IN ASSOCIATION WITH THE NSPKU
PHENYLALANINE NEUROTOXICITY AND THE CHALLENGE OF ‘DIET FOR LIFE’* IN PKU Lifelong phenylalanine (Phe) restriction, with intake of protein substitutes, is essential for the prognosis of PKU, but is burdensome, considerably demanding and often difficult to follow. This article looks at the mechanisms for brain damage in PKU and outlines some of the evidence supporting ‘Diet for Life’. Phenylketonuria (PKU) is a rare autosomal disorder of phenylalanine (Phe) metabolism. It was first discovered in 1934 and occurs due to inherited mutations in the gene encoding Phe hydroxylase. Lifelong Phe restriction and intake of protein substitutes are both essential, yet demanding and often difficult to follow. Consequently, many patients stop following the PKU diet and may also become disengaged from metabolic review. Furthermore, non-metabolic dietitians may discover patients with PKU who have been ‘lost to follow-up’ and have been referred into other dietetic caseloads. Irrespective of their discovery, it is important that these patients are offered metabolic specialist input to facilitate a return to diet, or, at the very least, provided with robust scientific evidence so they can make informed choices about being off diet and the chance to be under detailed nutritional scrutiny by metabolic dietitians and other members of the multidisciplinary metabolic team. WHAT IS THE PATHOPHYSIOLOGY AND MANAGEMENT OF PKU?
PKU is characterised by disrupted catabolism of Phe into tyrosine and its metabolites. The metabolites of tyrosine act as precursors of several neurotransmitters, catecholamines and hormones, including dopamine, norepinephrine, epinephrine, thyroxine and melanin. Without appropriate management, Phe accumulates in the blood and becomes neurotoxic.
For the unmanaged or poorly managed individual, chronically elevated Phe manifests in a spectrum of progressive and irreversible neuroanatomical and neurophysiological disturbances. With the introduction of newborn screening, PKU became the first metabolic disorder identifiable in the absence of clinical symptoms. Early identification (via newborn screening) and immediate (before 10-14 days of age) dietary intervention is essential for the prognosis of this disorder, whereby patients can achieve almost normal clinical outcome in comparison to their non-PKU counterparts if blood Phe concentrations are maintained at a necessary level. WHAT IS THE CURRENT ADVICE FOR PATIENTS?
PKU management is by way of a lowprotein diet and intake of protein substitutes virtually devoid of Phe. The PKU diet is well established, safe and effective and, consequently, remains the cornerstone of PKU management and has been since its conception in 1953. The duration and stringency of Phe restriction necessary to avert the metabolic consequences of PKU, has been the centre of controversy for decades. Historically, lifelong Phe restriction was generally unsupported. Many practitioners assumed that the diet could be discontinued from age six with no adverse effect.1,2 This practice was fuelled by the belief that elevated Phe is only neurotoxic during periods of growth, development and maximal myelinisation (the development of a protective
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Suzanne Ford RD Dietetic Team Leader, Bristol Southmead Hospital; Society Dietitian (Adults), The National Society for Phenylketonuria
Dr Ben Green PhD Medical Affairs Research Advisor, Nutricia Advanced Medical Nutrition
REFERENCES Please visit the Subscriber zone at NHDmag.com
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"Mental health problems occurred after stopping the diet."** cover around a nerve fibre called myelin), as is experienced during childhood. Several early studies also failed to demonstrate adverse effects on neurocognitive and psychosocial development with early diet discontinuation.3-5 These studies, however, consisted of small sample sizes and varied considerably in methodological validity with little practical and/or clinical application. Although brain development happens mostly in the first years of life, it has long been known that development of the prefrontal cortex and myelinisation continues through adolescence and is not complete until adulthood. It is suggested that the toxicity of Phe is, therefore, present well into adult life and this was recently strengthened with publication of The European Guidelines for Diagnosis and Management of PKU,6 which were based on a significant amount of research. Adult patients who stop the PKU diet appear to experience poor executive functioning, information processing (reaction times, attention) and mood (increased inhibition, anxiety, depression and low self-esteem) compared with adults who have continued Phe restriction throughout life and also metabolically healthy controls.7-11 On some occasions, reports of neurological problems have also been noted, even with good metabolic control and continued Phe restriction.12-14 Importantly, research shows that returning to a Phe-restricted diet can reverse these complications.15,16 ‘Diet for life’ is now encouraged, but because it can be difficult to follow, many patients decide to come off diet. WHAT ARE THE PROPOSED MECHANISMS FOR BRAIN DAMAGE IN PKU?
