PKU watch - case study
by Dr Anita MacDonald Consultant Dietitian in Inherited Metabolic Disorders
One of the UK's top paediatric dietitians, Anita’s specialism lies with inherited metabolic disorders. She spends 50 percent of her professional time in clinical work with children and 50 percent researching and teaching.
Is there a role for non-dietary treatments in the management of PKU?
The traditional treatment for phenylketonuria (PKU) is a life-long low phenylalanine diet, supplemented with a phenylalanine-free protein substitute. In 1999, a drug, tetrahydrobiopterin (BH4), an essential cofactor for the phenylalanine hydroxylase enzyme, was found to decrease blood phenylalanine concentrations in four mild patients with PKU (5), introducing the possi- bility of non-dietary treatments.
Although many patients cope well with dietary man- agement, others have more difficulty. A strict low phenyla- lanine diet does require discipline, commitment and good organisational skills from both patients and their caregivers. It also requires caregiver cooking skills as well as coopera- tion from a child to eat food and a special protein substi- tute that renders patients different from their peers. Undoubtedly in PKU, improved childhood neurocogni- tive outcome is associated with lower blood phenylalanine concentrations. However, even with early and well-treated patients, some may have subtle deficits in executive function, such as strategic planning, inhibitory control and working memory (2). In addition, there may be impairments with information processing, speed, fine motor control and perception and visual-special abilities, although there are wide individual differences (4). There may also be social and emotional difficulties due to the rigorous constraints of diet therapy.
The contribution of sapropterin
In the UK, there is little recent published information de- scribing blood phenylalanine control achieved by PKU clin- ics or studies identifying patients ability to cope with diet. Therefore, any safe additional therapy that may contribute to improving blood phenylalanine control in PKU should be considered. Sapropterin dihydrochloride (6R-BH4/referred to as sapropterin) is a biologically active synthetic form of tetrahydrobiopterin (BH4). Kuvan® (sapropterin dihy- drochloride; Merck Serono and BioMarin) was granted a marketing authorisation by the European Commission in 2008 for patients with hyperphenylalaninaemia in patients >or=four years of age. It was introduced in the UK in 2009 for the treatment of PKU. This is the first non-dietary treat- ment that has been shown in a randomised, double blind trial (6) to lower blood phenylalanine concentrations in PKU patients. There is suggestion that it may decrease fluctua- tions in blood phenylalanine concentrations and lower phenylalanine/tyrosine ratios (3). It also improves phenyla- lanine tolerance and in a randomised placebo controlled trial in four to 12-year-old children, it increased phenylala- nine tolerance by 17.7mg/kg/day (7). It is prescribed for a subset of patients, mainly with mild or moderate pheno- types of PKU, who are proven to be BH4 responsive. It is esti-
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mated that between 20 to 50 percent of patients achieve a reduction in blood phenylalanine concentration of ≥ 30 percent (1). There are many unanswered questions about the long-
term benefit of sapropterin, particularly with regard to patient neurocognitive and neuromotor outcome, nutri- tional state, compliance and quality of life. However, there is evidence that BH4 treatment may allow a more relaxed low phenylalanine diet, with suggestion that it may have positive impact on weight gain and quality of life (8). Data on long-term safety sapropterin is limited, although head- ache, upper respiratory tract infections and rhinorrhea were the most common reported side effects in clinical trials. So far, there is only very limited experience with this drug in the UK, although some understanding of its practical use has been gained through trials and case studies. Any contribution to improving dietary phenylalanine tolerance may help decrease psychosocial difficulties associated with diet. However, there is much to learn about assess- ing sapropterin, responsiveness, relaxing diet therapy and monitoring the drug’s efficacy and safety long term. Here we present a case study of a teenage boy treated with diet and sapropterin to illustrate its use.
Case Study
A boy aged 14, with well-controlled PKU (mutations F39L/ IVS 12+1G>A), was very disciplined and compliant with di- etary treatment, despite a long history of neophobia to all low protein foods. He was thin, had poor weight gain and complained of frequent hunger pains. He usually tolerated 9g/daily of natural protein, supplemented with 60g/daily of protein equivalent from protein substitute. He particularly found it difficult to discuss his diet with friends and he would not eat any special foods in front of them. He commonly ate very little during the day at school; although lack of food commonly affected his school performance and his sporting ability (he naturally excelled at most sporting activities). There were many family disputes about diet that affected the entire family. His father heard about sapropterin and requested that his son be tried on this. He even agreed to purchase the drug, if local funding could not be secured. The father believed that if the diet could be relaxed, without loss of blood phenylalanine control, it may alleviate many of the psychological and social issues that both the boy and family were experiencing. Four weeks prior to starting sapropterin, this boy was given extra dietary phenylalanine to ensure consistent blood phenylalanine concentrations
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with Shauna Kearney
Consultant Clinical Psychologist Birmingham Children’s Hospital
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