RESUMO
Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4). We have identified a new transcript, encoding a protein (bo, +AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.
Assuntos
Sistemas de Transporte de Aminoácidos Básicos , Proteínas de Transporte/genética , Cistinúria/genética , Mutação da Fase de Leitura , Glicoproteínas de Membrana/genética , Mutação de Sentido Incorreto , Sequência de Aminoácidos , Animais , Células COS , Cromossomos Humanos Par 19 , Cistinúria/etnologia , DNA Complementar/análise , Feminino , Humanos , Itália , Judeus , Líbia , Masculino , Modelos Biológicos , Dados de Sequência Molecular , América do Norte , Linhagem , Homologia de Sequência de Aminoácidos , Espanha , Distribuição TecidualRESUMO
BACKGROUND: Lateral humeral condyle fractures are the second most common fracture around the elbow in children. However, the association of an elbow dislocation is a rare entity. Therefore, literature on young patients with this uncommon combination is sparse. We aimed to perform a systematic review of the literature searching for pediatric lateral condyle humerus fractures associated to elbow dislocation. METHODS: A systematic review of the PubMed and Embase databases was conducted for peer-reviewed literature between 1960 and 2020. Two reviewers filtered the results, looking for articles in English and Spanish that reported fractures of the lateral condyle of the humerus associated to elbow dislocation in skeletally immature patients. Outcomes included patient and injury characteristics, treatment strategies, complications, and final outcomes including range of motion. RESULTS: The initial search yielded a total of 851 studies. After initial screening, 16 studies were included, with 67 patients available for review. Age reported at the time of injury ranged from 2 to 12 years. The lesion occurred more commonly in males (60%) with Milch II, and Jakob type 3 fractures. The direction of the dislocation was posteromedial in most cases. Open reduction by lateral approach and Kirschner pin placement was the most performed treatment. The reported follow-up ranged from 3 to 156 months. Fourteen studies reported complications in 1/3 of the patients including: limited range of motion, cubitus varus, instability, hardware prominence, delayed union, nonunion, malunion, heterotopic ossification, neurological injury, and hardware failure. Thirteen studies reported clinical outcomes, which were rated as fair or poor in 2out of 10patients. CONCLUSIONS: Current evidence is level IV and suggests that the complication rate after surgical management of lateral condyle fractures is substantial in the context of an associated elbow dislocation, with an elevated percentage of suboptimal results. The most frequent complications in this series were elbow stiffness and cubitus varus.
RESUMO
This study aimed to investigate the clinical variability and factors implied in the outcome of 6-pyruvoyl-tetrahydropterin synthase deficiency (PTPSd). Biochemical and clinical phenotype, treatment variables, and 6-pyruvoyl-tetrahydropterin synthase (PTS) genotype, were explored retrospectively in 19 Italian patients (12 males and 7 females, aged 4 months to 33 years). According to the level of biogenic amines in cerebrospinal fluid (CSF) at the diagnosis, the patients were classified as mild (6) (normal level) or severe (13) (abnormal low level) form (MF and SF, respectively). Blood Phe ranged from 151 to 1053 micromol/l in MF (mean +/- SD: 698 +/- 403) and 342-2120 micromol/l in SF (mean +/- SD: 1175 +/- 517) (p = 0.063). Patients with MF showed a normal neurological development (a transient dystonia was detected in one), while all SF patients except one presented with severe neurological impairment and only four had a normal neurological development. The outcome of the SF was influenced by the precocity of the treatment. Serial CSF examinations revealed a decline of 5-hydroxyindolacetic acid in MFs and an incomplete restoration of neurotransmitters in SFs: neither obviously affected the prognosis. PTS gene analysis detected 17 different mutations (seven so far unreported) (only one affected allele was identified in three subjects). A good correlation was found between genotype and clinical and biochemical phenotype. The occurrence of brain neurotransmitter deficiency and its early correction (by the therapy) are the main prognostic factors in PTPSd.
Assuntos
Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/fisiopatologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/fisiopatologia , Fósforo-Oxigênio Liases/deficiência , Adolescente , Adulto , Aminas Biogênicas/líquido cefalorraquidiano , Encefalopatias Metabólicas Congênitas/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Doenças do Sistema Nervoso/patologia , Fenilcetonúrias/diagnóstico , Estudos Retrospectivos , Adulto JovemRESUMO
The ferritins present in the first day human colostrum and mature milk were compared with serum and tissue ferritins on the basis of their iron content, immunological reactivity and glycosylation. Both had a low iron content. The degree of glycosylation and immunochemical properties of colostrum ferritin showed strong similarities with serum ferritin. The isoelectric points and immunochemical properties of milk ferritin were similar to heart ferritin. The concentration of colostrum ferritin was more significantly correlated to body iron stores than milk ferritin.
