Flashcards in Inherited disorders of amino acid catabolism Deck (40):
How is PKU now tested?
Tandem mass spec
What type of genetic disorder is PKU?
Autosomal recessive disorder
What does PKU stand for?
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:
-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
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), gets converted to what by PAH?
Dihydrobiopterin (BH2), gets converted to Tetrahydrobiopterin (BH4) by which enzyme?
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?
What are the characteristics of PKU-I (classic) in untreated patients?
-Developmental milestone delay
-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?
-Congenital heart defects
Does Maternal PKU syndrome occur even though the fetus is NOT deficient in PAH
What reaction does Homogentistic acid oxidase catalyze?
Homogentistic acid ---> Maleylacetoacetate
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
A 71-year-old male patient was referred for the evaluation of a high-grade aortic stenosis. His medical history revealed prosthetic hip and joint replacement due to degenerative arthritisat the age of 55. On physical examination, kyphosis, and a bluish-black discoloration of the sclera and auriculumwere noted (Panels A and B). The patient reported that his urine darkens since childhood(Panel C). Cardiac catheterization demonstrated a severely calcified aortic stenosis. On the basis of the bluish-black discolouration of collagenous tissue (sclera, auriculum, aortic valve), history of degenerative arthropathy, and blackening of the urine on standing. What is the diagnosis?
Deficiency of what enzyme causes Tyrosinosis (Tyrosinemia Type I)?
Fumaryl Acetoacetate Hydroxylase
What compound accumulates in Tyrosinemia type I?
A child was admitted on the second day of life for observation and did well until breathing problems developed on the third day. The baby became irritable, had peculiar cries and stiffened. The peculiar urinary odorwas noticed on day six. The mother had noticed that smell on two of her previous newborns who died soon after birth, and said it smelled like maple syrup.
•The neurologic symptoms progressed very rapidly. The baby became stiff, unable to suck, could not breathe, and finally seizured. He then developed convulsions and pneumonia and died at 14 days of age. Doctors could do nothing for him.
•Not all of the children in this family showed the symptoms.
•Disorders of breathing were the first signs noted and were associated with brain stem swelling. What is the diagnosis?
Maple Syrup Urine Disease (MSUD)
Branched chain alpha-keto acid dehydrogenase (deficiency enzyme in MSUD), needs what coenzyme?
Which amino acids are restricted in treatment of MSUD?
Lara was born in a private hospital in Portugal where my husband and I had been living for some years. The birth followed a normal pregnancy but it became immediately apparent that Lara had feeding problems, refusing to suckand then vomitingafter a bottle feed. However, this settled after a while and at four days we were allowed home. It was only after a few hours of being home that Lara developed breathing problemsand we rushed her straight back to hospital where we were told that she was extremely dehydrated.Characteristic features were metabolic acidosis, poor feeding & lethargy.
•On admission,methylmalonatelevelsin circulation were elevated. What is the diagnosis?
Children with Methylmalonic Aciduria are places on special diets low in
branched chain amino acids
Methylmalonic aciduria is caused by deficiency of what enzyme?
Methylmalonyl CoA mutase
Methylmalonyl CoA mutase deficiency leads to what?
-Elevated levels of methylmalonnic acid in circulation which leads to metabolic acidosis
Methylmalonyl CoA mutase requires what coenzyme?
What is the reaction catalyzed by Methylmalonyl CoA mutase?
Methylmalonyl CoA ---> Succinyl CoA
A patient with dislocation of lens (ectopia lentis), skeletal abnormalities, mental retardation, premature arterial disease, and high plasma and urinary levels of homocysteine has a deficiency of what enzyme?
Cysathionine B-synthase requires which coenzyme?
PLP (Vitamin B6)
Sulfur of homocysteine may be transferred to _______ to form ________, and the carbon skeleton eventually forms succinyl-coA for entry into TCA cycle
Cysteine (req PLP/B6)