dos Metais , Anemia/classificação , Anemia/genética , Anemia/metabolismo , Anemia/patologia , Humanos , Erros Inatos do Metabolismo dos Metais/classificação , Erros Inatos do Metabolismo dos Metais/genética , Erros Inatos do Metabolismo dos Metais/metabolismo , Erros Inatos do Metabolismo dos Metais/patologia
11.
Artigo em Inglês | MEDLINE | ID: mdl-32014857

RESUMO

Neonatal encephalopathy with seizures is a presentation in which rapid whole-genome sequencing (rWGS) has shown clinical utility and improved outcomes. We report a neonate who presented on the third day of life with seizures refractory to antiepileptic medications and neurologic and computerized tomographic findings consistent with severe generalized brain swelling. rWGS revealed compound heterozygous variants in the molybdenum cofactor synthesis gene, type 1A (MOCS1 c.*7 + 5G > A and c.377G > A); a provisional diagnosis of molybdenum cofactor deficiency on day of life 4. An emergency investigational new drug application for intravenous replacement of the MOCS1 product, cyclic pyranopterin monophosphate, was considered, but felt unsuitable in light of the severity of disease and delay in the start of treatment. The patient died on day of life 9 despite having a precise molecular diagnosis within the first week of life. This case illustrates that an rWGS-based molecular diagnosis within the first week of life may be insufficient to improve outcomes. However, it did inform clinical decision-making with regard to resuscitation and predicted long-term outcome. We suggest that to achieve optimal reductions in morbidity and mortality, rWGS must be implemented within a comprehensive rapid precision medicine system (CRPM). Akin to newborn screening (NBS), CRPM will have onboarding, diagnosis, and precision medicine implementation components developed in response to patient and parental needs. Education of health-care providers in a learning model in which ongoing data analyses informs system improvement will be essential for optimal effectiveness of CRPM.


Assuntos
Atenção à Saúde , Mortalidade Infantil , Erros Inatos do Metabolismo dos Metais/diagnóstico , Erros Inatos do Metabolismo dos Metais/mortalidade , Medicina de Precisão , Alelos , Tomada de Decisão Clínica , Gerenciamento Clínico , Suscetibilidade a Doenças , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo dos Metais/etiologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Medicina de Precisão/métodos , Sequenciamento Completo do Genoma
12.
Eur J Med Genet ; 63(5): 103874, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32028041

RESUMO

Congenital atransferrinemia is an extremely rare autosomal recessive disorder resulting in the complete absence or extremely reduced amount of transferrin. In this study, we describe the first case of congenital atransferrinemia in Tunisia and the 18th patient in the reported data. The patient was referred to our hospital to explore a severe hypochromic and microcytic anemia. The laboratory evaluation including hematological and biochemical examination was performed in the proband and her parents. All exons of the transferrin gene were PCR amplified. The products were screened for mutations by direct sequencing. Based on laboratory and clinical findings, diagnosis of congenital atransferrinemia was confirmed. DNA sequencing revealed the presence of a novel homozygous deletion (c.293-63del) in the intron 13. This mutation is predicted to generate a higher score cryptic branch point leading to the production of an altered mRNA molecule. The second previously reported missense mutation p.Arg609Trp. Crystallographic structure analyzes demonstrate that the mutation would probably lead to significant conformational change not allowing the expression of transferrin protein. Current molecular characterization of this novel transferrin abnormality puts to the proof the variability in onset, first blood transfusion, and phenotypic expression in atransferrinemic patients.


Assuntos
Erros Inatos do Metabolismo dos Metais/genética , Mutação , Sítios de Splice de RNA , Transferrina/deficiência , Transferrina/genética , Feminino , Homozigoto , Humanos , Lactente , Erros Inatos do Metabolismo dos Metais/patologia , Domínios Proteicos , Transferrina/química , Transferrina/metabolismo
13.
Brain Dev ; 42(2): 157-164, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31806255

