2-25-16-Genetic Disorders Of Metabolic Pathways (Seidler)

Question 1

Defects in the biosynthesis or regeneration of ___ can lead to secondary phenylketonuria

Answer 1

THB

Question 2

The pathways for the production of monoamine neurotransmitters (dopamine, norepi, and serotonin) from Tyr and Trp are disrupted when ___ is deficient, leading to neurologic dysfunction

Answer 2

THB

Question 3

___ is used in the treatment of secondary PKU

Answer 3

Synthetic THB (Sapropterin)

Question 4

Defects in the activity of ___ causes phenylketonuria (PKU), the most common inborn error of AA metabolism. Phe in these patients is converted to ___ and then to phenylacetate

Answer 4

Phenylalanine hydroxylase

Phenylpyruvate

Question 5

In ___, a pts urine may have a musty odor and the synthesis of melanin is impaired due to decreased production of Tyr

Answer 5

Phenylketonuria

Question 6

Consequences of excess phenylalanine leads to inhibition of:

___ enzyme–> leads to decrease in pigmentation

___ enzyme –> decrease in serotonin synthesis

___ enzyme –> decrease in GABA synthesis and possible decrease in all catecholamines

Answer 6

Tyrosinase

5HT decarboxylase

Glutamate decarboxylase

Question 7

What are 2 lab tests for measuring phenylalanine levels?

Answer 7

Guthrie test-bacterial inhibition assay

Mass tandem spectrophotometry (MS/MS)

Question 8

___ is characterized by phenylalanine crossing the placenta and PAH in the fetal liver is unable to convert Phe to Tyr

Answer 8

Maternal PKU

Question 9

___ is due to a defect in homogentisate oxidase, an enzyme in the Tyr degradative pathway

Answer 9

Alkaptonuria

Question 10

In alkaptonuria, autooxidation of homogentisic acid (with light) and polymerization of products produces ___ in urine

Answer 10

Dark-colored pigments

Black pigmentation in the IV disks of patients with degenerative arthritis and ochronosis (darkened sclera) are also observed

Question 11

___ is an autosomal recessive disorder that typically presents in 20’s-30’s with discoloration of sclera (ochronosis) and dark-colored urine. There is an accumulation of homogentisic acid and severe degeneration of cartilage of spine and major joints as well as kidney disease is observed

Answer 11

Alkaptonuria

Question 12

___ is an essential cofactor in the hydroxylations of the aromatic AA’s Phe, Tyr, and Trp, as well as in the production of NO from Arg. It is biosynthesized from GTP via a pathway involving 3 enzymes and is regenerated by the reduced form of NADPH-dependent reduction of DHB catalyzed by dihydropteridine reductase.

Answer 12

THB

Question 13

___ is an autosomal recessive disease due to a severe lack of melanin. It results in partial or complete absence of normal pigment in skin, hair, and eyes.

Answer 13

Albinism

Question 14

In albinism, the conversion of tyrosine to melanin is blocked due to defects in the enzyme ___

Answer 14

Tyrosinase

Question 15

This type of tyrosinemia is the most common and infants will have cabbage-like odor and possible liver failure

Answer 15

Type I tyrosinemia

Question 16

Infants with tyrosinemia type I will excrete a lot of ___ in the urine due to the build up of fumarylacetoacetate

Answer 16

Succinylacetone

Question 17

Hereditary infantile tyrosinemia (tyrosinemia type I) is the result of a defect in the gene encoding __ enzyme

Answer 17

Fumarylacetoacetate hydrolase

Converts fumarylacetoacetate to acetoacetate/fumarate

Question 18

List the defective enzymes in the following disorders:

Phenylketonuria-____

Albinism- ___

Alkaptonuria- ___

Tyrosinemia type I- ___

Answer 18

Phenylketonuria-Phenylalanine hydroxylase

Albinism-Tyrosinase

Alkaptonuria-Homogentisate oxidase

Tyrosinemia Type I-Fumarylacetoacetate hydrolase

Question 19

What is the front-line treatment for tyrosinemia type I?

Answer 19

Nitisinone–> reversible inhibitor of para-hydroxyphenylpyruvate oxidase. It prevents the formation of fumarylacetoacetate, which is the precursor for the toxic succinylacetone

Question 20

___ result from defective metabolism of homocysteine due to vitamin deficiencies (B6, B12, and folic acid) or due to inherited defects in enzymes such as cystathionine beta synthase

Answer 20

Hyperhomocysteinemia and homocystinuria

Question 21

DVT, stroke, atherosclerosis, marfan-like habitus, MR, and joint contractures are all clinical features of ___

Answer 21

Homocystinuria

Question 22

__ is an autosomal recessive disease in which symptoms appear 3-4 days after birth including feeding difficulties, vomiting, lethargy, progressive neurodegeneration, abnormal muscle tone, coma, and death. There is an elevation in urine and plasma BCAA’s and alpha keto acids, as well as a burnt sugar smell in urine

Answer 22

Maple syrup urine disease

Question 23

Which AAs are of interest in maple syrup urine disease?

Answer 23

Valine, Isoleucine, and Leucine–> All BCAAs

Question 24

A defect in ___ enzyme is characteristic of maple syrup urine disease

Answer 24

Branched-chain Alpha-ketoacid decarboxylase (dehydrogenase in blue box)

Question 25

In some forms of mild Maple syrup urine disease, the acivity of branched chain alpha keto acid dehydrogenase may be restored to normal by __ supplementation of the diet

Answer 25

Thiamine (B1)

Question 26

Vitamin B1 is AKA ___ Vitamin B5 is AKA ___ Vitamin B2 is AKA ___ Vitamin B3 is AKA ___

Answer 26

TPP (thiamine, B1) Coenzyme A (Pantothenate, B5) Flavin adenine dinucleotide (FAD; riboflavin, B2) Nicotinamide adenine dinuceotide (NAD+; Niacin, B3)

Question 27

___ galactosemia occurs when the conversion of galactose to glucose-1-phosphate is prevented due to galactose-1-phosphate uridyl transferase deficiency

Answer 27

Classic

Question 28

___ galactosemia occurs when the conversion of galactose to galactose-1-phosphate is prevented due to a defect in galactokinase

Answer 28

Nonclassic

Question 29

List the enzyme deficiency in: Nonclassic galactosemia- ___ Classic galactosemia- ____

Answer 29

Galactokinase Galactose-1-P- uridyl transferase

Question 30

In galactosemia, ___ deposition in the eye leads to cataracts in early infancy

Answer 30

Galactitol

Question 31

___ is when infants are unable to utilize galactose found in milk. Infants suffer from malnutrition and failure to thrive. There is damage to the liver, brain, eyes in first few days and may develop MR

Answer 31

Galactosemia