RESUMEN
Researchers must assess similarities and differences in colour from an animal's eye view when investigating hypotheses in ecology, evolution and behaviour. Nervous systems generate colour perceptions by comparing the responses of different spectral classes of photoreceptor through colour opponent mechanisms, and the performance of these mechanisms is limited by photoreceptor noise. Accordingly, the receptor noise limited (RNL) colour distance model of Vorobyev and Osorio (Vorobyev & Osorio 1998 Proc. R. Soc. Lond. B265, 351-358 (doi:10.1098/rspb.1998.0302)) generates predictions about the discriminability of colours that agree with behavioural data, and consequently it has found wide application in studies of animal colour vision. Vorobyev and Osorio (1998) provide equations to calculate RNL colour distances for animals with di-, tri- and tetrachromatic vision, which is adequate for many species. However, researchers may sometimes wish to compute RNL colour distances for potentially more complex colour visual systems. Thus, we derive a simple, single formula for the computation of RNL distance between two measurements of colour, equivalent to the published di-, tri- and tetrachromatic equations of Vorobyev and Osorio (1998), and valid for colour visual systems with any number of types of noisy photoreceptors. This formula will allow the easy application of this important colour visual model across the fields of ecology, evolution and behaviour.
RESUMEN
Congenital disorders of glycosylation form a rapidly growing group of inherited metabolic diseases. As glycosylation affects proteins all over the organism, a mutation in a single gene leads to a multisystemic disorder. We describe a patient with TMEM165-CDG with facial dysmorphism, nephrotic syndrome, cardiac defects, enlarged cerebral ventricles, feeding problems, and neurological involvement. Having confirmed the diagnosis via prenatal diagnostics, we were able to observe the glycosylation right from birth, finding a pathological pattern already on the first day of life. Within the next few weeks, hypoglycosylation progressed to less sialylated and then also to hypogalactosylated isoforms. On the whole, there has not been much published evidence concerning postnatal glycosylation and its adaptational process. This is the first paper reporting changes in glycosylation patterns over the first postnatal weeks in TMEM165-CDG.
Asunto(s)
Alcalosis Respiratoria/diagnóstico , Alcalosis Respiratoria/etiología , Hiperamonemia/complicaciones , Hiperamonemia/diagnóstico , Alcalosis Respiratoria/terapia , Diagnóstico Diferencial , Femenino , Humanos , Hiperamonemia/terapia , Recién Nacido , Enfermedades del Recién Nacido/diagnóstico , Enfermedades del Recién Nacido/etiología , Enfermedades del Recién Nacido/terapia , Resultado del TratamientoRESUMEN
Deficiency of propionyl CoA carboxylase (PCC), a dodecamer of alpha and beta subunits, causes inherited propionic acidemia. We have studied, at the molecular level, PCC in 54 patients from 48 families comprised of 96 independent alleles. These patients of various ethnic backgrounds came from research centers and hospitals in Germany, Austria and Switzerland. The thorough clinical characterization of these patients was described in the accompanying paper (Grünert et al. 2012). In all 54 patients, many of whom originated from consanguineous families, the entire PCCB gene was examined by genomic DNA sequencing and in 39 individuals the PCCA gene was also studied. In three patients we found mutations in both PCC genes. In addition, in many patients RT-PCR analysis of lymphoblast RNA, lymphoblast enzyme assays, and expression of new mutations in E.coli were carried out. Eight new and eight previously detected mutations were identified in the PCCA gene while 15 new and 13 previously detected mutations were found in the PCCB gene. One missense mutation, p.V288I in the PCCB gene, when expressed in E.coli, yielded 134% of control activity and was consequently classified as a polymorphism in the coding region. Numerous new intronic polymorphisms in both PCC genes were identified. This study adds a considerable amount of new molecular data to the studies of this disease.