RESUMO

BACKGROUND: Isolated sulfite oxidase deficiency (ISOD) is a rare autosomal recessively inherited inborn error of metabolism, caused by mutation in SUOX gene. ISOD has two kind of presentation; early and late-onset. The late-onset form is extremely rare and only 10 cases have been reported. METHODS: We report two new cases of late-onset ISOD with biochemical and genetic confirmation. We did a review of the previously published cases of late-onset ISOD. RESULTS: Together with the presented two cases, 12 cases were available for analysis. The median age at symptom onset and at diagnosis was 8.5 and 23 months respectively. Almost all children had acute regression of milestones followed by slow recovery. The common presenting signs and symptoms were movement disorders, seizures, ectopia lentis and hypertonia. Five children had antecedent events. Trivial trauma precipitating the metabolic crisis was unique to the two cases we report. The most common MRI feature was globus pallidi changes followed by cerebellar white matter changes, vermian hypoplasia and thinned out corpus callosum. Diffusion weighted sequence was performed in 3 children and all had diffusion restriction in the affected area. CONCLUSION: Trivial trauma can precipitate metabolic crisis in late-onset ISOD. Low plasma homocysteine and involvement of globus pallidi with diffusion restriction on the MRI are important diagnostic clues. Early diagnosis and intervention with special diet may be effective in preventing long term neurodisability.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/etiologia , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Traumatismos Craniocerebrais/complicações , Sulfito Oxidase/deficiência , Criança , Pré-Escolar , Traumatismos Craniocerebrais/metabolismo , Feminino , Globo Pálido/patologia , Homocisteína/metabolismo , Humanos , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino , Erros Inatos do Metabolismo dos Metais/metabolismo , Convulsões/etiologia , Sulfito Oxidase/metabolismo
14.
Med Mol Morphol ; 53(1): 50-55, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31161407

RESUMO

Idiopathic copper toxicosis (ICT) is characterized by marked copper deposition, Mallory-Denk body (MDB) formation and severe hepatic injury. Although the characteristics are apparently different from Wilson disease, large amounts of copper accumulate in the liver of the patients. We extensively treated a patient with ICT to reduce the body copper, however, the patient needed liver transplantation. Previous liver biopsy revealed high copper content. But extirpated liver contained an extremely small amount of copper, although MDBs and severe inflammation remained. These phenomena suggest abnormal copper metabolism is not the principle cause of ICT but some other abnormality must exist.


Assuntos
Carcinoma Hepatocelular/patologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cobre/metabolismo , Cobre/toxicidade , Degeneração Hepatolenticular/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Transplante de Fígado , Erros Inatos do Metabolismo dos Metais/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/cirurgia , Ceruloplasmina/metabolismo , Quelantes/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/cirurgia , Feminino , Hepatócitos/metabolismo , Hepatócitos/patologia , Degeneração Hepatolenticular/tratamento farmacológico , Degeneração Hepatolenticular/metabolismo , Degeneração Hepatolenticular/cirurgia , Humanos , Fígado/metabolismo , Fígado/patologia , Fígado/cirurgia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Cirrose Hepática/cirurgia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirurgia , Erros Inatos do Metabolismo dos Metais/tratamento farmacológico , Erros Inatos do Metabolismo dos Metais/metabolismo , Erros Inatos do Metabolismo dos Metais/cirurgia , Trientina/uso terapêutico , Adulto Jovem
15.
An Bras Dermatol ; 94(6): 713-716, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31789267

RESUMO

Hyperzincemia and hypercalprotectinemia is a rare inflammatory disease caused by a mutation in the PSTPIP1 gene, with a dysregulation of calprotectin metabolism. Calprotectin is a zinc-binding protein with antimicrobial properties and pro-inflammatory action. The authors report the case of a 20 year-old girl with cutaneous ulcers comparable with pyoderma gangrenosum, growth failure and chronic anemia, who was given the diagnosis of hyperzincemia and hypercalprotectinemia. Measurement of serum zinc and calprotectin concentrations are indicated in these cases.


Assuntos
Erros Inatos do Metabolismo dos Metais/patologia , Pioderma Gangrenoso/patologia , Ciclosporina/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Complexo Antígeno L1 Leucocitário/sangue , Erros Inatos do Metabolismo dos Metais/tratamento farmacológico , Prednisolona/uso terapêutico , Resultado do Tratamento , Adulto Jovem , Zinco/sangue
16.
An. bras. dermatol ; 94(6): 713-716, Nov.-Dec. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1054898

RESUMO

Abstract Hyperzincemia and hypercalprotectinemia is a rare inflammatory disease caused by a mutation in the PSTPIP1 gene, with a dysregulation of calprotectin metabolism. Calprotectin is a zinc-binding protein with antimicrobial properties and pro-inflammatory action. The authors report the case of a 20 year-old girl with cutaneous ulcers comparable with pyoderma gangrenosum, growth failure and chronic anemia, who was given the diagnosis of hyperzincemia and hypercalprotectinemia. Measurement of serum zinc and calprotectin concentrations are indicated in these cases.