Assuntos
Ferritinas/metabolismo , Leite Humano/metabolismo , Colostro/metabolismo , Feminino , Ferritinas/sangue , Ferritinas/imunologia , Glicosilação , Humanos , Concentração de Íons de Hidrogênio , Imunoensaio , Ferro/análise , Ponto Isoelétrico , Lactação , Peso Molecular , GravidezRESUMO
Prenatal diagnosis of tetrahydrobiopterin (BH4) deficiency was undertaken by evaluating the pterin patterns in amniotic fluid and the specific enzyme activities in fetal or extrafetal tissues. This allowed the prenatal diagnosis in 19 pregnancies at risk. In 8 families with a child already affected by dihydropteridine reductase deficiency 4 fetuses were diagnosed as homozygotes and 4 as heterozygotes for the defect. In 11 families with a child affected by 6-pyruvoyl tetrahydropterin synthase deficiency 4 fetuses were homozygous, 4 heterozygous and 3 normal. This study also advanced our knowledge of tetrahydrobiopterin metabolism during fetal development. The key enzymes involved in the biosynthesis of BH4 are expressed early and allow the fetus to be autotrophous for its cofactor requirement. In a twin pregnancy, both fetuses were diagnosed to be heterozygotes for dihydropteridine reductase deficiency and primapterin (7-biopterin) in amniotic fluid was increased. This indicates that pterin-4 alpha-carbinolamine dehydratase activity seems to be differently expressed during fetal life. As a consequence, pterins detected in amniotic fluid are of fetal origin and 6- and 7-substituted pterins can be present in amniotic fluid in higher proportions when compared with other body fluids.
Assuntos
Líquido Amniótico/química , Biopterinas/análogos & derivados , Feto/enzimologia , Fósforo-Oxigênio Liases , Diagnóstico Pré-Natal/métodos , Pterinas/análise , Oxirredutases do Álcool/deficiência , Biopterinas/análise , Biopterinas/deficiência , Feminino , GTP Cicloidrolase/deficiência , Humanos , Hidroliases/deficiência , Neopterina , Fenilcetonúrias , Gravidez , Xantopterina/análiseRESUMO
The relationship between blood phenylalanine concentrations and serum and erythrocyte biopterin and neopterin concentrations was investigated in 20 phenylketonuric patients with different dietary compliance. At serum phenylalanine concentrations ranging from 43 to 1004 mumol/l, a good correlation was found with serum biopterin (r = 0.76, P < 0.001) and with red blood cell biopterin (r = 0.62, P < 0.001). A similar correlation was found between serum neopterin and phenylalanine (r = 0.60, P < 0.001). The correlation between red blood cell neopterin and serum phenylalanine was less evident, however (r = 0.47, P < 0.005). After oral loading with phenylalanine (100 mg/kg body weight), serum and red blood cell biopterin concentrations increased in patients with classical phenylketonuria as well as in one patient with dihydropteridine reductase deficiency in response to the induced acute hyperphenylalaninemia. One patient suffering from 6-pyruvoyl tetrahydropterin synthase deficiency was loaded orally with tetrahydrobiopterin (20 mg/kg body weight). The kinetics of administered cofactor confirmed its rapid absorption, with early increase of serum concentrations followed by its transport into the red blood cells. The half-life of biopterin was approximately 7 h in serum and 15 h in red blood cells. Because both values are less than the half-life of phenylalanine (20-30 h) in serum, biopterin measurement offers no advantage in monitoring dietary control in hyperphenylalaninemic patients.