Asunto(s)
Análisis Mutacional de ADN , Acidemia Propiónica/diagnóstico , Acidemia Propiónica/genética , Adolescente , Alelos , Niño , Preescolar , Escherichia coli/genética , Femenino , Humanos , Lactante , Intrones , Linfocitos/citología , Masculino , Mutagénesis , Mutación , Polimorfismo Genético , Proteínas Recombinantes/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodosRESUMEN
BACKGROUND: Whereas propionic acidemia (PA) is a target disease of newborn screening (NBS) in many countries, it is not in others. Data on the benefit of NBS for PA are sparse. STUDY DESIGN: Twenty PA patients diagnosed through NBS were compared to 35 patients diagnosed by selective metabolic screening (SMS) prompted by clinical findings, family history, or routine laboratory test results. Clinical and biochemical data of patients from 16 metabolic centers in Germany, Austria, and Switzerland were evaluated retrospectively. Additionally, assessment of the intelligent quotient (IQ) was performed. In a second step, the number of PA patients who have died within the past 20 years was estimated based on information provided by the participating metabolic centers. RESULTS: Patients diagnosed through NBS had neither a milder clinical course regarding the number of metabolic crises nor a better neurological outcome. Among NBS patients, 63% were already symptomatic at the time of diagnosis, and <10% of all patients remained asymptomatic. Among all PA patients, 76% were found to be at least mildly mentally retarded, with an IQ <69. IQ was negatively correlated with the number of metabolic decompensations, but not simply with the patients' age. Physical development was also impaired in the majority of patients. Mortality rates tended to be lower in NBS patients compared with patients diagnosed by SMS. CONCLUSION: Early diagnosis of PA through NBS seems to be associated with a lower mortality rate. However, no significant benefit could be shown for surviving patients with regard to their clinical course, including the number of metabolic crises, physical and neurocognitive development, and long-term complications.
Asunto(s)
Tamizaje Neonatal/métodos , Acidemia Propiónica/diagnóstico , Adolescente , Austria , Niño , Preescolar , Femenino , Alemania , Humanos , Lactante , Recién Nacido , Pruebas de Inteligencia , Masculino , Pacientes Ambulatorios , Estudios Retrospectivos , Encuestas y Cuestionarios , SuizaAsunto(s)
Pruebas con Sangre Seca/métodos , Fluorometría/métodos , Espectrometría de Masas/métodos , Errores Innatos del Metabolismo/diagnóstico , Tamizaje Neonatal , Enfermedad de Fabry/sangre , Enfermedad de Fabry/diagnóstico , Enfermedad de Gaucher/sangre , Enfermedad de Gaucher/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Humanos , Recién Nacido , Errores Innatos del Metabolismo/sangre , RiesgoRESUMEN
Published data on treatment of fatty acid oxidation defects are scarce. Treatment recommendations have been developed on the basis of observations in 75 patients with long-chain fatty acid oxidation defects from 18 metabolic centres in Central Europe. Recommendations are based on expert practice and are suggested to be the basis for further multicentre prospective studies and the development of approved treatment guidelines. Considering that disease complications and prognosis differ between different disorders of long-chain fatty acid oxidation and also depend on the severity of the underlying enzyme deficiency, treatment recommendations have to be disease-specific and depend on individual disease severity. Disorders of the mitochondrial trifunctional protein are associated with the most severe clinical picture and require a strict fat-reduced and fat-modified (medium-chain triglyceride-supplemented) diet. Many patients still suffer acute life-threatening events or long-term neuropathic symptoms despite adequate treatment, and newborn screening has not significantly changed the prognosis for these severe phenotypes. Very long-chain acyl-CoA dehydrogenase deficiency recognized in neonatal screening, in contrast, frequently has a less severe disease course and dietary restrictions in many patients may be loosened. On the basis of the collected data, recommendations are given with regard to the fat and carbohydrate content of the diet, the maximal length of fasting periods and the use of l-carnitine in long-chain fatty acid oxidation defects.
