Overview
Definition:
Phenylketonuria (PKU) is an autosomal recessive genetic disorder characterized by a deficiency of the enzyme phenylalanine hydroxylase (PAH)
This enzyme is responsible for converting the essential amino acid phenylalanine (Phe) into tyrosine
A deficiency leads to the accumulation of Phe in the blood and tissues, causing significant neurotoxicity and intellectual disability if left untreated.
Epidemiology:
PKU is one of the most common inherited metabolic disorders
Its incidence varies significantly by ethnicity and geographic region, with higher prevalence in Caucasian populations of Northern European descent
In Europe and North America, the incidence is typically around 1 in 8,000 to 1 in 15,000 live births
In India, the incidence is generally lower, though screening programs are expanding
Newborn screening programs have dramatically reduced the incidence of severe intellectual disability due to PKU.
Clinical Significance:
PKU is a critical condition for pediatricians and residents preparing for DNB and NEET SS examinations due to its high prevalence among inborn errors of metabolism and the profound preventable neurodevelopmental consequences
Early diagnosis through newborn screening and lifelong adherence to a strict low-phenylalanine diet are paramount for preventing severe cognitive impairment and ensuring a normal developmental trajectory
Understanding the nuances of dietary management and long-term neurocognitive follow-up is essential for optimal patient outcomes.
Clinical Presentation
Symptoms:
In untreated infants, symptoms typically manifest after the first few months of life and include: failure to thrive
developmental delay
intellectual disability
microcephaly
seizures
eczema
a characteristic musty or mousy odor to the urine and body odor due to phenylacetic acid excretion
hyperactivity
behavioral problems
vomiting.
Signs:
Physical examination findings in untreated infants may include: poor feeding
recurrent vomiting
generalized hypotonia
spasticity
abnormal reflexes
fair skin and hair due to impaired melanin production (tyrosine is a precursor)
eczema
neurological signs such as tremor or myoclonus.
Diagnostic Criteria:
Diagnosis is primarily established through newborn screening programs using tandem mass spectrometry (MS/MS) or fluorometric assays to measure blood phenylalanine (Phe) levels
Diagnostic criteria typically involve elevated Phe levels
Classical PKU is defined by Phe levels typically above 20 mg/dL (1200 µmol/L) on two separate occasions after 24 hours of age
Other forms, such as mild PKU or biochemical variants, have lower but still elevated Phe levels and may require further genetic testing and metabolic assessment.
Diagnostic Approach
History Taking:
Key history points include: family history of similar symptoms or diagnosed metabolic disorders
maternal history of PKU (maternal PKU requires strict control during pregnancy to prevent fetal effects)
feeding history and weight gain
developmental milestones
presence of characteristic odor
any reported seizures or behavioral changes.
Physical Examination:
A systematic physical examination should focus on: general appearance for features of developmental delay or microcephaly
assessment of skin for eczema
neurological examination for tone, reflexes, and any signs of seizures or spasticity
assessment of head circumference
observation for characteristic odor (though this is less reliable in modern practice).
Investigations:
Initial diagnosis is via newborn screening measuring blood phenylalanine levels
Confirmatory testing includes: quantitative amino acid analysis in plasma to confirm elevated Phe and assess tyrosine levels
Phe/Tyr ratio is often used
Urine testing for phenylketones (e.g., ferric chloride test, which is qualitative and less sensitive)
Genetic testing for mutations in the PAH gene confirms the diagnosis and can identify specific mutations, which can sometimes have prognostic implications
Liver biopsy for PAH enzyme activity assay is rarely needed but can be definitive.
Differential Diagnosis:
Differential diagnosis for elevated phenylalanine includes: transient hyperphenylalaninemia (due to immaturity of PAH or other transient factors)
tyrosinemia type I, II, or III
other inborn errors of amino acid metabolism
conditions causing severe liver dysfunction
dietary excess of phenylalanine (rarely the sole cause of significant elevation)
disorders mimicking developmental delay or neurological impairment.
Management
Initial Management:
Immediate management involves: initiating a low-phenylalanine diet as soon as diagnosis is confirmed
referral to a metabolic specialist or center for comprehensive management
initiation of specialized infant formula low in Phe and supplemented with tyrosine.
