RESUMO
Lesch-Nyhan disease is a genetic disorder of purine metabolism caused by defective activity of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT), resulting from mutation in the corresponding gene on the long arm of the X chromosome (Xq26). The classical phenotype, which includes spasticity, involuntary movements, developmental disability, and self-injurious behavior, occurs exclusively in males, while heterozygous, carrier females are clinically normal. We analyzed an Argentine family in which there were male and female siblings with clinically identical classic features of Lesch-Nyhan disease. The mother and an older daughter were carriers and had normal phenotypes. We identified the HPRT mutation in the family. It is a C --> T transition at position 508 of the cDNA (c.508 C --> T) that changes the CGA codon for Arg(169) to the TGA stop codon (R169X). The female patient was karyotypically normal and heterozygous for the mutation. She inherited the HPRT mutation from her mother, but she also had unexpected nonrandom inactivation of the paternal X chromosome carrying the normal HPRT gene. This additional genetic alteration is the cause of the clinical expression of disease in this female patient.
Assuntos
Hipoxantina Fosforribosiltransferase/genética , Síndrome de Lesch-Nyhan/genética , RNA não Traduzido , Adulto , Argentina , Células Cultivadas , Criança , Pré-Escolar , DNA/genética , Análise Mutacional de DNA , DNA Complementar/química , DNA Complementar/genética , Mecanismo Genético de Compensação de Dose , Saúde da Família , Evolução Fatal , Feminino , Humanos , Hipoxantina Fosforribosiltransferase/deficiência , Síndrome de Lesch-Nyhan/enzimologia , Síndrome de Lesch-Nyhan/patologia , Masculino , Mutação , Linhagem , Fenótipo , Mutação Puntual , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas , RNA Longo não Codificante , Fatores de Transcrição/genética , Cromossomo X/genéticaRESUMO
The association of ectrodactyly and absence of long bones of the upper or lower extremities has been recognized previously in nine families. We report 24 additional individuals in four families who are similarly affected. Two of these families manifest the unusual feature of unilateral preaxial polydactyly of a lower extremity. Data from these four families plus the nine previously reported suggest that ectrodactyly associated with absence of long bones of the upper or lower limbs is a genetically determined disorder, inherited as an autosomal dominant trait with widely variable expression or nonpenetrance.
Assuntos
Braço/anormalidades , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Perna (Membro)/anormalidades , Adulto , Aberrações Cromossômicas/genética , Transtornos Cromossômicos , Feminino , Genes Dominantes , Humanos , Recém-Nascido , Masculino , LinhagemRESUMO
The molecular nature of the glycine cleavage system was investigated in eight patients with typical (neonatal) and two patients with atypical (late onset) nonketotic hyperglycinemia (NKH). The overall activity of the glycine cleavage system was found to be decreased in all of the liver and brain tissue studied, but it was undetectable or extremely low in typical NKH, whereas there was some residual activity in atypical NKH. Six patients with typical NKH had a specific defect in the P protein, and one a defect in the T protein; the activity of the T protein was defective in one patient with atypical NKH.
