Background
Methods
Levels of evidence | |
1++ | High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias |
1+ | Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias |
1- | Meta-analyses, systematic reviews, or RCTs with a high risk of bias |
2++ | High quality systematic reviews of case control or cohort or studies High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal |
2+ | Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal |
2- | Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal |
3 | Non-analytic studies, e.g. case reports, case series |
4 | Expert opinion |
Grades of recommendations | |
At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or
A body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results | |
A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+ | |
A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or
Extrapolated evidence from studies rated as 2++ | |
Evidence level 3 or 4; or
Extrapolated evidence from studies rated as 2+ | |
Good practice points | |
Recommended best practice based on the clinical experience of the guideline development group |
Key recommendations
Diagnosis
Diagnosis
Differential diagnosis of BH4 deficiencies
Genotyping
PKU classification
Initiation of treatment and treatment for life
Initiation of treatment
Treatment for life
Life-long follow up
Treatment goals and follow-up
-
- Studies report blood Phe in different ways (e.g. concurrent, lifetime as a mean, lifetime as median, or lifetime means of medians). Studies use different methods to measure blood Phe (past data were sometimes based on the semi-quantitative Guthrie or more reliable fluorometric enzyme analysis but more recently amino acid concentrations were usually measured by high-performance liquid chromatography and tandem mass spectrometry that are more precise). Differences between the methods (except for Guthrie method) are relatively small [83‐85].
-
- Studies use different Phe samples such as venous serum, venous plasma and DBS. Past studies are largely based on plasma Phe levels, where it is now routine practice to perform DBS measurements. Differences between venous serum and venous plasma are usually regarded as minimal with a variation of 1% [86], but differences between DBS and plasma may be greater with DBS being reported to be 8–26% lower [84, 86, 87]. It should be considered that a higher plasma Phe is likely to result in a higher variation between DBS and plasma.
-
- Studies do not consistently include confounding factors such as maternal education, socioeconomic status and age at start of treatment.
Target Phe levels for children and adolescents
Target Phe levels during adulthood
Biochemical marker used for assessment of metabolic control
Frequency of blood Phe measurements and outpatient visits
Childhood (<12 y) | Adolescence (12–18 y) | Adulthood (≥18 y) excluding maternal PKU | Maternal PKU | |
---|---|---|---|---|
Outpatient visit | Given good clinical and metabolic control: Age 0–1 years: every 2 months Age 1–12 years: twice per year Extra clinic visit as indicated | Given good clinical and metabolic control: twice per year Extra clinic visit as indicated | Given good clinical and metabolic control: once per year Extra clinic visit as indicated | Given good clinical and metabolic control: once per trimester Extra clinic visit as indicated |
