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1.
Orphanet J Rare Dis ; 13(1): 164, 2018 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-30231941

RESUMEN

BACKGROUND: Classical Galactosaemia (CG) (OMIM #230400) is a rare inborn error of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). Long-term complications persist in treated patients despite dietary galactose restriction with significant variations in outcomes suggesting epigenetic glycosylation influences. Primary Ovarian Insufficiency (POI) is a very significant complication affecting females with follicular depletion noted in early life. We studied specific glycan synthesis, leptin system and inflammatory gene expression in white blood cells as potential biomarkers of infertility in 54 adults with CG adults (27 females and 27 males) (age range 17-51 yr) on a galactose-restricted diet in a multi-site Irish and Dutch study. Gene expression profiles were tested for correlation with a serum Ultra-high Performance Liquid Chromatography (UPLC)-Immunoglobulin (IgG)-N-glycan galactose incorporation assay and endocrine measurements. RESULTS: Twenty five CG females (93%) had clinical and biochemical evidence of POI. As expected, the CG female patients, influenced by hormone replacement therapy, and the healthy controls of both genders showed a positive correlation between log leptin and BMI but this correlation was not apparent in CG males. The strongest correlations between serum leptin levels, hormones, G-ratio (galactose incorporation assay) and gene expression data were observed between leptin, its gene and G-Ratios data (rs = - 0.68) and (rs = - 0.94) respectively with lower circulating leptin in CG patients with reduced IgG galactosylation. In CG patients (males and females analysed as one group), the key glycan synthesis modifier genes MGAT3 and FUT8, which influence glycan chain bisecting and fucosylation and subsequent cell signalling and adhesion, were found to be significantly upregulated (p < 0.01 and p < 0.05) and also the glycan synthesis gene ALG9 (p < 0.01). Both leptin signalling genes LEP and LEPR were found to be upregulated (p < 0.01) as was the inflammatory genes ANXA1 and ICAM1 and the apoptosis gene SEPT4 (p < 0.01). CONCLUSIONS: These results validate our previous findings and provide novel experimental evidence for dysregulation of genes LEP, LEPR, ANXA1, ICAM1 and SEPT4 for CG patients and combined with our findings of abnormalities of IgG glycosylation, hormonal and leptin analyses elaborate on the systemic glycosylation and cell signalling abnormalities evident in CG which likely influence the pathophysiology of POI.


Asunto(s)
Galactosa/metabolismo , Galactosemias/sangre , Galactosemias/fisiopatología , Infertilidad/sangre , Infertilidad/fisiopatología , Adolescente , Adulto , Femenino , Fucosiltransferasas/genética , Fucosiltransferasas/metabolismo , Galactosemias/metabolismo , Humanos , Infertilidad/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Leptina/sangre , Persona de Mediana Edad , N-Acetilglucosaminiltransferasas/genética , N-Acetilglucosaminiltransferasas/metabolismo , Insuficiencia Ovárica Primaria/sangre , Insuficiencia Ovárica Primaria/metabolismo , Insuficiencia Ovárica Primaria/fisiopatología , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Septinas/genética , Septinas/metabolismo , Adulto Joven
2.
J Inherit Metab Dis ; 33 Suppl 3: S181-5, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20300853

RESUMEN

Two young girls without a notable medical history except for asthma presented with an acute toxic encephalopathy with very low serine concentrations both in plasma and cerebrospinal fluid (CSF) comparable to patients with 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency. Clinical symptoms and enzyme measurement (in one patient) excluded 3-PGDH deficiency. Deficiencies in other serine biosynthesis enzymes were highly unlikely on clinical grounds. On basis of the fasting state, ketone bodies and lactate in plasma, urine and CSF, we speculate that reduced serine levels were due to its use as gluconeogenic substrate, conversion to pyruvate by brain serine racemase or decreased L-serine production because of a lack of glucose. These are the first strikingly similar cases of patients with a clear secondary serine deficiency associated with a toxic encephalopathy.


Asunto(s)
Edema Encefálico/etiología , Encéfalo/metabolismo , Síndromes de Neurotoxicidad/etiología , Serina/líquido cefalorraquídeo , Serina/deficiencia , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Glucemia/metabolismo , Edema Encefálico/sangre , Edema Encefálico/líquido cefalorraquídeo , Edema Encefálico/diagnóstico , Niño , Preescolar , Metabolismo Energético , Resultado Fatal , Femenino , Humanos , Cuerpos Cetónicos/sangre , Ácido Láctico/sangre , Síndromes de Neurotoxicidad/sangre , Síndromes de Neurotoxicidad/líquido cefalorraquídeo , Síndromes de Neurotoxicidad/diagnóstico , Valor Predictivo de las Pruebas , Ácido Pirúvico/metabolismo , Serina/sangre
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