Medical Management:
The cornerstone of PKU management is a lifelong strict low-phenylalanine diet
This involves: restricting natural protein intake (found in milk, meat, fish, eggs, nuts, legumes) to provide only the required amount of Phe for growth and protein synthesis
using specially formulated PKU medical foods or formulas that provide all essential amino acids except Phe, along with adequate calories, vitamins, and minerals
supplementation with tyrosine is crucial as it becomes conditionally essential
monitoring blood Phe levels regularly (weekly in infancy, then monthly to quarterly) to maintain Phe levels within target ranges (e.g., 120-360 µmol/L for children up to 12 years, 180-480 µmol/L for adolescents, and 120-600 µmol/L for adults, though targets can vary)
Sapropterin dihydrochloride (Kuvan), a synthetic form of tetrahydrobiopterin (BH4), can be used in some patients with BH4-responsive PKU to help lower blood Phe levels.
Nutritional Support:
Nutritional management is complex and requires a multidisciplinary team including a metabolic dietitian
Key aspects include: ensuring adequate protein intake from PKU formula and low-Phe foods
monitoring growth and nutritional status
managing potential deficiencies of vitamins, minerals, and essential fatty acids
providing education and support to families regarding dietary adherence
introducing low-Phe fruits, vegetables, and specific low-protein breads and pastas as the child grows
Phenylalanine content of foods must be meticulously tracked.
Supportive Care:
Ongoing supportive care involves: regular monitoring by a metabolic team
management of any intercurrent illnesses that may affect Phe levels
psychosocial support for patients and families
genetic counseling
adherence monitoring for dietary management.
Complications
Early Complications:
Inadequate dietary control in early infancy can lead to: rapid onset of severe intellectual disability
failure to thrive
developmental regression
seizures
neurological damage.
Late Complications:
Even with adequate treatment, long-term complications can arise from suboptimal dietary control or adherence issues: milder cognitive deficits
learning difficulties
attention deficit hyperactivity disorder (ADHD)-like symptoms
behavioral problems
psychiatric issues
subtle motor deficits
neurological abnormalities on MRI (e.g., white matter changes)
In adults, uncontrolled Phe can lead to impaired executive functions and mood disorders.
Prevention Strategies:
Prevention of complications relies on: universal newborn screening for early diagnosis
strict adherence to the low-Phe diet from infancy throughout life
regular monitoring of blood Phe levels and growth
consistent follow-up with a specialized metabolic team
effective management of maternal PKU to prevent fetal effects.
Neurocognitive Follow Up
Assessment Frequency:
Neurocognitive and behavioral assessments should be conducted regularly throughout childhood, adolescence, and adulthood
Frequency depends on age and adherence to treatment, typically annually or biannually
This includes formal neuropsychological testing, developmental assessments, and behavioral evaluations.
Monitoring Parameters:
Key parameters to monitor include: blood Phe levels (primary indicator of dietary control)
tyrosine levels (to ensure adequacy)
nutritional status (growth parameters, micronutrient levels)
cognitive function (IQ, processing speed, executive functions, memory)
academic performance and school reports
behavioral assessments (e.g., questionnaires for ADHD, anxiety, depression)
quality of life measures.
Interpreting Findings:
Interpreting neurocognitive findings requires correlation with Phe levels and adherence
Elevated Phe levels, even if transiently, are associated with poorer cognitive outcomes
Persistent elevation or significant fluctuations impact neurodevelopment
Difficulties in executive functions are common even in well-treated individuals
Long-term adherence is critical for maintaining cognitive function and preventing decline.
Management Adjustments:
Based on neurocognitive and biochemical monitoring, dietary adjustments may be necessary
This might involve fine-tuning Phe intake, increasing tyrosine supplementation, or exploring adjunctive therapies like sapropterin if indicated
Psychological support and behavioral interventions may also be implemented to address specific challenges.
Long Term Surveillance:
Long-term surveillance is essential to ensure sustained metabolic control and monitor for late-onset neurological or psychiatric manifestations
This includes annual or biennial comprehensive evaluations by the metabolic team, including neurocognitive and behavioral assessments.
Key Points
Exam Focus:
Early diagnosis via newborn screening is critical
Lifelong, strict low-phenylalanine diet is the mainstay of treatment
Regular monitoring of blood phenylalanine levels is essential
Tyrosine supplementation is crucial
Maternal PKU poses significant risks to the fetus.
Clinical Pearls:
Involve a multidisciplinary team (metabolic physician, dietitian, genetic counselor, neuropsychologist)
Educate families thoroughly on dietary management and monitoring
Remember that tyrosine is conditionally essential and needs supplementation
Be aware of sapropterin as a potential adjunctive therapy for responsive patients.
Common Mistakes:
Discontinuing the diet after infancy or during adolescence
Inadequate monitoring of blood phenylalanine levels
Insufficient tyrosine supplementation
Underestimating the importance of lifelong adherence for preventing neurocognitive deficits
Poor control of maternal PKU during pregnancy.