Asunto(s)
Conferencias de Consenso como Asunto , Directrices para la Planificación en Salud , Errores Innatos del Metabolismo Lipídico/terapia , Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Carnitina/uso terapéutico , Preescolar , Dieta con Restricción de Grasas , Suplementos Dietéticos , Ácidos Docosahexaenoicos/uso terapéutico , Ácidos Grasos/metabolismo , Humanos , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico/diagnóstico , Tamizaje Neonatal , Oxidación-ReducciónRESUMEN
At present, long-chain fatty acid oxidation (FAO) defects are diagnosed in a number of countries by newborn screening using tandem mass spectrometry. In the majority of cases, affected newborns are asymptomatic at time of diagnosis and acute clinical presentations can be avoided by early preventive measures. Because evidence-based studies on management of long-chain FAO defects are lacking, we carried out a retrospective analysis of 75 patients from 18 metabolic centres in Germany, Switzerland, Austria and the Netherlands with special regard to treatment and disease outcome. Dietary treatment is effective in many patients and can prevent acute metabolic derangements and prevent or reverse severe long-term complications such as cardiomyopathy. However, 38% of patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency had intermittent muscle weakness and pain despite adhering to therapy. Seventy-six per cent of patients with disorders of the mitochondrial trifunctional protein (TFP)-complex including long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, had long-term myopathic symptoms. Of these, 21% had irreversible peripheral neuropathy and 43% had retinopathy. The main principle of treatment was a fat-reduced and fat-modified diet. Fat restriction differed among patients with different enzyme defects and was strictest in disorders of the TFP-complex. Patients with a medium-chain fat-based diet received supplementation of essential long-chain fatty acids. l-Carnitine was supplemented in about half of the patients, but in none of the patients with VLCAD deficiency identified by newborn screening. In summary, in this cohort the treatment regimen was adapted to the severity of the underlying enzyme defect and thus differed among the group of long-chain FAO defects.
Asunto(s)
Congresos como Asunto , Errores Innatos del Metabolismo Lipídico/terapia , Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Adolescente , Adulto , Niño , Preescolar , Ácidos Grasos/metabolismo , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico/diagnóstico , Persona de Mediana Edad , Tamizaje Neonatal , Oxidación-Reducción , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Pregnancy management in phenylketonuric women includes continuous dietary control starting before conception, aiming to maintain blood phenylalanine concentrations in a desirable range, irrespective of the fetal genetic PKU status. While the maternal phenylalanine hydroxylase (PAH) genotype will influence metabolic control, an effect of the fetal genetic PKU status on maternal metabolic control during pregnancy has not been described. We monitored three pregnancies of women with classical PKU by dietary protocols of daily phenylalanine intake, phenylalanine blood concentrations, and obstetric care. Patients 1 and 2 carried a heterozygous (not PKU-affected) fetus, while patient 3 was pregnant with a PKU-affected fetus (PAH p.R408W and p.R408W). The expected increase in phenylalanine tolerance during the course of pregnancy was observed in patients 1 and 2 in whom phenylalanine intake could be steadily increased from 400 to 1700 mg/day while phenylalanine blood concentrations remained in the desired range. Gain of body weight was 13.0 and 17.7 kg, respectively. In patient 3, the phenylalanine tolerance did not rise above 600 mg/day, and phenylalanine blood concentrations were above the desired range on several occasions. Caloric intake was therefore encouraged, which led to a weight gain of 20.0 kg. The course of pregnancy was otherwise normal in all three cases, and infants with normal birth weight and head circumference were born. The different phenylalanine tolerance in pregnancies with PKU-affected and non-affected fetuses suggests that PAH genotype and metabolic situation of the fetus influence maternal metabolic control. A phenylalanine tolerance remaining low in the third trimester of pregnancy may indicate fetal PKU.
