Inborn disorders of cell and tissue structuresvyuka-data.lf3.cuni.cz/CVSE1M0001/inborn disorders of... · 2015. 9. 29. · arrangement of elastic fibers in connective tissue •Fibrillin

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)