Disease

CLASSIFICATION, TERMS & DEFINITIONS

DR. STEFAN FISCHER 1

How can diseases be classified
Disease = “not normal”, impaired body function

Classification by:
◦ Cause (e.g. genetic, metabolic, toxin-induced, viral infection, bacterial infection…)
◦ Pathogenesis (chronic autoimmune, cancer, demyelinating diseases,…)
◦ Symptoms (psychiatric, cerebral, musculoskeletal diseases)

In fact, no clear classification; i.e.:

- there are autoimmune disease with a genetic cause leading to impaired cerebral outcome…
- genetic disease leading to demyelination of nerve fibers affecting the muscles….
- viral infection which can induce a cancerous disease

DR. STEFAN FISCHER 2

Dr. Stefan Fischer

NAD(P)- RedOx-equivalent

NAD-Nicotinamide Adenosin Dinucleotide

Inherited and genetic diseases/disorders
IMPORTANT: classification of diseases are different in every state!

In Germany, e.g. Cancer is a genetic disease which is of course not inherited (except of few
disorders, see below).
In U.S. genetic disease are all inherited diseases.

There is an international classification system which is adapted in each country:

ICD-11 by WHO

DR. STEFAN FISCHER 6

Inherited and genetic diseases/disorders
Genetic disease is caused by a mutation or chromosomal change in the genome.
You can distinguish:
◦ X-linked disorders (dominant or recessive)
◦ Y-linked disorders
◦ Autosomal disorders (dominant or recessive)
◦ Mitochondrial related disorders
◦ Chromosomal abnormalities
◦ Multifactorial disorders

Inherited disease means the cause is inside the genome of the germline cells (egg, sperm, fertilized egg)

DR. STEFAN FISCHER 10

Genetic or inherited disease ?
Example: Breast Cancer
* 5-10% of all patients with breast cancer might be caused by genetics
* 90% of genetic caused breast cancers are due to mutations inBRCA1 and BRCA2
* these patients show a risk up to 80 % to suffer from breast cancer
* in this cases it is believed to be autosomal-dominat

DR. STEFAN FISCHER 11

“Localisation” of
different genetic
disorders in the
genome

Wiki Creative Commons

DR. STEFAN FISCHER 12
Chorea Huntington
* autosomal-dominant inherited disease
* neural cells of striatum are dying (mechanism so far not clear)
* symptoms: change in physical skills and cognition (restlessness, not controlled movements,
abstract thinking loss, …)
* no cure, lethal disease, prevalence 5-10 / 100,000 inhabitants (Germany:10,000)
* cause is the increase of CAG triple repeats in the gene encoding for the protein huntingtin

DR. STEFAN FISCHER 13

 Chorea Huntington
* autosomal-dominant inherited disease
* neural cells of striatum are dying (mechanism so far not clear)
* symptoms: change in physical skills and cognition (restlessness, not controlled movements,
abstract thinking loss, …)
* no cure, lethal disease, prevalence 5-10 / 100,000 inhabitants (Germany:10,000)
* cause is the increase of CAG triple repeats in the gene encoding for the protein huntingtin
>sp|P42858|HD_HUMAN Huntingtin OS=Homo sapiens OX=9606 GN=HTT PE=1 SV=2
MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQPPPPPPPPPPPQLPQPPPQAQPLLPQPQPPPPPPPPPPGPAVAEEPLHRPKKELSATKKDRVNHCLTICENIVAQSVRNSPEFQKLLGIAMELFLLCSDDAESDVRMVADECLNKVIKALMDS
NLPRLQLELYKEIKKNGAPRSLRAALWRFAELAHLVRPQKCRPYLVNLLPCLTRTSKRPEESVQETLAAAVPKIMASFGNFANDNEIKVLLKAFIANLKSSSPTIRRTAAGSAVSICQHSRRTQYFYSWLLNVLLGLLVPVEDEHSTLLILGVLLTLRYLVPLLQQQVKDT
SLKGSFGVTRKEMEVSPSAEQLVQVYELTLHHTQHQDHNVVTGALELLQQLFRTPPPELLQTLTAVGGIGQLTAAKEESGGRSRSGSIVELIAGGGSSCSPVLSRKQKGKVLLGEEEALEDDSESRSDVSSSALTASVKDEISGELAASSGVSTPGSAGHDIITEQPRS
QHTLQADSVDLASCDLTSSATDGDEEDILSHSSSQVSAVPSDPAMDLNDGTQASSPISDSSQTTTEGPDSAVTPSDSSEIVLDGTDNQYLGLQIGQPQDEDEEATGILPDEASEAFRNSSMALQQAHLLKNMSHCRQPSDSSVDKFVLRDEATEPGDQENKPCRI
KGDIGQSTDDDSAPLVHCVRLLSASFLLTGGKNVLVPDRDVRVSVKALALSCVGAAVALHPESFFSKLYKVPLDTTEYPEEQYVSDILNYIDHGDPQVRGATAILCGTLICSILSRSRFHVGDWMGTIRTLTGNTFSLADCIPLLRKTLKDESSVTCKLACTAVRNCVM
SLCSSSYSELGLQLIIDVLTLRNSSYWLVRTELLETLAEIDFRLVSFLEAKAENLHRGAHHYTGLLKLQERVLNNVVIHLLGDEDPRVRHVAAASLIRLVPKLFYKCDQGQADPVVAVARDQSSVYLKLLMHETQPPSHFSVSTITRIYRGYNLLPSITDVTMENNLSRVI
AAVSHELITSTTRALTFGCCEALCLLSTAFPVCIWSLGWHCGVPPLSASDESRKSCTVGMATMILTLLSSAWFPLDLSAHQDALILAGNLLAASAPKSLRSSWASEEEANPAATKQEEVWPALGDRALVPMVEQLFSHLLKVINICAHVLDDVAPGPAIKAALPSLT
NPPSLSPIRRKGKEKEPGEQASVPLSPKKGSEASAASRQSDTSGPVTTSKSSSLGSFYHLPSYLKLHDVLKATHANYKVTLDLQNSTEKFGGFLRSALDVLSQILELATLQDIGKCVEEILGYLKSCFSREPMMATVCVQQLLKTLFGTNLASQFDGLSSNPSKSQGRQR
LGSSSVRPGLYHYCFMAPYTHFTQALADASLRNMVQAEQENDTSGWFDVLQKVSTQLKTNLTSVTKNRADKNAIHNHIRLFEPLVIKALKQYTTTTCVQLQKQVLDLLAQLVQLRVNYCLLDSDQVFIGFVLKQFEYIEVGQFRESEAIIPNIFFF………………

