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Phenylketonuria: A Case Study of a 13-Month-Old Boy with Developmental Delay

This case study explores the history, physical examination, lab data, and clinical features of a 13-month-old boy with developmental delay, irritability, recurrent vomiting, and seizures. The diagnosis of phenylketonuria (PKU), an autosomal recessive disorder caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH), is discussed.

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Phenylketonuria: A Case Study of a 13-Month-Old Boy with Developmental Delay

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  1. .

  2. Case history • 13 month old boy with developmental delay • NL at birth • Irritability& Recurrent vomiting from 2 week age

  3. Case history • Recurrent seizure with poor response to antiepileptic drugs from 3 month ago. • No sitting , no walking • speech delay • Relative parents

  4. Physical examination • HT=75.2 cm • WT=10.300 kg • HC=42cm • Prominent maxilla • Fair sparse hair

  5. Physical examination • Enamel hypoplasia • Left internal strabismus • Mild Eczematoid rash • No organomgaly • Hypertonic with hyperactive deep tendon reflexes • unusual odor of sweet and urine • Ophtalmologist consult : NL retin , no cataract, Left internal strabismus were seen

  6. Lab data • CBC • TFT • VBG • ELECTROLYTES • LFT • TORCH • Ammonia • lactate • U/A • EEG: AbNL • .

  7. Lab data • Brain MRI:a symmetrical increase of T2-weighted signal in the periventricular white matter

  8. Classic Phenylketonuria

  9. Phenylketonuria • Autosomal recessive • Incidence :one of every 15,000 infants • PKU in most cases is caused by deficiency of hepatic enzyme phenylalanine hydroxylase PAH • PAH catalyzes the conversion of phenylalanine to tyrosine • This pathway accounts for the catabolism of 75 % of dietary phenylalanine • Tetrahydrobiopterin (BH4) is a cofactor required for PAH activity

  10. L-aminoacid transporter • Phenylalanine’s entry into the brain is mediated by the large neutral aminoacid carrier 1(LAT1). • Two other large neutral aminoacids—tyrosine, a precursor of dopamine and norepinephrine, and tryptophan, a precursor of serotonin—also enter the brain via the LAT1 carrier. • High concentrations of phenylalanine can inhibit LAT1 from entering the brain, increasing the potential for neurotransmitter dysfunction.

  11. Phenylketonuria

  12. Phenylketonuria The defect of PAH • Elevated blood and urine phenylalanine and its metabolites, phenylacetate and phenyllactate The defect of recycling or regeneration BH4. In 2% of infants with hyperphenylalaninemia,

  13. The defect of recycling or regeneration BH4 • Analysis of DBS or urine for neopterin and biopterin and measurement of dihydropteridine reductase (DHPR) activity in the DBS is essential for the exact diagnosis and should be performed as early as possible

  14. Mistake in evaluation of DHPR • Diseases that cause activation of the immune system increase and methotrexate, trimetoprinsulfamethoxazole decrease DHPR • Some patients with DHPR deficiency show a normal neopterin and biopterin • So DHPR activity is essential in all patients with HPA, regardless of pterin measurements.

  15. Clinical Features • Because of neonatal screening, overt clinical manifestations are rare. • the onset of PKU is insidious and may not cause symptoms until early infancy. • hallmark of the disease is intellectual disability

  16. Clinical Manifestations • Infants with cofactor deficiency are identified during screening programs for PKU because of evidence of HPA. . • Neurologic manifestations, such as loss of head control, truncal hypotonia ,drooling, swallowing difficulties, and myoclonic seizures, develop after 3 mo of age despite adequate dietary therapy

  17. Clinical features • Mental impairment worsens during myelination in early childhood with increasing dietary exposure, but stabilizes when brain maturation is complete. • 25% may develop seizures- more with BH4 deficiency. • some patients had loss of motor function over time • Autism • aberrant behavior, and psychiatric symptoms • Hyperactivity. • Seizure,self mutilation ,

  18. Microcephaly • prominent maxillae with widely spaced teeth • enamel hypoplasia • Growth retardation • Persistant crying

  19. Clinical features • Abnormalities of gait, sitting posture, and stance • . spasticity, hyperreflexia, tremors. • Frequently have blond hair,pale skin and blue eyes eczematous rash. • "mousy" odor due to increased phenylacetic acid. • Cataract

  20. Atlas Metabolic Diseases, Nyhan et al

  21. Diagnosis & DDx

  22. Neonatal Screening for Hyperphenylalaninemia • Blood phenylalanine in affected infants with PKU may rise to diagnostic levels as early as 4 hr after birth even in the absence of protein feeding. • It is recommended, however, that the blood for screening be obtained in the 1st 24–48 hr of life after feeding protein to reduce the possibility of false negative results, especially in the milder forms of the condition

  23. Diagnosis • Newborn Screening – Virtually 100% • The most useful method for newborn screening is tandem mass spectrometry • Phe cut-off for diagnosis by TMS is 2.1-4mg/dl • Blood Phenylalanine is high,Tyrosine level will be low or low normal • Plasma phenylalanine/tyrosine ratio ( >2-3 HP) • .