Assuntos
Aminoácido Oxirredutases/metabolismo , Proteínas de Transporte/metabolismo , Glicina/sangue , Hidroximetil e Formil Transferases , Erros Inatos do Metabolismo/sangue , Complexos Multienzimáticos/metabolismo , Transferases/metabolismo , Aminometiltransferase , Encéfalo/enzimologia , Glicina/líquido cefalorraquidiano , Humanos , Lactente , Recém-Nascido , Fígado/enzimologia , Erros Inatos do Metabolismo/líquido cefalorraquidiano , Fenótipo , Transtornos Psicomotores/sangueRESUMO
A severe form of vitamin D-resistant rickets is associated with the linear sebaceous nevus syndrome. We investigated the pathophysiology underlying defective bone mineralization in two individuals and examined the effects of 1,25-dihydroxyvitamin D (1,25(OH)2D, calcitriol) therapy on the clinical and biochemical abnormalities. Both patients had fasting hypophosphatemia, markedly diminished TmP/GFR, and elevated alkaline phosphase activity in the presence of normocalcemia. Before treatment with calcitriol, serum 1,25(OH)2D concentrations were reduced but serum 25-hydroxyvitamin D (25(OH)D) concentrations were normal. Administration of calcitriol increased serum 1,25(OH)2D concentrations and led to an increase in TmP/GFR and serum phosphorus levels and to a decrease in alkaline phosphatase activity. However, the renal tubular maximum for reabsorption of inorganic phosphate, normalized according to glomerular filtration rate, and serum phosphorus levels remained abnormally low even in the patient who also received phosphate supplementation. Bone histomorphologic studies in the adult patient showed extreme osteomalacia, which partially improved with calcitriol. These data demonstrate that the putative skin lesion-derived factor results in both a renal tubular defect in phosphate reabsorption and in 1,25-(OH)2 D deficiency. The vitamin D-resistant rickets of linear sebaceous nevus syndrome is a variant of tumor-induced osteomalacia.
Assuntos
Hipofosfatemia Familiar/complicações , Nevo Pigmentado/complicações , Osteomalacia/complicações , Fosfatos/sangue , Neoplasias das Glândulas Sudoríparas/complicações , Adulto , Fosfatase Alcalina/sangue , Calcitriol/sangue , Calcitriol/uso terapêutico , Cálcio/sangue , Criança , Feminino , Humanos , Hidroxicolecalciferóis/sangue , Hipofosfatemia Familiar/tratamento farmacológico , Masculino , Osteomalacia/tratamento farmacológico , Fósforo/metabolismo , Fósforo/uso terapêutico , SíndromeAssuntos
Erros Inatos do Metabolismo dos Aminoácidos , Propionatos/sangue , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Biotina/uso terapêutico , Carboxiliases/metabolismo , Diagnóstico Diferencial , Feminino , Triagem de Portadores Genéticos , Humanos , Recém-Nascido , Metilmalonil-CoA Descarboxilase , Gravidez , Diagnóstico Pré-Natal , Prognóstico , Propionatos/metabolismo , Desequilíbrio Hidroeletrolítico/etiologia , Desequilíbrio Hidroeletrolítico/terapiaAssuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Doenças do Sistema Nervoso Central/etiologia , Glicina/metabolismo , Doenças do Sistema Nervoso Central/patologia , Córtex Cerebral/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Degeneração Neural , Serina/sangue , Valina/sangueRESUMO
Two infants have been studied with glutaric aciduria Type II. The clinical presentation was of an overwhelming illness very early in life; both infants died in the neonatal period. One had dysmorphic features. An acrid odor may be a clue to the diagnosis. Neonatal acidosis, hypoglycemia, and hyperammonemia are characteristic. Organic acid analysis revealed massive lactic aciduria and glutaric aciduria. A variety of other dicarboxylic acids and hydroxy acids and amino acids were found in elevated amounts in body fluids, along with elevated concentrations of butyric, isobutyric, 2-methylbutyric, and isovaleric acids. The pattern of metabolites accumulated is consistent with deficient activity of a number of acyl-CoA dehydrogenases.
Assuntos
Glutaratos/urina , Erros Inatos do Metabolismo/urina , Aminoácidos/sangue , Ácidos Dicarboxílicos/sangue , Ácidos Dicarboxílicos/urina , Genes Recessivos , Humanos , Hidroxiácidos/sangue , Hidroxiácidos/urina , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/genética , Aminoacidúrias Renais/diagnósticoRESUMO
A variant form of hypoxanthine-guanine phosphoribosyl transferase has been found in a neurologically normal pediatric patient who presented with hematuria an episodes of oliguria and azotemia. The level of erythrocyte enzyme activity was 3% of normal. Electrophoretic mobility was more rapid than normal. The Km for hypoxanthine was approximately ten times normal. Immunochemical analysis indicated that the variant enzyme cross reacted with antibody to normal HPRT. A system is described for the systematic characterization of a variant HPRT.
