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Background: The dietary management of methylmalonic acidaemia (MMA) is a low-protein diet providing sufficient energy to avoid catabolism and to limit production of methylmalonic acid. The goal is to achieve normal growth, good nutritional status and the maintenance of metabolic stability. Aim: To describe the dietary management of patients with MMA across Europe. Methods: A cross-sectional questionnaire was sent to European colleagues managing inherited metabolic disorders (IMDs) (n=53) with 27 questions about the nutritional management of organic acidaemias. Data were analysed by different age ranges (0–6 months; 7–12 months; 1–10 years; 11–16 years; >16 years). Results: Questionnaires were returned from 53 centres. Twenty-five centres cared for 80 patients with MMA vitamin B12 responsive (MMAB12r) and 43 centres managed 215 patients with MMA vitamin B12 non-responsive (MMAB12nr). For MMAB12r patients, 44% of centres (n=11/25) prescribed natural protein below the World Health Organization/Food and Agriculture Organization/United Nations University (WHO/FAO/UNU) 2007 safe levels of protein intake in at least one age range. Precursor-free amino acids (PFAA) were prescribed by 40% of centres (10/25) caring for 36% (29/80) of all the patients. For MMAB12nr patients, 72% of centres (n=31/43) prescribed natural protein below the safe levels of protein intake (WHO/FAO/UNU 2007) in at least one age range. PFAA were prescribed by 77% of centres (n=33/43) managing 81% (n=174/215) of patients. In MMAB12nr patients, 90 (42%) required tube feeding: 25 via a nasogastric tube and 65 via a gastrostomy. Conclusions: A high percentage of centres used PFAA in MMA patients together with a protein prescription that provided less than the safe levels of natural protein intake. However, there was inconsistent practices across Europe. Long-term efficacy studies are needed to study patient outcome when using PFAA with different severities of natural protein restrictions in patients with MMA to guide future practice. [ABSTRACT FROM AUTHOR]

In order to ascertain whether polygenic hypercholesterolemia (PH), the most common cause of small increases in plasma lipids during childhood, is associated with rheological alterations, we determined the hemorheological and lipid profile of 21 PH children (12 males, 9 females) and a well-matched control group (CG). In addition, a carotid ultrasound was done on all the PH children, but showed no alterations. When compared with the CG, PH children showed increased erythrocyte aggregation both at stasis (EAM[sub 0]) (4.39 ± 1.15 vs. 3.75 ± 1.02), p < 0.05, and at low shear rate (EAM[sub 1]) (8.22 ± 1.42 vs. 7 ± 1.39), p < 0.01, and increased plasma viscosity (PV) (1.19 ± 0.04 cP vs. 1.15 ± 0.04 cP), p < 0.01. These results reinforce the hypothesis that lipid metabolic alterations are associated with specific rheological modifications in absence of a demonstrable atherosclerotic lesion. [ABSTRACT FROM AUTHOR]

In order to ascertain whether hemorheological alterations precede the atherosclerotic lesion in familial hypercholesterolemia (FH), we studied the lipid and hemorheological profile of 29 heterozygous FH children (12 males and 17 females), aged 12 ± 3 years, and a well-matched control group (CG), and assessed their plasma thrombomodulin level as an early marker of endothelial injury. No differences were found between FH children's plasma thrombomodulin values (31.7 ± 11.2 ng/ml) and those of the CG (27.8 ± 15 ng/ml). However, the rheological variables of FH children and the CG were statistically different (p < 0.001) for fibrinogen (Fbg): 266 ± 48 mg/dl vs. 205 ± 32 mg/dl; erythrocyte aggregation at stasis (EAM[sub 0]): 4.6 ± 1.2 vs. 3.3 ± 0.9; erythrocyte aggregation at low shear (EAM[sub 1]): 7.9 ± 1.7 vs. 6.1 ± 0.8; and plasma viscosity (PV): 1.18 ± 0.03 cP vs. 1.12 ± 0.04 cP. Correlations between rheological parameters and lipids were found. The normal values obtained in FH children for plasma thrombomodulin suggest that the hemorheological alterations appear prior to the vascular injury, are in part related to dyslipemia and could contribute to the development of the atherosclerotic process by modifyng blood flow conditions. [ABSTRACT FROM AUTHOR]

In order to ascertain whether young familial hypercholesterolemic subjects without atherosclerotic lesions demonstrable on a carotid echo-Doppler show decreased erythrocyte deformability, we determined the erythrocyte elongation index (EEI) by means of a shear stress diffractometer (Rheodyn SSD) in twenty-four children with heterozygous familial hypercholesterolemia (FH), aged 12 ± 3 years, and their corresponding affected parent. The parents were twenty-three adults with heterozygous FH aged, 32 ± 6 years. The control group was made up of a similar number of well matched healthy volunteers. The EEI at 6, 12, 30 and 60 Pa showed no statistical differences between FH children and their control group, or between FH parents and their control group. No correlations were found between EEI and plasma lipids or lipoproteins at any of the shear stresses used. These results suggest that the red blood cells of young familial hypercholesterolemic subjects who show no deterioration of the vascular tree are not less deformable than those of healthy normolipemic subjects, and that dyslipemia itself does not produce alterations that damage the rheological properties of the red blood cell. [ABSTRACT FROM AUTHOR]

