RESUMO
L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of L2HGA can be made based on magnetic resonance imaging (MRI), biochemical analysis, and mutational analysis of L2HGDH. About 200 patients with elevated concentrations of 2-hydroxyglutarate (2HG) in the urine were referred for chiral determination of 2HG and L2HGDH mutational analysis. All patients with increased L2HG (n=106; 83 families) were included. Clinical information on 61 patients was obtained via questionnaires. In 82 families the mutations were detected by direct sequence analysis and/or multiplex ligation dependent probe amplification (MLPA), including one case where MLPA was essential to detect the second allele. In another case RT-PCR followed by deep intronic sequencing was needed to detect the mutation. Thirty-five novel mutations as well as 35 reported mutations and 14 nondisease-related variants are reviewed and included in a novel Leiden Open source Variation Database (LOVD) for L2HGDH variants (http://www.LOVD.nl/L2HGDH). Every user can access the database and submit variants/patients. Furthermore, we report on the phenotype, including neurological manifestations and urinary levels of L2HG, and we evaluate the phenotype-genotype relationship.
Assuntos
Oxirredutases do Álcool/genética , Encefalopatias Metabólicas Congênitas/enzimologia , Encefalopatias Metabólicas Congênitas/genética , Estudos de Associação Genética , Mutação/genética , Animais , Encefalopatias Metabólicas Congênitas/patologia , Modelos Animais de Doenças , HumanosRESUMO
OBJECTIVES: Preprandial insulin injection in preschool children is complicated by irregular eating habits. Postprandial injection of rapid-acting insulin analogs such as insulin aspart (IAsp) offers the convenience of adjusting insulin dose to match food consumed. This trial compared safety and efficacy - including parental treatment satisfaction - of two basal-bolus regimens [IAsp plus Neutral Protein Hagedorn (NPH) insulin vs. regular human insulin (HI) plus NPH] in preschool children with type 1 diabetes. METHODS: This study is a randomized, 12-wk, crossover trial comparing IAsp and regular HI in 26 children (17 boys and 9 girls; age: 2.4-6.9 yr). Regular HI was injected 30 min before and IAsp after or shortly before meals. Treatment satisfaction was assessed by a modified version of the WHO Diabetes Treatment Satisfaction Questionnaire (DTSQ-M). RESULTS: Glycemic control for IAsp treatment was not different from that for regular HI treatment as assessed by mean postprandial blood glucose increment (IAsp vs. regular HI: 2.0 vs. 1.6 mmol/L), fructosamine (300 vs. 302 micromol/L), and hemoglobin A(1c) (HbA(1c)) (7.7 vs. 7.6%). The relative risk of hypoglycemia was not significantly different [relative risk for IAsp/regular HI (95% CI): 1.06 (0.96-1.17), p = 0.225]. Mean total daily insulin dose (0.7 U/kg) remained constant throughout the trial with both treatments. The DTSQ-M score tended to be better for IAsp and reached statistical significance regarding the parental satisfaction with continuing IAsp treatment (p < 0.05). CONCLUSION: In preschool children, a basal-bolus treatment scheme with postprandial IAsp as bolus insulin was equally effective and safe compared with preprandial regular HI, although the parents showed a preference for the IAsp treatment.