Transition from paediatric care to adult care for patients with mucopolysaccharidosis. / Transición desde la asistencia pediátrica a la adulta en pacientes con mucopolisacaridosis.

Mucopolysaccharidosis are multisystem diseases that require large multidisciplinary teams for their care. Specific recommendations are therefore needed for the transition from childhood to adulthood in this patient group. To overcome the barriers that might arise during the transition, the authors consider it essential to implement a flexible plan with a coordinator for the entire process, systematising the information through a standardised paediatric discharge report and educating the patient and their family about the disease, showing the characteristics of the healthcare system in this new stage. The final objective is that, once the transition to adulthood has been completed, the patient's autonomy and potential development are maximised and that the patient receives appropriate healthcare during this transition.

Residual enzymatic activity as a prognostic factor in patients with Gaucher disease type 1: correlation with Zimran and GAUSS-I index and the severity of bone disease.

BACKGROUND: Gaucher disease (GD) is an autosomal recessive disorder produced by mutations in the glucocerebrosidase gene (GBA), causing storage of glucosylceramide in reticuloendothelial cells in multiple organs. Traditionally, the prediction of the phenotype based on the genotype has been reported to be limited. SUBJECTS AND METHODS: We investigated the correlation between the enzymatic residual activity (ERA) and the phenotype at diagnosis of the disease in 45 GD Spanish patients (44 with type I and 1 with type III GD). The genotype involved two of the following previously expressed proteins: c.517A > C (T134P), 1%; c.721G > A (G202R), 17%; c.1090G > T (G325W), 13.9%; c.1208G > A (S364N), 4.1%; c.1226A > G (N370S), 17.8%; c.1246G > A (G377S), 17.6%; c.1289C > T (P391L), 8.5%; c.1448T > C (L444P), 3%; and c.1504C > T (R463C), 24.5%. Recombinant alleles, deletion of 55 bp in exon 9 and 84GG mutation were considered as mutations with no residual enzymatic activity. RESULTS: The ERA showed a statistically significant correlation with chitotriosidase (P < 0.001), age (P < 0.001), spleen size (P < 0.001), 'Zimran's Severity Score Index' (P < 0.01) and the 'Gaucher Disease Severity Score Index-Type I' (P < 0.0001) at diagnosis of the disorder. Previous to any medical intervention, a comparison between the ERA and bone involvement, demonstrated a statistically significant relationship (P < 0.01) between the two variables. CONCLUSIONS: This study data allowed us to define a new criterion for prognostic assessment of the disease at diagnosis, called Protein Severity Index, which expresses the theoretical severity of the genotype presented by patients, according to the corresponding ERA.

[Rare complication in a patient with giant cell arteritis]. / Paciente con complicación poco frecuente de arteritis de células gigantes.

Giant cell arteritis (temporal arteritis) is a chronic vasculitis that usually affects older people. Although this is a systemic disease, it most often affects the cranial arteries. The most frequent complication of this disorder is visual loss. We report the case of a patient who suffered several rare complications, including tongue necrosis, as a result of being diagnosed with giant cell arteritis following the start of treatment.

High prevalence of the 55-bp deletion (c.1263del55) in exon 9 of the glucocerebrosidase gene causing misdiagnosis (for homozygous N370S (c.1226A > G) mutation) in Spanish Gaucher disease patients.

Gaucher disease (GD) is the most frequent lysosomal storage disease, caused by mutations in the acid beta-glucosidase gene (GBA). The c.1226A > G (N370S) mutation is associated with non-neuronopathic disease (type 1). However, we have observed some discrepancy between genotype and phenotype in Spanish Gaucher disease patients homozygous for the c.1226A > G mutation. A deletion of 55 bp in the exon 9 GBA gene, corresponding to the deleted portion of the beta-glucosidase pseudogene, has been previously reported as a cause of erroneous assignment of 1226G/1226G homozygous patients when the genotype has been performed by PCR assay. We had originally identified 25 (out of 124) unrelated Gaucher disease patients as being putative homozygotes for the c.1226A > G mutation. By means of a new PCR-based assay, we were able to distinguish between the true homozygous patients and the carriers of the 55-bp deletion in exon 9 of the GBA gene. The 55-bp deletion was detected in 10 out of 25 samples (40%) [7 with the 55-bp deletion, 1 RecTL, 1 RecNciI (both including the deletion) and one rearrangement]. Such a high prevalence in this sample suggests that this allele can be more common than expected among GD patients.

Identification and characterization of a novel mutation c.1090G>T (G325W) and nine common mutant alleles leading to Gaucher disease in Spanish patients.

