Diagnosis and management of glutaric aciduria type I – revised recommendations

Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalopathic crises precipitated by infectious diseases, immunizations and surgery during a finite period of brain development, or develops insidiously without clinically apparent crises. Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. This defect gives rise to elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine which can be detected by gas chromatography/mass spectrometry (organic acids) or tandem mass spectrometry (acylcarnitines). Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia is often difficult to treat, and the efficacy of available drugs cannot be predicted precisely in individual patients. The major aim of this revision is to re-evaluate the previous diagnostic and therapeutic recommendations for patients with this disease and incorporate new research findings into the guideline

Phosphorus bioaccessibility measured in four amino acid-based formulas using in-vitro batch digestion translates well into phosphorus bioavailability in mice

OBJECTIVE: To quantify the bio-accessibility of phosphorus (P) from amino acid-based formulas (AAFs) under different digestive conditions. METHODS: We developed in vitro batch digestion models with stomach digestion at different pH mimicking normal digestive condition and conditions representing use of acid suppressive medication. To validate bio-accessibility findings we devised a low P murine model to test P bio-availability under compromised digestive conditions using proton pump inhibitors (PPI) to neutralize stomach pH. RESULTS: In vitro P bio-accessibility of AAFs Neocate(®) Infant and Neocate(®) Junior ranged between 57% and 65% under normal digestive conditions for infants (stomach pH 3.5) and between 38% and 46% under conditions that simulate bypass of stomach acidification, which is comparable to control diet and two EleCare(®) AAFs. In vivo bioavailability analysis showed that both Neocate(®) formulas were able to normalize plasma P levels when administered to low P mice along with PPI (control diet+PPI 8.0±0.4, Neocate(®) Infant 10.1±0.9, Neocate(®) Junior 9.2±0.6, EleCare(®) Infant 8.6±0.4, EleCare(®) Junior 8.7±0.5, n=8–10, p<0.0001 vs. baseline 3.4±0.2 mg/dl). In comparison, plasma P levels remained lower on low P diet (5.7±0.2 mg/dl). Furthermore, urinary P/creatinine and intact fibroblast growth factor 23 (iFGF23) were significantly lowered by low P diet. In contrast, intact parathyroid hormone (iPTH) and 1,25-dihydroxy vitamin D (1,25-D) decreased and increased, respectively, and these parameters likewise normalized in mice administered AAFs. CONCLUSION: Our findings indicate that P bio-accessibility in the in vitro batch digestion model translates well into P bio-availability in mice even under compromised digestive conditions that bypass gastric acidification

Nutritional Therapy Improves Growth and Protein Status of Children with a Urea Cycle Enzyme Defect

Background Poor growth has been described in patients with urea cycle enzyme defects treated with protein-restricted diets, while protein status is seldom reported. Objective To assess the effects of nutritional therapy with a medical food on growth and protein status of patients with a urea cycle enzyme defect. Methods A 6-mo multicenter outpatient study was conducted with infants and toddlers managed by nutrition therapy with Cyclinex-1 Amino Acid-Modified Medical Food with Iron (Ross Products Division, Abbott Laboratories, Columbus, OH). Main outcome variables were anthropometrics and plasma amino acids (selected), albumin, and transthyretin concentrations. Results Seventeen patients completed the study. Mean (±SE) baseline age was 11.30 ± 3.20 months (median 4.40 months; range 0.22–38.84 months). Length and weight z-scores increased significantly during the 6-month study. Head circumference increased, but not significantly. Three patients were stunted and two were wasted (−2.0 z-score) at baseline while at study end, only one patient was both stunted and wasted. The majority of patients increased in length, head circumference, and weight z-scores during study. Mean (±SE) plasma albumin concentration increased from 34 ± 2 g/L at baseline to 38 ± 1 g/L at study end. Plasma transthyretin increased from a mean (±SE) of 177 ± 13 mg/L at baseline to 231 ± 15 mg/L at study end. No correlation was found between plasma NH3 concentrations and medical food intake. Plasma NH3concentration was positively correlated with the percentage of Food and Agriculture Organization/World Health Organization/United Nations recommended protein ingested. Conclusions Intakes of adequate protein and energy for age result in anabolism and linear growth without increasing plasma NH3 concentrations. Medical food intakes did not correlate with plasma NH3 concentrations