RESUMEN
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.
Asunto(s)
Atención a la Salud , Mortalidad Infantil , Errores Innatos del Metabolismo de los Metales/diagnóstico , Errores Innatos del Metabolismo de los Metales/mortalidad , Medicina de Precisión , Alelos , Toma de Decisiones Clínicas , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Errores Innatos del Metabolismo de los Metales/etiología , Fenotipo , Polimorfismo de Nucleótido Simple , Medicina de Precisión/métodos , Secuenciación Completa del GenomaRESUMEN
Copper is an essential trace nutrient metal involved in a multitude of cellular processes. Hereditary defects in copper metabolism result in disorders with a severe clinical course such as Wilson disease and Menkes disease. In Wilson disease, copper accumulation leads to liver cirrhosis and neurological impairments. A lack in genotype-phenotype correlation in Wilson disease points toward the influence of environmental factors or modifying genes. In a number of Non-Wilsonian forms of copper metabolism, the underlying genetic defects remain elusive. Several pure bred dog populations are affected with copper-associated hepatitis showing similarities to human copper metabolism disorders. Gene-mapping studies in these populations offer the opportunity to discover new genes involved in copper metabolism. Furthermore, due to the relatively large body size and long life-span of dogs they are excellent models for development of new treatment strategies. One example is the recent use of canine organoids for disease modeling and gene therapy of copper storage disease. This review addresses the opportunities offered by canine genetics for discovery of genes involved in copper metabolism disorders. Further, possibilities for the use of dogs in development of new treatment modalities for copper storage disorders, including gene repair in patient-derived hepatic organoids, are highlighted.
Asunto(s)
Cobre/metabolismo , Modelos Animales de Enfermedad , Errores Innatos del Metabolismo de los Metales/etiología , Errores Innatos del Metabolismo de los Metales/metabolismo , Animales , Terapia por Quelación , Mapeo Cromosómico , Dietoterapia , Perros , Estudios de Asociación Genética , Degeneración Hepatolenticular/genética , Degeneración Hepatolenticular/metabolismo , Degeneración Hepatolenticular/terapia , Homeostasis , Humanos , Errores Innatos del Metabolismo de los Metales/terapia , Trasplante de ÓrganosRESUMEN
Human growth hormone (GH) causes a variety of physiological and metabolic effects in humans and plays a pivotal role in postnatal growth. In somatotroph cells of the anterior pituitary, GH is stored in concentrated forms in secretory granules to be rapidly released upon GH-releasing hormone stimulation. During the process of secretory granule biogenesis, self-association of GH occurs in the compartments of the early secretory pathway (endoplasmic reticulum and Golgi complex). Since this process is greatly facilitated by the presence of zinc ions, it is of importance to understand the potential role of zinc transporters that participate in the fine-tuning of zinc homeostasis and dynamics, particularly in the early secretory pathway. Thus, the role of zinc transporters in supplying the secretory pathway with the sufficient amount of zinc required for the biogenesis of GH-containing secretory granules is essential for normal secretion. This report, illustrated by a clinical case report on transient neonatal zinc deficiency, focuses on the role of zinc in GH storage in the secretory granules and highlights the role of specific zinc transporters in the early secretory pathway. © 2013 S. Karger AG, Basel.
