RESUMO
Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes involved in genomic stability. Although they may be recognized by the association of typical clinical features, variable penetrance and expressivity are common, and clinical diagnosis is often challenging. DNAJC21, which is involved in ribosome biogenesis, was recently linked to bone marrow failure. However, the specific phenotype and natural history remain to be defined. We correlate molecular data, phenotype, and clinical history of 5 unreported affected children and all individuals reported in the literature. All patients present features consistent with IBMFS: bone marrow failure, growth retardation, failure to thrive, developmental delay, recurrent infections, and skin, teeth or hair abnormalities. Additional features present in some individuals include retinal abnormalities, pancreatic insufficiency, liver cirrhosis, skeletal abnormalities, congenital hip dysplasia, joint hypermobility, and cryptorchidism. We suggest that DNAJC21-related diseases constitute a distinct IBMFS, with features overlapping Shwachman-Diamond syndrome and Dyskeratosis congenita, and additional characteristics that are specific to DNAJC21 mutations. The full phenotypic spectrum, natural history, and optimal management will require more reports. Considering the aplastic anemia, the possible increased risk for leukemia, and the multisystemic features, we provide a checklist for clinical evaluation at diagnosis and regular follow-up.
Assuntos
Anormalidades Múltiplas/genética , Anemia Aplástica/genética , Doenças da Medula Óssea/genética , Instabilidade Genômica/genética , Proteínas de Choque Térmico HSP40/genética , Hemoglobinúria Paroxística/genética , Anormalidades Múltiplas/fisiopatologia , Anemia Aplástica/diagnóstico , Anemia Aplástica/patologia , Anemia Aplástica/fisiopatologia , Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/fisiopatologia , Transtornos da Insuficiência da Medula Óssea , Pré-Escolar , Disceratose Congênita/genética , Disceratose Congênita/fisiopatologia , Insuficiência Pancreática Exócrina/genética , Insuficiência Pancreática Exócrina/fisiopatologia , Feminino , Efeito Fundador , Hemoglobinúria Paroxística/diagnóstico , Hemoglobinúria Paroxística/fisiopatologia , Humanos , Lactente , Lipomatose/genética , Lipomatose/fisiopatologia , Masculino , Mutação , Fenótipo , Ribossomos/genética , Síndrome de Shwachman-Diamond , Telômero/genéticaRESUMO
Ciliopathies are heterogeneous disorders sharing different clinical signs due to a defect at the level of the primary cilia/centrosome complex. Postaxial polydactyly is frequently reported in ciliopathies, especially in Bardet-Biedl syndrome (BBS). Clinical features and genetic results observed in a pair of dizygotic twins with BBS are reported. The following manifestations were present: retinitis pigmentosa, bilateral insertional polydactyly, cognitive impairment and renal dysfunction. X-rays of the hands confirmed the presence of a 4th mesoaxial extra-digit with Y-shaped metacarpal bones. The sequencing of LZTFL1 identified a missense mutation (NM_020347.2: p.Leu87Pro; c.260T>C) and a nonsense mutation (p.Glu260*; c.778G>T), establishing a compound heterozygous status for the twins. A major decrease of LZTFL1 transcript and protein was observed in the patient's fibroblasts. This is the second report of LZTFL1 mutations in BBS patients confirming LZTFL1 as a BBS gene. Interestingly, the only two families reported in literature thus far with LZTFL1 mutations have in common mesoaxial polydactyly, a very uncommon feature for BBS. This special subtype of polydactyly in BBS patients is easily identified on clinical examination and prompts for priority sequencing of LZTFL1 (BBS17).
