Inherited disorders of amino acid catabolism

Question 1

How is PKU now tested?

Answer 1

Tandem mass spec

Question 2

What type of genetic disorder is PKU?

Answer 2

Autosomal recessive disorder

Question 3

What does PKU stand for?

Answer 3

Phenylketonuria

Question 4

Why do some centers test infants twice for PKU?

Answer 4

-First test might be false negative
-Due to maternal clearance

Question 5

Describe the diet to recommend to patients with PKU.

Answer 5

Low Phe diet:
-Low protein
-Avoid eggs, milk and meat
-Avoid aspartame (artificial sweetener)

Question 6

What is the biochemical defect in patients with Classic PKU (type I)

Answer 6

Phenylalanine Hydroxylase (PAH)

Question 7

What is the biochemical defect in patients with Benign PKU (type II)

Answer 7

Deficiency of dihydrobiopterin synthesis or dihydrobiopterin reductase (BH2/BH4)

Question 8

What is the biochemical defect in patients with MSUD?

Answer 8

Branched chain alpha-keto acid dehydrogenase (BCKD)

Question 9

What is the biochemical defect in patients with Homocystinura

Answer 9

Cystathioneine B-synthase

Question 10

What is the biochemical defect in patients with Alkoptonuria

Answer 10

Homogentisic Acid Oxidase

Question 11

Besides Phenylalanine, what other factors are needed by PAH to form tyrosine?

Answer 11

Tetrahydrobiopterin (BH4)

Question 12

Tetrahydrobiopterin (BH4), gets converted to what by PAH?

Answer 12

Dihydrobiopterin (BH2)

Question 13

Dihydrobiopterin (BH2), gets converted to Tetrahydrobiopterin (BH4) by which enzyme?

Answer 13

Dihydrobiopterin reductase

Question 14

Deficiency of BH2/BH4 leads to what?

Answer 14

1) Elevated PHE and its metabolites
2) Deficient catecholamine formation
3) Deficient serotonin production

Question 15

Which is more severe, PKU-I or PKU-II?

Answer 15

PKU-II

Question 16

What are the characteristics of PKU-I (classic) in untreated patients?

Answer 16

-Developmental milestone delay
-low IQ
-Seizures if blood Phe are high
-MOUSEY ODOR of urine
-decreased pigmentation of skin and hair

Question 17

Why is there decreased pigmentation of skin and hair in patients with classic PKU?

Answer 17

Elevated Phy levels inhibits tyosinase, therefore tyrosine conversion to melanin is inhibited.

Question 18

What is Sapropterin?

Answer 18

-Synthetic form of BH4
-used to treat patients with mild to moderate form of PKU
-considered the first non-dietary treatment for PKU

Question 19

What is maternal PKU syndrome?

Answer 19

Women with PKU must maintain low Phe levels before conception and during pregnancy.
–Strict adherence must be maintained prior to conception and throughout pregnancy

Question 20

What fetal defects do high maternal blood Phe lead to?

Answer 20

-Microcephaly
-Mental retardation
-Congenital heart defects

Question 21

Does Maternal PKU syndrome occur even though the fetus is NOT deficient in PAH

Answer 21

Yes

Question 22

What reaction does Homogentistic acid oxidase catalyze?

Answer 22

Homogentistic acid —> Maleylacetoacetate
(Alkaptonuria)

Question 23

What are the manifestations of Homogentistic acid accumulation in patients with Alkoptonuria?

Answer 23

-Homogentistic acid deposits in cartilage and connective tissue (Ochronosis)
-Homogentistic acid is excreted in the urine (brown discoloration of urine)

Question 24

Dietary restriction of what may reduce deposition of homogentistic acid in Alkoptonuria?

Answer 24

Phe and Tyrosine

Question 25

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?

Answer 25

Alkaptonuria

Question 26

Deficiency of what enzyme causes Tyrosinosis (Tyrosinemia Type I)?

Answer 26

Fumaryl Acetoacetate Hydroxylase

Question 27

What compound accumulates in Tyrosinemia type I?

Answer 27

Fumaryl Acetoacetate

Question 28

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?

Answer 28

Maple Syrup Urine Disease (MSUD)

Question 29

Branched chain alpha-keto acid dehydrogenase (deficiency enzyme in MSUD), needs what coenzyme?

Answer 29

Thiamine-PP (TPP)
(Vitamin B1)

Question 30

Which amino acids are restricted in treatment of MSUD?

Answer 30

Leucine
Isoleucine
Valine

Question 31

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?

Answer 31

Methylmalonic Aciduria

Question 32

Children with Methylmalonic Aciduria are places on special diets low in

Answer 32

branched chain amino acids

Question 33

Methylmalonic aciduria is caused by deficiency of what enzyme?

Answer 33

Methylmalonyl CoA mutase

Question 34

Methylmalonyl CoA mutase deficiency leads to what?

Answer 34

-Elevated levels of methylmalonnic acid in circulation which leads to metabolic acidosis
-Seizures, encephalopathy

Question 35

Methylmalonyl CoA mutase requires what coenzyme?

Answer 35

Vitamin B12

Question 36

What is the reaction catalyzed by Methylmalonyl CoA mutase?

Answer 36

Methylmalonyl CoA —> Succinyl CoA

Question 37

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?

Answer 37

Cysathionine B-synthase

Question 38

Cysathionine B-synthase requires which coenzyme?

Answer 38

PLP (Vitamin B6)

Question 39

Sulfur of homocysteine may be transferred to _______ to form ________, and the carbon skeleton eventually forms succinyl-coA for entry into TCA cycle

Answer 39

Serine
Cysteine (req PLP/B6)

Question 40

Methionine can be converted to Homocysteine using what?

Answer 40

SAM