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Inborn errors of metabolism

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

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Inborn errors of metabolism

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  1. Phenylketonuria苯丙酮尿症Xue Fan Gu, MD, PhDXinhua HospitalShanghai Jiao Tong University School of Medicine

  2. 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.

  3. Phenylketonuria • 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

  4. Phenylalanine metabolic pathway diet protein phenylalanine hydroxylase(PAH) phenylalanine tyrosine BH4 phenylpyruvic acid phenyllactate phenylacetate thyroxin dopa adrenaline

  5. Biosynthesis and regeneration of tetrahydrobiopterin Guanosine triphosphate（GTP） GTPch p35 NeopterinDihydroneopterin triphosphate (N) PTPS - + 6-Pyruvoyl-tetrahydropterin SR Phe Tyrosine Tryptophan tetrahydropterin(BH4) DHPR PAH TH TPH PCD q-dihydrobiopterin(BH2) pterin- TryL-DOPA 5-OH-Tryptophan 4a-carbinolamine biopterin(B)Dopamine serotonin

  6. 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

  7. 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  1200mol/L ( 20mg/dl)

  8. Transient PKU • Delay in PAH maturity • The Phe level was 1200mol/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

  9. Differential diagnosisTetrahydrobiopterin 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

  10. Neonatal Screening for PKU • No PKU symptoms in neonatal period • higher Phe level in blood • Neonatal screening program can make diagnosis, treatment earlier and prevent mental retardation • NS program has been carried out in China since 1981

  11. Neonatal Screening method Subject： • Newborns who should be breast-fed for 3 days after birth • Method of Phe determination on Guthrie cardby bacterial inhibition assay (semi-quantity) or fluorescence analysis, the positive cut off of Phe is 120umol/L

  12. Laboratory findings • Urine FeCl3 test and DNPH test used in clinical screening for PKU • Blood Phe measurement • Urinary pterin analysis by HPLC • BH4 loading test • PAH gene analysis, common PAH gene mutations are in exon 7 in Chinese PKUs

  13. Treatment • Low or free Phe milk powder was developed in 1953 • Low-Phe diet can not only provide proper protein, but also reduce the Phe taking • Phe restriction should be continued at least 18 years old or throughout life • Female patients must be treated before and whole pregnancy to avoid maternal PKU

  14. The series products of low-Phe diet Milk powder • component: Protein 15%, Fat 8%,CHO 68% • two kinds of: free Phe formula low-Phe formula • Flour,Biscuitpure,aminoacid powder

  15. Control range of blood Phe level in different age for treated PKU/HPA Age（Y） phe level（mol/L） _____________________________ 0～3 120～240 3～8 180～360 8～13 180～480 13～18 180～600 >18 180～900 ______________________________

  16. Treatment for BH4D • To control Phe concentration <120 mol/L BH4 tablet 2～10mg.Kg-1.d-1 • to improve neurological symptoms L-DOPA/ Carbidopa 5-15mg.Kg-1.d-1 5-hydroxytryptophan5-10mg.Kg-1.d-1 • Patient with DHPR deficiency should be treated with BH4(20mg.Kg-1.d-1)and given folic acid(10-20mg/d) as well as neurotransmitte precursors

  17. PKU patients at the 2 years old untreated patient daignosed by NS and treated

  18. M469 4-year old,diagnosed by NS and treated by local-made low-Phe diet

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