Clinical nutritional assessment | Every outpatient visit: dietary assessment (3-day food record/24 h recall), anthropometric parameters (weight, height, BMI) and clinical features of micronutrient and Phe deficiency (especially anorexia, listlessness, alopecia, perineal rash) | Every outpatient visit: dietary assessment (3-day food record/24 h recall), anthropometric parameters (weight, height, BMI) and clinical features of micronutrient and Phe deficiency | Every 12–24 months: dietary assessment (3-day food record/24 h recall), anthropometric parameters (weight, height, BMI) and clinical features of micronutrient and Phe deficiency | Every outpatient visit:dietary assessment (3-day food record/24 h recall) and weight |
Metabolic control | Age 0–1 year weekly Phe Age 1–12 years fortnightly Phe Increased frequency as indicated Annually: plasma amino acids | Monthly Phe Increased frequency as indicated Annually: plasma amino acids | Monthly Phe Increased frequency as indicated Annually: plasma amino acids | Pre-conceptionally: weekly Pregnancy: twice weekly Increased frequency as indicated Pre-conceptionally: plasma amino acids |
Biochemical nutritional assessment | Annual measurement of plasma homocysteine and/or methylmalonic acid, haemoglobin, MCV and ferritin. All other micronutrients (vitamins and minerals including calcium, zinc, selenium) or hormones (parathyroid hormone) if clinically indicated | Pre-conception and at the start of pregnancy: folic acid, vitamin B12, plasma homocysteine and/or methylmalonic acid, ferritin, full blood count Pregnancy: when indicated | ||
Bone Density | BMD measurement only indicated when there are specific clinical reasons or when patients are known to be at particular risk of metabolic bone disease | The first measurement of BMD should be undertaken during late adolescence - When BMD is abnormal, DXA (with or without change of treatment) should be repeated after 1 year. If osteoporosis (BMD < -2.5 SD) persists despite optimization of diet and physical activity, other possible causes of osteoporosis should be investigated. Treatment (including consideration of bisphosphonates) should be determined by osteoporosis severity. - If BMD results are still low but stable, yearly measurement is unnecessary. - When BMD is normal, no repeat measurement is necessary. Further study need only be considered when there are clinical reasons to do so. | BMD measurement is only indicated when there are specific clinical reasons or when patients are known to be at particular risk of metabolic bone disease | Not indicated |
Neurocognitive functions | Only neurocognitive tests when indicated. | Testing at age 12 years Proposed domains of neurocognitive testing: IQ, perception/visuospatial functioning, EF (divided into inhibitory control, working memory and cognitive flexibility) and motor control. Extra neurocognitive tests as indicated. | Testing at age 18 years Proposed domains of neurocognitive testing: IQ, perception/visuospatial functioning, EF (divided into inhibitory control, working memory and cognitive flexibility) and motor control. Extra neurocognitive tests as indicated. | Not indicated |
Adaptive issues (e.g. clinical relevant behavioural problems) | Annually: clinical assessment/discussion | Annually: clinical assessment/discussion Screening at age 12 years | Annually: clinical assessment/discussion Screening at age 18 years | Not indicated |
Neurological complications | If neurodegeneration occurs | If neurodegeneration occurs | Annually: clinical examination | Not indicated |
Psychosocial functioning and wellbeing and QOL | Annually: Clinical assessment/discussion Once during childhood: (PKU-)QOL questionnaire | Annually: Clinical assessment/discussion Once during adolescence: (PKU-)QOL questionnaire | Annually: Clinical assessment/discussion Once during adulthood: (PKU-)QOL questionnaire | Especially in case of not becoming pregnant, the patient may need support |