Asunto(s)
Fenilalanina Hidroxilasa/genética , Fenilalanina/administración & dosificación , Fenilcetonuria Materna/dietoterapia , Fenilcetonuria Materna/genética , Adulto , Peso al Nacer , Femenino , Feto/enzimología , Genotipo , Heterocigoto , Homocigoto , Humanos , Recién Nacido , Fenilalanina/sangre , Fenilcetonuria Materna/enzimología , Embarazo , Aumento de PesoRESUMEN
AIM: FDG PET in hyperglycaemic subjects often suffers from limited statistical image quality, which may hamper visual and quantitative evaluation. In our study the following insulin bolus protocol is proposed for acute correction of hyperglycaemia (>7.0 mmol/l) in brain FDG PET. (i) Intravenous bolus injection of short-acting insulin, one I.E. for each 0.6 mmol/l blood glucose above 7.0. (ii) If 20 min after insulin administration plasma glucose is Asunto(s)
Encéfalo/diagnóstico por imagen
, Fluorodesoxiglucosa F18/farmacocinética
, Hiperglucemia/tratamiento farmacológico
, Insulina/uso terapéutico
, Tomografía de Emisión de Positrones
, Encéfalo/metabolismo
, Simulación por Computador
, Humanos
, Hiperinsulinismo/diagnóstico por imagen
, Hiperinsulinismo/metabolismo
, Hipoglucemiantes/uso terapéutico
, Cinética
, Radiografía
, Radioisótopos/farmacocinética
RESUMEN
The attachment of the Achilles tendon is part of an 'enthesis organ' that reduces stress concentration at the hard-soft tissue interface. The organ also includes opposing sesamoid and periosteal fibrocartilages, a bursa and Kager's fat pad. In addition, the deep crural and plantar fasciae contribute to Achilles stress dissipation and could also be regarded as components. Here we describe the sequence in which these various tissues differentiate. Serial sections of feet from spontaneously aborted foetuses (crown rump lengths 22-322 mm) were examined. All slides formed part of an existing collection of histologically sectioned embryological material, obtained under Spanish law and housed in the Universidad Complutense, Madrid. From the earliest stages, it was evident that the Achilles tendon and plantar fascia had a mutual attachment to the calcaneal perichondrium. The first components of the enthesis organ to appear (in the 45-mm foetus) were the retrocalcaneal bursa and the crural fascia. The former developed by cavitation within the mesenchyme that later gave rise to Kager's fat pad. The tip of the putative fat pad protruded into the developing bursa in the 110-mm foetus and fully differentiated adipocytes were apparent in the 17-mm foetus. All three fibrocartilages were first recognisable in the 332-mm foetus--at which time adipogenesis had commenced in the heel fat pad. The sequence in which the various elements became apparent suggests that bursal formation and the appearance of the crural fascia may be necessary to facilitate the foot movements that subsequently lead to fibrocartilage differentiation. The later commencement of adipogenesis in the heel than in Kager's pad probably reflects the non-weight environment in utero. The direct continuity between plantar fascia and Achilles tendon that is characteristic of the adult reflects the initial attachment of both structures to the calcaneal perichondrium rather than to the skeletal anlagen itself.
Asunto(s)
Tendón Calcáneo/anatomía & histología , Envejecimiento/fisiología , Imagen por Resonancia Magnética , Tendón Calcáneo/embriología , Tejido Adiposo/anatomía & histología , Tejido Adiposo/embriología , Adulto , Bolsa Sinovial/anatomía & histología , Bolsa Sinovial/embriología , Calcáneo/anatomía & histología , Calcáneo/embriología , Femenino , Desarrollo Fetal/fisiología , Fibrocartílago/anatomía & histología , Fibrocartílago/embriología , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Fucosidosis is a rare autosomal recessive lysosomal storage disease, resulting from a deficiency of alpha- L-fucosidase. We report on the clinical and MRI findings of a girl with this disorder. Developmental delay became obvious at an age between 6 and 12 months. Cranial MRI at 16 months revealed severe global hypomyelination of both supra- and infratentorial white matter but no involvement of basal ganglia or thalamus. No clinical signs typical for fucosidosis were present at this time, and psychomotor development still progressed slowly. Since the age of 2 years, progressive neurological deterioration occurred. The diagnosis was established by severely decreased activity of alpha- L-fucosidase in plasma and leukocytes and confirmed by the detection of compound heterozygosity for two missense mutations of the FUCA1 gene. A follow-up imaging at the age of 4 years showed progression of neuroradiological abnormalities, particularly progressive involvement of basal ganglia and thalami. The course of this patient and her MRI findings enlarge the clinical and neuroradiological spectrum of fucosidosis.
