RESUMEN
From Sir Archibald Garrod's initial description of the tetrad of albinism, alkaptonuria, cystinuria, and pentosuria to today, the field of medicine dedicated to inborn errors of metabolism has evolved from disease identification and mechanistic discovery to the development of therapies designed to subvert biochemical defects. In this review, we highlight major milestones in the treatment and diagnosis of inborn errors of metabolism, starting with dietary therapy for phenylketonuria in the 1950s and 1960s, and ending with current approaches in genetic manipulation.
Asunto(s)
Albinismo/terapia , Alcaptonuria/terapia , Cistinuria/terapia , Errores Innatos del Metabolismo/terapia , Albinismo/genética , Albinismo/metabolismo , Albinismo/patología , Alcaptonuria/genética , Alcaptonuria/metabolismo , Alcaptonuria/patología , Errores Innatos del Metabolismo de los Carbohidratos/genética , Errores Innatos del Metabolismo de los Carbohidratos/metabolismo , Errores Innatos del Metabolismo de los Carbohidratos/patología , Errores Innatos del Metabolismo de los Carbohidratos/terapia , Cistinuria/genética , Cistinuria/metabolismo , Cistinuria/patología , Humanos , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Errores Innatos del Metabolismo/patología , Fenilcetonurias/genética , Fenilcetonurias/metabolismo , Fenilcetonurias/patología , Fenilcetonurias/terapia , Deshidrogenasas del Alcohol de Azúcar/deficiencia , Deshidrogenasas del Alcohol de Azúcar/genética , Deshidrogenasas del Alcohol de Azúcar/metabolismo , Xilulosa/genética , Xilulosa/metabolismoRESUMEN
White diseases are a heterogenous group characterized by hypopigmentation or depigmentation. Skin and eye color are determined by the number and size of melanosomes present. Melanin is produced by melanosomes in the melanocytes present within the epidermis of the skin, uvea, and retinal pigmented epithelium (RPE). Conditions altering the number of melanocytes or concentration of melanin result in a lack of pigmentation, appearing as "white diseases" ranging from the well-known albinism and vitiligo to more esoteric white hand syndrome and Degos disease.
Asunto(s)
Hipopigmentación/diagnóstico , Hipopigmentación/etiología , Albinismo/diagnóstico , Albinismo/etiología , Albinismo/terapia , Color , Cosméticos/efectos adversos , Diagnóstico Diferencial , Humanos , Hipopigmentación/patología , Hipopigmentación/terapia , Inflamación/complicaciones , Liquen Escleroso y Atrófico/diagnóstico , Liquen Escleroso y Atrófico/etiología , Liquen Escleroso y Atrófico/patología , Liquen Escleroso y Atrófico/terapia , Papulosis Atrófica Maligna/diagnóstico , Papulosis Atrófica Maligna/etiología , Papulosis Atrófica Maligna/patología , Membrana Mucosa , Enfermedades de la Uña/etiología , Nevo con Halo/diagnóstico , Nevo con Halo/etiología , Nevo con Halo/patología , Pitiriasis Liquenoide/diagnóstico , Pitiriasis Liquenoide/etiología , Pitiriasis Liquenoide/terapia , Pronóstico , Preparaciones para Aclaramiento de la Piel/efectos adversos , Tiña Versicolor/diagnóstico , Tiña Versicolor/tratamiento farmacológico , Tiña Versicolor/etiología , Vibración/efectos adversos , Vitíligo/diagnóstico , Vitíligo/etiología , Vitíligo/terapia , Síndrome de Waardenburg/diagnóstico , Síndrome de Waardenburg/etiologíaRESUMEN
Adenine base editors (ABEs) composed of an engineered adenine deaminase and the Streptococcus pyogenes Cas9 nickase enable adenine-to-guanine (A-to-G) single-nucleotide substitutions in a guide RNA (gRNA)-dependent manner. Here we demonstrate application of this technology in mouse embryos and adult mice. We also show that long gRNAs enable adenine editing at positions one or two bases upstream of the window that is accessible with standard single guide RNAs (sgRNAs). We introduced the Himalayan point mutation in the Tyr gene by microinjecting ABE mRNA and an extended gRNA into mouse embryos, obtaining Tyr mutant mice with an albino phenotype. Furthermore, we delivered the split ABE gene, using trans-splicing adeno-associated viral vectors, to muscle cells in a mouse model of Duchenne muscular dystrophy to correct a nonsense mutation in the Dmd gene, demonstrating the therapeutic potential of base editing in adult animals.