Asunto(s)
Hormona de Crecimiento Humana/metabolismo , Zinc/fisiología , Animales , Trastornos del Crecimiento/etiología , Trastornos del Crecimiento/metabolismo , Humanos , Recién Nacido , Errores Innatos del Metabolismo de los Metales/diagnóstico , Errores Innatos del Metabolismo de los Metales/etiología , Errores Innatos del Metabolismo de los Metales/metabolismo , Leche Humana/química , Leche Humana/metabolismo , Zinc/deficiencia , Zinc/metabolismoAsunto(s)
Lactancia Materna , Alimentos Infantiles , Anemia Ferropénica/etiología , Lactancia Materna/psicología , Lactancia Materna/estadística & datos numéricos , Trastornos del Crecimiento , Humanos , Lactante , Errores Innatos del Metabolismo de los Metales/etiología , Leche Humana/química , Guías de Práctica Clínica como Asunto , Factores de Tiempo , Deficiencia de Vitamina D/etiología , Zinc/deficienciaRESUMEN
Iron is a vitally important element in mammalian metabolism because of its unsurpassed versatility as a biologic catalyst. However, when not appropriately shielded or when present in excess, iron plays a key role in the formation of extremely toxic oxygen radicals, which ultimately cause peroxidative damage to vital cell structures. Organisms are equipped with specific proteins designed for iron acquisition, export, transport, and storage as well as with sophisticated mechanisms that maintain the intracellular labile iron pool at an appropriate level. These systems normally tightly control iron homeostasis but their failure can lead to iron deficiency or iron overload and their clinical consequences. This review describes several rare iron loading conditions caused by genetic defects in some of the proteins involved in iron metabolism. A dramatic decrease in the synthesis of the plasma iron transport protein, transferrin, leads to a massive accumulation of iron in nonhematopoietic tissues but virtually no iron is available for erythropoiesis. Humans and mice with hypotransferrinemia have a remarkably similar phenotype. Homozygous defects in a recently identified gene encoding transferrin receptor 2 lead to iron overload (hemochromatosis type 3) with symptoms similar to those seen in patients with HFE-associated hereditary hemochromatosis (hemochromatosis type 1). Transferrin receptor 2 is primarily expressed in the liver but it is unclear how mutant forms cause iron overload. Mutations in the gene encoding the iron exporter, ferroportin 1, cause iron overload characterized by iron accumulation in macrophages yet normal plasma iron levels. Plasma iron, together with dominant inheritance, discriminates iron overload due to ferroportin mutations (hemochromatosis type 4) from hemochromatosis type 1. Heme oxygenase 1 is essential for the catabolism of heme and in the recycling of hemoglobin iron in macrophages. Homozygous heme oxygenase 1 deletion in mice leads to a paradoxical accumulation of nonheme iron in macrophages, hepatocytes, and many other cells and is associated with low plasma iron levels, anemia, endothelial cell damage, and decreased resistance to oxidative stress. A similar phenotype occurred in a child with severe heme oxygenase 1 deficiency. Recently, a mutation in the L-subunit of ferritin has been described that causes the formation of aberrant L-ferritin with an altered C-terminus. Individuals with this mutation in one allele of L-ferritin have abnormal aggregates of ferritin and iron in the brain, primarily in the globus pallidus. Patients with this dominantly inherited late-onset disease present with symptoms of extrapyramidal dysfunction. Mice with a targeted disruption of a gene for iron regulatory protein 2 (IRP2), a translational repressor of ferritin, misregulate iron metabolism in the intestinal mucosa and the central nervous system. Significant amounts of ferritin and iron accumulate in white matter tracts and nuclei, and adult IRP2-deficient mice develop a movement disorder consisting of ataxia, bradykinesia, and tremor. Mutations in the frataxin gene are responsible for Friedreich ataxia, the most common of the inherited ataxias. Frataxin appears to regulate mitochondrial iron (or iron-sulfur cluster) export and the neurologic and cardiac manifestations of Friedreich ataxia are due to iron-mediated mitochondrial toxicity. Finally, patients with Hallervorden-Spatz syndrome, an autosomal recessive, progressive neurodegenerative disorder, have mutations in a novel pantothenate kinase gene (PANK2). The cardinal feature of this extrapyramidal disease is pathologic iron accumulation in the globus pallidus. The defect in PANK2 is predicted to cause the accumulation of cysteine, which binds iron and causes oxidative stress in the iron-rich globus pallidus.
Asunto(s)
Sobrecarga de Hierro/genética , Animales , Salud de la Familia , Hemocromatosis/clasificación , Hemocromatosis/etiología , Hemocromatosis/genética , Trastornos Heredodegenerativos del Sistema Nervioso/etiología , Trastornos Heredodegenerativos del Sistema Nervioso/genética , Humanos , Sobrecarga de Hierro/etiología , Proteínas de Unión a Hierro/genética , Proteínas de Unión a Hierro/metabolismo , Errores Innatos del Metabolismo de los Metales/etiología , Errores Innatos del Metabolismo de los Metales/genética , Mutación , Receptores de Transferrina/deficiencia , Receptores de Transferrina/genética , Receptores de Transferrina/metabolismoRESUMEN
Iron and copper are essential nutrients that must be meticulously regulated to exploit their usefulness in biological reactions while protecting against their tendency to promote formation of toxic free-radicals. This review summarizes recently described steps in the transport of these metals, and explores how defects in these steps lead to human diseases including hemochromatosis, Menkes disease and Wilson disease.
