RESUMO
Methylmalonic aciduria is an inborn error of metabolism characterized by neonatal or infantile ketoacidosis. Leukocytes isolated from the peripheral blood of a 1-year-old child with this disorder converted negligible quantities of propionate-3-C(14) to carbon dioxide, but oxidized succinate-1,4-C(14) normally, an indication of a block in the conversion of propionate to succinate. Parenteral administration of vitamin B(18) resulted in a reduction in methylmalonic acid excretion and an increase in propionate oxidation by leukocytes in vitro. The results suggest a mutation of methylmalonyl-CoA isomerase, a vitamin B(12), dependent enzyme which converts methylmalonyl-CoA to succinyl-CoA, and provide the first demonstration of vitamin B(12) "dependency" in man.
Assuntos
Acidose/sangue , Leucócitos/metabolismo , Malonatos/urina , Erros Inatos do Metabolismo/sangue , Propionatos/metabolismo , Succinatos/metabolismo , Vitamina B 12/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/urina , Dióxido de Carbono/metabolismo , Isótopos de Carbono , Coenzima A , Humanos , Hidroliases , Lactente , Isomerases/metabolismo , Biologia Molecular , Mutação , Fosfato de Piridoxal/metabolismo , Xanturenatos/urinaRESUMO
Cultured fibroblasts from a young girl with ketotic hyperglycinemia were unable to oxidize propionate-(14)C to (14)CO(2), but oxidized methylmalonate-(14)C and succinate-(14)C normally. This block in propionate catabolism was shown to result from a lack of propionyl-CoA carboxylase activity. The carboxylase deficiency was not due to the presence of an intracellular inhibitor and it was not corrected by biotin, a known cofactor for the enzyme. Both of her parents' fibroblasts had approximately 50% of normal propionyl-CoA carboxylase activity. These results demonstrate that ketotic hyperglycinemia and propionicacidemia are the same disease, caused by a mutation of the propionyl-CoA carboxylase apoenzyme, which is inherited as an autosomal recessive trait. This enzymatic localization provides an explanation for the remarkable clinical and chemical similarity between ketotic hyperglycinemia and methylmalonicaciduria and offers a potential means of antenatal detection of this disorder.
Assuntos
Acidose , Erros Inatos do Metabolismo dos Aminoácidos , Isótopos de Carbono , Criança , Cromatografia , Aconselhamento , HumanosRESUMO
After a decade of intensive clinical and molecular genetic efforts the von Hippel-Lindau (VHL) gene was cloned in 1993. The open reading frame encodes the putative protein of 284 amino acids. A large number of different mutations have been identified so far, including single base mutations, deletions, rearrangements and more complex mutations. So far, in about 75% of the VHL families germline mutations were detected. Geno-phenotypic comparison has revealed specific mutations with distinct manifestation patterns. Not all of the 6 classical lesions (hemangioblastoma of the CNS, retinal angiomatosis, pancreatic cysts, renal cysts and carcinoma, pheochromocytoma and epididymal cystadenoma) are present in VHL families. Pedigrees with pheochromocytoma but without renal cancer in general have point mutations. These recent results provide insight in the pathogenesis of a multiorgan cancer susceptibility tumor suppressor gene and allow determination of carrier status.
Assuntos
Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/patologia , Encéfalo/patologia , Humanos , Doença de von Hippel-Lindau/terapiaRESUMO
We present a 6-generation kindred of over 221 members, 43 of whom were affected with von Hippel-Lindau (vHL) disease. Through a simple screening protocol, we diagnosed vHL retrospectively in 15 cases, and for the first time in 28, 11 of whom were presymptomatic. We found many complications of vHL in previously diagnosed relatives and in new cases. This study has demonstrated the utility and benefit of preventive surveillance in those known to have vHL, and of presymptomatic screening for affected relatives in families with vHL. The features of vHL were reviewed in our 43 cases and 511 cases from the medical literature. The patterns, frequencies, and ages of onset for each lesion were compared. Renal malignancies caused almost as much mortality in vHL as CNS malignancies. This family was exceptional for absence of pheochromocytoma and erythrocythemia, for more renal and pancreatic cysts and malignancies, and for slightly fewer eye or CNS lesions. Bilateral renal adenocarcinomata were found presymptomatically in five young subjects, who had bilateral nephrectomy and hemodialysis. Three survived long-term after renal transplants. Five relatives had pancreatic malignancies, which are definite although uncommon manifestations of vHL. Recommendations are made for family screening, which was economical and effective. Bayesian calculations help to predict risks for genetic counseling. The molecular basis of vHL may soon be found, since it has been linked to DNA markers on the short arm of chromosome 3.
