RESUMO
Studies have been carried out on activities of lysosomal beta-N-acetylhexosaminidase (hex), beta-galactosidase (beta-gal), alpha-glucosidase (alpha-glu), and acid phosphatase (AP) in serum and urine from patients with juvenile diabetes and matched controls. There is a large increase in blood and urinary hex activity (the former presenting three distinct patterns of abnormality), a moderate increase in urinary beta-gal, and a small increase in urinary alpha-glu activity, but no elevation of blood or urinary AP in the diabetics. Urinary alpha-glu activity in the diabetics shows striking inhibition by glucose, and this may reflect a similar phenomenon in vivo. Although glycohydrolase activities are elevated in patients with no detectable microangiopathy, more striking changes may be observed in patients with severe small-vessel disease. These alterations may be associated with increased glycoprotein catabolism in the diabetic, an area in need of further studies in the human and experimental diabetic animal.
Assuntos
Fosfatase Ácida/metabolismo , Diabetes Mellitus Tipo 1/enzimologia , Glicosídeo Hidrolases/metabolismo , Lisossomos/enzimologia , Adolescente , Adulto , Estabilidade de Medicamentos , Feminino , Galactosidases/urina , Glucose/farmacologia , Glucosidases/urina , Hexosaminidases/metabolismo , Humanos , Masculino , Fatores SexuaisRESUMO
A 7-year-old Ashkenazi Jewish boy with normal early development started to regress at 8 months of age and made no further developmental progress. Corneal clouding was noted at age 10 months. Corneal and conjunctival biopsy at 14 months, cerebral biopsy at 24 months, and fibroblast cultures at 32 months showed lysosomal inclusions, suggesting the storage of lipid-like and mucopolysaccharide-like material. In the brain, dense fluorescent inclusions resembled those in ceroid-lipofuscinosis. Total ganglioside content of white matter was raised, but the pattern was normal. The level of nonlipid hexosamine in the brain was normal. The cornea and conjunctiva contained electronlucent vacuoles resembling those in the mucopolysaccharidoses. Cornea, brain, and lymphocytes contained concentric membranous lamellar structures reminiscent of those in the gangliosidoses. The clinical picture and ultrastructural findings support the impression that this case belongs to a new variant of the mucolipidoses, mucolipidosis IV.
Assuntos
Mucolipidoses , Córtex Cerebral/ultraestrutura , Criança , Túnica Conjuntiva/ultraestrutura , Córnea/ultraestrutura , Fibroblastos/ultraestrutura , Humanos , Corpos de Inclusão/ultraestrutura , Masculino , Mucolipidoses/metabolismo , Mucolipidoses/patologia , Neurônios/ultraestrutura , Oligodendroglia/ultraestruturaRESUMO
A patient with ring chromosome 6 had most of the manifestations previously reported in this syndrome and also had albinoid fundi and unilateral aniridia, findings not previously described. In most peripheral leukocyte metaphases analyzed, one chromosome 6 was replaced by a monocentric ring chromosome with deletion of the 6p and 6q. Fifteen other patients with a ring chromosome 6 have been reported. The most frequent findings were mental retardation, prenatal and postnatal failure, epicanthal folds, flat nasal bridge, short neck, apparently low-set and/or malformed ears, microphthalmia, and micrognathia. Studies of coagulation Factors XII and XIII and of the P blood group for possible assignment on distal 6p and 6q did not provide evidence for localization of the genes for these factors on the pter----p24 part of chromosome 6.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 6 , Fundo de Olho/anormalidades , Iris/anormalidades , Cromossomos em Anel , Fator XII/genética , Fator XIII/genética , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Sistema do Grupo Sanguíneo P/genéticaRESUMO
Although reduced acid beta-glucosidase activity appears to be the primary enzyme defect in type I Gaucher disease, patients with this disorder also have marked elevation of serum acid phosphatase and beta-hexosaminidase activities but with a normal level of lactic dehydrogenase activity. Moreover, there is a characteristic alteration in the hexosaminidase isozyme distribution with a striking increase in hexosaminidase B. Since these changes appear to be consistent and unlike those associated with other disorders or the hormonally induced alterations associated with pregnancy, routine serum testing for the Tay-Sachs carrier state may offer a useful approach for the presumptive diagnosis and screening for Gaucher disease. Unlike the changes in affected homozygotes, there are no characteristic alterations of acid phosphatase or hexosaminidase in heterozygotes for Gaucher disease.