DR. STEFAN FISCHER 14

An mRNA Sequence Is Decoded in Sets
of Three Nucleotides
Chorea Huntington

DR. STEFAN FISCHER 16

Chorea Huntington

DR. STEFAN FISCHER 17

 Chorea Huntington
* autosomal-dominant inherited disease
* neural cells of striatum are dying (mechanism so far not clear)
* symptoms: change in physical skills and cognition (restlessness, not controlled movements,
abstract thinking loss, …)
* no cure, lethal disease, prevalence 5-10 / 100,000 inhabitants (Germany:10,000)
* cause is the increase of CAG triple repeats in the gene encoding for the protein huntingtin
>sp|P42858|HD_HUMAN Huntingtin OS=Homo sapiens OX=9606 GN=HTT PE=1 SV=2
MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQPPPPPPPPPPPQLPQPPPQAQPLLPQPQPPPPPPPPPPGPAVAEEPLHRPKKELSATKKDRVNHCLTICENIVAQSVRNSPEFQKLLGIAMELFLLCSDDAESDVRMVADECLNKVIKALMD
SNLPRLQLELYKEIKKNGAPRSLRAALWRFAELAHLVRPQKCRPYLVNLLPCLTRTSKRPEESVQETLAAAVPKIMASFGNFANDNEIKVLLKAFIANLKSSSPTIRRTAAGSAVSICQHSRRTQYFYSWLLNVLLGLLVPVEDEHSTLLILGVLLTLRYLVPLLQQQVKD
TSLKGSFGVTRKEMEVSPSAEQLVQVYELTLHHTQHQDHNVVTGALELLQQLFRTPPPELLQTLTAVGGIGQLTAAKEESGGRSRSGSIVELIAGGGSSCSPVLSRKQKGKVLLGEEEALEDDSESRSDVSSSALTASVKDEISGELAASSGVSTPGSAGHDIITEQPR
<27 repeats Normal
SQHTLQADSVDLASCDLTSSATDGDEEDILSHSSSQVSAVPSDPAMDLNDGTQASSPISDSSQTTTEGPDSAVTPSDSSEIVLDGTDNQYLGLQIGQPQDEDEEATGILPDEASEAFRNSSMALQQAHLLKNMSHCRQPSDSSVDKFVLRDEATEPGDQENKPC
27-35 repeats elevated risk for children
RIKGDIGQSTDDDSAPLVHCVRLLSASFLLTGGKNVLVPDRDVRVSVKALALSCVGAAVALHPESFFSKLYKVPLDTTEYPEEQYVSDILNYIDHGDPQVRGATAILCGTLICSILSRSRFHVGDWMGTIRTLTGNTFSLADCIPLLRKTLKDESSVTCKLACTAVRNCV
MSLCSSSYSELGLQLIIDVLTLRNSSYWLVRTELLETLAEIDFRLVSFLEAKAENLHRGAHHYTGLLKLQERVLNNVVIHLLGDEDPRVRHVAAASLIRLVPKLFYKCDQGQADPVVAVARDQSSVYLKLLMHETQPPSHFSVSTITRIYRGYNLLPSITDVTMENNLSR
>36 repeats affected, 50 % risk for children
VIAAVSHELITSTTRALTFGCCEALCLLSTAFPVCIWSLGWHCGVPPLSASDESRKSCTVGMATMILTLLSSAWFPLDLSAHQDALILAGNLLAASAPKSLRSSWASEEEANPAATKQEEVWPALGDRALVPMVEQLFSHLLKVINICAHVLDDVAPGPAIKAALPSL
TNPPSLSPIRRKGKEKEPGEQASVPLSPKKGSEASAASRQSDTSGPVTTSKSSSLGSFYHLPSYLKLHDVLKATHANYKVTLDLQNSTEKFGGFLRSALDVLSQILELATLQDIGKCVEEILGYLKSCFSREPMMATVCVQQLLKTLFGTNLASQFDGLSSNPSKSQGRQ
RLGSSSVRPGLYHYCFMAPYTHFTQALADASLRNMVQAEQENDTSGWFDVLQKVSTQLKTNLTSVTKNRADKNAIHNHIRLFEPLVIKALKQYTTTTCVQLQKQVLDLLAQLVQLRVNYCLLDSDQVFIGFVLKQFEYIEVGQFRESEAIIPNIFFF………………