Assuntos
Síndrome de Bardet-Biedl/genética , Dedos/anormalidades , Mutação/genética , Polidactilia/genética , Dedos do Pé/anormalidades , Fatores de Transcrição/genética , Adulto , Síndrome de Bardet-Biedl/fisiopatologia , Análise Mutacional de DNA , Feminino , Dedos/fisiopatologia , Heterozigoto , Humanos , Linhagem , Polidactilia/fisiopatologia , Dedos do Pé/fisiopatologia , GêmeosRESUMO
BACKGROUND Genome-wide screening of large patient cohorts with mental retardation using microarray-based comparative genomic hybridisation (array-CGH) has recently led to identification several novel microdeletion and microduplication syndromes. METHODS Owing to the national array-CGH network funded by the French Ministry of Health, shared information about patients with rare disease helped to define critical intervals and evaluate their gene content, and finally determine the phenotypic consequences of genomic array findings. RESULTS In this study, nine unrelated patients with overlapping de novo interstitial microdeletions involving 4q21 are reported. Several major features are common to all patients, including neonatal muscular hypotonia, severe psychomotor retardation, marked progressive growth restriction, distinctive facial features and absent or severely delayed speech. The boundaries and the sizes of the nine deletions are different, but an overlapping region of 1.37 Mb is defined; this region contains five RefSeq genes: PRKG2, RASGEF1B, HNRNPD, HNRPDL and ENOPH1. DISCUSSION Adding new individuals with similar clinical features and 4q21 deletion allowed us to reduce the critical genomic region encompassing two genes, PRKG2 and RASGEF1B. PRKG2 encodes cGMP-dependent protein kinase type II, which is expressed in brain and in cartilage. Information from genetically modified animal models is pertinent to the clinical phenotype. RASGEF1B is a guanine nucleotide exchange factor for Ras family proteins, and several members have been reported as key regulators of actin and microtubule dynamics during both dendrite and spine structural plasticity. CONCLUSION Clinical and molecular delineation of 4q21 deletion supports a novel microdeletion syndrome and suggests a major contribution of PRKG2 and RASGEF1B haploinsufficiency to the core phenotype.
Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 4/genética , Transtornos do Crescimento/patologia , Deficiência Intelectual/patologia , Transtornos do Desenvolvimento da Linguagem/patologia , Anormalidades Múltiplas/patologia , Adolescente , Criança , Pré-Escolar , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Hibridização Genômica Comparativa , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Síndrome , Adulto JovemRESUMO
Branchio-oculo-facial syndrome (BOFS) is an autosomal-dominant condition characterized by three main features, respectively: branchial defects, ocular anomalies, and craniofacial defects including cleft lip and/or palate (CL/P). We report on one family with three affected, and two sporadic cases that have been found to carry missense mutations in the newly reported BOFS gene: TFAP2A. This report confirms the involvement of this transcription factor in this developmental syndrome with clinical variability. Moreover, we present CT scan temporal bone anomalies in the familial cases, related to branchial arch defects, highlighting the importance of radiological investigations for differential diagnosis.
Assuntos
Síndrome Brânquio-Otorrenal/genética , Osso Temporal/anormalidades , Fator de Transcrição AP-2/genética , Sequência de Aminoácidos , Sequência de Bases , Síndrome Brânquio-Otorrenal/complicações , Criança , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Fator de Transcrição AP-2/fisiologiaRESUMO
To study the oribatid mite community inhabiting microhabitats in the canopy of montane Abies amabilis [(Douglas ex D. Don) Lindl.] and Tsuga heterophylla [(Raf.) Sarg] tree species across five elevational sites, we collected 180 branch tips and 180 foliose/crustose lichen samples over three time periods. Thirty-three species of oribatid mites were identified from the study area. Mite species richness and abundance was significantly affected by microhabitat, and this association was independent of sampling time. At the microhabitat scale, distinct species assemblages were associated with lichen and branch tip habitats, and to a lesser degree, tree species. Conifer specificity was most apparent in the closely related species of Jugatala, where Jugatala tuberosa Ewing was only found on branch tips from A. amabilis and Jugatala sp. was primarily found on branch tips from T. heterophylla. Microhabitat specificity was most pronounced in Dendrozetes sp. where most individuals were found on branch tips and Anachiperia geminus Lindo et al. that occurred primarily on lichens. Principal components analysis of oribatid mite community composition further showed a high degree of association with microhabitat and tree species. Habitat profiles are difficult to discern for many species because tree, microhabitat, and elevation preferences confound distribution patterns. Given the significant tree-microhabitat associations in species composition in this montane canopy study, we suggest that sampling multiple microhabitats across elevations to look for patterns in community structure offers opportunities to explicitly test organizing principles in community ecology.
