Inborn disorders of cell and tissue structures Josef Fontana Structure - 1
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Inborn disorders of cell and
tissue structures
Josef Fontana
Structure - 1
Inborn disorders of cell and
tissue structures
Why does John have kidney
and heart problems and
his hands burn?
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
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
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
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
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.
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
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
John's future
• His son is healthy - he could not
inherit the disease
• Daughter could, but son could not
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
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
In Class Questions
• What are lysosomes?
• What is their function in our cells?
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
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
Enzyme deficiency leads to an
accumulation of substrate
Infiltration of endothelial lysosomes
material of prof. Elleder
Fabry disease - enzyme defect
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
Hypertrophic CMP in Fabry
disease (MRI)
Glycosphingolipids deposits in
glomerular epithelial cells
In Class Questions
• Why are John's sons healthy?
• And why can his daughters inherit this
disease?
Why can his daughters inherit this
disease?
Gene is located on the chromosome X
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
Inborn disorders of cell and
tissue structures
Why could Paganini so
good play the violin and
Rachmaninoff the piano?
Niccolò Paganini (1782-1840)
• Italian violinist, guitarist
and composer
Sergei Vasilievich Rachmaninoff
(1873-1943)
• Russian pianist,
composer and
conductor
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
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
Marfan syndrome
• Affected gene encodes glycoprotein
fibrillin 1 - FBN 1
• Chromosome 15
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
Elastic connective tissue
NORMAL
MARFAN
Pluses and minuses
• Change in the structure of the
connective tissue (as a result of the
fibrillin defect) has many positive and
negative consequences
In Class Questions
• What are the negative
consequences?
• And which one could threaten
patient's life?
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
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
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
Elastic connective tissue
NORMAL
MARFAN
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
In Class Questions
• What was the risk of inheriting the
disease for children of both virtuosos?
• Is the risk greater for boys or girls?
What was the risk of inheriting the
disease for children of both virtuosos?
• The gene is located on chromosome
15
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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