Assuntos
Eritrócitos/metabolismo , Fenilalanina/sangue , Fenilcetonúrias/sangue , Fósforo-Oxigênio Liases , Pterinas/sangue , Oxirredutases do Álcool/deficiência , Biopterinas/análogos & derivados , Biopterinas/sangue , Feminino , Meia-Vida , Humanos , Cinética , Masculino , Neopterina , Fenilcetonúrias/enzimologiaRESUMO
BACKGROUND: Cystinuria is an inherited disorder of cystine and dibasic amino acids transport that results in urolithiasis because of poor cystine solubility. Three cystinuria phenotypes, differentiated according to urinary amino acid excretion in obligate heterozygotes, were regarded as allelic variants of a monogenic disease. Two mutated amino acid transporter genes, however, have been recently identified as responsible for cystinuria. Mutations in the SLC3A1 gene. encoding for the heavy subunit of the transporter protein rBAT, were associated with type I cystinuria, whereas type II and III cystinuria were associated with mutations in the SLC7A9 gene, encoding for a light subunit of rBAT. Lysine and arginine metabolism have, therefore, been evaluated in cystinuria homozygotes and heterozygotes to better define the cystinuria phenotypes and their correlations with these emerging genotypes. PATIENTS AND METHODS: Lysine and arginine intestinal absorption and renal excretion were assessed by oral loading and compared to normal controls. Seven cystinuria homozygotes and 7 obligate heterozygotes belonging to the different types received alternately an oral dose of 0.5 mmol/kg body weight lysine or arginine. Plasma concentrations of lysine, arginine, ornithine (derived from rapid arginine conversion) were measured 0, 1, 2, and 3 hours after loading. Their urinary concentrations were measured in morning urine and in urine collected 0-6 hours after loading. RESULTS: Gut lysine absorption was deficient in type II and III, and normal in type I cystinuria homozygotes. Impaired arginine intestinal absorption, as well as massive lysine, arginine, and ornithine hyperexcretion were shared by all homozygotes, irrespective of the type. All heterozygotes shared normal lysine absorption, whereas arginine absorption was slightly impaired in type II and III heterozygotes, which also displayed high lysine, arginine, and ornithine urinary excretion after loading. CONCLUSIONS: Two cystinuria phenotypes, type I and non-type I, can be identified in both homozygous and heterozygous cystinuric subjects by oral loading tests with lysine and arginine. In agreement with recent molecular findings, non-type I cystinuria comprises mentioned type II and type III, which constitute allelic variants of a cystine and dibasic amino acid transport disorder distinct from type I cystinuria.
Assuntos
Sistemas de Transporte de Aminoácidos Básicos , Arginina/metabolismo , Cistinúria/genética , Cistinúria/metabolismo , Lisina/metabolismo , Fenótipo , Adolescente , Adulto , Alelos , Arginina/urina , Proteínas de Transporte/genética , Cistinúria/complicações , Feminino , Heterozigoto , Homozigoto , Humanos , Absorção Intestinal/fisiologia , Lisina/urina , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Ornitina/metabolismo , Ornitina/urina , Cálculos Urinários/etiologiaRESUMO
Tetrahydrobiopterin deficiency, a variant of hyperphenylalaninemia, may be caused by deficiency of one of the following enzymes: guanosine triphosphate cyclohydrolase 1,6-pyruvoyltetrahydropterin synthase, dihydropteridin reductase and pterin-4a-carbinolamine dehydratase. The first two enzymes are involved in the biosynthesis of tetrahydrobiopterin, the last two in its regeneration. Although these diseases are rare, early detection by selective screening is essential for the treatment and outcome. Tetrahydrobiopterin deficiencies are very heterogenous ranging from mild forms requiring only marginal if any treatment to severe forms which are in some cases very difficult to treat. All variants of tetrahydrobiopterin deficiency can be differentiated from the classical phenylketonuria (PKU) by measurement of pterin metabolites in patients' urine, tetrahydrobiopterin loading test, and by dihydropteridine reductase activity in erythrocytes from the Guthrie card.
Assuntos
Biopterinas/análogos & derivados , Erros Inatos do Metabolismo , Fenilalanina/sangue , Biopterinas/deficiência , Biopterinas/genética , Biopterinas/metabolismo , Di-Hidropteridina Redutase/sangue , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/enzimologia , Erros Inatos do Metabolismo/terapia , Prognóstico , Pterinas/urinaAssuntos
Células da Medula Óssea , Medula Óssea , Divisão Celular , Leucemia Linfoide/patologia , Contagem de Células Sanguíneas , Criança , Pré-Escolar , Feminino , Hepatomegalia , Humanos , Lactente , Masculino , Esplenomegalia , Timidina , TrítioRESUMO
OBJECTIVE: To report the efficacy, tolerability, and safety of the dopamine agonist pramipexole in a series of 5 patients affected by inherited 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency and needing l-3,4 dihydroxyphenylalanine (l-dopa) therapy. METHODS: Patients included 4 males and 1 female with ages ranging from 2 to 26 years. Their medication included tetrahydrobiopterin (BH4), 5-hydroxytryptophan, l-dopa, carbidopa, selegiline, and entacapone. All experienced residual symptoms of dopamine deficiency, movement and behavioral disability, and complications of l-dopa therapy, associated with fluctuating hyperprolactinemia. Patients had full assessment of clinical and biochemical condition, including evaluation by an adapted Unified Parkinson's Disease Rating Scale (UPDRS) and measurement of plasma prolactin (PRL) and catecholamines, before and after a 6-week trial with pramipexole. Pramipexole was administered twice daily as an adjunct to l-dopa therapy in dosages upwardly titrated, with a concurrent reduction of l-dopa dosage. Clinical follow-up went on for 1 year. RESULTS: Pramipexole was well tolerated by all patients, with marked improvement and stabilization of their clinical picture. The mean improvement on the total UPDRS score was 43% (range 33.3%-55.6%) from baseline. Diurnal profiles of plasma PRL normalized and plasma catecholamine levels lasted unchanged. The daily administrations of l-dopa were curtailed from 3 or 4 to 2, and the l-dopa dosage was reduced up to 40%. CONCLUSIONS: The addition of pramipexole to the treatment of 6-pyruvoyl tetrahydropterin synthase deficiency improves the results of l-3,4 dihydroxyphenylalanine therapy. Similar benefits may be expected in other forms of inherited tetrahydrobiopterin deficiency.
