Inherited disorders of amino acid catabolism Flashcards
•Outline the catabolic pathway of the following amino acids: –Phenylalanine and tyrosine and associated disorders •Phenylketonuria(Classic-PKU I and tetrahydrobiopterindeficiency –PKU II, maternal PKU), Alkaptonuria, Tyrosinosis –Branched chain amino acids •Maple syrup urine disease •Methylmalonicaciduria –Methionineand cysteine •Homocystinuria •Outline the two possible fates of homocysteine •For each of the disorders listed above –Specify the enzyme deficient and coenzyme requ
How is PKU now tested?
Tandem mass spec
What type of genetic disorder is PKU?
Autosomal recessive disorder
What does PKU stand for?
Phenylketonuria
Why do some centers test infants twice for PKU?
-First test might be false negative
-Due to maternal clearance
Describe the diet to recommend to patients with PKU.
Low Phe diet:
-Low protein
-Avoid eggs, milk and meat
-Avoid aspartame (artificial sweetener)
What is the biochemical defect in patients with Classic PKU (type I)
Phenylalanine Hydroxylase (PAH)
What is the biochemical defect in patients with Benign PKU (type II)
Deficiency of dihydrobiopterin synthesis or dihydrobiopterin reductase (BH2/BH4)
What is the biochemical defect in patients with MSUD?
Branched chain alpha-keto acid dehydrogenase (BCKD)
What is the biochemical defect in patients with Homocystinura
Cystathioneine B-synthase
What is the biochemical defect in patients with Alkoptonuria
Homogentisic Acid Oxidase
Besides Phenylalanine, what other factors are needed by PAH to form tyrosine?
Tetrahydrobiopterin (BH4)
Tetrahydrobiopterin (BH4), gets converted to what by PAH?
Dihydrobiopterin (BH2)
Dihydrobiopterin (BH2), gets converted to Tetrahydrobiopterin (BH4) by which enzyme?
Dihydrobiopterin reductase
Deficiency of BH2/BH4 leads to what?
1) Elevated PHE and its metabolites
2) Deficient catecholamine formation
3) Deficient serotonin production
Which is more severe, PKU-I or PKU-II?
PKU-II
What are the characteristics of PKU-I (classic) in untreated patients?
-Developmental milestone delay
-low IQ
-Seizures if blood Phe are high
-MOUSEY ODOR of urine
-decreased pigmentation of skin and hair
Why is there decreased pigmentation of skin and hair in patients with classic PKU?
Elevated Phy levels inhibits tyosinase, therefore tyrosine conversion to melanin is inhibited.
What is Sapropterin?
-Synthetic form of BH4
-used to treat patients with mild to moderate form of PKU
-considered the first non-dietary treatment for PKU
What is maternal PKU syndrome?
Women with PKU must maintain low Phe levels before conception and during pregnancy.
–Strict adherence must be maintained prior to conception and throughout pregnancy
What fetal defects do high maternal blood Phe lead to?
-Microcephaly
-Mental retardation
-Congenital heart defects
Does Maternal PKU syndrome occur even though the fetus is NOT deficient in PAH
Yes
What reaction does Homogentistic acid oxidase catalyze?
Homogentistic acid —> Maleylacetoacetate
(Alkaptonuria)
What are the manifestations of Homogentistic acid accumulation in patients with Alkoptonuria?
-Homogentistic acid deposits in cartilage and connective tissue (Ochronosis)
-Homogentistic acid is excreted in the urine (brown discoloration of urine)
Dietary restriction of what may reduce deposition of homogentistic acid in Alkoptonuria?
Phe and Tyrosine