Assuntos
Abies , Ecossistema , Ácaros/fisiologia , Tsuga , Animais , Colúmbia Britânica , Especificidade da Espécie , ÁrvoresRESUMO
There is unmet contraceptive need among Haitian immigrants and Haitian-American women (Haitian women). The study explored associations of three measures of acculturation with contraceptive/reproductive health history among Haitian women residing in the Little Haiti community of Miami. This was a cross-sectional, exploratory study among 57 Haitian women. We conducted descriptive univariate analyses, then bivariate analyses to investigate the association of acculturation with reproductive health risk behavior including contraceptive use, tampon use, and parity, as well as interest in a female-initiated barrier contraceptive method. The most commonly ever-used contraceptive methods were male condoms (78.9 %) and oral contraceptives (OC 19.3 %). Women who primarily spoke Créole at home were less likely than those who did not to use OC (11.9 vs. 42.9 %, p = .01). Among women who resided in the U.S. ≥10 years, tampon use was 51.9 % compared to 16.7 % among those who were in the U.S. for less time (p = .005). Among U.S. born women, 60 % were tampon users compared to 22.7 % among those born in Haiti (p = .05). Women not speaking primarily Créole at home (p = .06) and those born in U.S. (p = .008) had fewer children. Contraceptive use was low among Haitian women but influenced by acculturation, where greater acculturation was associated with protective reproductive health behavior. Despite traditional norms discouraging contraceptive use, and little experience with female barriers, Haitian women indicated an interest in learning about and using a female-initiated barrier contraceptive. Increasing contraceptive uptake of potential multipurpose technologies is a potential point of intervention for decreasing HIV/STI transmission in this at-risk population.
Assuntos
Aculturação , Anticoncepção/estatística & dados numéricos , Emigrantes e Imigrantes/estatística & dados numéricos , Idioma , Saúde Reprodutiva/etnologia , Adolescente , Adulto , Anticoncepção/métodos , Estudos Transversais , Feminino , Florida/epidemiologia , Haiti/etnologia , Comportamentos Relacionados com a Saúde , Humanos , Pessoa de Meia-Idade , Paridade , Assunção de Riscos , Adulto JovemRESUMO
We explored whether the oxidation of valine and by implication the physiological requirement for this amino acid are affected by changes in leucine intake over a physiological range. Six young adult men received, in random order, four L-amino acid-based diets for 5 d supplying either 20 or 10 mg valine.kg body wt-1.d-1, each in combination with 80 or 40 mg leucine.kg-1.d-1. On day 6 subjects were studied with an 8-h continuous intravenous infusion of [1-13C]valine (and [2H3]leucine) to determine valine oxidation in the fasted state (first 3 h) and fed state (last 5 h). Valine oxidation in the fasted state was similar among all diets but was lower (P less than 0.05) in the fed state for the 10 vs 20 mg valine.kg-1.d-1 intake. Leucine intake did not affect valine oxidation. Mean daily valine balance approximated +1.3 mg.kg-1.d-1 for the 20-mg intake and -1.6 mg.kg-1.d-1 for the 10-mg intake. These findings support our previously suggested mean valine requirement estimate of approximately 20 mg.kg-1.d-1.