Psychiatric examination | At onset of symptoms of psychiatric disturbances | At onset of symptoms of psychiatric disturbances | At onset of symptoms of psychiatric disturbances | Not indicated |
White matter abnormalities (MRI) | When there is an unexpected clinical course and/or unexpected neurological deficits | When there is an unexpected clinical course and/or unexpected neurological deficits | When there is an unexpected clinical course and/or unexpected neurological deficits | Not indicated |
Age group specific investigations | / | / | / | Ultrasound at 18–22 weeks of pregnancy with screening for organ development (especially if there is lack of optimal metabolic control) |
Echocardiogram in all infants who are conceived by women with either high blood Phe levels or poor maternal blood Phe control during pregnancy |
Metabolic team and transition
Nutritional follow-up
Bone density
Osteopenia and PKU
Fracture risk in PKU
Pathophysiology of osteopenia in PKU
Brain magnetic resonance imaging
Neurocognitive functioning
Psychosocial functioning
Mental health problems in early treated PKU
Oxidative stress
Dietary treatment
Natural protein restriction
Requirements for Phe
Phe deficiency
Protein requirements
Protein requirements for growth/physiological needs
Age | FAO/WHO/UNU 2007 Report | FAO/WHO/UNU 1985 Report | % change between 2007 and 1985 safe levels of protein intake |
---|---|---|---|
Years | Safe level (+1.96SD) | Safe level (+1.96SD) | |
g/kg/day | g/kg/day | ||
0.5 | 1.31 | 1.75 | −25% |
1 | 1.14 | 1.57 | −27% |
1.5 | 1.03 | 1.26 | −18% |
2 | 0.97 | 1.17 | −17% |
3 | 0.90 | 1.13 | −20% |
4 | 0.86 | 1.09 | −21% |
5 | 0.85 | 1.06 | −20% |
6 | 0.89 | 1.02 | −13% |
7 | 0.91 | 1.01 | −10% |
8 | 0.92 | 1.01 | −9% |
9 | 0.92 | 1.01 | −9% |
10 | 0.91 | 0.99 | −8% |
Girls | |||
11 | 0.90 | 1 | −10% |
12 | 0.89 | 0.98 | −9% |
13 | 0.88 | 0.98 | −10% |
14 | 0.87 | 0.94 | −7% |
15 | 0.85 | 0.87 | −2% |
Boys | |||
11 | 0.91 | 0.99 | −8% |
12 | 0.90 | 0.98 | −8% |
13 | 0.90 | 1 | −10% |
14 | 0.89 | 0.97 | −8% |
15 | 0.88 | 0.96 | −8% |
Age y | Brussels Belgium [6],a
| Munich Germany [6],a
| Copenhagen Denmark [6],a
| Madrid Spain [6],a
| Milan Italy [6],a
| Oslo Norway [6],a
| Groningen Netherlands [6],a
| Warsaw Poland [6],a
| Ankara Turkey [6],a
| Birmingham United Kingdom [6],b
| Portugal [485],c
| United Kingdom (Medical Research Counsil PKU) [486] | France [487] | USA [223] |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
0.1y | ≤2 | 2–2.3 | 2–3 | 3 | Depends on Phe tolerance | 2.5 | 2–2.5 | 2.4 | 2 | 3 | 2–3 | 3 | EAR age | 2.5–3.5 |
1-3y | 1.2 | 1.7 | 2 | 2.5 | 2–2.5 | 1.8–2 | 1.6 | 1.5 | 3 | 2–2.5 | 3 | EAR age | ≥30 g/d | |
4-10y | 1.2 | 1.4–1.6 | 2 | 2 | 1.5–2 | 1.5 | 1.6 | 1.5 | 2 | 1–2 | 2 | EAR age | ≥40 g/d | |
>10y | 1 | 0.8–1.1 | 10-14y: 1.5 >14y: 1 | 1.5 | 1–1.5 | 1–1.2 | 1.2 | 1.2 | 10-14y: 1.5 >14y: 1 | 1–1.5 | unreported | EAR age | ≥50 g/d to ≥65 g/d | |
Adult | No data collected | No data collected | No data collected | No data collected | No data collected | No data collected | No data collected | No data collected | No data collected | 1 | 1 | unreported | EAR age | ≥70 g/d |
Digestibility and bioavailability of L-amino acids
Functional effect of Phe-free L-amino acid supplements
Adverse effects of Phe-free L-amino acid supplements
Supplementation of L-amino acids
Supplementation of Phe-free L-amino acids with added nutrients
Balance of L-amino acids in supplements
Presentation of Phe-free L-amino acid supplements
Transitioning of Phe-free L-amino acid supplements
Alternative sources of protein substitute
Nutritional requirements
Calorie requirement and energy expenditure
Micronutrient requirement
