HiperCKemia paucisintomática secundaria a mutación en el gen ANO5 / Paucisymptomatic hyperCKemia due to a mutation in the ANO5 gene

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Septo-optic dysplasia caused by a novel FLNA splice site mutation: a case report.

BACKGROUND: Septo-optic dysplasia (SOD), also known as de-Morsier syndrome, is a rare disorder characterized by any combination of optic nerve hypoplasia, pituitary gland hypoplasia, and midline abnormalities of the brain including absence of the septum pellucidum and corpus callosum dysgenesis. The variable presentation of SOD includes visual, neurologic, and/or hypothalamic-pituitary endocrine defects. The unclear aetiology of a large proportion of SOD cases underscores the importance of identifying novel SOD-associated genes. CASE PRESENTATION: To identify the disease-causing gene in a male infant with neonatal hypoglycaemia, dysmorphic features, and hypoplasia of the optic nerve and corpus callosum, we designed a targeted next-generation sequencing panel for brain morphogenesis defects. We identified a novel hemizygous deletion, c.6355 + 4_6355 + 5delAG, in intron 38 of the FLNA gene that the patient had inherited from his mother. cDNA studies showed that this variant results in the production of 3 aberrant FLNA transcripts, the most abundant of which results in retention of intron 38 of FLNA. CONCLUSIONS: We report for the first time a case of early-onset SOD associated with a mutation in the FLNA gene. This finding broadens the spectrum of genetic causes of this rare disorder and expands the phenotypic spectrum of the FLNA gene.

[De novo sporadic mutation in the KCND3 gene in a patient with early onset chronic ataxia]. / Mutacion puntual de novo en el gen KCND3 en un paciente con ataxia cronica de inicio precoz.

TITLE: Mutacion puntual de novo en el gen KCND3 en un paciente con ataxia cronica de inicio precoz.

Evolution of maple syrup urine disease in patients diagnosed by newborn screening versus late diagnosis.

Maple syrup urine disease (MSUD) is a rare metabolic disorder for which the newborn screening (NBS) is possible but it has not been yet implemented for most Spanish regions. In the present study, we assess the clinical features and outcome of 14 MSUD Spanish patients with similar treatment protocol diagnosed either by NBS or by clinical symptoms. Eight patients were detected by NBS, four classic and four moderate MSUD. The average age at detection was 4.6 days, the mean plasmatic concentration of leucine at diagnosis was 1807 µM; the average number of days with leucine >1000 µM was 0.7 (0-4) and the mean number of total hospitalizations was 1.6 (0-5). Mean follow-up time was 70 months. They had good evolution: all remain asymptomatic, but 2 patients have attention deficit and hyperactivity disorder. Six patients with late diagnosis of classic MSUD were followed during 41 months. All presented with acute encephalopathy during the first month of life, mean leucine levels of 2355 µM, mean number of days with leucine >1000 µM of 6.6 (1-13) and mean number of total hospitalizations of 5.3 (4-7). Only two patients have a psychomotor development index in the lower limit (80 and 83). For all patients a good genotype-phenotype correlation was found and four novel mutations were identified: p.A311H, p.T84S, p.T397L, pL398P. Our study support that NBS improves prognosis of MSUD patients. But early diagnosis and an aggressive treatment together with a close monitoring of leucine levels improve neurological evolution in MSUD patients, even for those not detected by NBS.

Molecular epidemiology and BH4-responsiveness in patients with phenylalanine hydroxylase deficiency from Galicia region of Spain.