Assuntos
Leucina/administração & dosagem , Necessidades Nutricionais , Valina/metabolismo , Adulto , Isótopos de Carbono , Deutério , Jejum , Alimentos , Humanos , Infusões Intravenosas , Isoleucina/sangue , Cinética , Leucina/sangue , Masculino , Oxirredução , Valina/administração & dosagem , Valina/sangueRESUMO
Recent estimates of the leucine requirement of adult men based on 13C-tracer studies are substantially higher than those proposed by FAO/WHO/UNU (1985). To explore whether leucine oxidation and requirements are affected by the dietary amount of valine. 11 healthy young adult men received, in random order, for 5 d, one of four L-amino acid diets providing 40 or 15 mg leucine.kg-1.d-1 together with variable amounts mg.kg-1.d-1 of valine and isoleucine in the following combinations (Val:Ile): 80:62 and 20:62 (six subjects; phase 1); 20:62 and 20:20 (five subjects, phase 2). On the morning of day 6, a continuous intravenous infusion of L-[1-13C]leucine was given for 7-8 h; the subject was in the fasting state for the initial 2.5 or 3 h and in the fed state for the remainder of the time. Also, [2H3]leucine was added to the diet. Leucine oxidation was similar for all diet groups in the fasted state. During the fed state, leucine oxidation was not affected by the Val:Ile pattern. Thus, changes in the pattern of branched-chain amino acid intake within a physiological range do not affect isotopically derived estimates of the leucine requirement.
Assuntos
Isoleucina/administração & dosagem , Leucina/metabolismo , Necessidades Nutricionais , Valina/administração & dosagem , Adulto , Isótopos de Carbono , Humanos , Isoleucina/sangue , Cetoácidos/sangue , Cinética , Leucina/administração & dosagem , Leucina/sangue , Masculino , Oxirredução , Valina/sangueRESUMO
The fate of dietary leucine and phenylalanine was studied in five healthy, young adult men, by using a dual, stable isotope-tracer infusion approach to estimate amino acid fluxes, splanchnic (Sp) uptake, and dietary of absorbed amino acid to the peripheral circulation. Subject received two, 4-h tracer infusions of [1-13C]leucine and [15N]phenylalanine infused through a feeding tube placed in the duodenum, and [5,5,5-2H3]leucine, [ring-2H5]phenylalanine, and [6,6-2H2]glucose infused simultaneously by vein. In one experiment subjects received an amino acid mixture (83 mg amino acid.kg-1.h-1) via the feeding tube and in the other experiment amino acids were supplied with carbohydrate (CHO) (167 mg.kg-1.h-1). Sp uptake of dietary leucine decreased with added dietary CHO (29% of ingested leucine for amino acids alone vs 20% with CHO; P < 0.05) but was not different for phenylalanine (P > 0.05). Addition of CHO decreased both release of leucine via protein breakdown and leucine oxidation and increased body leucine balance (P < 0.05).
Assuntos
Dieta , Carboidratos da Dieta/farmacologia , Leucina/farmacocinética , Fenilalanina/farmacocinética , Adulto , Glicemia/metabolismo , Isótopos de Carbono , Deutério , Humanos , Cetoácidos/metabolismo , Leucina/administração & dosagem , Leucina/sangue , Masculino , Isótopos de Nitrogênio , Oxirredução , Fenilalanina/administração & dosagem , Fenilalanina/sangue , Circulação EsplâncnicaAssuntos
Anormalidades Múltiplas/genética , Defeitos Congênitos da Glicosilação/genética , Cirrose Hepática/patologia , Enteropatias Perdedoras de Proteínas/patologia , Anormalidades Múltiplas/patologia , Defeitos Congênitos da Glicosilação/enzimologia , Análise Mutacional de DNA , DNA Complementar/química , DNA Complementar/genética , Diarreia Infantil/patologia , Saúde da Família , Haplótipos , Humanos , Lactente , Manose-6-Fosfato Isomerase/deficiência , Manose-6-Fosfato Isomerase/genética , Mutação de Sentido Incorreto , Quebeque , SíndromeRESUMO
Ectopia lentis (EL) is a zonular disease where alteration of the zonular fibers leads progressively to lens dislocation. It is most often associated with systemic diseases such as Marfan syndrome, Weill-Marchesani syndrome or homocystinuria. Isolated non syndromic ectopia lentis (IEL) is reported in families with autosomal inheritance, with dominant forms being more common than recessive. LTBP2 truncating mutations have been described as a cause of autosomal recessive ectopia lentis as a primary or secondary feature in patients showing ocular (eg, glaucoma) or extraocular manifestations (eg, Marfanoid habitus). Recently, ADAMTSL4 has been shown to be responsible for isolated autosomal recessive ectopia lentis in an inbred family. Herein we show a consanguineous family that carries a novel homozygous splice mutation IVS4-1G>A/IVS4-1G>A in ADAMTSL4 responsible for isolated autosomal recessive EL, thus confirming the involvement of this gene in this condition and underlining the major role of ADAMTS proteases in zonular fibers homeostasis.