BACKGROUND: Gaucher disease is an autosomal recessive disorder resulting from mutations in the glucocerebrosidase gene (GBA). The lack of full genotype/phenotype correlation complicates counseling regarding clinical outcome and treatment recommendations. SUBJECTS AND METHODS: Several mutations in the human beta-glucosidase gene associated with Gaucher disease in 16 Spanish families were identified utilizing a combination of methods: enzymatic restriction, PCR-SSCP, and sequence analyses. Expression studies were performed following the introduction of the mutagenized human acid beta-glucosidase cDNA into COS-1 cells, and the residual enzyme activities of the mutant protein were measured and compared with the normal cDNA. RESULTS: The identified mutations and corresponding residual enzyme activities of the expressed protein are as follows: c.517A>C (T134P), 1%; c.721G>A (G202R), 17%; c.1090G>T (G325W), 13.9%; c.1093G>A (E326K), 26%; c.1208G>A (S364N), 4.1%; c.1226A>G (N370S), 17,8%; c.1246G>A (G377S), 17.6%; c.1289C>T (P391L), 8.5%; c.1448T>C (L444P), 3%; and c.1504C>T (R463C), 24.5%. CONCLUSIONS: Site-directed mutagenesis and expression in COS-1 cells are useful methods to increase our understanding of causality in Gaucher disease and the correlation between disease severity, gene defects, and residual enzyme activity. Our study demonstrates the functional consequences of the identified human beta-glucosidase mutations (T134P, S364N, G377S, P391L, and G325W) and provide evidence for the molecular and biochemical basis of Gaucher disease, among patients of Spanish ancestry.

[The effects of enalapril on exercise capacity and right ventricular function in patients with chronic cor pulmonale]. / Efectos del enalapril sobre la capacidad de ejercicio y la función ventricular derecha en pacientes con cor pulmonale crónico.

BACKGROUND: Chronic cor pulmonale (CPC) in patients with chronic obstructive pulmonary disease (COPD) is a predictor of mortality. ACE inhibitors (ACEIs) improve the symptoms and reduce mortality of left ventricular or congestive failure, however their long term use in patients with CPC has not been tested. The aim of this study is to assess the effect on exercise tolerance and cardiorespiratory function of long term administration of enalapril in patients with CPC. METHODS: Placebo-controlled, double blind, randomized study. 28 patients (24 men and 4 women, mean age of 68.11 +/- 7.78, range 51-79) with CPC and without exacerbation of their respiratory symptoms at baseline were double blind randomised to receive enalapril or placebo for 6 months, added to their previous therapy. Respiratory function test, exercise tolerance ("six minutes walking test") and isotopic ventriculography were performed at baseline and at the end of the study. RESULTS: At baseline there were no differences in FEV1, FVC, FEV1/FVC and exercise tolerance. Both placebo and enalapril were well tolerated. At the end of the study, patients taking enalapril increased their exercise tolerance an 8.9% (19 m) vs 4.7% (33 m) in the placebo group (p 0.44; 95 percent confidence interval, -41.10 to 91.99). RVEF improved a 6.4% with enalapril but worsened a 7.09% in placebo group (p 0.15; 95 percent confidence interval, -12.87 to 2.10). CONCLUSIONS: Long term administration of enalapril do not improve neither exercise tolerance, nor right ventricular (RV) function, although given in increasingly doses is well tolerated and might prevent further worsening in RV systolic function.

Efectos del enalapril sobre la capacidad de ejercicio y la función ventricular derecha en pacientes con Cor pulmonale crónico / Effects of enalapril on exercise capacity and rigth ventricular function in patients with chronic cor pulmonale

Fundamentos: El Cor Pulmonale Crónico (CPC) en pacientes con limitación crónica al flujo aéreo es un predictor de mortalidad. Los IECA reducen la morbimortalidad en pacientes con fallo ventricular izquierdo o congestivo. Su efecto a largo plazo en pacientes con CPC no ha sido investigado. Nos propusimos investigar el efecto del enalapril sobre la capacidad de esfuerzo y función cardiorrespiratoria en pacientes con CPC. Métodos: Estudio prospectivo, doble ciego, randomizado, controlado con placebo. 28 pacientes (24 hombres y 4 mujeres, con edad media de 68,11 ñ 7,78, rango 51-79) con CPC, clinicamente estables, fueron randomizados para recibir enalapril o placebo, vía oral, durante 6 meses, añadido a su terapia habitual. Antes del inicio y a los 6 meses se realizaron test de función respiratoria, de tolerancia al esfuerzo ("test de 6 minutos caminando") y ventriculografía isotópica Resultados: No existían diferencias en los valores basales de FEV1, FVC, FEV1/FVC y tolerancia al esfuerzo. Al final del estudio los pacientes del grupo enalapril mostraban un incremento de tolerancia al ejercicio del 8,9 porciento (19 m) vs 4,7 porciento (33 m) los del grupo placebo (p 0,44; 95 porciento IC, -41,10 a 91,99). La fracción de eyección ventrícular derecha mejoró un 6,4 porciento con enalapril pero empeoró un 7,09 porciento con placebo (p 0,15; 95 porciento IC, -12,87 a 2,10). Conclusiones: La administración a largo plazo de enalapril en dosis crecientes aunque se tolera bien en el CPC no mejora significativamente la tolerancia al esfuerzo, ni la función ventricular derecha (AU)

Co-morbidity in Gaucher's disease results of a nationwide enquiry in Spain.