Asunto(s)
Edición Génica/métodos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Adenina/química , Albinismo/embriología , Albinismo/genética , Albinismo/terapia , Animales , Secuencia de Bases , Biotecnología , ADN/genética , Modelos Animales de Enfermedad , Distrofina/deficiencia , Distrofina/genética , Terapia Genética/métodos , Células HEK293 , Humanos , Ratones , Ratones Noqueados , Ratones Mutantes , Monofenol Monooxigenasa/genética , Reparación del Gen Blanco/métodosAsunto(s)
Albinismo , Derechos Humanos , Prejuicio , Discriminación Social , Albinismo/epidemiología , Albinismo/genética , Albinismo/psicología , Albinismo/terapia , Congresos como Asunto/organización & administración , Congresos como Asunto/normas , Cultura , Educación en Salud , Humanos , Mitología , Enfermedades Raras , Sociedades Médicas/organización & administración , Sociedades Médicas/normas , Factores SocioeconómicosRESUMEN
Hemophagocytic lymphohistiocytosis (HLH) is not an independent disease but rather a life-threatening clinical syndrome that occurs in many underlying conditions and in all age groups. HLH is the consequence of a severe, uncontrolled hyperinflammatory reaction that in most cases is triggered by an infectious agent. Persistent stimulation of lymphocytes and histiocytes results in hypercytokinemia, leading to the characteristic symptoms of HLH. Genetic defects in familial HLH and in immunodeficiency syndromes associated with albinism affect the transport, processing, and function of cytotoxic granules in natural killer cells and cytotoxic T lymphocytes. This leads to defective killing of target cells and a failure to contract the immune response. The defects are increasingly found also in adolescents and adults. Acquired HLH occurs in autoinflammatory and autoimmune diseases (macrophage activation syndrome) and in patients with iatrogenic immunosuppression or with malignancies, but also in otherwise healthy persons with infections. Treatment of HLH aims at suppressing hypercytokinemia and eliminating the activated and infected cells. In genetic HLH, hematopoietic stem cell transplantation (HSCT) is needed for the correction of the immune defect. Treatment modalities include immunosuppressive, immunomodulatory, and cytostatic drugs; T-cell antibodies; and anticytokine agents. Using immunochemotherapy, familial HLH, which had been invariably fatal, has become a curable disease with more than 50% survivors. Reduced intensity conditioning for HSCT, which is associated with less transplantation-related mortality, will further improve cure rates.
Asunto(s)
Linfohistiocitosis Hemofagocítica , Albinismo/complicaciones , Albinismo/genética , Albinismo/metabolismo , Albinismo/mortalidad , Albinismo/terapia , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/mortalidad , Enfermedades Autoinmunes/patología , Enfermedades Autoinmunes/terapia , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/metabolismo , Inmunodeficiencia Variable Común/mortalidad , Inmunodeficiencia Variable Común/terapia , Humanos , Infecciones/complicaciones , Infecciones/genética , Infecciones/metabolismo , Infecciones/mortalidad , Infecciones/terapia , Linfocitos/metabolismo , Linfocitos/patología , Linfohistiocitosis Hemofagocítica/etiología , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/metabolismo , Linfohistiocitosis Hemofagocítica/mortalidad , Linfohistiocitosis Hemofagocítica/terapia , Síndrome de Activación Macrofágica/complicaciones , Síndrome de Activación Macrofágica/genética , Síndrome de Activación Macrofágica/metabolismo , Síndrome de Activación Macrofágica/patología , Síndrome de Activación Macrofágica/terapia , Neoplasias/complicaciones , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/terapiaAsunto(s)
Albinismo/patología , Síndromes de Inmunodeficiencia/patología , Síndromes Mielodisplásicos/patología , Albinismo/diagnóstico , Albinismo/terapia , Examen de la Médula Ósea , Análisis Citogenético , Diagnóstico Diferencial , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/terapia , Lactante , Síndrome , Resultado del TratamientoRESUMEN
In order to induce melanin production in mammalian cells with pigment disorders such as albino hair, a recombinant retrovirus containing the mel locus of Streptomyces antibioticus was constructed. The S. antibioticus mel locus, which consists of the open reading frame (ORF)-438 and the tyrosinase gene, was specifically derived by polymerase chain reaction (PCR) from Streptomyces plasmid pIJ702. The ORF-438 is required for the transfer of copper to apotyrosinase, which is essential for tyrosinase enzymatic activity. The tyrosinase gene was inserted into the XhoI/BamHI cloning site of the pLXSN retroviral vector to obtain pLtyrSN. An internal ribosome entry site (IRES) suitable for mammalian cell expression was obtained from the pLXIN retroviral vector by PCR. The ORF-438 and IRES DNA fragments were inserted into the pLtyrSN vector to obtain the tyrosinase-expression retroviral vector pLmelSN. The expression vector was amplified in murine PT67 packaging cells, where the ORF-438 and tyrosinase genes were also co-expressed as determined by reverse transcription-PCR. In order to evaluate the vector's ability to restore pigment production in cells with a pigment disorder, albino-mouse skins were histocultured and then infected with the pLmelSN retrovirus. Six days after infection, melanin granules were observed in approximately 60% of albino-mouse hair follicles in the histocultured skin. These results demonstrated that the S. antibioticus mel operon could express an active tyrosinase and produce melanin in the albino-mouse hair follicles. This novel gene therapy approach, using a small and simple tyrosinase operon in a high-expression vector, has a potentially wide application for therapy of pigment disorders in hair follicles.
