inborne errors of metabolism, lysosomal and glycogen storage disorders

Question 1

what causes alkaptonuria?

Answer 1

defect in homogentisic acid deoxygenase

Question 2

alkaptonuria represents a problem with metabolising what AA?

Answer 2

impaired tyrosine and phenylalanine metabolism

Question 3

how can alkaptonuria be diagnosed?

Answer 3

high homogentisic acid in urine

Question 4

what is a late complication of undiagnosed maply sugar uine disease?

Answer 4

cerebral edema

Question 5

what disease is associated with deficient acid alpha-clucosidase?

Answer 5

pompe disease

Question 6

what enzyme defect causes:

normal glucose levels
severe cardiomegaly
glycogen accumulation in lysosomes

Answer 6

acid alpha-glucosidase

pompe disease

aka α-1,4-glucosidase and acid maltase

Question 7

deffect in debranching enzymes alpha 1-4 transferase or alpha1-6 glucosidase leads to what symptoms? What is a key feature of the abnormal enzyme product?

Answer 7

hepatomegaly
keototic hypoglycemia
hypotonia & weakness

abnormal glycogen with very short outer chains

Cori disease (cori can’t cut anderson can’t add)

AB-CD
anderson-branching defect- cori debranching defect

Question 8

what enzyme is defective in mcardle disease?

Answer 8

muscle glycogen phsphorylase

Question 9

what step in glycogen processing is defective in mcardle disease?

Answer 9

muscle glycogen phsphorylase degreades glycogen into glucose-1-phosphate which can then be used for energy in muscle

sometimes referred to as myophosphrylase

Question 10

what disease? what defect?

hepatomegaly and steatosis
fasting hypoglycemia
lactic acidosis
hyperuricemia
hyperlipidemia

Answer 10

von gierke disease

glucose 6 phosphatase

Question 11

deficiency in what enzyme causes lactic acidosis, neurologic dysfunction and early death?

Answer 11

pyruvate dehydrogenase

Question 12

Sphingomyelinase deficiency is found in what disease?

Answer 12

Niemann-Pick disease

Question 13

peripheral neuropathy
        - especially in hands and feet
    angiokeratomas (small purple blemishes on skin)
    cardiovascular disease
    renal disease

Answer 13

α-galactosidase A deficiency

Fabry’s disease

ceramide trihexose accumulates

Question 14

hepatosplenomegaly
anemia
cherry red spots on macula
death

Answer 14

Niemann-Pick disease - Sphingomyelinase deficiency

sphingomyelin accumulates 
    histiocytes look "foamy"

Question 15

hyperactive reflexes
optic atrophy
developmental delay

Answer 15

β-galactocerebrosidase deficiency - Krabbe’s disease

galactocerebroside accumulates

Question 16

hepatosplenomegaly
aseptic necrosis of heads of long bones
mild anemia
possible to live a normal lifespan

if CNS involved
death

Answer 16

β-glucocerebrosidase deficiency - Gaucher’s disease

glucocerebroside accumulates in lysosomes of phagocytic cells

        histiocytes (dendritic cells) look like wrinkled tissue paper

called Gaucher’s cells

Question 17

CNS degeneration
    blindness
    cherry red spot on macula
    startle reflex
    death

Answer 17

Hexosaminidase A

deficient in Tay-Sachs disease 
    GM2 ganglioside accumulates
    lysosomes with onion skin

Question 18

demyelination in CNS and PNS

resulting in ataxia and dementia

Answer 18

Arylsulfatase A

deficient in metachromatic leukodystrophy
    cerebroside sulfate accumulates

Question 19

gargoyle-like facies
corneal clouding
progressive mental retardation

Answer 19

α-L-iduronidase deficiency - Hurler’s syndrome

heparan sulfate and dermatan sulfate accumulates in heart and liver

Question 20

gargoyle-like facies
progressive mental retardation
all of which are less severe than Hurler’s syndome

aggressive behavior

Answer 20

Iduronate sulfatase deficiency - Hunter’s syndrome
heparan sulfate and dermatan sulfate accumulates

corneal clouding absent

remember: hunter’s are aggressive

Question 21

skeletal abnormalities
    restricted joint movement
    psychomotor retardation
    early death
    coarse facial features
    high plasma levels of lysosomal enzymes

Answer 21

defect in N-acetylglucosamine-phosphotransferase causes - I-cell disease

 Normally: proteins marked for localization to lysosomes are post-translationally modified in the Golgi mannose residues are phosphorylated by N-acetylglucosamine-phosphotransferase enzyme

without mannose-6-phosphate designation, the enzymes are secreted instead of being targeted to the lysosome

cells also cannot degrade endocytosed material becuase they can’t be tagged due to enzyme deficiency

inclusion bodies build up intracellularly

Lysosomal enzymes are not activated extracellularly due to pH optimum for enzyme activation

Question 22

what enzyme is deficiency in Hurler’s disease? What builds up? What organs does it affect?

Answer 22

α-L-iduronidase

heparan sulfate and dermatan sulfate accumulates in heart and liver

Question 23

What is deficient in metachromatic leukodystrophy? What accumulates?

Answer 23

Arylsulfatase A

cerebroside sulfate accumulates

Question 24

What is deficient in Tay-Sachs disease? What accumulates? What is the appearance of lysosomes?

Answer 24

Hexosaminidase A

GM2 ganglioside accumulates
    lysosomes with onion skin

Question 25

What is deficient in Gaucher’s disease? What accumulates? What is the appearance of the affected cells?

Answer 25

β-glucocerebrosidase

glucocerebroside accumulates in lysosomes of phagocytic cells

        histiocytes (dendritic cells) look like wrinkled tissue paper

called Gaucher’s cells

Question 26

What is deficient in Niemann-Pick disease? What accumulates? What is the appearance of the affected cells?

Answer 26

Sphingomyelinase

sphingomyelin accumulates 
    histiocytes look "foamy"

Question 27

what is the defect in I-cell disease?

Answer 27

N-acetylglucosamine-phosphotransferase

Normally: proteins marked for localization to lysosomes are post-translationally modified in the Golgi mannose residues are phosphorylated by N-acetylglucosamine-phosphotransferase enzyme

without mannose-6-phosphate designation, the enzymes are secreted instead of being targeted to the lysosome

cells also cannot degrade endocytosed material becuase they can’t be tagged due to enzyme deficiency

inclusion bodies build up intracellularly

Lysosomal enzymes are not activated extracellularly due to pH optimum for enzyme activation

Question 28

What is deficient in Krabbe’s disease? What accumulates?

Answer 28

β-galactocerebrosidase deficiency -

galactocerebroside accumulates

Question 29

What is deficient in von gierke disease? What are the clinical symptoms?

Answer 29

glucose 6 phosphatase

hepatomegaly and steatosis
fasting hypoglycemia
lactic acidosis
hyperuricemia
hyperlipidemia