Knowledge of hyperphenylalaninemia (HPA) mutational spectrum in a population allows in many cases an accurate prediction of the phenotype and tetrahydrobiopterin (BH4) responsiveness, thus selecting an adequate treatment. In this work, we have performed the molecular characterization of 105 HPA patients from Galicia, in the northwest region of Spain, evaluating their phenotype and BH4 response. The mutational spectrum analysis showed 47 distinct mutations in 89 families, 37 of them (78.7%) corresponding to missense mutations. Six mutations account for 47.2% of all the investigated alleles, each one with a frequency ≥ 5% (IVS10-11G>A, p.R261Q, p.V388M, p.R176L, p.E280K, p.A300S). The most prevalent HPA mutations in Galicia are the common Mediterranean mutation IVS10-11G>A and p.R261Q, with frequencies of 13.8% and 10.5%, respectively. One novel mutation (p.K361Q; c.1081A>C) was also reported. Although a good genotype-phenotype correlation is observed, there is no exact correlation for some genotypes involving mutations p.R261Q, p.I65T or IVS10-11G>A. Forty seven patients were monitored for post-challenge BH4, establishing genotype-based predictions of BH4-responsiveness in all of them. All phenylketonuric patients with 2 nonresponsive mutations were unresponsive to BH4 and patients with mutations previously associated with BH4 responsiveness in the two alleles had a clear positive response to the test, with the exception of 5 patients with mutations p.R261Q, p.I65T and p.R68S. Our study supports a similar degree of heterogeneity of the HPA mutation spectrum in Galicia compared to reported data from Southern Europe. Patients carrying null mutations in both alleles showed the highest degree of concordance with the most severe phenotypes. Genotype is a good predictor of BH4 response.

Perspectivas actuales en el tratamiento del hiperinsulinismo congénito / Current views on the therapeutic management of congenital hyperinsulinism

El hiperinsulinismo congénito (HIC) engloba a un grupo de entidades clínica, genética y morfológicamente heterogéneas, que presentan en común una hipoglucemia persistente hipocetósica asociada a valores inapropiadamente elevados de insulina para dichos estados de hipoglucemia. Su diagnóstico se realiza, en muchas ocasiones, demasiado tarde y de forma incompleta debido, entre otras razones, al desconocimiento acerca de esta rara enfermedad, a su resolución muchas veces mortal antes del diagnóstico, a la expresividad altamente variable y heterogénea, que dificulta el diagnóstico, y a una incorrecta clasificación histopatológica de la enfermedad. Sin embargo, el conocimiento reciente de las bases moleculares de esta enfermedad en nuestro país abre un nuevo abanico de posibilidades diagnósticas y terapéuticas. En el presente trabajo queremos proponer un esquema global de actuación para el tratamiento de esta enfermedad, intentando resumir los conocimientos clínicos y moleculares de los que se dispone hasta el momento, de manera que pueda servir como guía básica para los pediatras que se encuentren en su práctica clínica ante un caso de HIC. El propósito fundamental es contribuir a mejorar tanto el diagnóstico como el pronóstico y el tratamiento de esta enfermedad en nuestro país (AU)

Congenital hyperinsulinism comprises a group of clinically, genetically and histopathologically heterogeneous entities; however, all of them coincide in that the patients have recurrent and persistent hypoketotic hypoglycemia associated withab normally elevated insulin levels. It is often diagnosed toolate and employing inadequate means due to, among other reasons, the ignorance with regard to this uncommon disease, the high rate of mortality prior to diagnosis, the wide heterogeneity of the clinical symptoms and treatment responses that make the diagnosis difficult and, in all probability, an erroneous histopathological classification of the disease. However, the recent knowledge of the molecular basis of this disease in Spain opens up new diagnostic and therapeutic possibilities. In the present review, we propose an overall strategy for the therapeutic management of this disease, summarizing the clinical and molecular concepts available to date, which could serve as basic guidelines for any pediatrician treating a patient with congenital hyperinsulinism. Thus, we attempt to improve the clinical management of this disease in Spain (AU)

[18F-fluoro-L-DOPA PET-CT imaging combined with genetic analysis for optimal classification and treatment in a child with severe congenital hyperinsulinism]. / Estudio PET-TC con 18F-fluoro-L-DOPA combinado con el análisis genético para la optimización de la clasificación y tratamiento de un niño con hiperinsulinismo congénito grave.

BACKGROUND: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in infancy. The differential diagnosis between focal and diffuse forms of CHI is of great importance when planning surgery. The aim of this article is to show the first case of focal CHI diagnosed in Spain using PET-CT imaging combined with genetic analysis. METHODS: A 13 month child with CHI and normal conventional radiological investigations treated with diazoxide, diet control and feeding by gastrostomy is presented. Genetic analysis of ABCC8 and KCNJ11 genes and PET-TAC using 18F-fluoro-L-DOPA were performed. RESULTS: A pathological mutation (G111R) in the paternal allele of ABCC8 was detected. PET-CT scanning using 18F-fluoro-L-DOPA showed a focus of high uptake in the body of the pancreas compatible with adenoma that was hystopathologically confirmed. After surgical resection the patient is asymptomatic without needing either pharmacological treatment or dietetic control. CONCLUSIONS: The combination of genetic analysis and 18F-fluoro-L-DOPA PET-TAC shows a great potential for the identification, location and guideline for surgery in CHI.

