inborn disorders of cell and tissue structuresvyuka-data.lf3.cuni.cz/cvse1m0001/inborn disorders...
TRANSCRIPT
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Inborn disorders of cell and
tissue structures
Josef Fontana
Structure - 1
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Inborn disorders of cell and
tissue structures
Why does John have kidney
and heart problems and
his hands burn?
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How does John look today?
• John is 40 years old, though all say that he
is 55
• He has visited your department for inborn
errors of metabolism for 10 years
• Today's visit is different. You decide,
whether he has to undergo dialysis every
three days, or it can be postponed
• However, once it will be vital for him
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How does it all begin?
• When he recalls his childhood,
everything was strange
• Even before school he felt sick after
meal and often had a diarrhea
• Doctors said, that it's nothing serious
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How does it all begin?
• Then he suffered from pain, his hands and
feet burn
• He was often febrile also, although he had
no cold
• His parents took him to the doctor again
• He said "some kind of rheumatism" and
prescribed painkillers
• It helped a little but not much
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John's life continued…
• He wasn't very good student, because he had to
stay at home quite often, when he was ill
• After all, he finished the high school and wanted
to start working
• He was sent once more to the doctor, now for
the entrance examination
• This time, they found something - he had protein
in urine, but otherwise kidneys worked well
• They sent him to nephrology to be carefully
monitored
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How did John's life continue?
• He coped with his problems alone for
few years. Then appeared new
troubles
• He had strange red spots on his body
and their number grew
• They were on the hands, chest,
abdomen etc.
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How did John's life continue?
• Therefore he went to the doctor again,
who sent him to the dermatologist
• This dermatologist, the tenth doctor in
the row, expressed a suspicion of the
diagnosis, that stayed with John till
today
• They took John's blood and confirmed
the disease
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After the diagnosis
• He has visited your department for the
last ten years, last seven years with the
infusion therapy
• He needs them every 14 days. They are
not very pleasant, he feels always a little
sick
• Since undergoing them, he feels
certainly better, he is not so tired
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John's future
• His son is healthy - he could not
inherit the disease
• Daughter could, but son could not
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True story
• This story seems to be unlikely
• Unfortunately is not
• It is a quite exact transcript of the story of one
patient that was published in the journal
Medicine after Graduation 4 / 2011 in the
article Fabry disease - more common than
you think, Authors: Aleš Linhart / Gabriela
Dostálová / Lubor Golan
• This patient suffers from Fabry disease
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Why Fabry disease today?
• The most common inherited
lysosomal storage disease
• Cause: genetic defect that leads to a
reduced activity or total inactivity of one
lysosomal enzyme - α-galactosidase
• Gene is located on the chromosome
X
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In Class Questions
• What are lysosomes?
• What is their function in our cells?
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Lysosomes
• Cellular organelles that contain acid hydrolases
(approx. 50 types) to break down waste
materials and cellular debris
• Animal cells
• Membrane around lysosomes allows the
digestive enzymes to work at pH 4.5
• pH is maintained by pumping protons (H+) from
the cytosol across the membrane via proton
pump
• Size varies from 0.1-1.2 μm
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Enzyme deficiency leads to an
accumulation of substrate
• Problems appear, when any of lysosomal
enzymes, or proteins regulating their function
is incorrectly coded
• The compound usually broken down
accumulates in lysosomes, especially in
long-living cells (neurons, heart cells) and
macrophages
• Due to the accumulation of material in the
cells, these diseases are called lysosomal
storage diseases
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Enzyme deficiency leads to an
accumulation of substrate
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Infiltration of endothelial lysosomes
material of prof. Elleder
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Fabry disease - enzyme defect
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Why Fabry disease today?
• Impairment of structure of endothelial
cells and other cells, especially those
in parenchymatous organs
• Progressive multiorgan impairment
with the dominance of kidney failure
or cerebro- and cardiovascular
damage
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Hypertrophic CMP in Fabry
disease (MRI)
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Glycosphingolipids deposits in
glomerular epithelial cells
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In Class Questions
• Why are John's sons healthy?
• And why can his daughters inherit this
disease?
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Why can his daughters inherit this
disease?
Gene is located on the chromosome X
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Historical Perspectives
• The signs of Fabry disease were first identified in
1898 by two dermatologists working
independently, Dr William Anderson in England
and Dr Johannes Fabry in Germany
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Inborn disorders of cell and
tissue structures
Why could Paganini so
good play the violin and
Rachmaninoff the piano?
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Niccolò Paganini (1782-1840)
• Italian violinist, guitarist
and composer
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Sergei Vasilievich Rachmaninoff
(1873-1943)
• Russian pianist,
composer and
conductor
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Both had
• Tall and thin body type
• Long arms and legs
• Long and thin fingers (arachnodactylia)
• Flexible joints
• The last two mentioned points enabled them
to excel in playing a musical instrument,
Paganini - the violin and Rachmaninoff - the
piano
• Both had problems with eyes
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When a disease is an advantage
• Not every disease must bring only drawbacks to life
• According to current knowledge, both virtuosos
suffered from disease affecting structure of
connective tissue
• Connective tissue forms tendons, ligaments, walls
of blood vessel, cartilage, heart valves and other
structures
• As a result, the structures mentioned above can
weaken
• Disease is called Marfan syndrome
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Marfan syndrome
• Affected gene encodes glycoprotein
fibrillin 1 - FBN 1
• Chromosome 15
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Why do we need fibrillin?
• Glycoprotein that is necessary for the proper
arrangement of elastic fibers in connective tissue
• Fibrillin is secreted from fibroblasts to the
extracellular matrix, where it is subsequently
incorporated into insoluble microfibrils
• They form a kind of scaffolding, in which is stored
tropoelastin and then matures in elastin
• Fibrillin defect results in a reduction in strength of
connective tissue, especially elastic connective
tissue
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Elastic connective tissue
NORMAL
MARFAN
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Pluses and minuses
• Change in the structure of the
connective tissue (as a result of the
fibrillin defect) has many positive and
negative consequences
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In Class Questions
• What are the negative
consequences?
• And which one could threaten
patient's life?
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Skeleton and muscles
• Not only limbs are affected - also the
spine that is prone to the formation of
scoliosis (deviation from the axis of
the spine) and other deformities
• Also breastbone can be affected
(sternum)
• Muscle mass is weakened
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Eyes
• Eye impairment is
called ectopia of the
lens (ectopia lentis -
defective fixation
apparatus of the lens
causes a change in the
position of the lens)
• Myopia
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Cardiovascular system
• The most severe symptoms are associated with
heart and aorta
• Usually, the disease causes the formation of aortic
dilatation and aortic dissection
• Aortic dissection is typical for Marfan syndrome
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Elastic connective tissue
NORMAL
MARFAN
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Cardiovascular system
• Other defects associated with Marfan
syndrome include impaired heart
valves, which in turn may or may not
clinically manifest as shortness of
breath and fatigue
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In Class Questions
• What was the risk of inheriting the
disease for children of both virtuosos?
• Is the risk greater for boys or girls?
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What was the risk of inheriting the
disease for children of both virtuosos?
• The gene is located on chromosome
15
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Historical Perspectives
• In 1896 Antoine Marfan, the first professor of pediatrics in
France, presented the case of a 5-year-old girl, Gabrielle
P. She had a severe skeletal abnormalities, which
progressed to the time of her death in early adolescence,
probably from tuberculosis
Antoine Bernard-Jean Marfan
(1858 - 1942)
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