  24. Rescreening • sick neonates • parenteral nutrition • Blood transfusion • Not sufficient protein intake

  25. Pah deficiency may be classified to four different type Classical PKU phe > 20 mg/dL. • mild PKU • phe 10 to 15 mg/dL • Moderate PKU • phe 15 to 20 mg/d • MildHyperphenylalanemia • phe 2.5(4) to 10 mg/dl

  26. Normal range 0.8-1.8 mg/dL

  27. Hyperphenylalanaemia • Classic Phenlyketonuria (6%) • Benign • Partial hydroxylase deficiency (6-30%) • Transient PAH deficiency • Phenylalanine transaminase deficiency • Malignant • Dihydropteridine reducatase deficiency • Tetrahydrobiopterin synthesis deficiency • Tyrosinaemia • Transient tyrosinaemia • Tyrosinosis • Liver disease • Galactose 1-phosphate uridyltransferase deficiency

  28. Diagnosis • Genotyping of phenylalanine hydroxylase (PAH): > 400 mutations

  29. There is also a lack of consensus about the severity of hyperphenylalaninaemia • Most clinical centrs use one of three phenylalanine threshold: • Greater than 6mg/dl • Greater than 7mg/dl • Greater than 10mg/dl

  30. Treatment • The goal of therapy is to reduce phenylalanine in the body • The diet should be started as soon as diagnosis is established.

  31. treatment • . First, whether the patient has a defect in BH4 synthesis or recycling • whether the patient can be treated with diet restrictions only • whether can be helped with BH4 alone or together with a restricted diet

  32. TREATMENT . • patients who do need strict dietary treatment (PKU) • patients who do not need any treatment (non-PKU HPA) • patients who may be treated with BH4 (BH4-responsive PKU)

  33. Hyperphenylalaninemia 4-7MG/DL NOMAL DIET • Vomiting • Family history of MR • Hypotonia / Hypertoinia Monitor phe , montHly pediatrician visit until 6 -12 m

  34. Treatment • persistent phenylalanine >6 mg should be treated. • Discontinuation of therapy, even in adulthood, may cause deterioration of IQ and cognitive performance .

  35. Transient Hyperphenylalaninemia • Isolated delay in the maturation of PAH • Challenged with dietary phe during the first year of life

  36. Protein Challenge test : • At age : 5 months • one yr • 3-days intake of 100-180 mg/Kg/d of phenylalanine • check phe. 72hr after : • if : phe > 20 mg/dl classic pku • phe :10- 20 mg/dl mild pku • phe :>7 mg/dl Diet therapy

  37. MILDER FORMS OF HPA, NON-PKU HPA • Group of infants with initial plasma concentrations of phe between 2-20 mg/dL. • These infants do not excrete phenylketones. • Clinically, these infants may remain asymptomatic, but progressive brain damage may occur gradually with age. • These patients have milder deficiencies of phenylalanine hydroxylase or its cofactor (BH4) than those with classic PKU.

  38. Initial Dietary Therapy for Classic PKU means delete phenylalanie from diet as follows • phe(mg/dl) delete phe. Monitor • 10-20 48 hrs Q7d • 20-40 72 hrs Q7d • > 40 96 hrs Q7d

  39. When p.phe(2-6 mg/dl ) • Guidelines for initial dietary phenylalanine content dependent on the maximum pretreatment plasma levels : • Plasma phe(mg/dl) Dietary phe (mg/Kg) • (<10) 70 • (10-20) 55 • (20-30) 45 • (30-40) 35 • (>40) 25

  40. Recommended phe (mg/kg/day) and protein (g/kg/day) in pku patients

  41. TREATMENT • The restriction of dietary phenylalanine before one week of age.

  42. Babies with PKU may drink breast milk, while also taking their special metabolic formula, • Iron,zinc,calcium, • selenium • Carnitin < 24 months • Fish oil,coenzyme Q10 • Vitamin A,c,E,B12, B6,folinic acid • Vitamin D

  43. Breast milk • Breast milk has lower content phe in compared with standard formula • It has optimal PHE/Tyr ratio • It contains LCPUFAs • First special formula then breast fed • It contain 200-1000nmol/li BH4

  44. PHE content • Breast milk 53mg/100 PHE • Formula 60mg/dl • Cows milk 150mg/dl

  45. Treatment • Because phenylalanine is not synthesized by the body, overtreatment may lead to phenylalanine deficiency manifested by lethargy, failure to thrive, anorexia, anemia, rashes, diarrhea, and death; • tyrosine is an essential amino acid and its adequate intake must be ensured.

  46. treatment • Long chain polyunsaturated fats(LCPUFA) : Because of restricted animal protein, low LCPUFA and docosahexanoic acid (DHA), which may compromise neurodevelopment . • supplementation for 12 months with LCPUFA including DHA improved visual function • supplementation with fish oil (omega-3 LCPUFA) for three months improved the motor skills of children

  47. Large neutral amino acids (LNAAs) • Arginine, histidine, isoleucine, leucine, lysine, methionine, threonine, tryptophan, tyrosine and valine) compete with phenylalanine for the same amino transporter at the blood brain barrier. • Prekunil tablet compete withphe • 2 tablet for 10 kg • Supplementation with LNAAs may therefore significantly reduce the influx of phenylalanine into the brain in patients with PKU .

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