Assuntos
Doença de Gaucher/diagnóstico , Triagem de Portadores Genéticos , Hexosaminidases/sangue , Doença de Tay-Sachs/diagnóstico , Fosfatase Ácida/sangue , Diabetes Mellitus Tipo 1/enzimologia , Feminino , Doença de Gaucher/enzimologia , Humanos , Gravidez , Doença de Tay-Sachs/enzimologia , Doença de Tay-Sachs/genéticaRESUMO
A family study was performed in order to diagnose X-linked lymphoproliferative (XLP) disease in a fetus. The molecular genetic analysis indicated that the fetus, as well as its healthy 7-year-old brother, inherited XLP. Analysis of immunoglobulin subclasses from the 7-year-old brother supported the DNA-based diagnosis. This is the first XLP family of African descent.
Assuntos
Doenças Fetais/diagnóstico , Ligação Genética , Transtornos Linfoproliferativos/diagnóstico , Diagnóstico Pré-Natal , Cromossomo X , Autorradiografia , Feminino , Doenças Fetais/genética , Heterozigoto , Humanos , Transtornos Linfoproliferativos/genética , Masculino , Linhagem , Polimorfismo de Fragmento de RestriçãoRESUMO
We report on a woman with incontinentia pigmenti (IP), who had two successive term pregnancies. The first pregnancy ended in the birth of a male infant, who is alive and well at 2 years. A second liveborn male had early postnatal distress and died after 1 day of life, after a fulminating clinical course. Polymorphic microsatellite markers, closely linked to the IP gene on the X chromosome, showed that each son inherited a different X chromosome from his mother. Although in most instances IP appears to be prenatally lethal for the male, the phenotype is not completely known. We propose that the neonatal phenotype may be characterized by lethal disturbances in the hematopoietic and immunologic systems.
Assuntos
DNA/química , Incontinência Pigmentar/genética , Adulto , Alelos , Mecanismo Genético de Compensação de Dose , Feminino , Ligação Genética , Humanos , Recém-Nascido , Masculino , Análise de Sequência de DNA , Aberrações dos Cromossomos Sexuais/genética , Cromossomo XRESUMO
The polymorphic mutation C677T in the gene of MTHFR is considered a risk mutation for spina bifida and vascular disease. Another common mutation on the MTHFR gene, A1298C, has also been described as another risk mutation. We studied the frequencies of these two mutations on DNA samples from healthy Jewish individuals and compared them to the frequency of these mutations in DNA samples obtained from healthy individuals in South Texas. The presence of the C677T allele was determined by PCR and Hinf I digestion, and mutation A1298C by PCR and Mbo II digestion. A total of 310 alleles was examined for C677T in the Ashkenazi samples and 400 alleles in the non-Jewish samples. The rate of C677T among the Ashkenazi Jewish alleles was 47.7% as compared to 28.7% among the alleles from the non-Jewish population. The difference is statistically significant, P < 0.0005. Mutation A1298C was examined in 298 alleles of Jewish individuals and 374 alleles of non-Jewish counterparts from Texas. The rate of the A1298C mutation in the Jewish samples was 27.2% whereas in the non-Jewish was 35%. This was also statistically significant, P < 0.031. No individuals were homozygous for both mutations or were found to be homozygous for one mutation with heterozygosity of the other mutation, and that the C677T and the A1298C alleles did not occur in cis position. This study shows a unique distribution of C677T and the A1298C alleles among the Ashkenazi Jews. In spite of high frequency of C677T mutation, spina bifida is less common among Ashkenazi Jews. Further studies are needed to establish whether the C677T and the A1298C mutations have an impact on vascular disease in the Ashkenazi Jewish population.
