ESPEN Congress Madrid 2018

Transcription

1 ESPEN Congress Madrid 2018 Inborn Errors Of Metabolism Phenylketonuria A. Macdonald (UK)

2 Approach to Dietary Management of PKU

3 Conflicts of interest Anita MacDonald has received research funding and honoraria from Nutricia, Vitaflo International, Biomarin, Mevalia and Pharma Galen. She is a member of the European Nutrition Expert Panel (Biomarin), member of the following Advisory Boards: European PKU Group Board (Biomarin), Element (Danone- Nutricia), Excemed, Arla and Applied Pharma Research

4 The first child to be treated with diet and protein substitute in Nov, 1952

5 What is PKU? Dietary Protein Phenylpyruvic acid Phenylalanine X Phenylalanine hydroxylase Tyrosine Melanin Proteins Dopamine

6 Untreated PKU global intellectual disability significant delays in developmental milestones hyperactive behaviour with autistic features seizures eczema musty body odour light pigmentation (eyes, hair and skin)

7 Outcomes On treatment from early infancy Dietary treatment discontinued in adulthood normal intelligence lower than healthy controls IQ executive function attention high Phe levels correlate with impaired neuropsychological performance minor neurological signs tremor brisk deep tendon reflexes poor motor co-ordination spastic paresis ataxia and tremor

8 Other issues Psychological problems depression anxiety phobias e.g. agoraphobia low self-esteem neuroses may improve with strict Phe control also reported in early treated, well controlled PKU patients Other Issues nutritional deficiencies vitamins B12 iron zinc, selenium reduced bone density and osteopenia obesity / overweight MANY PKU PATIENTS HAVE BEEN SUCCESSFUL IN THEIR LIVES & CAREERS

9 Recommendations

10 Target blood phenylalanine concentrations age 0-12y: µmol/l age >12y: µmol/l European PKU guidelines, 2017 Age Blood sampling frequency 0-1 y Weekly >1y 12y Once every 2 weeks >12y Monthly Pre-conception Weekly Pregnancy Twice weekly

11 Treatment options Low phenylalanine diet BH4/sapropterin

12 treat all patients with blood phe >360 µmol/l restriction of phenylalanine to individual tolerance High protein foods Small phenylalanine tolerance + aspartame Low phenylalanine foods Phe free infant formula Liquid/pouch protein substitutes Phenylalanine-free L-amino acids

13 Phenylalanine tolerance severe PKU: 4-6g/daily natural protein moderate PKU: 7-12g/daily natural protein mild PKU: 13-30g/daily natural protein Phenylalanine allocation by 50 mg Phe exchange system 35g Kale 25g spinach 80g potato 60g cauliflower 25g peas 35g sweetcorn

14 Low protein foods: exchange-free foods energy requirements are normal low energy intake = blood phenylalanine calories help protein synthesis help growth add variety prevent hunger

15 Vegetables containing <75 mg/100g phenylalanine

16 Vegetables containing <75 mg/100g phenylalanine

17 Low protein staple foods: low protein Tapioca/Cassava Sago Wheat starch Arrowroot Potato starch Sugar

18 150 Low Protein Foods if contain free ingredients allow without measurement Prot ein free milk

19 Low protein vegan foods

20 5 years of age: 5 phenylalanine exchanges Breakfast Midday meal Evening meal Cereal + Low protein milk (2 x 50 Phe exchanges) Menu plan Indian toast and vegetable soup (2 x 50 Phe exchanges) Sweet potato corncakes (1 x 50 Phe exchange)

21 Protein substitute essential on diet treatment in classical phenotypes, L-amino acids will supply >75% of protein intake contain tyrosine nutritional supplement + pharmacological impact - reduces blood phenylalanine levels - helps prevent phenylalanine from entering brain take with natural protein and carbohydrate source Total protein intake should supply the age-related safe levels of protein intake [WHO/UNU/FAO 2007 with an additional 40% L-amino acids (European guidelines 2017)

22 BH4 recommendations European PKU Recommendations Every patient deserves consideration of BH4-responsiveness either by genotyping or BH4 loading. In case of a patient with a known genotype, BH4-responsiveness does not need to be considered further in case of 2 null-variants, while a patient with a genotype with 2 BH4-responsive variants may directly proceed to a treatment trial rather than a BH4 loading test A clinical benefit to continue with BH4 treatment is considered if 100% increase in natural protein and / or improved biochemical control (>75% of Phe levels in target range)

23 Adjusted mean (95% CI) dietary Phe tolerance, mg/kg/day Phenylalanine tolerance with BH4 in children under 4 years: Spark study Phe tolerance based on prescribed Phe Week 26 adjusted difference 30.5 mg/kg/day (95% CI ); p< Baseline mean value Week Sapropterin + Phe-restricted diet (N=27) Phe-restricted diet only (N=27) Muntau AC et al. Orphanet J Rare Dis. 2017

24 Infant feeding: breast milk with infant Phefree amino acid Since the early days of breast feeding infants with PKU; health professionals have adopted many different practices for breast feeding in PKU techniques include: o a measured amount of expressed breast milk prior to a Phe-free infant formula o a pre-measured amount of Phe-free infant formula prior to breastfeeding until satiety o a pre-measured amount of Phe-free infant formula prior to time-controlled breastfeeding o alternate breast and Phe-free infant formula feeds

25 Impact of low phe diet on caregivers of children with PKU Dietary care is: Time demanding Relentless Overwhelming Life changing

26 Transitioning teenagers with PKU adult clinics for PKU more prevalent process starts early childhood: lay foundation/ self-care transfer to teenage clinic: 12 years of age - teenagers speak for themselves - parents part of process - continue to learn - get to know adult team/joint working - difficult time with diet - move over to adult clinic at aged 16/17y PROCESS TAKES TIME TO PERFECT!

27 Median blood Phe µmol/l Blood phenylalanine control worsens with age Age (y) Studies: 70-80% of patient phe levels not within target range at 18 years of age Loss of patients (particularly male patients) in adult clinics

28 Overall outcome good in adults Engineer International rugby player Student doctor

29 Adults Difficulties with focus and organisation Forgetfulness Extreme tiredness Mental health issues Disordered eating Social exclusion

30 Maternal PKU Adverse effects on infant Intellectual disability Microcephaly Low birth weight Birth defects Congenital heart defects Recommendations Maternal PKU must be treated pre-conception Significant effort should be taken to avoid any unplanned pregnancies in PKU women

31 Illness management Diet L-amino acid supplement High carbohydrate intake Natural protein intake Medications Dietary advice Maintenance protein substitute intake to support protein synthesis. It is better to give smaller, frequent doses throughout the day Encourage frequent high carbohydrate supplements, e.g. glucose polymer solution In practice, a reduced appetite leads to a lower natural protein intake All treatment specific medication should be continued during illness Medications should be free of aspartame in PKU Treat precipitating factors e.g. anti-pyretics for pyrexia, antibiotics (aspartamefree) for bacterial infections

32 Long term monitoring and outcome home blood spot monitoring for Phe clinic review and education weight and exercise quality of life and coping neurocognitive outcome annual biochemical nutritional monitoring

33 Family and patient education

34 BCH metabolics