Phenylketonuria 苯丙酮尿症 Xue Fan Gu. MD, PhD Xinhua Hospital Shanghai Jiao Tong University School of medicine
Phenylketonuria 苯丙酮尿症 Xue Fan Gu, MD, PhD Xinhua Hospital Shanghai Jiao Tong University School of Medicine
Inborn errors of metabolism Overview Disorders in which defects of single gene cause clinically significant blocks in metabolic pathways Many kinds of disorders Lower incidence Clinical manifestations vary widely: mental retardation, seizure, hypotonia, failure to thrive. vomiting/anorexia, special odor, hypoglycemia, yperammonemia, metabolic acidosis, elevated lactate/pyruvate etc
Inborn errors of metabolism Overview • Disorders in which defects of single gene cause clinically significant blocks in metabolic pathways • Many kinds of disorders • Lower incidence • Clinical manifestations vary widely: mental retardation, seizure, hypotonia, failure to thrive, vomiting/anorexia, special odor, hypoglycemia, hyperammonemia, metabolic acidosis, elevated lactate/pyruvate etc
Phenylketonuria O An autosomal recessive disease The incidence of pku in China is about 1/11800 o The incidence of pku in Shanghai is about 1/16000
⚫ An autosomal recessive disease ⚫ The incidence of PKU in China is about 1/11 800 ⚫ The incidence of PKU in Shanghai is about 1/16 000 Phenylketonuria
Phenylalanine metabolic pathway diet protein phenylalanine hydroxylase(PAh) phenylalanine tvrosine BH4 thyroxin dopa phenylpyruvic acid d I rename phenyllactate phenylacetate
Phenylalanine metabolic pathway diet protein phenylalanine hydroxylase(PAH) phenylalanine tyrosine BH4 phenylpyruvic acid phenyllactate phenylacetate thyroxin dopa adrenaline
Biosynthesis and regeneration of tetrahydrobiopterin Guanosine triphosphate(GTP) GTPch 35 Neopterin+-Dihydroneopterin triphosphate PTPS 6-Pyruvoyl-tetrahydropterin v SR Phe Tyrosine Tryptophan tetrahydropterin( BH4) DHPR PAH TH TPH PCD q-dihydrobiopterin(BH2) pterin Try L-DOPA 5-OH- Tryptophan 4a-carbinolamine
Biosynthesis and regeneration of tetrahydrobiopterin Guanosine triphosphate（GTP） GTPch p35 Neopterin Dihydroneopterin triphosphate (N) PTPS - + 6-Pyruvoyl-tetrahydropterin SR Phe Tyrosine Tryptophan tetrahydropterin(BH4 ) DHPR PAH TH TPH PCD q-dihydrobiopterin(BH2 ) pterin- Try L-DOPA 5-OHTryptophan 4a-carbinolamine biopterin Dopamine
Clinical manifestations to appear symptoms after 3 months of birth fair hair, hypopigmentation in skin. eczema special odor(mouse-like) discharged from urine, sweat mental retardation nod-like seizure or infantile spasm
Clinical manifestations • to appear symptoms after 3 months of birth • fair hair, hypopigmentation in skin, eczema • special odor (mouse-like) discharged from urine,sweat • mental retardation • nod-like seizure or infantile spasm
Classical pKu o pah activity is about 0-4.4o of normal o Persistent elevation of phe or its metabolites is neurotoxic, the result is profound intellectual handicap Typical pKu symptoms Strong positive result of urinary Fecl3 and dnph test Blood Phe level is 1200umol/L 20mg/dl)
Classical PKU ⚫ PAH activity is about 0-4.4% of normal ⚫ Persistent elevation of Phe or its metabolites is neurotoxic, the result is profound intellectual handicap ⚫ Typical PKU symptoms ⚫ Strong positive result of urinary FeCl3 and DNPH test ⚫ Blood Phe level is 1200mol/L ( 20mg/dl)
Transient pKu ● Delay in pah maturity o The Phe level was <1200umol/L at neonatal period o The phe level is gradually dropped to normal even on free diet after 2-years o Dietary restriction is only temporary, if required at all
Transient PKU ⚫ Delay in PAH maturity ⚫ The Phe level was 1200mol/L at neonatal period ⚫ The Phe level is gradually dropped to normal even on free diet after 2-years ⚫ Dietary restriction is only temporary, if required at all
Differential diagnosis Tetrahydrobiopterin deficiency BH4D) Deficiency of PAH cofactor - BH4 6-Pyruvoyl-tetrahydropterin synthese (PTPS) deficiency is the most common of BhD The incidence of bhD is 10% among HPA patients in Chinese The blood Phe is slightly increased at early stage in most patients Some cases were misdiagnosed as having pah deficiency
Differential diagnosis Tetrahydrobiopterin deficiency （BH4D） • Deficiency of PAH cofactor -- BH4 • 6-Pyruvoyl-tetrahydropterin synthese (PTPS) deficiency is the most common of BH4D • The incidence of BH4D is 10% among HPA patients in Chinese • The blood Phe is slightly increased at early stage in most patients • Some cases were missdiagnosed as having PAH deficiency