Low protein foods, fruits and vegetables
Reference | N | Fruit/veg criteria | Study design | Change in Phe intake | Blood Phe control | Grade of evidence |
---|---|---|---|---|---|---|
MacDonald et al. 2003 [276] | 15 | Free use of fruit and veg ≤75 mg/100 g Phe Not potatoes | 15 week systematic challenge | Mean Phe # Approx 50 mg/day | No impact on Phe control | 2−/C |
Rohde et al. 2012 [191] | 14 | Free use of fruit and veg ≤75 mg/100 g Phe | 2 week randomised cross-over -trial | Mean Phe # Approx 50–60 mg/day | No impact on Phe control | 1−/B |
Rohde et al. 2014 [277] | 19 | Free use of fruit and veg ≤75 mg/100 g Phe | 1 year follow up study | Mean Phe # Approx 60–70 mg/day | No impact on Phe control | 2−/C |
Zimmermann et al. 2012 [278] | 50 | Free use of fruit and veg ≤100 mg/100 g Phe Not potatoes | Up to 3 year follow up study | Unreported | No impact on Phe control | 2−/C |
Breast-feeding
Aspartame
Tyrosine supplementation
Large neutral amino acids
Illness
Diet | Dietary advice |
---|---|
Phe-free L-amino acid supplement | Maintenance of Phe-free L-amino acid supplement intake to support protein synthesis. It is better to give smaller, frequent doses throughout the day. |
High carbohydrate intake | Encourage frequent high carbohydrate supplements, e.g. glucose polymer solution. |
Natural protein intake | In practice, a reduced appetite leads to a lower natural protein intake. |
Medications | All treatment specific medication should be continued during illness. Continue BH4 if already prescribed. Medications should be free of aspartame in PKU. |
Treat precipitating factors | e.g. anti-pyretics for pyrexia, antibiotics (aspartame-free) for bacterial infections. |
Parenteral nutrition
Support
Treatment in specific patient groups
Maternal PKU
Risk of CHD
≥1200 μmol/l | 900–1200 μmol/l | 600–900 μmol/l | 180–600 μmol/l | Control group/normal population | |
---|---|---|---|---|---|
Lenke and Levy 1980 [318] | 12% of n = 225 | 15% of n = 46 | 6% of n = 33 | 0% of n = 44 | 0.8% in normal population |
MPKUCS Koch 2003 [319] | 11% of n = 257 | 5% | 3% | 2% of n = 66 | 1% CHD of n = 100 control pregnancies |
n = 91 with 600–1200 μmol/l |
Malformations | |
---|---|
Congenital heart defects - Tetralogy of Fallot - ventricular septal defect - mitral/aortic stenosis - patent ductus arteriosus | |
Dysmorphology - microcephaly - coloboma - malformed eyelid, ptosis - hypertelorism - cleft palate - malformed ears - simian creases - fused digits - widely spaced toes | |
Other: - anencephaly - oesophageal atresia - renal agenesis, Potter syndrome - hypospadias - hydrocele - anal fistula, anal atresia |
No treatment
Treatment goals/target Phe levels
Pregnancy planning and medical follow-up
Prevention of unplanned pregnancies
Nutritional recommendation in maternal PKU
Reference | Number of patients | 1st trimester | 2nd trimester | 3rd trimester |
---|---|---|---|---|
Vockley et al. 2014 [102] | 0 (USA guidelines) | 265–770 mg/day | 400–1650 mg/day | 700–2275 mg/day |
Acosta et al. 2001 [350] | 240 | 456 ± 233 to 684 ± 413 mg/day | 528 ± 269 to 528 ± 269 mg/day | 938 ± 542 to 1248 ± 513 mg/day |
Thompson et al. 1991 [351] | 1 | 6 mg/kg bodyweight/day | 30 mg/kg bodyweight/day | |
Kohlschutter et al. 2009 [343] | 3 | 400 mg/day | 1700 mg/day (non-foetal PKU) maximum 600 mg/day (foetal PKU) | |
Duran et al. 1999 [232] | 5 | 250–500 mg/day | 300–500 mg/day | |
Rohr et al. 1987 [369] | 3 | 450–800 mg/day | 720–1300 mg/day | 1300–1500 mg/day |
References | Additional energy requirements in pregnancy (kcal/day) | ||
---|---|---|---|
1st trimester | 2nd trimester | 3rd trimester | |
UK SACN (2011) [353] | None | None | 191 kcal/day |