Assuntos
Judeus/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Mutação Puntual , Alelos , Frequência do Gene , Heterozigoto , Homozigoto , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2) , New York , Polimorfismo Genético , Fatores de Risco , Disrafismo Espinal/genética , Texas , Doenças Vasculares/genéticaRESUMO
The correct identification of Tay-Sachs heterozygotes requires a reliable procedure for separation and quantiation of the hexosaminidase isozymes. The most commonly employed method involves thermal inactivation of the heat labile hexosaminidase A assay of residual enzyme activity. This procedure, however, consistently yields a significantly lower absolute and relative activity of hexosaminidase A and a higher activity of the thermostable components (B and I) in comparison with the results obtained by DEAE-cellulose chromatography. DEAE-cellulose chromatographic separation of the hexosaminidase isozymes in serum following thermal inactivation reveals the presence of relative and absolute increase in the activity of the B and I components in addition to loss of the heat-labile A isozyme. Because the conversion of hexosaminidase A into thermostable forms by heating may vary according to the conditions employed, the thermal inactivation procedure may lead to ambiguity in heterozygote identification. This difficulty can be minimized by fractionation of the hexosaminidase isozymes by DEAE-cellulose chromatography followed by assay of the individual components. In addition to the Tay-Sachs carrier state, other conditions can alter the distribution of the hexosaminidase isozymes in tissues and body fluids. For example in serum of patients with juvenile diabetes mellitus there is a characteristic elevation of hexosaminidase B and less consistently, of hexosaminidase A. Since the activity of hexosaminidase A in serum of diabetics fractionated by ion exchange chromatography is at least as high as the activity in serum of healthy non-carriers, patients with diabetes can be easily differentiated from Tay-Sachs heterozygotes. Similarly, the distribution of the hexosaminidase isozymes in serum is altered during pregnancy, where there is usually a significant rise in hexosaminidase A and I (P). However, during pregnancy activities of hexosaminidase A and I in serum of obligate Tay-Sachs carriers are only 50% of the values observed in non-carriers at comparable gestational periods. Since the absolute activities of hexosaminidase A in serum of pregnant carriers obtained by ion exchange chromatography do not overlap with the activities in serum of non-carrier pregnant women at comparable gestational periods, this method has obvious advantages for identification of pregnancies where the fetus may be at risk for Tay-Sachs disease.
Assuntos
Heterozigoto , Hexosaminidases/sangue , Isoenzimas/sangue , Lipidoses/enzimologia , Adolescente , Adulto , Líquido Amniótico/enzimologia , Diabetes Mellitus Tipo 1/enzimologia , Feminino , Hexosaminidases/isolamento & purificação , Homozigoto , Humanos , Lipidoses/diagnóstico , GravidezRESUMO
Studies have been carried out on the activities and properties of the isozymes of alpha-mannosidase, alpha-glucosidase and beta-glucosidase in granulocytes, monocytes, lymphocytes and platelts from peripheral blood of heatlhy adult donors. The findings reveal the differences in activities as well as a characteristic distribution of the different molecular forms of these lysosomal hydrolases in specific cell types. Therefore, the results obtained with unfractionated total leukocyte smples from different subjects may vary according to the distribution of cell types in the circulation. Granulocytes and monocytes show only the acid alpha-mannosidase activity whereas lymphocytes and platelets show both acid and neutral activities. The specific activity of acid alpha-mannosidase in granulocytes and monocytes is higher than in lymphocytes and platelets. By DEAE-cellulose chromatography, the acid alpha-mannosidase in granulocyte and monocyte extracts elutes as two peaks, but only one peak is seen in lymphocytes. All cell types show both acid and neutral alpha-glucosidase activities. The specific activities of both isozymes are higher in granulocytes and monocytes than in lymphocytes and platelets. Monocytes show a higher acid than neutral activity. All other cell types show a higher neutral activity. Beta-Glucosidase in all cell types is mainly membrane-bound and it can be released by Triton X-100 and sodium taurocholate. Taurocholate also stimulates the beta-glucosidase activity of granulocytes, monocytes and lymphocytes whereas it inhibits the activity of this enzyme in platelets. These results indicate that variations in the total number of leukocytes and in the relative proportion of the various cell types in health and disease may yield inconsistent or unreliable values for enzyme activity in the diagnosis of lysosomal storage disease and in carrier detection.