DR. STEFAN FISCHER 20

Topics in Pathology
 Cause of disease (Germ, Mutation, etc)
 Mechanism of development: Pathogenesis
 Structural alterations of cell
 Consequences of changes: clinical manifestation

=> Common theme in disease: death of cells

DR. STEFAN FISCHER 21

Chromatography (proteins, metabolites, …)

Different properties used for separation

Plasmaproteins of the blood

• Mainly synthesized in the liver and

Immune cells
• Albumin, α, β, γ, δ fractions Monoclonal gammopathie
• δ are antibodies

Löffler, Biochemie
Polymerase chain reaction (PCR)
Polymerase chain reaction (PCR)
Polymerase chain reaction (PCR)
 STR – short tandem reapeats
(2nt repeats in non-coding regions)

PCR for DNA fingerprinting

Blood metabolite detection, e.g. Ethanol ADH – Alcohol Dehydrogenase

ADH
Ethanol + NAD+ Acetaldehyd + NADH+H+

Measurement principle of Spectrophotometer

Cell death
NECROSIS AND PROGRAMMED CELL DEATH

DR. STEFAN FISCHER 52

Cell death: when?
* Infection (viral bursting of the cell, toxins from bacteria)
* Development
* physiological process (gut epithelia)
* immune cell selection

=> Necrosis (different types) & Programmed Cell Death (Apoptosis)

DR. STEFAN FISCHER 54

Necrosis &
Apoptosis

DR. STEFAN FISCHER 55

Necrosis – acute injury
* area of cells
* process is called: Oncosis
* ATP depletion
* blebbing of cell
* disruption of cells (opening of membrane)
* monocytes and neutrophils will start immune reaction
* organs with little regenerative capacities form a scar (e.g. brain, heart)

DR. STEFAN FISCHER 56

Programmed Cell death - Apoptosis
* stimulus results in distinct cellular pathways resulting in dead cell
* unphysiological stress or during development
* no membrane opening, but zeiotic blebs with organelles leading to apoptotic bodies
* correct digestion by phagocates
* no inflammation
* distinct digestion of genome (internucleosomal digestion)
* pathway of caspases

DR. STEFAN FISCHER 57

Extrinsic &
intrinsic
pathway of
apoptosis
• Death receptors like FasL & TNFa
are present in all cells

• FasR can be activated by cytotoxic

T cells

• Balance between anti- and pro-

apoptotic signals is dependant on
extracellular and intracellular
situation

Intrinsic pathway

Extrinsic pathway
DR. STEFAN FISCHER 63
Necrosis & Apoptosis
Comparison
Necrosis Apoptosis
Accidential cell death Controlled cell deletion
Contiguous region of cells Singel cell separating from neighbors
Cell swelling Cell shrinkage
Plasmalemmal blebs without organells Zeiotic blebs containing lagre organelles
Small chromatin aggregates Nuclear condensation and lobulation
Random DNA degradation Internucelosomal DNA degradation
Cell lysis with release of intracellular contents Fragmentation into apoptotic bodies

Inflammation and scarring Absence of inflammation and scarring

Cell death precipitated by plasma membrane Intact plasma membrane

rupture
DR. STEFAN FISCHER 64