FAO/WHO/UNU (2001) (based on gestational weight gain of 12 kg) [393] | 85 kcal/day | 360 kcal/day | 475 kcal/day |
aIOM dietary reference intakes (2005) [382] For women 19–50 years | None | 340 kcal/day | 452 kcal/day |
aIOM dietary reference intakes (2005) [382] for girls 14–18 years | None | 340 kcal/day | 452 kcal/day |
Pre-pregnancy BMIa
| Total weight gain kg | Rates of Weight Gain+ 2nd and 3rd Trimester kg |
---|---|---|
Mean (range) in kg/week | ||
Underweight (<18.5 kg/m2 ) | 12.5–18 | 0.51 (0.44–0.58) |
Normal weight (18.5–24.9 kg/m2 ) | 11.5–16 kg | 0.42 (0.35–0.50) |
Overweight (25.0–29.9 kg/m2 ) | 7–11.5 kg | 0.28 (0.23–0.33) |
Obese (≥30.0 kg/m2) | 5–9 kg | 0.22 (0.17–0.27) |
Author | Tyr supplementation |
---|---|
Coutts 1979 [358] | >10 g/day |
6000 to 7600 mg/day | |
Rohr et al. 1987 [369] | Up to 6 g/d (did not ↑ blood Tyr >30 μmol/l) |
Davidson et al. 1989 [364] | 6.4–11.9 g/day |
Brenton et al. 1996 [363] | 2 g/day |
Maillot et al. 2007 [333] | 8 g/day (total from Phe-free L-amino acid supplements and Tyr supplements) |
Thompson et al. 1991 [351] | 160 mg/kg/day- starting point and then titrate according to Tyr levels |
Blood Phe concentration (μmol/L) | Initial amount of daily Phe to give at the start of dietary treatment mg/day |
---|---|
>2000 | 150 |
1600–2000 | 200 |
1200–1600 | 300 |
1000–1200 | 300 |
Dietary and lifestyle approaches
| Small frequent low protein meals and snacks that are high in carbohydrate (e.g. low protein toast, crackers) and low in fat to avoid an empty stomach, feelings of hunger, and abdominal distension [375]. Cold meals may be better if nausea is associated with food smells. For women who have difficulty in eating solid foods, additional drinks of cold water supplemented with glucose polymer may be tolerated if sipped throughout the day. Women should avoid lying down immediately after meals. |
Phe-free L-amino acid supplements
| Give Phe-free L-amino acid supplements chilled and encourage up to 5 or 6 times during the day in small doses. The high osmolality of Phe-free L-amino acid supplements may aggravate nauseas [347] and so may be better tolerated if given with extra fluid. If the smell of liquid or powdered Phe-free L-amino acid supplements is not tolerated, Phe-free L-amino acid tablets are worth consideration. |
Any doses of Phe-free L-amino acid supplements lost through vomiting should be re-given. In extreme cases of vomiting and Phe-free L-amino acid supplements intolerance, hospital admission and administration of Phe-free L-amino acid supplement via a nasogastric tube could be considered. | |
Medication
| Safe antiemetic therapy and acid reducing medications should be considered with persistent vomiting and symptoms of dyspepsia and indigestion. |
Country | Average nutrient level μg/day | Individual nutrient level μg/day |
---|---|---|
Australia and New Zealanda
| 520 | 600 |
Austria, Germany and Switzerlanda
| 600 | |
Denmark, Ireland and Swedena
| 500 | |
European Community | 400 | |
Mexico | 750 (safe level) | |
Polanda
| 520 | 600 |
The Netherlandsa
| 600 (safe level) | |
USAa
| 520 | 600 |
UKa
| 300 | |
FAO/WHO/UNU | 520 | 600 (safe level) |
Late diagnosed and untreated PKU
Late diagnosed PKU
Untreated PKU
Behaviour | |
Less aggressive behaviour, self-injury, hyperactivity, restlessness, irritability, sleep disorders, anxiety, stereotyped behaviour | |
Improved mood change, social interaction, verbal communication, daily living skills | |
Neurology | |
Improvement of attention span, alertness, short-term memory processes, motor skills, seizures, spasticity, tremors | |
Other clinical parameters | |