Estudio PET-TC con 18F-fluoro-L-DOPA combinado con el análisis genético para la optimización de la clasificación y tratamiento de un niño con hiperinsulinismo congénito grave / 18F-fluoro-L-DOPA PET-CT imaging combined with genetic analysis for optimal classification and treatment in a child with severe congenital hyperinsulinism

Fundamento: La distinción entre el hiperinsulinismo congénito (CHI) focal y difuso es esencial de cara al tratamiento y pronóstico de la enfermedad. El objetivo es presentar el primer caso de CHI focal diagnosticado en España combinando los estudios genético y PET-TC. Métodos: Paciente de 13 meses con CHI y pruebas de imagen convencionales normales, tratado con diazóxido, control dietético y alimentación por gastrostomía. Se analizó la secuencia de los genes ABCC8 y KCNJ11, y realizó una PET-TC con 18F-fluoro-L-DOPA. Resultados: Se detectó una mutación patogénica (G111R) en el alelo paterno de ABCC8. La PET-TC demostró un foco hipercaptante en el cuerpo del páncreas compatible con un adenoma confirmado histopatológicamente. Tras la cirugía el paciente continúa asintomático sin tratamiento farmacológico ni medidas dietéticas. Conclusiones: La combinación del análisis genético y la PET-TC con 18F-fluoro-L-DOPA muestra un gran potencial para la identificación, localización y guía de la cirugía del CHI (AU)

Background: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in infancy. The differential diagnosis between focal and diffuse forms of CHI is of great importance when planning surgery. The aim of this article is to show the first case of focal CHI diagnosed in Spain using PET-CT imaging combined with genetic analysis. Methods: A 13 month child with CHI and normal conventional radiological investigations treated with diazoxide, diet control and feeding by gastrostomy is presented. Genetic analysis of ABCC8 and KCNJ11 genes and PET-TAC using 18F-fluoro-L-DOPA were performed. Results: A pathological mutation (G111R) in the paternal allele of ABCC8 was detected. PET-CT scanning using 18F-fluoro-L-DOPA showed a focus of high uptake in the body of the pancreas compatible with adenoma that was hystopathologically confirmed. After surgical resection the patient is asymptomatic without needing either pharmacological treatment or dietetic control. Conclusions: The combination of genetic analysis and 18F-fluoro-L-DOPA PET-TAC shows a great potential for the identification, location and guideline for surgery in CHI (AU)

Hipoglucemia neonatal / No disponible

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Comparison of predose vs 2-h postdose blood metabolites/cyclosporine ratios in kidney and liver transplant patients.

OBJECTIVES: It has recently been suggested that when adjusting doses of cyclosporine (CsA), determining its concentration in blood samples taken 2 h postdose (C(2)) is more clinically beneficial than using the predose concentration (C(0)). We determined C(0) and C(2) concentrations of CsA and their metabolites in samples taken from nine kidney and seven liver transplant patients. Similarly, the so-called metabolic ratios (MR)-metabolites to CsA parent ratios-were calculated to characterise the most suitable moment of blood sampling for obtaining a greater analytical specificity with monoclonal immunoassays. METHODS: The determination of CsA and CsA + metabolites was made using the enzyme multiplied immunotechnique and the polyclonal fluorescence polarization immunoassay Abbott TDx, respectively. RESULTS: The poor correlation between C(0) and C(2) of CsA (n = 82, r = 0.387, p < 0.001) is greatly inferior to that obtained between C(0) and C(2) of metabolites (n = 82, r = 0.912, p < 0.001). A highly significant difference (p < 0.001) was found between MR(0) values (mean 2.87 +/- 0.12, median 2.48) and MR(2) values (mean 1.73 +/- 0.09, median 1.46), although there is a good correlation between them (r = 0.878, p < 0.001). CONCLUSIONS: The extent of the positive bias (deviation) of CsA immunoassays compared with the high-performance liquid chromatography results is related to the MR values. As the MR(2) values are significantly lower than the corresponding MR(0), in practice a greater analytical specificity would be obtained with the different monoclonal immunoassays in the determination of the 2 h postdose CsA concentration than in that of trough concentration.