Asunto(s)
Enfermedades Desmielinizantes/patología , Fucosidosis/genética , Fucosidosis/patología , alfa-L-Fucosidasa/genética , Secuencia de Aminoácidos , Niño , Preescolar , Enfermedades Desmielinizantes/etiología , Femenino , Estudios de Seguimiento , Fucosidosis/complicaciones , Heterocigoto , Humanos , Lactante , Datos de Secuencia Molecular , Mutación Missense , Fenotipo , Polimorfismo de Longitud del Fragmento de Restricción , Trastornos Psicomotores/etiología , Trastornos Psicomotores/patología , Homología de Secuencia de Aminoácido , alfa-L-Fucosidasa/sangreRESUMEN
An elevated serum biotinidase activity in patients with glycogen storage disease (GSD) type Ia has been reported previously. The aim of this work was to investigate the specificity of the phenomenon and thus we expanded the study to other types of hepatic GSDs. Serum biotinidase activity was measured in a total of 68 GSD patients and was compared with that of healthy controls (8.7 +/- 1.0; range 7.0-10.6 mU/ml; n = 26). We found an increased biotinidase activity in patients with GSD Ia (17.7 +/- 3.9; range: 11.4-24.8; n = 21), GSD I non-a (20.9 +/- 5.6; range 14.6-26.0; n = 4), GSD III (12.5 +/- 3.6; range 7.8-19.1; n = 13), GSD VI (15.4 +/- 2.0; range 14.1-17.7; n = 3) and GSD IX (14.0 +/- 3.8; range: 7.5-21.6; n = 22). The sensitivity of this test was 100% for patients with GSD Ia, GSD I non-a and GSD VI, 62% for GSD III, and 77% for GSD IX, indicating reduced sensitivity for GSD III and GSD IX, respectively. In addition, we found elevated biotinidase activity in all sera from 5 patients with Fanconi-Bickel Syndrome (15.3 +/- 3.7; range 11.0-19.4). Taken together, we propose serum biotinidase as a diagnostic biomarker for hepatic glycogen storage disorders.
Asunto(s)
Biomarcadores/metabolismo , Biotinidasa/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Hígado/metabolismo , Análisis Mutacional de ADN , Glucógeno/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo I/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo II/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Enfermedad del Almacenamiento de Glucógeno Tipo III/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo III/genética , Enfermedad del Almacenamiento de Glucógeno Tipo VI/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo VI/genética , Humanos , Hepatopatías/enzimología , Sensibilidad y Especificidad , Manejo de EspecímenesRESUMEN
This study set out to determine whether the fat pad at the attachment of the Achilles tendon has features enabling it to function as an immune organ and a mechanosensory device, and to be a source of pain in insertional tendon injuries. Sections for histology and immunohistochemistry were cut from the Achilles tendon enthesis organ of 1 day old, 1 month, 4 month and 24 month old rats. For fluorescence and peroxidase immunohistochemistry, cryosections were labelled with primary antibodies directed against PGP9.5, substance P, neurofilament 200, calcitonin gene related peptide, CD68, CD36, myeloid related protein 14, actin and vinculin. The fat pad contained not only adipocytes, but also fibrous tissue, mast cells, macrophages, fibroblasts and occasional fibrocartilage cells. It was richly innervated with nerve fibres, some of which were likely to be nociceptive, and others mechanoreceptive (myelinated fibres, immunoreactive for neurofilament 200). The fibres lay between individual fat cells and in association with blood vessels. In marked contrast, the enthesis itself and all other components of the enthesis organ were aneural at all ages. The presence of putative mechanoreceptive and nociceptive nerve endings between individual fat cells supports the hypothesis that the fat pad has a proprioceptive role monitoring changes in the insertional angle of the Achilles tendon and that it may be a source of pain in tendon injuries. The abundance of macrophages suggests that the adipose tissue could have a role in combating infection and/or removing debris from the retrocalcaneal bursa.