Assuntos
Plaquetas/enzimologia , Hidrolases/metabolismo , Leucócitos/enzimologia , Lisossomos/enzimologia , Adulto , Separação Celular , Cromatografia DEAE-Celulose , Granulócitos/enzimologia , Humanos , Concentração de Íons de Hidrogênio , Isoenzimas/metabolismo , Linfócitos/enzimologia , Manosidases/metabolismo , Monócitos/enzimologia , alfa-Glucosidases/metabolismo , beta-Glucosidase/metabolismoRESUMO
Identification of carriers of the Tay-Sachs gene during pregnancy is difficult because of the increase in serum of a heat stable hexosaminidase isozyme I (or P) as well as changes in the relative and absolute activities of the various molecular forms of the enzyme with advancing pregnancy. In contrast, isolation of blood platelets followed by ion exchange chromatographic separation and assay of the hexosaminidase isozymes in platelet extracts by an automated method provides a sensitive and reliable method for heterozygote identification during pregnancy. This method appears superior to procedures involving thermal inactivation of extracts of peripheral blood leukocytes because of significant differences in the content of the hexosaminidase isozymes in granulocytes, lymphocytes and other cell types, as well as variations in the proportion of these cell types in samples of peripheral blood. It also alleviates the problem inherent in any method involving thermal inactivation of hexosaminidase A by avoiding possible interconversion of the various molecular forms of the enzyme associated with heating.
Assuntos
Plaquetas/enzimologia , Triagem de Portadores Genéticos , Hexosaminidases/sangue , Isoenzimas/sangue , Doença de Tay-Sachs/genética , Adolescente , Adulto , Cromatografia DEAE-Celulose , Ensaios Enzimáticos Clínicos , Feminino , Triagem de Portadores Genéticos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , GravidezRESUMO
This report describes a reliable and reproducible method for the identification of carriers of Type I Gaucher disease using blood platelets as the source of beta-glucosidase and 4-methylumbelliferyl-beta-D-glucoside as substrate. Platelet lysates have at least two identifiable beta-glucosidase activities with the synthetic substrate. One is maximally active at pH 5.0 in the absence of sodium taurocholate and the other at pH 5.6 in the presence of taurocholate. In platelets of Gaucher homozygotes and heterozygotes, the beta-glucosidase activity at pH 5.6 with the bile salt is reduced whereas the activity at pH 5.0 is the same in non-carriers, carriers and affected patients. In addition to differences in specific activity, the ratio of beta-hexosaminidase to beta-glucosidase activities is a useful parameter in the evaluation of the carrier state. Since carriers have normal activity of hexosaminidase and a reduced activity of beta-glucosidase, their mean activity ratio is about 70% higher than in non-carriers. Therefore we propose that the specific activity of beta-glucosidase at pH 5.6 in the presence of sodium taurocholate with the ratio of beta-hexosaminidase to beta-glucosidase serve as useful and reliable indices in the evaluation of the carrier state for Gaucher disease.