Assuntos
Hipoxantina Fosforribosiltransferase/deficiência , Ácido Úrico/sangue , Anticorpos/análise , Pré-Escolar , Eritrócitos/enzimologia , Feminino , Hematúria/enzimologia , Hematúria/etiologia , Humanos , Hipoxantina Fosforribosiltransferase/sangue , Hipoxantina Fosforribosiltransferase/imunologia , Oligúria/enzimologia , Oligúria/etiologia , Gravidez , Uremia/enzimologia , Uremia/etiologiaRESUMO
A patient has been studied in whom an atypical ichthyosiform erythroderma was associated with congenital neurosensory deafness, vascularization of the corneas progressing to blindness, alopecia totalis, abnormalities of the teeth and nails, and postnatal growth deficiency. Twelve other patients with a similar pattern of malformation have been reported previously. This syndrome appears to represent a distinct disorder with a pattern of inheritance which is most likely autosomal recessive.
Assuntos
Surdez/congênito , Ictiose/complicações , Dermatopatias Vesiculobolhosas/complicações , Adolescente , Alopecia/complicações , Biópsia , Córnea/irrigação sanguínea , Surdez/complicações , Transtornos do Crescimento/complicações , Humanos , Masculino , Unhas , Pele/patologia , Dermatopatias/complicações , Síndrome , Anormalidades Dentárias/complicaçõesRESUMO
A premature infant presented with elevated concentrations of tyrosine in blood and urine, evidence of hepatocellular damage, demineralization of the bones, and a renal Fanconi syndrome. This is the clinical picture found in hereditary tyrosinemia. The infant also had a perinatal infection with cytomegalovirus.
Assuntos
Infecções por Citomegalovirus/complicações , Doenças do Recém-Nascido/complicações , Tirosina/sangue , Diagnóstico Diferencial , Humanos , Recém-Nascido , Lactatos/urina , Fígado/metabolismo , Masculino , Metionina/sangue , Fenóis/urina , Tirosina/metabolismoRESUMO
A patient with neonatal onset citrullinemia survived to 8 months of age when treated with a mixture of essential amino acids and their keto-analogues. The initial plasma citrulline concentration was 2.7 mM; the blood ammonia concentration was greater than 500 muM. During the first week of therapy, the blood ammonia concentration became normal and that of plasma citrulline was reduced by almost 50%. It was possible to institute progressive increases in dietary calories and protein; growth and developmetn with resolution of almost all clinical signs of disease ensued. The patient died at 8 months of age after an episode of diarrhea and dehydration, probably of viral origin.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Aminoácidos Essenciais/uso terapêutico , Citrulina/sangue , Arginina/uso terapêutico , Argininossuccinato Sintase/deficiência , Fibroblastos/enzimologia , Histidina/uso terapêutico , Humanos , Lactente , Recém-Nascido , Isoleucina/uso terapêutico , Leucina/uso terapêutico , Lisina/uso terapêutico , Masculino , Metionina/uso terapêutico , Fenilalanina/uso terapêutico , Treonina/uso terapêutico , Triptofano/uso terapêutico , Valina/uso terapêuticoRESUMO
Propionyl CoA carboxylase deficiency was found in a 7-month-old boy who presented with attacks of vomiting, anorexia, weight loss, weakness, and hypotonia. He failed to thrive and had generalized seizures. He had propionic acidemia and hyperglycinemia; these are the manifestations of the ketotic hyperglycinemia syndrome. However, ketonuria was not a consistent part of his clinical picture, and he had at least two episodes of acute overwhelming illness, the latter one fatal, in which ketones were never found in the urine. Large amounts of pyrrolidone carboxylic acid were found in body fluids.