Evaluation of dietary treatment and amino acid supplementation in organic acidurias and urea-cycle disorders: On the basis of information from a European multicenter registry.

Organic acidurias (OAD) and urea-cycle disorders (UCD) are rare inherited disorders affecting amino acid and protein metabolism. As dietary practice varies widely, we assessed their long-term prescribed dietary treatment against published guideline and studied plasma amino acids levels. We analyzed data from the first visit recorded in the European registry and network for intoxication type metabolic diseases (E-IMD, Chafea no. 2010 12 01). In total, 271 methylmalonic aciduria (MMA) and propionic aciduria (PA) and 361 UCD patients were included. Median natural protein prescription was consistent with the recommended daily allowance (RDA), plasma L-valine (57%), and L-isoleucine (55%) levels in MMA and PA lay below reference ranges. Plasma levels were particularly low in patients who received amino acid mixtures (AAMs-OAD) and L-isoleucine:L-leucine:L-valine (BCAA) ratio was 1.0:3.0:3.2. In UCD patients, plasma L-valine, L-isoleucine, and L-leucine levels lay below reference ranges in 18%, 30%, and 31%, respectively. In symptomatic UCD patients who received AAM-UCD, the median natural protein prescription lay below RDA, while their L-valine and L-isoleucine levels and plasma BCAA ratios were comparable to those in patients who did not receive AAM-UCD. Notably, in patients with ornithine transcarbamylase syndrome (OTC-D), carbamylphosphate synthetase 1 syndrome (CPS1-D) and hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) syndrome selective L-citrulline supplementation resulted in higher plasma L-arginine levels than selective L-arginine supplementation. In conclusion, while MMA and PA patients who received AAMs-OAD had very low BCAA levels and disturbed plasma BCAA ratios, AAMs-UCD seemed to help UCD patients obtain normal BCAA levels. In patients with OTC-D, CPS1-D, and HHH syndrome, selective L-citrulline seemed preferable to selective L-arginine supplementation.

Dietary management of urea cycle disorders: European practice.

BACKGROUND: There is no published data comparing dietary management of urea cycle disorders (UCD) in different countries. METHODS: Cross-sectional data from 41 European Inherited Metabolic Disorder (IMD) centres (17 UK, 6 France, 5 Germany, 4 Belgium, 4 Portugal, 2 Netherlands, 1 Denmark, 1 Italy, 1 Sweden) was collected by questionnaire describing management of patients with UCD on prescribed protein restricted diets. RESULTS: Data for 464 patients: N-acetylglutamate synthase (NAGS) deficiency, n=10; carbamoyl phosphate synthetase (CPS1) deficiency, n=29; ornithine transcarbamoylase (OTC) deficiency, n=214; citrullinaemia, n=108; argininosuccinic aciduria (ASA), n=80; arginase deficiency, n=23 was reported. The majority of patients (70%; n=327) were aged 0-16y and 30% (n=137) >16y. Prescribed median protein intake/kg body weight decreased with age with little variation between disorders. The UK tended to give more total protein than other European countries particularly in infancy. Supplements of essential amino acids (EAA) were prescribed for 38% [n=174] of the patients overall, but were given more commonly in arginase deficiency (74%), CPS (48%) and citrullinaemia (46%). Patients in Germany (64%), Portugal (67%) and Sweden (100%) were the most frequent users of EAA. Only 18% [n=84] of patients were prescribed tube feeds, most commonly for CPS (41%); and 21% [n=97] were prescribed oral energy supplements. CONCLUSIONS: Dietary treatment for UCD varies significantly between different conditions, and between and within European IMD centres. Further studies examining the outcome of treatment compared with the type of dietary therapy and nutritional support received are required.

Adherence issues in inherited metabolic disorders treated by low natural protein diets.

