Genetic Disorders of Metabolic Pathways

Question 1

A patient presents with: severe intellectual disability, microcephaly, light hair, bluish eyes, convulsion movements, characteristic body order as musty or mousy. what is the diagnosis?

Answer 1

Phenylketonuria. (blue eyes light hair is cuz it interferes with production of melanin

Question 2

In classical PKU, what enzyme is absent?

Answer 2

pheynlalanine hydoryxlase which converts Phe into tyrosine. THe conversion is halted

Question 3

what is the cause of secondary PKU

Answer 3

Insufficient BH4 leading to BH2 deficiency.

Question 4

What are some major clinical findings with secondary PKU?

Answer 4

abnormal response to diet , progressive detoerioation. May respond to BH4 treatment.

Question 5

Due to lack of BH4 what enzyme is not able to function as seen in secondary pku?

Answer 5

dihydropterine reductase

Question 6

what gives the mousy sell as seen in Pku?

Answer 6

build up of phenylacetate

Question 7

build up of what side product leads to problem with shutting of glucose to the brain?

Answer 7

phenylpyruvate

Question 8

what can be detected in urine in PKU?

Answer 8

phenylketones

Question 9

what are some consequences of excess phenylalanine and its metabolites as seen in PKU?

Answer 9

• toxic to infant neurological tissues: inhibits: tyrosinase - decrease in pigmentation, seraotnin decarboxylase - decrease in serotonin synthesis; glutamate decarboxylase - decrease in GBA synthesis and posisble decrease in all catecholamines.
• loss of IQ

Question 10

what is the normal blood level of Phe and what is in in PKU?

Answer 10

normal 1mg

PKU: 10-60 mx/dL (target is to get to 3-15 in tx)

Question 11

what are two lab tests used to check Phe in diagnosing PKU?

Answer 11

Guthrie test - bacterial inhibition essay

Mass tendem spectorphtometry

Question 12

In alkapturia, what aminoa acid is defective?

Answer 12

tyrosine

Question 13

in alkapturia, what enzyme is defective and what is the build up product?

Answer 13

hoogentisate oxidase is defective so homogentisate builds up as it cannot go to maleylacetoacetate.

Question 14

around what are does alkpatouria usually present and what are some physical finding?

Answer 14

around 20-30s with discoloration of sclera (ochronosis), dark-colored urine (or, darkens on standing)

Question 15

As a result of build up of homogentisate as seen in alkaptouria, what clinical signs are seen?

Answer 15

severe degeneraiton of cartilage of the spine and other major joints (osteoarthris),
kidney disease

Question 16

In albinism what enzyme is defective and what is the build up productive?

Answer 16

tyrosinase is defective and so tyrosine builds up. Tyrosine metabolism is needed cuz it produces melanin which is needed for skin color.

Question 17

if an infant presnts with cabbage-like odor of urine and liver failure, what is the likely diagnosis?

Answer 17

Tyrosinemia

Question 18

In type I tyrosinemia, what enzyme is defective and what is the build up product?

Answer 18

fumarylacetoacetate hydrolase. build up product is fumarylacetoacetate. Cannot make acetoacetate fumerate

Question 19

In type I tyrosinemia, what is the toxic agent that causes the clinical signs?

Answer 19

Becuase fumerylacetoacetate builds up, it follows an alternate pathway and produces succinylacetone (succinylCoa as needed in TCA and heme synthessi)

Question 20

In classical homocystinuria, what enzyme is defective?

Answer 20

cystahionine beta-synthease which requires pyridoxine (B6)

Question 21

True or false: homocysteine is a normal metabolite?

Answer 21

True. It can build up in abnormal condition and spontaneous go to homocystine.

Question 22

homocysteine is needed for what physioogical compound?

Answer 22

glutathione

Question 23

Homocysteine can go back to methionine if what cofactors are present?

Answer 23

B6, B12 and folic acid

Question 24

In classica homocystinuria, what compound is produced as a result of homocysteine build up?

Answer 24

homocysteine thiolactone which reacts readily with proteins of cysine residues

Question 25

what clinical signs are seen in homocysteinuria?

Answer 25

• DVT
• stroke
• atherosclerosis
• Marfan-like habitus
• mental retardation
• joint contractures

Question 26

In maple syrup urine disease, what product builds up?

Answer 26

Branched chain amino acid and a-ketoaids

Question 27

build up which product in maple syrup urine disease is specially responsible for producing the nervous system issues?

Answer 27

a-ketoisocaproate

Question 28

what are some symptoms you’ll likely see with maple syrup urine disease?

Answer 28

feeding difficulties, vomiting, lethargic

• progressive neurodegeneration
• abnormal muscle tone
• coma
• death

Question 29

In galactosemia, what enzyme is defective?

Answer 29

galactokinase which is responsible for breaking down galactose into galacotse-1 phosphate and ultimately to glucose. (note this is different from lactose intolerance)

• galactose-1 phosphate uridyl transferase
• UDP-glactose 4 epimerase

Question 30

The classic cause of galactoseimia is due to defective in the enzyme

Answer 30

glactose 1 phosphate uridyl transferase. this builds up galactose 1 phosphate which is the toxic product.

Question 31

build up of what product leads to cataacts formation in a newborn as seen in galactosemia?

Answer 31

galactitol

Question 32

how does buiild up of galactose 1 phosphate cause symptoms as seen in galactosemia?

Answer 32

with gal 1 phosphtase uridyl transferase defect, gal 1 pohsphate buids up and is trapped inside of the cell. this causes removal intraellular phosphate and causes toxciites. these enzymes are found throughout the body but mainly in the liver so pt presents with hepatomegaly

Question 33

what are some clinical signs seen in galactosemia?

Answer 33

• infants unable to utilize galactose found in milk
• suffer from malnutrition; failure to thrive
• damage to liver, brain, eyes in first few days
• develop mental retardation
• cataracts within few weeks
• vomiting diarrhea, jaundice, hepatomegaly