Asunto(s)
Tendón Calcáneo/anatomía & histología , Tejido Adiposo/anatomía & histología , Tejido Adiposo/inmunología , Tejido Adiposo/inervación , Animales , Antígenos CD/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Biomarcadores/análisis , Péptido Relacionado con Gen de Calcitonina/análisis , Colágeno/análisis , Tejido Elástico/anatomía & histología , Fibrocartílago/anatomía & histología , Técnica del Anticuerpo Fluorescente , Inmunohistoquímica , Macrófagos/citología , Masculino , Ratas , Ratas Wistar , Ubiquitina Tiolesterasa/análisisRESUMEN
Fanconi-Bickel syndrome (FBS) is a rare disorder of glucose transport caused by autosomal recessive mutations in GLUT2. Clinically, FBS results in growth failure, hepatomegaly, renal Fanconi syndrome, and abnormal glucose homeostasis. We report a 23 month old female with FBS characterized by more severe and refractory hypoglycemia than typically seen in this disorder. Although previous reports indicate that FBS patients have diminished insulin secretion, our patient showed evidence of hyperinsulinism (HI). Sequence analysis showed that the patient was homozygous for a known null mutation in GLUT2, confirming the clinical diagnosis of FBS. Parental genotyping showed that the mother was heterozygous for the GLUT2 mutation, while the father was wild type. Tandem repeat marker analysis showed that the patient inherited the GLUT2 mutation via maternal isodisomy of chromosome 3. Further molecular testing showed that the patient was heterozygous for a mutation in ABCC8, a known cause of congenital HI. We discuss the patient's biochemical responses in light of the molecular findings.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Cromosomas Humanos Par 3/genética , Enfermedad del Almacenamiento de Glucógeno/patología , Mutación , Canales de Potasio de Rectificación Interna/genética , Canales de Potasio/genética , Receptores de Droga/genética , Secuencia de Bases , Análisis Mutacional de ADN , Glucosa/metabolismo , Transportador de Glucosa de Tipo 2/genética , Enfermedad del Almacenamiento de Glucógeno/genética , Enfermedad del Almacenamiento de Glucógeno/metabolismo , Humanos , Lactante , Insulina/metabolismo , Secreción de Insulina , Madres , Receptores de Sulfonilureas , Síndrome , Disomía UniparentalRESUMEN
The immunocytochemical localisation of vesicular glutamate transporters, VGLUT1 and VGLUT2, was employed to identify putative glutamatergic axon terminals innervating pelvic motoneurons. VGLUT1 terminals were sparsely distributed within lumbosacral spinal motoneuron pools, including the dorsolateral nucleus, retrodorsolateral nucleus and spinal nucleus of the bulbospongiosus. This was in marked contrast to VGLUT2 which was expressed in a robust innervation of these areas. Retrograde tracing was used to reveal motoneurons innervating the levator ani (LA) muscle. On these neurons, associations with VGLUT2 immunoreactive terminals were abundant while those with VGLUT1 were rare. Ultrastructural investigations revealed that VGLUT2 immunoreactive terminals made asymmetric synaptic contacts with dendrites of retrogradely labelled LA motoneurons. Quantification of VGLUT2 immunoreactive boutons in close association with these dendrites was carried out in young and aged animals using light microscopy. This revealed a significant decline in the numbers of VGLUT2 immunoreactive boutons on the more distal dendrites of motoneurons in aged rats. VGLUT2 boutons were reduced by approximately 21% from 11.25+/-0.5 per 35-mum length of dendrite in young rats to 8.89+/-0.5 in aged animals. This decline in glutamatergic input may reduce the excitability of LA motoneurons and consequently decrease the capacity of the rat to induce reflexive erections.
