Hyperphenylalaninaemia Sarah M. Alfaqaih ,MD MBBS , AB Clinical fellowship KHMC ( Royal medical services ) of inherited metabolic disorder

Content: Introduction Metabolic derangement Clinical presentation Diagnosis workup Treatment Prognosis

Defect in either PAH or the production or recycling of BH4 may cause hyper-PAH . Autosomal recessive defect The PAH gene located on long arm chromosome 12 No single prevalent mutation

The prevalence varies between different population : 1 in million in Finland 1 in 2400 in Turkey

Introduction Metabolic derangement Clinical presentation Diagnosis workup Treatment Prognosis

Pathogenesis of brain damage of PKU is not fully understood Tyrosine becomes semi-essential amino acid , with reduced blood levels leading to impaired synthesis of melanine , dopamine and norephinephrine Increased blood level of PHA results in an imbalance of other large neutral amino acid within the brain ( decrease TYR , serotonin )

Introduction Metabolic derangement Clinical presentation Diagnosis workup Treatment Prognosis

Mousy odour ( phenylacetic acid ) Eczema 20-40% Sever mental retardation IQ<= 50 Reduced hair , skin and iris pigmentation Reduced growth and microcephaly and neurological impairments: 25% epilepsy , 30% tremor , 5% spasticiy of limbs , 80% EEG abnormalities

The face of this patient with PKU illustrates the rather subtle eczematoid rash. The brown eyes remind us that all patients with this disease do not have blue eyes. In addition, he had epicanthal folds and a left internal strabismus Fig:1(2)

Severely retarded, institutionalized brothers with untreated PKU Severely retarded, institutionalized brothers with untreated PKU. They were quite fair of hair and skin. Fig:2(2)

Almost all untreated patients show behavioral problems , which include hyperactivity , purposeless movements , aggressiveness , anxiety and social withdrawal . The clinical phenotype correlate with PHE blood level .

Introduction Metabolic derangement Clinical presentation Diagnosis workup Treatment Prognosis

PKU is detected by neonatal secrening ( Guthrie , enzymatic techniques , tandum mass spectrometry ). PHE level that is taken as a positive result requiring further investigation (120-240µmol\l , also PHE\TYR ratio >3 used in some labs ).

A positive ferric chloride test in a patient with untreated PKU. Fig:3 (2)

Introduction Metabolic derangement Clinical presentation Diagnosis workup Treatment Prognosis

Principle of treatment Dietary treatment PHE free amino acid formula . Breast milk has a relatively low amount of PHE. Meat , fish , milk , yogurt ,cream , egg , rice and cheese contains a higher concentration of PHE.

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Treatment with BH4 BH4 can reduce level of PHE in some patient with PKU BH4 responsiveness is determined by reduction of >= 30% in blood PHE level after a single dose of 10mg\kg body weight

Monitoring of treatment(1)

Alternative treatment Gene therapy : the development of a safe and more successful gene transfere vector is still required before clinical trial in humans Liver transplantation : the risk of transplantation surgery and post-transplantation immune suppressive medication are too high for it to be a realistic alternative . Phenylalanine ammonia lyase

Introduction Metabolic derangement Clinical presentation Diagnosis workup Treatment Prognosis

The outcome is expected to be very good if the diet is closely followed, starting shortly after the child's birth. If treatment is delayed or the condition remains untreated, brain damage will occur. School functioning may be mildly impaired. If proteins containing phenylalanine are not avoided, PKU can lead to intellectual disability by the end of the first year of life.

Reference 1)Jean-Marie Saudubray ,Georges van den Berghe , John H. Walter (Editors) Inborn Metabolic Disease Diagnosis and Treatment, Fifth Edition 2)William L. Nyhan , Bruce A. Barsho , Pinar T. Ozand, Atlas of Metabolic Diseases Second edition

THANKS FOR ATTENSION