Assuntos
Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/uso terapêutico , Fósforo-Oxigênio Liases/deficiência , Adulto , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Levodopa/farmacologia , Levodopa/uso terapêutico , Masculino , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/enzimologia , Pramipexol , Adulto JovemRESUMO
The histochemical NBT test was performed on blood samples from ten healthy newborn infants. High spontaneous NBT reduction has been confirmed for neutrophils and assessed for monocytes. The stimulation of both neutrophils and monocytes with Escherichia coli endotoxin induces a statistically significant increase of NBT positive cells. The reason for the false positive test results in neonates was investigated by incubating neutrophils from adult donors and for different time periods in either neonatal or adult plasma before the addition of NBT. NBT reduction by adult neutrophils was increased after incubation in neonatal plasma, and this increase was related to the concentration of the plasma used. Maximum NBT reduction was observed after 90 min of incubation, at which time the NBT scores of adult cells incubated in neonatal plasma were similar to the results of tests performed on whole neonatal blood. It is concluded that neonatal leucocytes demonstrate efficient spontaneous and stimulated phagocytosis, and that there are, in the plasma of neonates, humoral factors which stimulated phagocytosis by neutrophils and are thus responsible for the false positive NBT test results observed in these subjects.
Assuntos
Recém-Nascido , Monócitos/metabolismo , Neutrófilos/metabolismo , Nitroazul de Tetrazólio , Fagocitose , Sais de Tetrazólio , Endotoxinas/farmacologia , Escherichia coli , Reações Falso-Positivas , HumanosRESUMO
18 neonatal colostrum samples were analyzed by urea-starch-gel electrophoresis to determine their casein patterns. It was found that precise typing of both alpha-and beta-casein could be obtained after the secretory burst. This genetic marker can be employed at the family level.
Assuntos
Caseínas/análise , Colostro/análise , Fenótipo , Eletroforese em Gel de Amido , Feminino , Frequência do Gene , Técnicas Genéticas , Humanos , Recém-Nascido , Masculino , Leite Humano/análise , Polimorfismo GenéticoRESUMO
Urea-starch-gel electrophoresis was used to examine 175 casein samples, 130 collected at random from women from the urban area of Turin, and 45 from women resident in villages in the Sardinian hinterland. Two polymorphic systems controlling alpha- and beta-casein were demonstrated in both groups, together with similar gene frequencies for individual alleles. In addition, a rare variant was discovered in the Sardinian group.
Assuntos
Caseínas , Polimorfismo Genético , Caseínas/análise , Eletroforese em Gel de Amido , Feminino , Frequência do Gene , Humanos , Itália , Leite Humano/análiseRESUMO
Urea-starch-gel electrophoresis of casein samples from women of the Kikuyu tribe (central Africa) shows that this Negroid population had the same alpha- and beta-casein polymorphic pattern as Caucasoids, though their gene frequencies for the beta-locus were inverted. A new beta-casein variant (named beta-E) was identified.
Assuntos
População Negra , Caseínas/biossíntese , Leite Humano/análise , Polimorfismo Genético , Feminino , Frequência do Gene , Humanos , Quênia , Conformação ProteicaRESUMO
Six hundred and seventy-three children (483 newborns and 190 older selected children) were screened for tetrahydrobiopterin (BH4) deficiency by HPLC of urine pterins and BH4 load test. One patient with GTP cyclohydrolase I deficiency, 36 patients with dihydrobiopterin synthetase (DHBS) deficiency (of which six were in the newborn and 30 in the older children) and 14 with dihydropteridine reductase deficiency (DHPR) were found. All 37 patients with defective BH4 biosynthesis responded to a BH4 load by lowering of the elevated serum phenylalanine concentration but four of 14 patients with DHPR deficiency did not. Measurement of DHPR activity in blood spots on Guthrie cards is recommended. Since subvariants of patients with BH4 deficiency exist, homovanillic acid, 5-hydroxyindole acetic acid, pterins, phenylalanine, and tyrosine in cerebrospinal fluid should be measured for diagnosis and the control of therapy. The activity of the phosphate-eliminating enzyme (a key enzyme in BH4 biosynthesis and part of "DHBS") was measured in human liver and activities of approx. 1 n U (mg protein)-1 were found. In the liver biopsy of a patient with DHBS deficiency no activity (less than 3% of controls) was demonstrated.