Asunto(s)
Envejecimiento/metabolismo , Neuronas Motoras/metabolismo , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo , Envejecimiento/patología , Animales , Inmunohistoquímica , Masculino , Microscopía Inmunoelectrónica , Neuronas Motoras/ultraestructura , Pelvis , Terminales Presinápticos/metabolismo , Terminales Presinápticos/ultraestructura , Ratas , Ratas Wistar , Proteína 1 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
INTRODUCTION: Pycnodysostosis is typically associated with short stature, multiple fractures without adequate trauma and high bone density on x-ray. The increased bone density is due to a genetic defect of cathepsin K, leading to dysfunctional osteoclastic bone resorption and bone remodeling. We wanted to know how this defect influences the trabecular and cortical volumetric bone mineral density of long bones as measured quantitatively by pQCT. METHODS: Three siblings of a consanguineous family were admitted to our hospital because of multiple fractures. Pycnodysostosis was diagnosed based on the clinical presentation with the characteristic dense appearance of their bones on x-ray. The distal and proximal radius of the patients and of control subjects was scanned using a Stratec XCT-2000 pQCT scanner and data were processed using the software provided by the manufacturer. Genomic DNA was extracted from blood samples of all three patients and their parents. The coding exons of the cathepsin K gene (CTSK) were amplified and sequenced. RESULTS: The patients displayed the typical features of pycnodysostosis: Short stature, delay of closure of the fontanelles, hypoplasia of the maxilla, spondylolysis of the lumbar spine, stubby hands and feet and a history of multiple fractures. Volumetric bone density was much higher in pycnodysostotic bone than in the control bones 686 +/- 28 mg/cm(3) in patients vs. 290 +/- 6 mg/cm(3) in controls; p = 0.001), especially in the trabecular compartment (733 +/- 26 mg/cm(3) in patients vs. 195 +/- 8 mg/cm(3) in controls; p < 0.001), but also in the cortical bone (1108 +/- 22 in patients vs. 1020 +/- 17 in controls; p < 0.01). In contrast to this finding, the patients displayed an elevation of alkaline phosphatase in the serum and free deoxypyridinoline-crosslinks (DPD) in the urine, suggesting osteomalacia. Sequencing of the cathepsin K gene revealed homozygosity for a novel missense mutation in all three patients predicting the amino acid exchange from arginine to tryptophan at position 46 (R46W). CONCLUSION: We present here for the first time quantitative data on the mineral density of bones of pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K. The elevated bone mineral density in the cortex and the changes in the serum markers suggest an effect of cathepsin K not only on bone volume, but also on bone mineralization. This might in part explain the increased susceptibility to fractures of patients with pycnodysostosis.
