PKU in adolescents and adults Andrew Morris Royal Manchester Children’s Hospital

Manchester PKU patients 60 50 children (n=115) adults (n=211) 40 Number 30 20 10 0-5 6- 11- 16- 21- 26- 31- 36- 41- 46- 51- 56- 61- 10 15 20 25 30 35 40 45 50 55 60 65 Age (yrs)

High phenylalanine levels are harmful to the developing brain Phenylalanine must be strictly controlled in infancy, childhood and in pregnancy Stopping the PKU diet after childhood does not have a major effect on IQ

Adult PKU management Prevention of Damage to children of PKU mothers Nutritional problems Late neurological problems (?)

PKU & Pregnancy Low risk of child having PKU (1:100) High risk of child being damaged by mother’s high phenylalanine levels

Untreated Maternal PKU Adverse effects on infant Mental retardation (92%) Abnormally small head (73%) Low birth weight (40%) Congenital heart disease (12%) Abnormal facial appearance Lenke & Levy, 1980

Congenital heart disease International study Diet pre- 0/23 conception (0%) Diet after 10 34/235 weeks gestation (14%)

Maternal PKU: when to start strict diet International study recommended levels down by 10 weeks gestation BUT - takes time to get levels down - vomiting in early pregnancy Pre-conception If unplanned as soon as possible If very late consider termination

Maternal PKU: Problems Diet is difficult Cost Waiting to conceive whilst on diet refer to reproductive medicine after 6 months Vomiting Learning difficulties in some patients Poor support from some doctors

Adult PKU management Prevention of Damage to children of PKU mothers Nutritional problems Late neurological problems (?)

Nutrition in PKU Adults On PKU diet Supplements often taken erratically Off PKU diet Diet often low in red meat & dairy foods low in vitamin B12 iron calcium

Vitamin B12 levels in PKUs on & off diet strict relaxed normal 600 n=25 n=30 n=29 500 Normal Range B12 level in blood (ng/l) 400 300 200 100 Pts with low B12 1 3 6

Adult PKU management Prevention of Damage to children of PKU mothers Nutritional problems Late neurological problems (?)

Adults with PKU High phenylalanine levels cause Minor symptoms in some patients Poor concentration Lethargy Irritability

Adults with PKU High phenylalanine levels cause Minor symptoms in some patients Abnormalities on brain scans White matter Reversible if phenylalanine lowered

increased water content Normal White matter changes Probably due to increased water content

Adults with PKU High phenylalanine levels cause Minor symptoms in some patients Abnormalities on brain scans Neurological problems (very rare)

Neurological problems after stopping PKU diet Stiffness Poor balance Epilepsy Poor short term memory Very rare Most patients had poor early control Often reversible on restarting diet

Adults with PKU High phenylalanine levels cause Minor symptoms in some patients Abnormalities on brain scans Neurological problems (very rare) Unknown effects in very long term No early treated patients have yet reached 50 yrs

Adolescents with PKU Poor dietary control may lead to disappointing exam results No good studies families with good dietary compliance also likely to encourage studying randomised controlled trials not possible

Adolescents: recommendations Dietary treatment Phenylalanine levels 120-700 mcmol/l Not worth pursuing if leads to Family breakdown Serious nutritional problems

What are we achieving? % phe samples outside target range Age 90 80 70 60 50 40 30 20 10 Age 2 4 6 8 10 12 14 16 18 20 Target range 120-360 120-480 120-700

Management of adults with PKU PKU clinics provide information Patients choose whether to stay on diet Everyone needs regular review to Support patients on diet Prevent nutritional problems Monitor for neurological problems Ensure strict diet during pregnancy

Treatment of PKU Phenylalanine restricted diet Amino acid supplements Low protein products Vitamins & Minerals Monitoring of phenylalanine levels

Adult PKU: neurological abnormalities Brisk reflexes Tremor Asymptomatic Common On or off diet

Scan abnormalities and phenylalanine level 2000 1500 1000 500 5 10 15 20 25 Severity of abnormality on scan

Phenylketonuria PA Hydroxylase Phenylalanine Tyrosine BH4 BH2 DHPR Phenylketones

Published guidelines UK (1993) pre-school: 120-360 µmol/l (2-6 mg/dl) school age: 120-480 µmol/l (2-8 mg/dl) adolescence: 120-700 µmol/l (2-11.7 mg/dl) German (1999) <10 y 40-240 µmol/l (0.7-4 mg/dl) 10-15 y 40-900 µmo/l (0.7-15 mg/dl) >15 y 40-1200µmol/l (0.7-20 mg/dl)

Management of PKU adults in UK UCH is the largest centre with 270 adult patients