Assuntos
Códon sem Sentido , Ectopia do Cristalino/genética , Genes Recessivos , Trombospondinas/genética , Proteínas ADAMTS , Afacia Pós-Catarata/etiologia , Afacia Pós-Catarata/terapia , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Óculos , Lateralidade Funcional , Humanos , Cristalino/cirurgia , Masculino , Repetições de Microssatélites , Linhagem , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , Acuidade VisualRESUMO
Peters plus syndrome is an autosomal recessive rare congenital disorder defined by corneal Peters anomaly with short disproportionate stature, development delay and dysmorphic facial features. In addition, cardiac, genito-urinary and/or central nervous system malformations can be present. Mutations in the beta-1,3-galactosyltransferase-like glycosyltransferase gene (B3GALTL) have been reported in patients with Peters plus syndrome prompting phenotype-genotype studies because of the variable clinical spectrum related to the syndrome. A 20 month old boy presenting with bilateral Peters anomaly in association with multiple developmental anomalies including cerebral malformations was found to carry a novel homozygous B3GALTL nonsense mutation [p.Tyr366X]. This is the first stop mutation described in association with this gene. The present report confirms the wide clinical spectrum of Peters plus syndrome, underlines the major clinical criteria of the syndrome and the major implication of B3GALTL gene in this condition. Ophthalmologic examination in multiple developmental anomalies remains an important clinical issue that may lead to specific gene screening. In Peters plus syndrome B3GALTL molecular test provides diagnosis confirmation and improves dramatically genetic counselling for the families.
Assuntos
Anormalidades Múltiplas/genética , Códon sem Sentido , Galactosiltransferases/genética , Glucosiltransferases/genética , Segmento Anterior do Olho/anormalidades , Opacidade da Córnea/genética , Deficiências do Desenvolvimento/genética , Anormalidades do Olho/genética , Humanos , Lactente , Masculino , Malformações do Sistema Nervoso/genética , Reação em Cadeia da Polimerase , SíndromeAssuntos
Raízes Nervosas Espinhais/anatomia & histologia , Nervo Trigêmeo/anatomia & histologia , Anatomia Comparada , Animais , Estimulação Elétrica , Haplorrinos , Humanos , Macaca , Microeletrodos , Propriocepção , Sensação , Temperatura Cutânea , Raízes Nervosas Espinhais/fisiologia , Sensação Térmica , Tato , Nervo Trigêmeo/fisiologia , Nervo Trigêmeo/fisiopatologia , Neuralgia do Trigêmeo/fisiopatologiaRESUMO
The purpose of this paper is to attempt to define the upper limit of the safe range of protein intake, with particular reference to the protein content of prepared fixed-formulas used for feeding healthy, term infants. For discussion purposes we use the current upper limit proposed by the U.S. Food and Drug Administration (FDA), namely, 4.5 g protein per 100 kcal, as our initial reference level. To help reach a conclusion, the concept and definitions of nutritional adaptation and accommodation are considered, followed by a brief review of selected studies in full-term infants fed varying levels of protein intake. Based on growth and blood biochemical data, principally plasma free amino acid levels, we conclude that the currently proposed FDA upper limit is probably too high. The available data support a recommendation for lowering the value to about 3.5 g of protein per 100 kcal. Concerns for renal solute load (RSL) may require a further, desirable refinement in the value proposed. Indeed RSL should perhaps serve as the primary basis for establishing a rational and safe upper limit for the protein content of prepared fixed-formula diets for the very young, healthy infant.