The pathogenesis of Phe toxicity is complex and far from being fully understood. Although elevated Phe is undoubtedly detrimental to the brain, the underlying causes for this effect remain 40
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hypothetical. Two likely mechanisms responsible for neurological decline have been identified and include white matter pathology (hypomyelination) and neurotransmitter abnormalities that act on prefrontal cortex function. WHITE MATTER PATHOLOGY AND HYPOMYELINATION
In the brain, white matter is found in the deeper tissues (subcortical). It contains nerve fibres (axons), which are extensions of nerve cells (neurons). Many of these nerve fibres are surrounded by a covering called myelin. Myelin gives the white matter its colour and acts to uphold the speed and transmission of electrical impulses.17 Increased concentrations and damage to the structure of white matter is highly prevalent in PKU, with an estimated 90% of patients experiencing abnormalities.18 Raised Phe appears to principally affect subcortical white matter. The progression and severity of white matter abnormalities appears to be influenced by: • age (with increased severity from 20 years onwards); • compliance to Phe restriction; and • long-term exposure to raised Phe levels.19 It is thought that long-term exposure to raised Phe stops the formation of myelin and the increased white matter reflects this (hypomyelination).18 As myelin plays a role in the transmission of electrical impulses, disturbances in executive functioning and the effectiveness of information processing supports the hypothesis that raised Phe levels influence myelinisation as a result of stopping the PKU diet. Interestingly, research shows that this pathology can be reversed when the PKU diet is restarted with strict compliance.18 The duration of strict metabolic control needed to significantly reduce white matter abnormalities is not known, but reversal is not instant. It is clear, however, that the reversal of white matter is associated with the lowering of blood Phe concentration. According to imaging studies,20 two months of strict Phe restriction may be needed as a minimum. NEUROTRANSMITTER ABNORMALITIES
Phe neurotoxicity is also associated with prefrontal cortex dysfunction as a consequence of neurotransmitter abnormalities. Due to disrupted
IMD WATCH Phe catabolism and a higher uptake of Phe into the brain,21 deficiencies in tyrosine and its metabolites occur with low levels reaching the brain,22 which is detrimental for neurotransmitter production. Phe, a large neutral amino acid (LNAA), is transported into the brain by the L-amino acid transporter 1 (LAT-1).21 This transporter also selectively transports other LNAA, including valine, isoleucine, methionine, threonine, tryptophan, tyrosine and histidine.22 The binding of LNAA to the LAT-1 transporter is a competitive process.23 This system has the highest attraction for Phe, therefore, high concentrations of Phe in the blood lead to an increased uptake of Phe into the brain and a concomitant decrease in the uptake of tyrosine and other LNAA.21 By influence of this activity, elevated brain Phe concentrations negatively impact the synthesis of catecholamines (dopamine, norepinephrine and epinephrine) and serotonin in the brain. This is due to the altered metabolism of tyrosine and tryptophan, which may subsequently affect the proper functioning of the brain, especially in the prefrontal cortex. In general, the prefrontal cortex exerts a role in planning complex cognitive behaviour, including decision making, executive functions and emotional stability. The abnormalities in neurotransmitter functions subsequently disturb cerebral protein synthesis and impact the aforesaid functions, even in patients who were managed early in life. Again, returning to a Phe-restricted diet results in improvements in executive functioning, decision making and emotional stability.15,16 Furthermore, there is evidence that the intake of protein substitutes containing high levels of large neutral amino acids reduces the uptake of Phe into the brain23 and further improves elements of executive functioning.24 IS ‘DIET FOR LIFE’ HAPPENING IN THE UK?
Unfortunately, poor compliance with lifelong Phe restriction in PKU is widespread.26-28 This is especially true in older adolescents and adult populations.29 A recent survey highlighted that 43% of adult PKU patients in the UK admitted to
"The psychological effects of high levels of Phe are entirely underestimated: minimal concentration and brain fog."** not following a low-protein, Phe-restricted diet.30 If the PKU diet has been stopped (either due to medical advice, or in the absence of any positive outcome, or support to continue on the diet), then returning to the diet is advisable. The PKU diet, however, is complex and highly restrictive and does require planning skills, motivation and discipline. Returning to the diet may, therefore, be especially difficult for patients who are/have been off diet due to compromised executive functioning. Collectively, there are many difficulties associated with re-establishing Phe restriction; thus, it seems prudent that efforts to maintain lifelong Phe restriction are needed. The patients’ multidisciplinary management team may represent the first-line defence for this and, with the evidence discussed above, the team can, and should, act as advocates to encourage a ‘Diet-for-Life’ philosophy. WHAT DOES A RETURN TO DIET MEAN FOR DIETITIANS AND THEIR PATIENTS?
Alongside improvements in white matter pathology and neurotransmitter metabolism, patients who return to the PKU diet also show marked improvements in quality of life.31 Strategies aimed at improving dietary compliance are, however, relatively understudied in PKU. No one method will be universally effective and an individualised approach to reinstating dietary compliance may be essential. Research is, therefore, needed to help build effective strategies that deliver metabolic, nutritional and cognitive benefits with the overarching aim of achieving lifelong dietary compliance over time.
* This information is intended for healthcare professionals only ** Quotations are taken and reproduced with permission from a recent UK survey30 capturing the issues of living with PKU in children and adults. In particular, the quotations used throughout this article are in response to the free text question, “Is there anything else about your experience of having PKU (or the person with PKU under your care) which you would like to share?” www.NHDmag.com May 2019 - Issue 144
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