Assuntos
Angiomatose/genética , Doença de von Hippel-Lindau/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Doença de von Hippel-Lindau/patologiaRESUMO
Multiple carboxylase deficiency is characterized by deficient activities of three biotin-dependent enzymes, propionyl coenzyme A carboxylase, pyruvate carboxylase, and beta-methylcrotonyl coenzyme A carboxylase. A newborn infant was seen with metabolic ketoacidosis, hyperammonemia, organic aciduria, seizures, and coma. Multiple carboxylase deficiency was subsequently confirmed by enzyme activity determinations in his peripheral blood leukocytes and cultured skin fibroblasts. The infant's neurologic and metabolic status improved markedly within a few days of administration of pharmacologic doses of oral biotin. His EEG, which was distinctly abnormal, became normal; his extensive computed tomography scan changes resolved, with the exception of ventricular dilation, over the next two months. After two weeks of biotin treatment the excretion of abnormal organic acid metabolites was reduced and his carboxylase activities increased to the normal range. However, the activities of these enzymes increased only to 30% to 55% of normal in fibroblasts incubated in supplemental biotin. This partial correction of enzyme activity differs from that observed in other individuals with multiple carboxylase deficiency and suggests biochemical heterogeneity in this disorder. Prompt diagnosis and intervention can avert some of the pathologic complications of this biotin-responsive condition.
Assuntos
Biotina/uso terapêutico , Carbono-Carbono Ligases , Carboxiliases/deficiência , Ligases/deficiência , Doença da Deficiência de Piruvato Carboxilase , Eletroencefalografia , Humanos , Recém-Nascido , Masculino , Metilmalonil-CoA Descarboxilase , Propionatos/deficiência , Tomografia Computadorizada por Raios XRESUMO
We report on the prenatal diagnosis of a baby with a de novo centromeric fission of chromosome 21. Both fission products were mitotically stable. Follow-up chromosome analysis after birth confirmed the centromere fission. This chromosome fission appears to be without clinical significance for this patient.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 21 , Centrômero , Feminino , Humanos , Recém-Nascido , Cariotipagem , Gravidez , Diagnóstico Pré-NatalRESUMO
Recurrence risks for primary congenital heart lesions are well defined. An infant with hypoplastic left heart syndrome is observed to have a short neck with a full skin fold on the right side, unilateral single palmar crease, and whorls on all ten fingers. She was found to have the Ullrich-Turner syndrome with mosaicism 45,X/46,XX/47,XXX. We believe the cardiac malformation was secondary to her aneuploidy. This could have important implications for prediction of recurrence risks to the parents. Chromosomal tests may be indicated for infants were severe congenital cardiac lesions, based on subtle clinical findings.
Assuntos
Cardiopatias Congênitas/genética , Mosaicismo , Trissomia , Síndrome de Turner/genética , Cromossomo X , Feminino , Cardiopatias Congênitas/patologia , Humanos , Recém-NascidoRESUMO
To further characterize the clinical, radiographic and chondro-osseous morphologic changes in the Desbuquois syndrome, 7 patients from three sibships are described. They all had prenatal onset severe rhizomelic and mesomelic shortness with marked joint laxity and marked micrognathia. Radiographic changes were distinct, consisting of a supernumerary ossification center between the proximal phalanx of the index finger and the second metacarpal, and variable thumb changes. The femoral necks showed enlargement of the lesser trochanter with metaphyseal breaking, producing a characteristic "monkey wrench" (Swedish key) appearance. Growth plate cartilage showed dilated cisterns of rough endoplasmic reticulum in reserve zone chondrocytes. Three of the 7 cases were diagnosed prenatally by second trimester ultrasound and one case by fetoscopy. This syndrome exhibits significant phenotypic variability and must be differentiated from the Catel-Manzke syndrome which exhibits similar radiographic changes in the hands.
Assuntos
Osso e Ossos/anormalidades , Nanismo/patologia , Instabilidade Articular/patologia , Adolescente , Pré-Escolar , Nanismo/diagnóstico por imagem , Feminino , Lâmina de Crescimento/patologia , Humanos , Corpos de Inclusão/patologia , Lactente , Instabilidade Articular/diagnóstico por imagem , Masculino , Radiografia , SíndromeRESUMO
Brachmann-de Lange syndrome is a congenital disorder of uncertain cause characterized by severe mental retardation, small stature, microbrachycephaly, hirsutism, limb deformities, and characteristic facies. Although more than 300 neonatal cases have been reported, a lack of specific fetal markers has precluded successful antepartum diagnosis. We describe a case of Brachmann-de Lange syndrome identified at 15 weeks' gestation by a low maternal serum alpha-fetoprotein (MSAFP) value. Sonography revealed a fetus with a posterior nuchal cystic hygroma and early-onset symmetrical intrauterine growth retardation (IUGR). The fetal karyotype was 46,XX, but the infant fulfilled the phenotypic criteria of the Brachmann-de Lange syndrome at delivery. The triad of an abnormally low MSAFP value, early-onset symmetrical IUGR, and characteristic ultrasound findings during the second trimester of pregnancy may define adequate criteria for prenatal diagnosis of Brachmann-de Lange syndrome.