Assuntos
Humanos , Feminino , Adulto Jovem , Pioderma Gangrenoso/patologia , Erros Inatos do Metabolismo dos Metais/patologia , Zinco/sangue , Prednisolona/uso terapêutico , Resultado do Tratamento , Ciclosporina/uso terapêutico , Complexo Antígeno L1 Leucocitário/sangue , Fármacos Dermatológicos/uso terapêutico , Glucocorticoides/uso terapêutico , Erros Inatos do Metabolismo dos Metais/tratamento farmacológico
17.
Pediatr Neurol ; 99: 55-59, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31201073

RESUMO

BACKGROUND: We explored the clinical and molecular characteristics of molybdenum cofactor deficiency due to MOCS2 muations. METHODS: We summarize the genetic and clinical findings of previously reported patients with a MOCS2 mutation. We also present a new patient with novel neuroradiological findings associated with molybdenum cofactor deficiency due to a novel homozygous variant in the 5' untranslated region of the MOCS2 gene. RESULTS: The study population comprised 35 patients with a MOCS2 gene mutation. All reported children had delayed motor milestones. The major initial symptom was seizures in neonatal period. Facial dysmorphism was present in 61% of the patients. Only one patient had ectopia lentis. Agenesis of the corpus callosum and an associated interhemispheric cyst in our case are novel neuroradiological findings. CONCLUSIONS: The occurrence of neonatal seizures and feeding difficulties can be the first clinical signs of molybdenum cofactor deficiency. Although there is no effective therapy for this condition, early diagnosis and genetic analysis of these lethal disorders facilitate adequate genetic counseling.


Assuntos
Erros Inatos do Metabolismo dos Metais/genética , Sulfurtransferases/deficiência , Regiões 5' não Traduzidas/genética , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/genética , Cisterna Magna/diagnóstico por imagem , Cisterna Magna/patologia , Bases de Dados Factuais , Encefalomalacia/diagnóstico por imagem , Encefalomalacia/genética , Face/anormalidades , Transtornos de Alimentação na Infância/genética , Feminino , Heterogeneidade Genética , Homozigoto , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Transtornos dos Movimentos/congênito , Transtornos dos Movimentos/genética , Neuroimagem , Fenótipo , Convulsões/congênito , Sulfurtransferases/genética , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
18.
Hum Genet ; 138(5): 541-546, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31062085

RESUMO

This preliminary study summarizes the genotypes of 42 Labrador Retrievers and Labrador Retriever-Golden Retriever crosses and phenotypes a subset of ten of these dogs that are homozygous mutant, heterozygous, or homozygous normal for mutations in the ATP7A and ATP7B genes that have been associated with the development of copper toxicosis in Labrador Retrievers. The purpose of this study is to evaluate whether there is a correlation between ATP7A and ATP7B genotypes and clinical evidence of hepatic pathology in young, asymptomatic Labrador Retrievers. We evaluated serum ALT levels, hepatic copper concentrations, and hepatic histopathology from ten offspring where both parents had a least one copy of the ATP7B mutation. Five were homozygous mutant, four were heterozygous, and one was homozygous normal for comparison. None had increased serum ALT activity. All dogs homozygous for the ATP7B mutation had elevated hepatic copper concentrations compared to dogs heterozygous for the ATP7B mutation regardless of sex or presence of an ATP7A mutation with the mean hepatic copper concentration being 1464 ppm (reference range 100-330 ppm). Mean hepatic copper concentration in homozygous normal and heterozygous dogs was 328 ppm. In this preliminary analysis, we found that dogs that carry two copies of the ATP7B mutation have abnormally elevated hepatic copper levels despite having normal serum ALT activity. Our findings support the hypothesis that the ATP7B DNA test can predict defects in hepatic copper metabolism. Veterinarians can test for the ATP7B gene mutation to identify Labrador Retrievers at risk for copper toxicosis so that they can take steps to prevent development of copper-associated chronic hepatitis in their patients.