Asunto(s)
Proteínas de Transporte de Catión/metabolismo , Cobre/farmacocinética , Hierro/farmacocinética , Transporte Biológico , Humanos , Errores Innatos del Metabolismo de los Metales/etiologíaAsunto(s)
Cobre/metabolismo , Errores Innatos del Metabolismo de los Metales , Ceruloplasmina/deficiencia , Cobre/deficiencia , Diagnóstico Diferencial , Degeneración Hepatolenticular/etiología , Humanos , Síndrome del Pelo Ensortijado/etiología , Errores Innatos del Metabolismo de los Metales/etiología , Enfermedades del Sistema Nervioso/etiología , PronósticoAsunto(s)
Hierro/metabolismo , Errores Innatos del Metabolismo de los Metales , Transferrina/deficiencia , Adulto , Anciano , Animales , Biomarcadores/análisis , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Masculino , Errores Innatos del Metabolismo de los Metales/diagnóstico , Errores Innatos del Metabolismo de los Metales/etiologíaAsunto(s)
Coenzimas , Errores Innatos del Metabolismo de los Metales , Metaloproteínas , Molibdeno/metabolismo , Pteridinas , Biomarcadores/orina , Cisteína/metabolismo , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Errores Innatos del Metabolismo de los Metales/diagnóstico , Errores Innatos del Metabolismo de los Metales/etiología , Cofactores de Molibdeno , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/deficiencia , Sulfitos/metabolismo , Xantina/metabolismoAsunto(s)
Errores Innatos del Metabolismo de los Metales , Molibdeno/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/deficiencia , Biomarcadores/análisis , Cisteína/metabolismo , Diagnóstico Diferencial , Humanos , Recién Nacido , Errores Innatos del Metabolismo de los Metales/diagnóstico , Errores Innatos del Metabolismo de los Metales/etiología , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/análisis , Diagnóstico Prenatal , Sulfitos/metabolismoRESUMEN
The role of metallothionein (MT) was assessed in the copper-loading disease prevalent in Bedlington terriers. Fractionation of tissue supernatants over Sephadex G-75 showed that most of the additional cytosolic copper present in liver tissue of these dogs was bound to MT, and that substantially more MT-bound copper could be solubilized by detergent plus mercaptoethanol. Zinc contents were only slightly raised, although most of the extra zinc was associated with a 4000-Mr ligand. Ion-exchange chromatography revealed two isoproteins, MT1 and MT2, in all the dog liver samples examined. In Bedlington terrier liver, copper associated with both isoproteins was increased, although the increase for MT2 was greater than for MT1. The content of MT protein was also raised, although cell-free translations and RNA blots of total liver RNA showed that this increase was not associated with a rise in MT mRNA. The significance of these results to the mechanism of copper accumulation in the Bedlington terrier disorder is discussed.
Asunto(s)
Cobre/metabolismo , Enfermedades de los Perros/metabolismo , Errores Innatos del Metabolismo de los Metales/veterinaria , Metalotioneína/metabolismo , Animales , Cromatografía en Gel , Cromatografía por Intercambio Iónico , Perros , Hígado/metabolismo , Errores Innatos del Metabolismo de los Metales/etiología , Errores Innatos del Metabolismo de los Metales/metabolismo , Metalotioneína/genética , Biosíntesis de Proteínas , ARN Mensajero/genética , Fracciones Subcelulares/metabolismo , Zinc/metabolismoRESUMEN
Genetic trace metal disturbances can be at three levels. Trace metals play an important role in the metabolism of genetic macromolecules and the information transfer system. Deficiency or excess of trace metals caused either by dietary or genetic factors will affect the normal functioning of the whole organism. The roles of trace metals in carcinogenesis/mutagenesis and ageing are typical of this category. The second level of genetic trace metal disturbances affect the metabolic pathway of the trace metal itself. Biochemical derangement resulting from genetic defects cause aberrant metabolism of the element and thus disease symptoms. Diseases caused by abnormal metabolism of copper, zinc, iron, and molybdenum are discussed. Trace metal disturbances can also be the result of other genetic diseases. This aspect of genetic trace metal disturbances is least investigated. However, information should be important for improving the existing treatment protocol for the more common inborn errors of metabolism, such as phenylketonuria.