Improvement/disappearance of eczema, skin rash, body odour Darker hair colour | |
Quality of life | |
Reduced nursing time | |
Medication | |
e.g. less use of sedative, anti-psychotic, anticonvulsants |
Dietary treatment and monitoring
Other therapies
Adherence
Pharmacological treatment and emerging therapies
BH4 treatment
BH4 loading test and treatment trial
Emerging therapies
Patients’ view
Implementation/impact of guidelines
Future requirements and research
Conclusion
Definitions
Concurrent Phe level | The Phe level measured at or close to the day of outcome assessment. |
ESPKU | The European Society for Phenylketonuria and Allied Disorders is the umbrella organization of national and regional associations from about 30 countries established by parents. |
Executive functioning | Executive functioning are cognitive processes that regulate behaviour; examples are inhibitory control, working memory and cognitive flexibility. |
High risk pregnancy | A pregnancy that threatens the health or life of the mother or her foetus. |
Late treated and/or untreated adults | Late diagnosed refers to children diagnosed aged between 3 months and 7 years (≥3 months - <7 years). Untreated refers to patients untreated aged 7 years and over. |
Lifetime Phe levels | Phe levels from birth to the age of testing. This is often expressed as the median Phe level of (semi)annual mean Phe levels. Also referred to as historical Phe levels. |
Maternal PKU syndrome | The teratogenic effects of elevated maternal phenylalanine levels during pregnancy to the foetus. |
Phenylalanine tolerance | The amount of phenylalanine (mg/kg/day or mg/day) that maintains plasma phenylalanine concentrations within the target range. This may also be described as natural protein tolerance expressed as g/day taking a phenylalanine content in natural protein as 50 mg phenylalanine/g natural protein. |
Protein requirements | The lowest level of dietary protein intake that will balance the losses of nitrogen from the body, and thus maintain the body protein mass in persons at energy balance with modest levels of physical activity. |
Protein substitutes (phenylalanine-free L-amino acid supplements and low phenylalanine glycomacropeptide protein) | Protein replacement/substitutes are essential to prevent protein deficiency and optimize metabolic control. Protein substitutes are mainly sourced from phenylalanine-free L-amino acids supplements and less commonly from low phenylalanine glycomacropeptide. |
Potential tetrahydrobiopterin (BH4) responsiveness | >30% reduction in blood phenylalanine in a BH4 loading test or 2 BH4 responsive variants. Long-term BH4-responsiveness should be proven in a treatment trial adjusting the BH4 dosing, natural protein intake and phenylalanine-free L- amino acid supplement. |
Tetrahydrobiopterin (BH4) | Cofactor of the phenylalanine hydroxylase. BH4 also acts as a chaperone molecule in phenylalanine hydroxylase-deficient patients harbouring specific gene variants. BH4 is also a cofactor of tyrosine and tryptophan hydroxylases and plays an important role in the conversion of L-arginine to nitric oxide (NO) by nitric oxide synthases (NOS). |
Tetrahydrobiopterin (BH4) deficiencies | Defects in BH4 metabolism (either synthesis or regeneration) result in a deficiency of BH4. These include 3 known defects for synthesis and 2 for regeneration. |
Tetrahydrobiopterin (BH4) responsiveness | In this report it is defined as an increase of ≥100% in natural protein and/or improved biochemical control (>75% of phenylalanine levels in target range) on a dose of BH4 that ranges between 1 and 20 mg perkg of body weight (with a maximum dose of 1000 or 1400 mg/day in some cntries). |