Background and Aims Phenylalanine-restricted diets have proven effective in treating phenylketonuria. However, such diets have occasionally been reported to hinder normal development. Our study aimed to assess whether treating 0–4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin might prevent growth retardation later in life. Methods We conducted a longitudinal retrospective study which examined anthropometric characteristics of phenylketonuric patients on 6R-tetrahydrobiopterin therapy (22 subjects), and compared them with a group of phenylketonuric patients on protein-restricted diets (44 subjects). Nutritional issues were also considered. We further explored possible relationships between mutations in the PAH gene, BH 4 responsiveness and growth outcome. Results No significant growth improvements were observed in either the group on 6R-tetrahydrobiopterin treatment (height Z-score: initial = − 0.57 ± 1.54; final = − 0.52 ± 1.29; BMI Z-score: initial = 0.17 ± 1.05; final = 0.18 ± 1.00) or the diet-only group (height Z-score: initial = − 0.92 ± 0.96; final = − 0.78 ± 1.08; BMI Z-score: initial = 0.17 ± 0.97; final = − 0.07 ± 1.03) over the 1-year observation period. Furthermore, we found no significant differences ( p > 0.05) between the two groups at any of the time points considered (0, 6 and 12 months). Patients on 6R-tetrahydrobiopterin increased their phenylalanine intake (from 49.1 [25.6–60.3] to 56.5 [39.8–68.3] mg kg − 1 day − 1 ) and natural protein intake (from 1.0 [0.8–1.7] to 1.5 [1.0–1.8] g kg − 1 day − 1 ), and some patients managed to adopt normal diets. Higher phenylalanine and natural protein intakes were positively correlated with better physical outcomes in the diet-only group (p < 0.05). No correlation was found between patient genotype and physical outcomes, results being similar regardless of the nutritional approach used. We did not detect any side effects due to 6R-tetrahydrobiopterin administration. Conclusions Our study indicates that treating 0–4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin is safe. However, poor developmental outcomes were observed, despite increasing the intake of natural proteins. Genotype could be a valid predictor of tetrahydrobiopterin-responsiveness, since patients who carried the same genotype responded similarly to the 6R-tetrahydrobiopterin loading test. On the other hand, harbouring 6R-tetrahydrobiopterin responsive genotypes did not predispose patients to better physical outcomes. [ABSTRACT FROM AUTHOR]

Background: Advances in the diagnosis and treatment of urea cycle disorders (UCDs) have led to a higher survival rate. The purpose of this study is to describe the characteristics of patients with urea cycle disorders in Spain., Methods: Observational, cross-sectional and multicenter study. Clinical, biochemical and genetic data were collected from patients with UCDs, treated in the metabolic diseases centers in Spain between February 2012 and February 2013, covering the entire Spanish population. Heterozygous mothers of patients with OTC deficiency were only included if they were on treatment due to being symptomatic or having biochemistry abnormalities., Results: 104 patients from 98 families were included. Ornithine transcarbamylase deficiency was the most frequent condition (64.4%) (61.2% female) followed by type 1 citrullinemia (21.1%) and argininosuccinic aciduria (9.6%). Only 13 patients (12.5%) were diagnosed in a pre-symptomatic state. 63% of the cases presented with type intoxication encephalopathy. The median ammonia level at onset was 298 μmol/L (169-615). The genotype of 75 patients is known, with 18 new mutations having been described. During the data collection period four patients died, three of them in the early days of life. The median current age is 9.96 years (5.29-18), with 25 patients over 18 years of age. Anthropometric data, expressed as median and z-score for the Spanish population is shown. 52.5% of the cases present neurological sequelae, which have been linked to the type of disease, neonatal onset, hepatic failure at diagnosis and ammonia values at diagnosis. 93 patients are following a protein restrictive diet, 0.84 g/kg/day (0.67-1.10), 50 are receiving essential amino acid supplements, 0.25 g/kg/day (0.20-0.45), 58 arginine, 156 mg/kg/day (109-305) and 45 citrulline, 150 mg/kg/day (105-199). 65 patients are being treated with drugs: 4 with sodium benzoate, 50 with sodium phenylbutyrate, 10 with both drugs and 1 with carglumic acid., Conclusions: Studies like this make it possible to analyze the frequency, natural history and clinical practices in the area of rare diseases, with the purpose of knowing the needs of the patients and thus planning their care.