Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision.

Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long-term outcomes is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75-101; Kolker et al., J Inherit Metab Dis 2011;34(3):677-694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5-22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes.

Hepatorenal Tyrosinaemia: Impact of a Simplified Diet on Metabolic Control and Clinical Outcome.

Background: Tyrosinaemia type 1 is a rare inherited metabolic disease caused by an enzyme defect in the tyrosine degradation pathway. It is treated using nitisinone and a low-protein diet. In a workshop in 2013, a group of nutritional specialists from Germany, Switzerland and Austria agreed to advocate a simplified low-protein diet and to allow more natural protein intake in patients with tyrosinaemia type 1. This retrospective study evaluates the recommendations made at different treatment centers and their impact on clinical symptoms and metabolic control. Methods: For this multicenter study, questionnaires were sent to nine participating treatment centers to collect data on the general therapeutic approach and data of 47 individual patients treated by those centers. Results: Dietary simplification allocating food to 3 categories led to increased tyrosine and phenylalanine blood concentrations without weighing food. Phenylalanine levels were significantly higher in comparison to a strict dietary regimen whereas tyrosine levels in plasma did not change. Non-inferiority was shown for the simplification and liberalization of the diet. Compliance with dietary recommendations was higher using the simplified diet in comparison to the stricter approach. Age correlates negatively with compliance. Conclusions: Simplification of the diet with increased natural protein intake based on three categories of food may be implemented in the diet of patients with tyrosinaemia type 1 without significantly altering metabolic control. Patient compliance is strongly influencing tyrosine blood concentrations. A subsequent prospective study with a larger sample size is necessary to get a better insight into the effect of dietary recommendations on metabolic control.

Effect of fish oil supplementation on fatty acid status, coordination, and fine motor skills in children with phenylketonuria.

OBJECTIVE: To investigate effects of long-chain omega-3 polyunsaturated fatty acids (LC-PUFA) on motor skills in patients with phenylketonuria (PKU). STUDY DESIGN: Thirty-six patients with PKU (1-11 years of age, good metabolic control: plasma phenylalanine < or = 360 micromol/L for > or = 6 months). We determined plasma phospholipid fatty acids, and in patients > 4 years of age (N = 24) the motometric Rostock-Oseretzky Scale (ROS), before and after supplementation with fish oil for 3 months (15 mg docosahexaenoic acid [DHA]/kg body weight daily). ROS was also assessed in 22 age-matched controls. RESULTS: Patients had low n-3 LC-PUFA in plasma phospholipids (DHA, 2.37 +/- 0.10%; eicosapentaenoic acid [EPA], 0.4 +/- 0.03%) and poorer ROS performance than controls (motor development index [MQ] 107 +/- 3 vs 117 +/- 3, P = .010). Supplementation increased phospholipid n-3 LC-PUFA (DHA 7.05 +/- 0.24%; EPA 3.31 +/- 0.19%; P < .001), decreased n-6 LC-PUFA (arachidonic acid, 9.26 +/- 0.23% vs 6.76 +/- 0.16%; P < .001) and improved ROS (MQ 115 +/- 3.54, P = .011, paired t test). ROS was unchanged in 11 retested controls (MQ 115 +/- 5.16, P = NS, paired t test multivariate analysis of variance [MANOVA] for time by group, P = .027). Patients tolerated fish oil well. Plasma phenylalanine remained unchanged. CONCLUSION: In patients with PKU, fish oil supplementation enhances n-3 LC-PUFA levels and improves motor skills.

Status of plasma folate after folic acid fortification of the food supply in pregnant African American women and the influences of diet, smoking, and alcohol consumption.

BACKGROUND: African American women and socioeconomically challenged women are at risk of compromised folate status and, thus, of folate-related birth defects. Data are limited on circulating folate concentrations in pregnant African American women after folic acid fortification of the food supply was implemented. OBJECTIVE: The objective was to determine the influence of smoking and alcohol consumption on plasma 5-methyltetrahydrofolic acid (5-MTHFA) concentrations in pregnant African American women. DESIGN: Alcohol consumption, smoking exposure, and other characteristics of pregnant African American women reporting to an inner-city antenatal clinic were assessed. At 24 wk of gestation, blood samples and food-frequency intake data were collected. Plasma 5-MTHFA concentrations were determined by liquid chromatography-mass spectrometry for 116 subjects and examined in a correlational study design. RESULTS: Dietary folate and markers of alcohol consumption were positively associated, whereas exposure to smoke was negatively associated with plasma 5-MTHFA. More than one-half of the participants in this population failed to meet the recommended dietary allowance for dietary folate equivalents of 600 microg/d during pregnancy. CONCLUSIONS: Most inner-city African American women are not meeting the recommended dietary allowance for dietary folate during pregnancy, and smoking may further compromise their folate status. Programs to reduce smoking and raise awareness about the importance of folate and multivitamin supplementation during pregnancy need to target this population.

Effects of alcohol intake during pregnancy on docosahexaenoic acid and arachidonic acid in umbilical cord vessels of black women.

OBJECTIVE: Alcohol influences the intake and metabolism of several nutrients including long-chain polyunsaturated fatty acids (LC-PUFAs). The LC-PUFAs docosahexaenoic acid (DHA) and arachidonic acid (AA) are particularly crucial for intrauterine growth and brain development. We hypothesized that alcohol consumption adversely affects LC-PUFA levels in pregnant women and their newborn infants. METHODS: Pregnant black women (N = 208) presenting at a core city antenatal clinic were screened and recruited. Shortly before delivery, maternal plasma was collected. After delivery, umbilical arteries and veins were dissected from the cords, total lipids were extracted from the vessel tissues and maternal plasma, and fatty acid levels were assayed by gas chromatography. For statistical analysis, subjects were categorized according to absolute alcohol intake per day (AAD) and absolute alcohol intake per drinking day (AADD) around the time of conception, with smoking and other potential confounders included in the analyses. RESULTS: Significant differences in fatty acid composition of total lipid extracts were detected in umbilical cord vessels among the AADD groups: abstainers (AADD = 0), moderate drinkers (AADD < 130 g), and heavy drinkers (AADD > or = 130 g). DHA and AA content in the arterial umbilical vessel wall was approximately 14% and approximately 10% higher in the moderate (n = 127) and heavy (n = 32) alcohol groups, respectively, than in abstainers (n = 49). A small, nonsignificant increase ( approximately 3%) was seen in the umbilical vein for AA but not for DHA. Alcohol intake was positively correlated to both DHA and AA concentrations in the arterial vessel wall but to neither in the venous wall nor maternal plasma. Maternal plasma DHA was positively correlated with both umbilical arteries and vein DHA, but there were no significant correlations for AA between maternal plasma and either umbilical vessel. CONCLUSIONS: Our findings indicate that alcohol intake during pregnancy is associated with altered DHA and AA status in fetal tissues. Although differences may be due to either metabolism and/or distribution, it is most likely a result of a direct influence of alcohol on fetal metabolism.