Assuntos
Proteínas Alimentares/normas , Alimentos Formulados/normas , Alimentos Infantis/normas , Adaptação Fisiológica , Feminino , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
During nephrotoxic nephritis in the rat, an increased urinary excretion of glucosyl-galactosyl hydroxylysine and of galactosyl-hydroxylysine has been observed in the autologous phase of the disease. This due mainly to an elevation of the polypeptide-bound fraction of these hydroxylysyl glucosides with a molecular weight over 1,000 daltons. The levels of both urinary hydroxylysyl glucosides were correlated with proteinuria. Their increased excretion appears to originate in the lysed glomerular basement membrane. At the same stage of nephrotoxic nephritis, an increased glucosyl transferase activity could be demonstrated in the isolated glomeruli, correlated with albuminuria, attesting a higher turn-over of the disaccharide units of the glomerular basement membrane.
Assuntos
Membrana Basal/metabolismo , Dissacarídeos/metabolismo , Glomerulonefrite/metabolismo , Glomérulos Renais/metabolismo , Albuminúria/metabolismo , Animais , Creatinina/urina , Dissacarídeos/urina , Diurese , Glomerulonefrite/urina , Hidroxilisina/análogos & derivados , Hidroxilisina/urina , Soros Imunes , Córtex Renal/metabolismo , Glomérulos Renais/enzimologia , Masculino , Coelhos , Ratos , Transferases/metabolismoRESUMO
Although often unobserved or ignored, mites usually exceed all other arthropods in abundance in forest canopies. Second in species richness only to canopy insects, the arboreal acarofauna is composed of multiple lineages of predators, scavengers, grazers, animal associates, and plant parasites that each have radiated extensively in canopy habitats. The canopy fauna is largely complementary to the mite fauna of the forest floor, suggesting that estimates of more than one million living species of mites are not extreme. Most mites are less than a millimeter in length as adults, and canopy mites tend to be smaller than species from other habitats. Even among mites, however, very small species are relatively rare, and diversity increases with decreasing size only to the penultimate size class (0.316-1 mm). This pattern may be explained by declines in microhabitat diversity or host specificity as the limit of body size in a group of organisms is approached.
RESUMO
Four infants had noninfectious intractable diarrhea, vomiting, anasarca, hepatomegaly, hypoglycemia, and malnutrition within the first 3 months of life. Their parents originated from the same Northeastern part of Quebec, and consanguinity was found in two kindreds. Diarrhea was secretory in three infants (mean stool volume 87 ml/kg/day, Na+ 108 mEq/L, Cl- 85 mEq/L). Hypoalbuminemia (mean 2.0 gm/dl), present in all infants, appeared to be secondary to a protein-losing enteropathy, which was documented in two infants. Histologic examination of the upper small intestine showed only mild to moderate villous atrophy. The remarkable findings were those of cystic dilation of the crypts and acute inflammation of crypts and lamina propria, all of which were most prominent in the colon and terminal ileum; the changes were progressive over time. Mild lymphangiectasia was found in all of the patients. Congenital hepatic fibrosis, present in all, was associated in one patient with a nonfunctional multicystic kidney. Prolonged total parenteral nutrition, intravenously administered albumin, antisecretory agents, and antibiotics were unsuccessful in controlling the disease. Although a total colectomy was followed by a temporary decrease in stool output and normalization of serum albumin concentration in one infant, the patients died between 4 and 21 months of age.