Asunto(s)
Densidad Ósea/genética , Catepsinas/genética , Fracturas Óseas/genética , Mutación Missense/genética , Osteocondrodisplasias/genética , Absorciometría de Fotón/métodos , Adolescente , Fosfatasa Alcalina/sangre , Aminoácidos/orina , Biomarcadores/análisis , Estatura , Catepsina K , Niño , Femenino , Fracturas Óseas/sangre , Fracturas Óseas/fisiopatología , Humanos , Vértebras Lumbares , Masculino , Osteocondrodisplasias/sangre , Osteocondrodisplasias/fisiopatología , Osteopetrosis/genética , Linaje , Radio (Anatomía)/fisiopatología , Espondilólisis/genética , SíndromeRESUMEN
Age-related changes in the number and size of large cholinergic terminals immunoreactive for vesicular acetylcholine transporter (VAChT), were documented for the dorsolateral nucleus (DLN), retrodorsolateral nucleus (RDLN) and spinal nucleus of the bulbospongiosus (SNB) of the lumbosacral spinal cord of male rats. The most significant changes were a large increase in the number and size of cholinergic terminals within the DLN of aged animals, together with a small decrease in terminal number within the RDLN. No significant age-associated differences in VAChT labeling were seen within the SNB. In both age groups, SNB motoneurons projecting to the levator ani muscle received about 9 to 10 contacts from large cholinergic terminals. Ultrastructural examination of the terminals revealed structures likely to be postsynaptic subsurface cisterns that are characteristic of type C terminal boutons. Since both the DLN and SNB contain motoneurons innervating pelvic muscles and sphincters, these findings provide further evidence for a central cholinergic influence on micturition and sexual reflexes and suggest that this may remain robust in the face of ageing.
Asunto(s)
Envejecimiento , Vías Eferentes/metabolismo , Neuronas Motoras/metabolismo , Pelvis/inervación , Médula Espinal/fisiología , Proteínas de Transporte Vesicular de Acetilcolina/metabolismo , Análisis de Varianza , Animales , Toxina del Cólera/metabolismo , Vías Eferentes/ultraestructura , Inmunohistoquímica , Región Lumbosacra , Masculino , Microscopía Inmunoelectrónica/métodos , Neuronas Motoras/ultraestructura , Ratas , Ratas WistarRESUMEN
A patient with early bilateral nuclear cataracts and subsequent diagnosis of Fanconi-Bickel syndrome is described. Despite impaired galactose and glucose metabolism, cataracts have been reported in only few cases with this disorder. We conclude that Fanconi-Bickel syndrome should be considered in the differential diagnosis of neonatal cataracts. The pathogenesis of this complication has not been fully elucidated.
Asunto(s)
Catarata/complicaciones , Catarata/diagnóstico , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/patología , Galactosa/metabolismo , Glucosa/metabolismo , HumanosRESUMEN
Preganglionic neurones in the lumbosacral spinal cord give rise to nerves providing the parasympathetic and sympathetic innervation of pelvic organs. These neurones are modulated by neurotransmitters released both from descending supra-spinal pathways and spinal interneurones. Though serotonin has been identified as exerting a significant influence on these neurones, few studies have investigated the circuitry through which it achieves this particularly in relation to sympathetic preganglionic neurones. Using a combination of neuronal tracing and multiple immunolabeling procedures, the current study has shown that pelvic preganglionic neurones receive a sparse, and probably non-synaptic, axosomatic/proximal dendritic input from serotonin-immunoreactive terminals. This was in marked contrast to dopamine beta hydroxylase-immunoreactive terminals, which made multiple contacts. However, the demonstration of both serotonin, and dopamine beta hydroxylase immunoreactive terminals on both parasympathetic and sympathetic preganglionic neurones provides evidence for direct modulation of these cells by both serotonin and norepinephrine. Serotonin-containing terminals displaying conventional synaptic morphology were often seen to contact unlabeled somata and dendritic processes in regions surrounding the labeled preganglionic cells. It is possible that these unlabeled structures represent interneurones that might allow the serotonin containing axons to exert an indirect influence on pelvic preganglionic neurones. Since many spinal interneurones employ GABA as a primary fast acting neurotransmitter we examined the relationship between terminals that were immunoreactive for serotonin or GABA and labeled pelvic preganglionic neurones. These studies were unable to demonstrate any direct connections between serotonin and GABA terminals within the intermediolateral or sacral parasympathetic nuclei. Colocalization of serotonin and GABA was very rare but terminals immunoreactive for each were occasionally seen to contact the same unlabeled processes in close proximity. These results suggest that in the rat, the serotonin modulation of pelvic preganglionic neurones may primarily involve indirect connections via local interneurones.