Assuntos
Síndrome de Cornélia de Lange/diagnóstico por imagem , Doenças Fetais/diagnóstico por imagem , Ultrassonografia Pré-Natal , alfa-Fetoproteínas/análise , Adulto , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Humanos , Recém-Nascido , Fenótipo , GravidezRESUMO
A female infant presented with absent vagina and uterus, absent left kidney, absent right gonad, growth failure, mental retardation, seizure disorder, and facial, limb, and hand anomalies. The chromosome karyotype was 46, XY in her blood and cultured cells, including cells from the sites of both gonads. Her H-Y antigen was positive. Specific dihydrotestosterone binding was reduced in cells from a labial skin biopsy. The case might be due to a minute deletion of the short arm of the X chromosome, resulting in loss of a gene for androgen receptors and of adjacent chromosomal material responsible for the growth failure and the somatic and neurologic anomalies.
Assuntos
Anormalidades Múltiplas , Síndrome de Resistência a Andrógenos/complicações , Anormalidades Múltiplas/genética , Adulto , Síndrome de Resistência a Andrógenos/genética , Feminino , Transtornos do Crescimento/complicações , Transtornos do Crescimento/genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Masculino , Gravidez , Convulsões/complicações , Convulsões/genéticaRESUMO
Polycystic kidney disease and the renal manifestations of von Hippel-Lindau disease have much in common. Making the distinction between these two diseases is important. There is a strong association of renal cell carcinoma with von Hippel-Lindau disease, whereas renal cell carcinoma is rare in polycystic kidney disease. Furthermore, the many extrarenal manifestations of von Hippel-Lindau disease are serious and can be fatal while those of polycystic kidney disease are generally benign. Early diagnosis of the lesions of von Hippel-Lindau disease could lead to effective surgical treatment and prevent death. A case of von Hippel-Lindau disease is presented which was incorrectly diagnosed as polycystic kidney disease for sixteen years. The case is instructive in that the possibility of making the correct diagnosis prior to the patient's terminal illness was only through careful assessment of the family. The case is also remarkable in that the patient suffered from progressive renal failure requiring hemodialysis, which has not been associated previously with von Hippel-Lindau disease.
Assuntos
Angiomatose/diagnóstico , Erros de Diagnóstico , Doenças Renais Policísticas/diagnóstico , Doença de von Hippel-Lindau/diagnóstico , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Doença de von Hippel-Lindau/genéticaRESUMO
A comparison of gray scale ultrasonography and computerized axial tomography in adults with known adult-type polycystic disease and of ultrasonography and high-dose nephrotomography in their progeny is being conducted. Although all three modalities have proved capable of demonstrating cysts of the kidney and liver, ultrasound has been the most consistent in identifying these lesions. Ultrasound is valuable in diagnosing polycystic disease in adult with large, poorly functioning kidneys; in addition, since cysts could be identified by ultrasound in children who had normal nephrotograms, it provides a safe and useful method of obtaining information for genetic counseling.
Assuntos
Hepatopatias/diagnóstico , Doenças Renais Policísticas/diagnóstico , Tomografia Computadorizada por Raios X , Ultrassonografia , Connecticut , Cistos/diagnóstico , Cistos/diagnóstico por imagem , Humanos , Rim/diagnóstico por imagem , Fígado/diagnóstico por imagem , Hepatopatias/diagnóstico por imagem , Doenças Renais Policísticas/diagnóstico por imagem , Estudos ProspectivosRESUMO
We studied the abnormal ocular and systemic findings in one case of true triploidy and two cases of triploid mosaicism. A liveborn triploid child 69,XXY, had abnormalities including cebocephaly, a single midline nostril, incomplete cleft palate, transverse palmar creases, partial syndactyly, and ambiguous genitalia. Ocular abnormalities included hypotelorism, blepharophimosis, microcornia, iris coloboma, cataract, persistent hyaloid vasculature, retinal dysplasia, and optic atrophy. A 16-year-old girl with triploid mosaicism had congenital left facial and body hemiatrophy, both growth and mental retardation, left-sided grand mal seizures, incontinentia pigmenti of both legs, partial syndactyly, and generalized weakness. Results of her ocular examination were within normal limits. A 13-year-old boy with triploid mosaicism exhibited both growth and mental retardation, truncal obesity, and required a brace to support his back. Ocular findings included synophrys, bilateral blepharoptosis, and abnormal results of Schirmer tear test. Studies indicate a wide spectrum of ocular and systemic abnormalities occur that are presumably associated with the chromosome error.
Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos , Anormalidades do Olho , Poliploidia , Anormalidades Múltiplas , Adolescente , Catarata/congênito , Coloboma , Córnea/anormalidades , Pálpebras/anormalidades , Face/anormalidades , Feminino , Humanos , Recém-Nascido , Deficiência Intelectual , Iris/anormalidades , Masculino , Atrofia Óptica/congênito , Retina/anormalidadesRESUMO
Amino acid contents were measured in four regions of autopsied brain from an infant who presented in coma at the age of 7 weeks and died with argininosuccinic aciduria. Argininosuccinic acid lyase activity was greatly reduced in liver, kidney and cultured skin fibroblasts; incorporation of [14C]citrulline into protein by fibroblasts was minimal. Argininosuccinic acid lyase activity in brain was only slightly lower than that in control infant brain. Nevertheless, the brain showed extensive microscopic changes and a marked accumulation of argininosuccinic acid, varying between regions from 1.8 to 4.4 mmol/l. Brain contents of glutamine, glutamic acid, and alpha-amino-n-butyric acid were also greatly elevated, with a lesser elevation of citrulline, and a normal arginine content. These studies suggest genetic heterogeneity of tissue enzymes in argininosuccinic aciduria and offer some clues about pathogenesis of the neurological damage often seen in this disorder.
Assuntos
Arginina/análogos & derivados , Argininossuccinato Liase/metabolismo , Ácido Argininossuccínico/urina , Liases/metabolismo , Aminoacidúrias Renais/metabolismo , Aminoácidos/metabolismo , Encéfalo/enzimologia , Encéfalo/metabolismo , Células Cultivadas , Humanos , Lactente , Rim/enzimologia , Fígado/enzimologia , Masculino , Pele/enzimologiaRESUMO
In the process of genetic counseling, many patients and their families need psychosocial evaluation and care to help them cope with the genetic information and its implications. Such psychosocial work may be routine or extended. For two years we assessed the actual psychosocial evaluation and care provided by us in a medical genetics clinic, using six categories to classify the nature of a patient's need for extended psychosocial work. Of 138 new patients, 82 (59%) required extended psychosocial evaluation and care. In particular, young patients, seen with many family members, and requiring multiple medical consultations, were found to need the most extensive psychosocial care. Ongoing clinic patients (N = 35) referred for psychosocial care were used as a comparison group. We concluded that a significant number of patients and their families receiving genetic counseling also require extended psychosocial evaluation and care, and that these patients may be identifiable early in the counseling procedure.
Assuntos
Aconselhamento Genético , Doenças Genéticas Inatas/psicologia , Adaptação Psicológica , Adolescente , Adulto , Feminino , Humanos , Masculino , Gravidez , Diagnóstico Pré-Natal , Psiquiatria , Psicoterapia , Encaminhamento e Consulta , Ajustamento SocialRESUMO
Both pigmentation and otic defects of Waardenburg Syndrome and Hirschsprung's disease have a common origin in neural crest cells and were described in 1951 and 1887, respectively. The clinical manifestations of both in the same patient were described in 1981 in 12 infants so afflicted. The authors present such a case of long segment aganglionosis in a 15-day-old Marshallese girl with Waardenburg-Shah syndrome and discuss diagnosis, treatment, and prognosis.
Assuntos
Doença de Hirschsprung/complicações , Síndrome de Waardenburg/complicações , Evolução Fatal , Feminino , Humanos , Recém-NascidoRESUMO
The differential diagnosis of microcytic anemias in Hawaii presents special problems because of the hereditary anemias prevalent in its large Asian subpopulations. Both the alpha- and beta-thalassemias are important because of morbidity and mortality. Heterozygous carriers for either type mimic iron deficiency, which may lead to inappropriate work-up or treatment. The thalassemias and hemoglobin (Hb) variants are all benign in heterozygotes, but if a couple are both heterozygous for the same or for incompatible variants, their children have 25% risk of inheriting a serious anemia. These can be prevented by detecting the heterozygotes, and by offering genetic counseling and fetal testing to couples at risk of having severely affected children. Early detection is also possible by the screening of newborns. Fetal diagnosis, or early detection and treatment, can greatly reduce the consequences of these anemias. Screening and prevention will cost far less than the cost of care for affected patients.