Assuntos
Plaquetas/enzimologia , Doença de Gaucher/genética , Triagem de Portadores Genéticos , Adulto , Doença de Gaucher/enzimologia , Glucosídeos/metabolismo , Hexosaminidases/sangue , Homozigoto , Humanos , Concentração de Íons de Hidrogênio , Himecromona/análogos & derivados , Himecromona/metabolismo , Cinética , Leucócitos/enzimologia , Ácido Taurocólico/metabolismo , beta-Glucosidase/sangueAssuntos
17-alfa-Hidroxipregnenolona/análise , Hiperplasia Suprarrenal Congênita/metabolismo , Líquido Amniótico/análise , Androstenodiona/análise , Anencefalia/metabolismo , Desidroepiandrosterona/análise , Hidroxiprogesteronas/análise , Esteroide Hidroxilases/deficiência , Testosterona/análise , Feminino , Feto/metabolismo , Idade Gestacional , Humanos , Masculino , GravidezAssuntos
Técnicas de Cultura , Doenças Genéticas Inatas/patologia , Erros Inatos do Metabolismo dos Carboidratos/patologia , Esclerose Cerebral Difusa de Schilder/patologia , Gangliosídeos/metabolismo , Doença de Gaucher/patologia , Doenças Genéticas Inatas/diagnóstico , Genética Médica , Glicosaminoglicanos/metabolismo , Humanos , Lipidoses/patologia , Doenças de Niemann-Pick/patologia , Doença de Refsum/patologiaAssuntos
Hiperplasia Suprarrenal Congênita/diagnóstico , Líquido Amniótico/imunologia , Esteroide 21-Hidroxilase , Esteroide Hidroxilases , Células Cultivadas , Citotoxicidade Imunológica , Feminino , Imunofluorescência , Antígenos HLA/genética , Teste de Histocompatibilidade , Humanos , Masculino , GravidezRESUMO
An adult female with typical features of Silver-Russell dwarfism gave birth to a viable infant. Despite the abnormalities in sexual development that may be associated with the Silver-Russell syndrome, fertility is not necessarily impaired, at least in females. The growth and development of children with the Silver-Russell syndrome have been studied (Silver, 1964; Tanner et al., 1975). There is, however, virtually no information available about adult patients with this syndrome. It is known that both male and female Silver-Russell dwarfs develop secondary sexual characteristics (Rimoin, 1969; McDowell and Sproles, 1973) but fertility of these patients has not been described previously.
Assuntos
Nanismo/fisiopatologia , Fertilidade , Adulto , Dermatoglifia , Nanismo/complicações , Nanismo/genética , Feminino , Gonadotropinas/urina , Humanos , Síndrome , Síndrome de Wolff-Parkinson-White/complicaçõesRESUMO
Five new casses of ectrodactyly are described. Two patients have the syndrome of ectrodactyly, extodermal dysplasia, and clefting (EEC). In one patient with the EEC syndrome, the disorder seems to represent a new mutation. One woman with isolated ectrodactyly has a daughter with the EEC syndrome. The variation in the clinical expression of this disorder among affected members of the same family makes it difficult to determine whether there may be several mutant alleles responsible for ectrodactyly and its related manifestations.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adulto , Alelos , Criança , Pré-Escolar , Fenda Labial/genética , Fissura Palatina/genética , Displasia Ectodérmica/diagnóstico , Feminino , Deformidades Congênitas do Pé , Deformidades Congênitas da Mão , Humanos , Lactente , Masculino , Mutação , SíndromeRESUMO
Data from a mass screening program for identification of persons who are heterozygous for Tay-Sachs disease have been analyzed for the effects of oral contraceptive steroids on the activity in serum of hexosaminidase (hex) and the various hex isozymes. Women using oral contraceptives show a significantly higher total serum hex activity, reflecting mainly an increase in the heat-stable hex isozyme (hex I), and a smaller increase in the heat-labile hex A than do women using no medications. The changes in women using oral contraceptives are qualitatively similar to those observed during pregnancy. The distribution of responses to oral contraceptives is unimodal, and some of the variations may be related to differences in amount of steroid ingested. In addition, underlying genetic variation may contribute to the observed differences in enzyme activities.