Lecture 35+36 Flashcards
Hurler syndrome
deficiency in Iduronidase
accumulation of dermatan sulfate and heparan sulfate
urine will be + for glycosaminoglycans
enzyme replacement therapy can be done
symptoms/signs: coarser facial features short developmental delay hepatomegaly and splenomegaly reduced joint motility corneal clouding
Hunter syndrome
milder form of hurler syndrome
X linked recessive (mainly males)
deficient in iduronate sulfatase
symptoms: coarser facial features hepatosplenomegaly mild developmental delay NO corneal clouding
enzyme replacement therapy
Tay-sachs disease
deficiency in beta-hexosaminidase A
accumulation of GM2
seen to have: progressive neurodegeneration blindness (cherry red spot on macula) developmental delay usually fatal between 2-6 years
Gaucher disease
most common lysosomal storage disorder
deficient in Beta-glucosidase
accumulation of glucosyl ceramide or glucocerebroside
symptoms:
no neurological damage
hepatosplenomegaly
osteoporosis of long bones (bone crisis)
can use enzyme replacement therapy
Fabry disease
X-linked recessive disorder (mainly males are affected)
deficiency in alpha-galactosidase
accumulation of globoside (ceramide trihexoside)
symptoms:
peripheral neuropathy
accumulation of globoside in blood vessels, skin, kidney, nerves, heart
Niemann-Pick disease
deficiency in Sphingomyelinase
accumulation of sphingomyelin in neuronal tissues (foamy cell appearance)
Type A:
severe infantile form
fatal by 2-3 years
cherry-red spot on macula (blindness)
Type B:
appears later in childhood
will have hepatosplenomegaly
Metachromatic leukodystrophy
deficient in aryl sulfatase A
accumulation of sulfatide
progressive paralysis and demyelination
Pompe disease
Generalized accumulation of glycogen in heart, muscle, kidney and liver as vacuoles in the lysosomes
glycogen storage disorder (II)
I-Cell disease
defect in trafficking enzymes to the lysosomes
the golgi fails to add the mannose-6 marker, thus they do not go to the lysosome
will be secreted into the blood
will have inclusion cells
symptoms similar to Hurler syndrome, but more severe and earlier age of onset
Migalastat
drug treatment for Fabry- pharmaceutical
chaperone which helps the mutated protein fold correctly and recover some activity
Miglustat
drug treatment for Gaucher type 1, inhibits the
formation of glycosphingolipids and this is called “substrate reduction”
role of copper in metabolism
used in lysyl oxidase (collagen)
tyrosinase (melanin synthesis)
cytochromes (ETC)
superoxide dismutase (ROS)
forms ceruloplasmin in the liver
copper transport protien
helps in iron metabolism
The life of copper
copper is transported to the liver via albumin
forms ceruloplasmin in the liver and then secreted into plasma (requires copper transporting ATPase)
aged ceruloplasmin is taken up by liver and secreted into the bile (copper transporting ATPase)
role of ceruloplasmin and iron metabolism
ceruloplasmin (ferroxidase) converts ferrous iron to the ferric form
incorporates the ferric ion into transferrin
mobilizes ferric ions from ferritin and hemosiderin
acute phase protein
copper deficiency
microcytic anemia (smaller RBCs) less iron mobilization
degradation of vascular tissue (decreased lysyl oxidase activity)
increased risk of bleeding
defects in pigmentation of hair
Menkes syndrome
inherited defect of dietary copper absorption
lower plasma copper levels
X-linked recessive disorder
hair is twisty and grayish
aneurysms and neurological dysfunction
early age of presentation (1-2 years)
Wilson’s disease
autosomal recessive disorder
accumulation of copper in liver, brain, and eye
mutation of copper transporting ATPase (no excretion of copper into bile)
kayser-fleischer rings (eye) (will have basal ganglia involvement)
neurological damage
hepatitis and cirrhosis
labs:
decreased ceruloplasmin
increased urinary excretion of copper
increased hepatic copper content
role of iron
heme synthesis
RBC’s contain iron
for redox reactions and component of ETC
lab test for iron levels
high serum ferritin = iron overload (hemochromatosis)
low serum ferritin = iron deficiency anemia
TIBC:
total number of iron binding sites on transferrin
high TIBC = iron deficiency
low TIBC = iron overload
normal = 30% saturation
iron deficiency anemia
most common nutritional deficiency
can be seen in those:
reduced intake of iron
infants, pregnant women, blood donors
chronic bleeding
clinical features: hypochromic microcytic fatigue and pallor weakness / dizziness brittle nails pica
iron deficiency labs
low serum ferritin low iron levels low saturation (less than 20%) low hemoglobin levels bone marrow iron stores are low Low MCV and low MCHC
Hereditary Hemochromatosis (Iron overload)
autosomal recessive disorder
common in white people
over absorption of iron (HFE gene mutation)
allelic heterogenicity and compound heterozygotes are present
delayed onset
males affected more
excessive accumulation of iron in skin, liver, and pancreas
hereditary hemochromatosis sign/symptoms
excessive iron leads to free radical formation and DNA damage
more common in males around age 40 will have chronic joint pain chronic fatigue hepatomegaly diabetes cardiac dysfunction brownish skin pigmentation
hereditary hemochromatosis labs
high serum ferritin levels
high serum iron levels
transferrin saturation (more than 50%)
TIBC is decreased
hemochromatosis management
phlebotomy- removal of blood dietary modifications (less iron)
Nutritional anemia
anemia is a clinical sign
reduced red cell mass
hemoglobin levels are low and RBC’s are low
reduced nutritional needs
microcytic anemia
due to reduced heme synthesis
deficiency in iron (most common)
deficiency in copper
deficiency in B6
macrocytic anemia
due to reduced cell division
deficiency in B12
deficiency in folate
normocytic anemia
protein-calorie deficiency (PEM)
Microcytic anemia: Iron deficiency labs
serum ferritin levels are low
serum iron low
microcytic RBC’s and hypochromatic RBC’s
vitamin C deficiency is a risk factor
Microcytic anemia: Vitamin B6 deficiency labs
vitamin B6 is needed for heme synthesis (ALA synthase)
iron is normal
homocysteine levels are high
hypochromic microcytic anemia
sideroblasts
Microcytic anemia: Copper deficiency
reduced ceruloplasmin levels
defect in iron metabolism
Macrocytic megaloblastic anemia
cytosol enlargement after DNA synthesis
hypersegmentation of neutrophils
seen in Vit B12 or folate deficiency
