Status of nutrients important in brain function in phenylketonuria: a systematic review and meta-analysis

Abstract

BackgroundDespite early and ongoing dietary management with a phe-restricted diet, suboptimal neuropsychological function has been observed in PKU. The restrictive nature of the PKU diet may expose patients to sub-optimal nutritional intake and deficiencies which may impact normal brain function. A systematic review of the published literature was carried out, where possible with meta-analysis, to compare the status of nutrients (Nutrients: DHA, EPA phospholipids, selenium, vitamins B6, B12, E, C, A, D, folic acid, choline, uridine, calcium, magnesium, zinc, iron, iodine and cholesterol) known to be important for brain development and functioning between individuals with PKU and healthy controls.ResultsOf 1534 publications identified, 65 studies met the entry criteria. Significantly lower levels of DHA, EPA and cholesterol were found for PKU patients compared to healthy controls. No significant differences in zinc, vitamins B12, E and D, calcium, iron and magnesium were found between PKU patients and controls. Because of considerable heterogeneity, the meta-analyses findings for folate and selenium were not reported. Due to an insufficient number of publications (< 4) no meta-analysis was undertaken for vitamins A, C and B6, choline, uridine, iodine and phospholipids.ConclusionsThe current data show that PKU patients have lower availability of DHA, EPA and cholesterol. Compliance with the phe-restricted diet including the micronutrient fortified protein substitute (PS) is essential to ensure adequate micronutrient status. Given the complexity of the diet, patients’ micronutrient and fatty acid status should be continuously monitored, with a particular focus on patients who are non-compliant or poorly compliant with their PS. Given their key role in brain function, assessment of the status of nutrients where limited data was found (e.g. choline, iodine) should be undertaken. Standardised reporting of studies in PKU would strengthen the output of meta-analysis and so better inform best practice for this rare condition.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0839-x) contains supplementary material, which is available to authorized users.

CRISPR/Cas9 generated knockout mice lacking phenylalanine hydroxylase protein as a novel preclinical model for human phenylketonuria

“…It is not clear whether these differences are due to the low protein diet or disruption of cholesterol biosynthesis. However, recent findings suggest that hyperphenylalaninemia rather than the low protein diet is the cause of altered lipid profile in PKU 30 , 31 . The underlying mechanism for low cholesterol biosynthesis in PKU patients is also not clear but it is widely believed that Phe induced inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA), the rate limiting enzyme for cholesterol synthesis could be the cause of low cholesterol.…”

“…Altered lipid profile characterized by significantly lower blood total cholesterol, LDL and HDL has been observed in some PKU patients 28 – 31 . It is not clear whether these differences are due to the low protein diet or disruption of cholesterol biosynthesis.…”

Bone Status in Patients with Phenylketonuria: A Systematic Review

“…PKU patients are detected early by newborn screening, put in place in the 1960s, and are treated predominantly using a Phe-restricted diet, which limits the intake of natural protein. As the first early treated PKU patients age, concerns have arisen about the long-term consequences of PKU and its treatment [ 10 , 11 , 12 , 13 , 14 ], including deleterious effects on bone health [ 15 , 16 ]. Osteoporosis is a silent disease until it is complicated by fractures that can occur due to minimal or no trauma.…”

“…More recently, enzyme substitution therapy has been approved to treat PKU in patients aged 16 years or older [ 9 ]. The success of treatment has, however, led to the discovery of secondary issues in the life-long outcome of PKU patients, including nutritional deficiencies in minerals, vitamins, and long chain polyunsaturated fatty acids [ 10 , 11 , 12 , 13 ], behavioral impairment [ 13 , 14 ], and mineral bone disease [ 15 , 16 ]. Such micronutrient nutritional deficiencies will be highly dependent on the compliance to the treatment.…”

Evaluation of Body Composition, Physical Activity, and Food Intake in Patients with Inborn Errors of Intermediary Metabolism

“…A long-standing concern is that dietary restrictions required to manage IEiM and maintain metabolic control may increase the risk of an inadequate nutrient status in both the short and long terms [ 14 , 15 , 16 ]. Dietary factors commonly linked to nutritional status include energy intake, protein quality and quantity, micronutrient intake, and the frequency and duration for which the diet must be modified during periods of increased physical activity or metabolic stress.…”