Assuntos
ATPases Transportadoras de Cobre/genética , Cobre/sangue , Cobre/toxicidade , Doenças do Cão/genética , Cirrose Hepática/diagnóstico , Cirrose Hepática/veterinária , Erros Inatos do Metabolismo dos Metais/diagnóstico , Erros Inatos do Metabolismo dos Metais/veterinária , Alanina Transaminase/sangue , Animais , Cães , Feminino , Predisposição Genética para Doença/genética , Genótipo , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/genética , Humanos , Masculino , Rodanina/metabolismo
19.
J Neurol Sci ; 400: 47-51, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30903859

RESUMO

Copper deficiency (hypocupremia) or toxicosis (hypercupremia) may cause disorders of central and peripheral nervous systems. Hypocupremia causes myeloneuropathy resembling vitamin B12 deficiency. However, the clinical manifestations, particularly peripheral neuropathy (PN), of hypercupremia have not been adequately evaluated. To compare clinical, laboratory and electrodiagnositc features of PN between patients with hypocupremia and hypercupremia, we retrospectively reviewed the charts of patients with abnormal copper levels. Subjects with zinc abnormalities were excluded. Five hypocupremia (Male/Female = 4/1; age: 54.6 ±â€¯17.1 years; copper = 55.0 ±â€¯8.5 µg/dL [normal = 72-175]; zinc = 74.4 ±â€¯15.5 µg/dL [normal = 60-130]) and 3 hypercupremia (M/F = 1/2; age: 57.0 ±â€¯8.2 years; copper = 215.0 ±â€¯10.8 µg/dL; zinc = 72.3 ±â€¯14.6 µg/dL) were studied. The notable clinical findings included ambulatory difficulty in hypocupremia (2/5); paresthesia in both hypocupremia (3/5) and hypercupremia (2/3) but pain was only seen in (3/3) hypercupremia patients. Tendon reflexes were decreased in hypocupremia (3/5) and hypercupremia (1/3) but hyperreflexias in hypocupremia (2/5) only. Preexisting comorbidity such as diarrhea were observed in (2/3) hypercupremia but not in hypocupremia patients. Laboratory findings showed vitamin D deficiency (16.4 ±â€¯5.6 ng/mL) in (2/2) hypercupremia but normal (40.4 ±â€¯4.7 ng/mL) in (2/2) hypocupremia. Neurophysiologic studies showed evidence of neuropathy in (3/5) hypocupremia only. Different patterns of clinical, neurological examination and electrophysiologic findings between hypocupremia and hypercupremia suggest different underlying pathophysiologies.


Assuntos
Cobre/sangue , Cobre/deficiência , Cobre/toxicidade , Eletrodiagnóstico/métodos , Cirrose Hepática/sangue , Erros Inatos do Metabolismo dos Metais/sangue , Doenças do Sistema Nervoso Periférico/sangue , Adulto , Idoso , Feminino , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/fisiopatologia , Masculino , Erros Inatos do Metabolismo dos Metais/diagnóstico , Erros Inatos do Metabolismo dos Metais/fisiopatologia , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Estudos Retrospectivos
20.
Mol Genet Genomic Med ; 7(6): e657, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30900395

RESUMO

BACKGROUND: Molybdenum cofactor deficiency (MoCD) is a rare autosomal-recessive disorder that results in the combined deficiency of molybdenum-dependent enzymes. Four different genes are involved in Molybdenum cofactor biosynthesis: MOCS1, MOCS2, MOCS3, and GEPH. The classical form manifests in the neonatal period with severe encephalopathy, including intractable seizures, MRI changes that resemble hypoxic-ischemic injury, microcephaly, and early death. To date, an atypical phenotype with late-onset has been reported in the literature in 13 patients. METHODS: We describe a late-onset and a relatively mild phenotype in a patient with MOCS2 homozygous mutation. RESULTS: Pyramidal and extrapyramidal signs are recognized in those patients, often exacerbated by intercurrent illness. Expressive language is usually compromised. Neurological deterioration is possible even in adulthood, probably due to accumulation of sulfite with time. CONCLUSION: Sulfite inhibition of mitochondrial metabolism could be responsible for the ischemic lesions described in patients with MoCD or alternatively could predispose the brain to suffer an ischemic damage through the action of other insults, for instance intercurrent illness. It is possible that sulfite accumulation together with other external triggers, can lead to neurological deterioration even in adulthood. The role of other factors involved in clinical expression should be investigated to establish the reason for phenotypic variability in patients with the same mutation.


Assuntos
Erros Inatos do Metabolismo dos Metais/genética , Erros Inatos do Metabolismo dos Metais/fisiopatologia , Sulfurtransferases/genética , Criança , Coenzimas/genética , Coenzimas/metabolismo , Feminino , Homozigoto , Humanos , Erros Inatos do Metabolismo dos Metais/metabolismo , Metaloproteínas/genética , Metaloproteínas/metabolismo , Mutação , Fenótipo , Pteridinas/metabolismo , Sulfurtransferases/metabolismo
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