SHORT INTRODUCTION: Gaucher's disease (GD) is an autosomal recessive disease produced by mutations of the Glucocerebrosidase gene. Carriers are considered to be healthy subjects because there is no manifestation of the disease, but they show signs of macrophage disfunction. The aim of the study was to determine if GD patients and non affected carriers risk suffering other diseases when compared to healthy non-carrier relatives. DESIGN: Epidemiologic study of historic cohorts. The fact that they have one or two mutated alleles has been considered to be the risk factor leading to other conditions (Dementia, Parkinson disease, Ischemic stroke, Ischemic heart disease, Non rheumatic valvular disease, Cancer hematological and non-hematological, Pulmonary fibrosis, Tuberculosis, Gallstones and Schizophrenia). All people, patients, carriers and healthy controls shared the same genetical background and environmental influence. - Patients and relatives enrolled on the Spanish Gaucher Disease Registry were evaluated. STATISTICS: For the Relative-Risk calculation the Mantel-Haenszel test was applied. Yates' correction was used when size sample was too small. A value of p <0.05 was accepted for statistical significance. RESULTS: 370 people, from 79 different families, were surveyed. We received evaluable information from 45 families (56%), totalling 258 people (69%): 59 healthy subjects (Mean age 32. 20, RANGE: 10-85; M 57.63%/F 42.37%), 132 carriers (Mean age 35.91, RANGE: 1-79; M 56.82%/F 43.18%) and 67 patients (Mean age 32.16, Range: 1-76; M 44.78%/F 55.22%. - Relative Risk of suffering any disease with regard to Gaucher's status: Patient vs Healthy 9.69 (95% Confidence interval [CI] 2.00-63.99; p 0.0006). Patient vs Carrier 3.74 (CI 1.53-9.27; p 0.001); Carrier vs Healthy 2.59 (CI 0. 52-12.50; p 0.21). Relative Risk of suffering any disease with regard to sex was 3.96 for female patients (CI 1.01-16.75; p 0.02) and 1.34 for female carriers (CI 0.27-6.75; p = 0.68). CONCLUSION: As a group, Gaucher's patients seem to have a greater risk of suffering other common unrelated diseases than carriers or healthy relatives. This excess of risk is particularly higher among female patients and can not be explained in terms of differences in age. Carrier status doesn't seem to highten the risk of suffering other diseases.

Beta-glucocerebrosidase gene locus as a link for Gaucher's disease and familial hypo-alpha-lipoproteinaemia.

BACKGROUND: Gaucher's disease is the most common lysosomal storage disorder, caused by deficiency of glucocerebrosidase resulting from homozygosity for any of several mutations of the glucocerebrosidase gene locus. Affected people have decreased concentrations of LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C). We assessed the association between mutations in the glucocerebrosidase locus and hypo-alpha-lipoproteinaemia. METHODS: We studied 258 people from 43 unrelated Spanish families. 57 participants were affected, 137 were non-affected carriers, and 64 were non-carriers. We determined glucocerebrosidase genotypes and measured plasmid lipids, apolipoproteins A-I, B, and E, and leucocyte glucocerebrosidase activity. FINDINGS: The most common glucocerebrosidase mutations were N370S (45%), L444P (23%), and G377S (5%). Deletions and recombinants accounted for another 5%, and point mutations in exons 5, 6, 9, and 10 were present in 12%. Affected participants had lower LDL-C and HDL-C concentrations than non-affected carriers (p<0.001) and non-carriers (p<0.001). HDL-C values were also significantly different between the non-affected carriers and non-carriers. Mutations at this locus may account for as much as 19.5% of the genetic variability in HDL-C in the population studied. INTERPRETATION: Heterozygosity for these mutations at the glucocerebrosidase locus does not result in clinical expression of Gaucher's disease but can decrease HDL-C concentrations. Given the high frequency of these mutations, the glucocerebrosidase locus might lead to familial low alpha-lipoproteinaemia in up to 2% of the general population and be one of the most common known genetic causes of HDL-C.