Asunto(s)
Albinismo/terapia , Terapia Genética/métodos , Enfermedades del Cabello/terapia , Monofenol Monooxigenasa/genética , Piel/metabolismo , Streptomyces antibioticus/enzimología , Albinismo/genética , Animales , Técnicas de Cultivo , Femenino , Expresión Génica , Genes Bacterianos , Vectores Genéticos , Melaninas/biosíntesis , Ratones , Ratones Endogámicos C57BL , Monofenol Monooxigenasa/metabolismo , Sistemas de Lectura Abierta , ARN Mensajero , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Retroviridae , Streptomyces antibioticus/genéticaRESUMEN
Partial albinism with immunodeficiency is a rare and fatal immunologic disorder characterized by pigmentary dilution and variable cellular immunodeficiency. To define the phenotype, therapy, and outcome, we retrospectively analyzed seven consecutive patients. Primary abnormalities included a silvery-grayish sheen to the hair, large pigment agglomerations in hair shafts, and an abundance of mature melanosomes in melanocytes, with reduced pigmentation of adjacent keratinocytes. Clinical onset occurred between the ages of 4 months and 4 years and was characterized by accelerated phases (lymphohistiocytic infiltration of multiple organs, including the brain and the meninges), triggered by viral and bacterial infections. Characteristic laboratory features included pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and hypoproteinemia. Consistent immunologic abnormalities were characterized by absent delayed-type cutaneous hypersensitivity and impaired natural killer cell function. Some patients had secondary hypogammaglobulinemia, impaired major histocompatibility complex-mediated cytotoxic effects, a decreased capacity of lymphocytes to trigger a mixed lymphocyte reaction, or various functional granulocytic abnormalities. The disease seems to be invariably lethal without bone marrow transplantation; the mean age at the time of death was 5 years. Bone marrow transplantation has been performed in three cases; two patients died in the immediate posttransplantation period of infectious complications, but one patient is cured after a follow-up of 5 years. We conclude that partial albinism with immunodeficiency (Griscelli syndrome) can be differentiated from Chédiak-Higashi syndrome by pathognomonic histologic features. One of the underlying immunologic defects may be a defective function of natural killer cells, predisposing the patient to virus-associated hemophagocytic syndrome or accelerated phases. The prognosis is very poor unless early bone marrow transplantation is carried out.
Asunto(s)
Albinismo/complicaciones , Síndromes de Inmunodeficiencia/complicaciones , Corticoesteroides/uso terapéutico , Albinismo/diagnóstico , Albinismo/genética , Albinismo/inmunología , Albinismo/terapia , Trasplante de Médula Ósea , Enfermedades del Sistema Nervioso Central/etiología , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Hipersensibilidad Tardía/inmunología , Inmunidad Celular , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/terapia , Terapia de Inmunosupresión , Lactante , Infecciones/etiología , Células Asesinas Naturales/inmunología , Masculino , Fenotipo , Recurrencia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
O presente trabalho mostra um caso de paciente com Albinismo óculo-cutâneo, tirosinase +, portador de Hanseníase na forma V., submetido à MDT. O paciente foi medicado por um período de 2 anos, mas näo se notou qualquer pigmentaçäo de pele e mucosas pela Clofazimina um dos componentes da multidrogaterapia (MDT). Já que o Albinismo é uma doença congênita, devido à deficiência na produçäo de Melanina, estaria o metabolismo da Clofazimina relacionado ao da Melaniana, explicando a falta de pigmentaçäo neste paciente?
Asunto(s)
Humanos , Masculino , Adulto , Albinismo/terapia , Clofazimina/administración & dosificación , Lepra , Brasil , Industria Química , Clofazimina/efectos adversos , IctiosisRESUMEN
Five patients with Hermansky-Pudlak syndrome: storage pool deficiency, albinism and ceroid containing bone marrow macrophages and three patients with uncomplicated storage pool deficiency were treated with cryoprecipitate from 16 donors. Within 2 h of transfusion, bleeding times decreased towards a third of initial values. This effect lasted for at least 4 h but had disappeared after 24 h. Six of these eight patients were also treated with an equal volume of human albumin solution. Infusion of albumin had no effect on the bleeding times. The abnormal platelet function tests and biochemical abnormalities (decreased values of platelet total adenosine diphosphate (ADP), adenosine triphosphate (ATP(I) and serotonin) remained unchanged. On four occasions infusion of cryoprecipitate twice daily protected patients with Hermansky-Pudlak syndrome and storage pool deficiency from bleeding during surgery. The mechanism of action of cryoprecipitate in this clinical situation is obscure.