Asunto(s)
Errores Innatos del Metabolismo de los Metales , Oligoelementos/metabolismo , Animales , Cobre/metabolismo , ADN/metabolismo , Enfermedades Genéticas Congénitas/complicaciones , Humanos , Hierro/metabolismo , Masculino , Errores Innatos del Metabolismo de los Metales/etiología , Molibdeno/metabolismo , Biosíntesis de Proteínas , Proteínas/metabolismo , ARN/metabolismo , ARN de Transferencia/metabolismo , Ratas , Zinc/metabolismoAsunto(s)
Cobre/metabolismo , Enfermedades Metabólicas/etiología , Errores Innatos del Metabolismo de los Metales/etiología , Albinismo/metabolismo , Anemia/etiología , Animales , Enfermedades Óseas/etiología , Enfermedades Cardiovasculares/etiología , Enfermedades del Sistema Nervioso Central/etiología , Cobre/deficiencia , Femenino , Degeneración Hepatolenticular/genética , Degeneración Hepatolenticular/metabolismo , Humanos , Lactante , Masculino , Síndrome del Pelo Ensortijado/etiología , Síndrome del Pelo Ensortijado/terapia , Errores Innatos del Metabolismo de los Metales/metabolismo , Metaloproteínas/metabolismo , Embarazo , Complicaciones del Embarazo/etiologíaRESUMEN
A 39-year-old man with a lifelong history of tetany and hypocalcaemia was found to have hypomagnesaemia (0.29 mmol/l) due to renal magnesium loss. His asymptomatic 29-year-old brother had a similar disorder. Both were infertile and had severe oligospermia but normal endocrine function. They had medullary nephrocalcinosis and glomerular filtration rate was reduced. Renal biopsy showed patchy interstitial fibrosis and some glomerular sclerosis. Electron microscopy showed thickened basement membranes in damaged glomeruli and in tubules in areas of fibrosis. Tests of renal tubule function were normal. Hypocalcaemia and tetany were corrected by oral magnesium supplements which raised the serum magnesium level to around 0.54 mmol/l.
Asunto(s)
Enfermedades Renales/complicaciones , Magnesio/metabolismo , Errores Innatos del Metabolismo de los Metales/etiología , Defectos Congénitos del Transporte Tubular Renal/complicaciones , Adulto , Antígenos HLA/análisis , Humanos , Infertilidad Masculina/complicaciones , Riñón/patología , Riñón/fisiopatología , Enfermedades Renales/genética , Óxido de Magnesio/uso terapéutico , Masculino , Errores Innatos del Metabolismo de los Metales/genética , Defectos Congénitos del Transporte Tubular Renal/patologíaRESUMEN
A patient suffering from a combined deficiency of sulfite oxidase (sulfite dehydrogenase; sulfite:ferricytochrome c oxidoreductase, EC 1.8.2.1) and xanthine dehydrogenase (xanthine:NAD+ oxidoreductase, EC 1.2.1.37) is described. The patient displays severe neurological abnormalities, dislocated ocular lenses, and mental retardation. Urinary excretion of sulfite, thiosulfate, S-sulfocysteine, taurine, hypoxanthine, and xanthine is increased in this individual, while sulfate and urate levels are drastically reduced. The metabolic defect responsible for loss of both enzyme activities appears to be at the level of the molybdenum cofactor common to the two enzymes. Immunological examination of a biopsy sample of liver tissue revealed the presence of the xanthine dehydrogenase protein in near normal amounts. Sulfite oxidase apoprotein was not detected by a variety of immunological techniques. The plasma molybdenum concentration was normal; however, hepatic content of molybdenum and the storage pool of active molybdenum cofactor present in normal livers were below the limits of detection. Fibroblasts cultured from this patient failed to express sulfite oxidase protein or activity, whereas those from the parents and healthy brother of the patient expressed normal levels of this enzyme.