inborne errors of metabolism, lysosomal and glycogen storage disorders Flashcards
what causes alkaptonuria?
defect in homogentisic acid deoxygenase
alkaptonuria represents a problem with metabolising what AA?
impaired tyrosine and phenylalanine metabolism
how can alkaptonuria be diagnosed?
high homogentisic acid in urine
what is a late complication of undiagnosed maply sugar uine disease?
cerebral edema
what disease is associated with deficient acid alpha-clucosidase?
pompe disease
what enzyme defect causes:
normal glucose levels
severe cardiomegaly
glycogen accumulation in lysosomes
acid alpha-glucosidase
pompe disease
aka α-1,4-glucosidase and acid maltase
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?
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
what enzyme is defective in mcardle disease?
muscle glycogen phsphorylase
what step in glycogen processing is defective in mcardle disease?
muscle glycogen phsphorylase degreades glycogen into glucose-1-phosphate which can then be used for energy in muscle
sometimes referred to as myophosphrylase
what disease? what defect?
hepatomegaly and steatosis fasting hypoglycemia lactic acidosis hyperuricemia hyperlipidemia
von gierke disease
glucose 6 phosphatase
deficiency in what enzyme causes lactic acidosis, neurologic dysfunction and early death?
pyruvate dehydrogenase
Sphingomyelinase deficiency is found in what disease?
Niemann-Pick disease
peripheral neuropathy
- especially in hands and feet
angiokeratomas (small purple blemishes on skin)
cardiovascular disease
renal diseaseα-galactosidase A deficiency
Fabry’s disease
ceramide trihexose accumulates
hepatosplenomegaly
anemia
cherry red spots on macula
death
Niemann-Pick disease - Sphingomyelinase deficiency
sphingomyelin accumulates
histiocytes look "foamy"
hyperactive reflexes
optic atrophy
developmental delay
β-galactocerebrosidase deficiency - Krabbe’s disease
galactocerebroside accumulates
hepatosplenomegaly
aseptic necrosis of heads of long bones
mild anemia
possible to live a normal lifespan
if CNS involved
death
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
CNS degeneration
blindness
cherry red spot on macula
startle reflex
deathHexosaminidase A
deficient in Tay-Sachs disease
GM2 ganglioside accumulates
lysosomes with onion skin
demyelination in CNS and PNS
resulting in ataxia and dementia
Arylsulfatase A
deficient in metachromatic leukodystrophy
cerebroside sulfate accumulates
gargoyle-like facies
corneal clouding
progressive mental retardation
α-L-iduronidase deficiency - Hurler’s syndrome
heparan sulfate and dermatan sulfate accumulates in heart and liver
gargoyle-like facies
progressive mental retardation
all of which are less severe than Hurler’s syndome
aggressive behavior
Iduronate sulfatase deficiency - Hunter’s syndrome
heparan sulfate and dermatan sulfate accumulates
corneal clouding absent
remember: hunter’s are aggressive
skeletal abnormalities
restricted joint movement
psychomotor retardation
early death
coarse facial features
high plasma levels of lysosomal enzymesdefect 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
what enzyme is deficiency in Hurler’s disease? What builds up? What organs does it affect?
α-L-iduronidase
heparan sulfate and dermatan sulfate accumulates in heart and liver
What is deficient in metachromatic leukodystrophy? What accumulates?
Arylsulfatase A
cerebroside sulfate accumulates
What is deficient in Tay-Sachs disease? What accumulates? What is the appearance of lysosomes?
Hexosaminidase A
GM2 ganglioside accumulates
lysosomes with onion skin
What is deficient in Gaucher’s disease? What accumulates? What is the appearance of the affected cells?
β-glucocerebrosidase
glucocerebroside accumulates in lysosomes of phagocytic cells
histiocytes (dendritic cells) look like wrinkled tissue paper
called Gaucher’s cells
What is deficient in Niemann-Pick disease? What accumulates? What is the appearance of the affected cells?
Sphingomyelinase
sphingomyelin accumulates
histiocytes look "foamy"
what is the defect in I-cell disease?
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
What is deficient in Krabbe’s disease? What accumulates?
β-galactocerebrosidase deficiency -
galactocerebroside accumulates
What is deficient in von gierke disease? What are the clinical symptoms?
glucose 6 phosphatase
hepatomegaly and steatosis fasting hypoglycemia lactic acidosis hyperuricemia hyperlipidemia