Common inborn errors of metabolism treated by low natural protein diets [amino acid (AA) disorders, organic acidemias and urea cycle disorders] are responsible for a collection of diverse clinical symptoms, each condition presenting at different ages with variable severity. Precursor-free or essential L-AAs are important in all these conditions. Optimal long-term outcome depends on early diagnosis and good metabolic control, but because of the rarity and severity of conditions, randomized controlled trials are scarce. In all of these disorders, it is commonly described that dietary adherence deteriorates from the age of 10 years onwards, at least in part representing the transition of responsibility from the principal caregivers to the patients. However, patients may have particular difficulties in managing the complexity of their treatment because of the impact of the condition on their neuropsychological profile. There are little data about their ability to self-manage their own diet or the success of any formal educational programs that may have been implemented. Trials conducted in non-phenylketonuria (PKU) patients are rare, and the development of specialist L-AAs for non-PKU AA disorders has usually shadowed that of PKU. There remains much work to be done in refining dietary treatments for all conditions and gaining acceptable dietary adherence and concordance, which is crucial for an optimal outcome.

Dietary management of urea cycle disorders: UK practice.

BACKGROUND: There is no published data describing UK dietary management of urea cycle disorders (UCD). The present study describes dietary practices in UK inherited metabolic disorder (IMD) centres. METHODS: Cross-sectional data from 16 IMD centres were collected by a questionnaire describing the management of UCD patients on prescribed protein-restricted diets. RESULTS: One hundred and seventy-five patients [N-acetylglutamate synthase deficiency, n = 3; carbamoyl phosphate synthase deficiency (CPS), n = 8; ornithine transcarbamoylase deficiency (OTC), n = 75; citrullinaemia, n = 41; argininosuccinic aciduria (ASA), n = 36; arginase deficiency, n = 12] were reported; 70% (n = 123) aged 0-16 years; 30% (n = 52) >16 years. Prescribed median protein intake decreased with age (0-6 months: 2 g kg(-1) day(-1); 7-12 months: 1.6 g kg(-1) day(-1); 1-10 years: 1.3 g kg(-1) day(-1); 11-16 years: 0.9 g kg(-1) day(-1) and >16 years: 0.8 g kg(-1) day(-1)) with little variation between disorders. Adult protein prescription ranged 0.4-1.2 g kg(-1) day(-1) (40-60 g day(-1)). In the previous 2 years, 30% (n = 53) were given essential amino acid supplements (EAAs) (CPS, n = 2; OTC, n = 20; citrullinaemia, n = 15; ASA, n = 7; arginase deficiency, n = 9). EAAs were prescribed for low plasma quantitative essential amino acids (n = 13 centres); inadequate natural protein intake (n = 11) and poor metabolic control (n = 9). From diagnosis, one centre prescribed EAAs for all patients and one centre for severe defects only. Only 3% (n = 6) were given branch chain amino acid supplements. Enteral feeding tubes were used by 25% (n = 44) for feeds and 3% (n = 6) for medications. Oral energy supplements were prescribed in 17% (n = 30) of cases. CONCLUSIONS: In the UK, protein restriction based on World Health Organization 'safe intakes of protein', is the principle dietary treatment for UCD. EAA supplements are prescribed mainly on clinical need. Multicentre collaborative research is required to define optimal dietary treatments.

New insights in nutritional management and amino acid supplementation in urea cycle disorders.

Sodium phenylbutyrate is used in the pharmacological treatment of urea cycle disorders to create alternative pathways for nitrogen excretion. The primary metabolite, phenylacetate, conjugates glutamine in the liver and kidney to form phenylacetylglutamine that is readily excreted in the urine. Patients with urea cycle disorders taking sodium phenylbutyrate have a selective reduction in the plasma concentrations of branched chain amino acids despite adequate dietary protein intake. Moreover, this depletion is usually the harbinger of a metabolic crisis. Plasma branched chain amino acids and other essential amino acids were measured in control subjects, untreated ornithine transcarbamylase deficiency females, and treated patients with urea cycle disorders (ornithine transcarbamylase deficiency and argininosuccinate synthetase deficiency) in the absorptive state during the course of stable isotope studies. Branched chain amino acid levels were significantly lower in treated patients with urea cycle disorders when compared to untreated ornithine transcarbamylase deficiency females or control subjects. These results were replicated in control subjects who had low steady-state branched chain amino acid levels when treated with sodium phenylbutyrate. These studies suggested that alternative pathway therapy with sodium phenylbutyrate causes a substantial impact on the metabolism of branched chain amino acids in patients with urea cycle disorders, implying that better titration of protein restriction can be achieved with branched chain amino acid supplementation in these patients who are on alternative pathway therapy.