Sunteți pe pagina 1din 86

Bolile monogenice

continuare

Beta talazemia majora (anemia Cooley)

Boala nu se evidentiaza la nastere, ci progresiv in cursul

primului an de viata apare o anemie severa, urmare a scaderii Hb F si respectiv deficitului din ce in ce mai mare de globina. Ca raspuns la aceasta anemie, maduva osoasa in care hematiile sunt distruse, adica inainte ca ele sa ajunga in sange este sediul unei eritropoieze care este intensa dar ineficienta. Ficatul si splina se maresc (hiperplazie); Hipotrofie staturo-ponderala, anomalii scheletice si fragilitate osoasa (oase subitri), facies usor mongoloid Analizele de laborator arata o anemie hemolitica, hipocroma cu sideremie crescuta, poliglobulie si microcitoza

Beta talazemia majora (anemia Cooley)

Fara tratament decesul survine inainte de varsta

de 10 ani, cu alterarea starii generale, paloare, lipsa poftei de mancare, cu anemie severa si infectii grave.
Complicatiile ce conduc la deces sunt: ciroza,

insuficienta hepatica si cea cardiaca.


Cu tratament se poate atinge varsta adulta

Modificari craniene (bose) datorita expansiunii maduvei rosii hematogene la acest nivel

Icter: o colorare galbena a pielii si sclerei

Splenomegalie; Splenectomia evidentiaza o splina giganta de 1 kg

In talazemia intermediara: fie ambele gene ale globinei sunt anormale, fie una este anormala si cealalta lipseste

Tratamentul -talazemiei
Tratamentul conventional: Transfuzii (risc in timp, de acumulare a Fe ce se depune in diferite organe: inima, ficat, pancreas) Deferoxamina (Desferal) chelator al Fe, favorizeaza excretia urinara a acestuia Tratamente posibile: Grefa medulara (din 1981, dar nr. mic de pacienti gasesc donor corespunzator; procedura in sine este si ea riscanta) Transplant de celule stem din cordonul ombilical

Tratamentul -talazemiei
Tratamentul genic (speranta pt. viitor): Transferul unei gene normale de globina in celulele stem, imature ale maduvei osoase, care sunt precursorii tuturor celorlalte celule sanguine. O alta forma de terapie genica ar putea implica folosirea unor medicamente sau a altor metode de reactivare a genelor globinei in vederea producerii de Hb F ceea ce ar compensa deficitul de Hb A al pacientilor

http://www.youtube.com/watch?v=2EqFTBj7eIM

Mucoviscidoza
LOCUSUL GENEI MUTANTE 7q31.2
FIBROZA CHISTICA ASPECTE CLINICE: disfunctie secretorie

epiteliala asociata cu obstructie ductala; obstructia cailor aeriene; infectii respiratorii cronice; insuficienta pancreatica; tulburari ale digestiei; depletie de sare.

Mucoviscidoza

Gena ABCC7 determina sinteza unei forme anormale de proteina numita CFTR
CFTR (or cystic fibrosis transmembrane conductance regulator) a fost identificata in celulele din plamani, ficat, pancreas, glandele sudoripare si tractul genitourinar.

Mucoviscidoza
Cand proteina CFTR este anormal sintetizata datorita

unei mutatii, celulele epiteliale nu mai pot regla modul in care clorul strabate membranele celulare Peste 66% dintre bolnavi au mutatia F508, adica o deletie de 3pb, ce are drept urmare disparitia a.a. fenilalanina din pozitia 508 a CFTR Heterogenitate alelica: exista peste 800 de mutatii ale genei Cauzele sunt: mutatii nonsens si cu sens gresit (missense), deletii si mutatii ce modifica matisarea (splicing-ul) ARN-ului
Gena ABCC7 este mare (peste 250kb) avand 27 exoni ce sunt supusi
unei matisari alternative Proteina are 1480 aa, este transmembranara si regleaza activitatea canalelor de clor

Mucoviscidoza
Exista o serie de teorii (wiki) care explica

mecanismele moleculare presupuse a fi implicate in aparitia bolii Toate acestea vin in sprijinul observatiei ca majoritatea modificarilor ce apar in cadrul bolii sunt datorate blocajului de la nivelul unor cai viscerale inguste prin ingrosarea / cresterea vascozitatii secretiilor lor. Aceste obstructii conduc la remodelari si infectii pulmonare recurente, tulburari digestive datorita acumularii enzimelor digestive in pancreas, malabsorbtiei, obstructiei tranzitului intestinal ( fecale cu consistenta crescuta), etc

Speranta medie de viata este de aprox. 30 de ani

Mucoviscidoza
Frecventa crescuta a heterozigotilor purtatori in

cadrul populatiei generale (1: 25) a condus la emiterea ipotezei ca si in acest caz exista un avantaj selectiv Exista mai multe teorii; astfel, de ex. se presupune
a fi implicata susceptibilitatea redusa la diareea epidemica (holera) ca purtatorii genei sunt rezistenti la febra tifoida si chiar tbc

Concluzia: heterozigotii sunt mai rezistenti la

aceste infectii determinand o frecventa crescuta a genei in populatia generala


Boala este destul de frecventa in Europa

(1: 2.500 nn)

Mostenirea bolilor ereditare este complexa


Majoritatea bolilor nu au un mod simplu de transmitere ereditara Multi factori influenteaza capacitatea genelor de a cladi proteine/polipeptide. Mutatii diferite in aceeasi gena pot produce o gama larga de efecte. In cazul mucoviscidozei, gena care controleaza productia mucusului poate suferi peste 300 de mutatii diferite; unele produc simptome severe (chiar decesul, fiind vorba de o gena letala); unele produc simptome usoare; si altele nu produc nici un fel de simptome

Tratamentul mucoviscidozei
dg. prenatal depistarea mutatiei fertilizare in vitro si dg. genetic preimplantatoriu tratamentul simptomelor, infectiilor

bronhopulmonare (antibiotice) stimularea eliminarii secretiilor (fizioterapie, gimnastica, aerosoli pot fi si cu alfa dornaza, o dezoxiribonucleaza umana recombinanta, care scindeaza ADN-ul din sputa, scazandu-i vascozitatea) cresterea imunitatii (mese hipercalorice si vitamine) transplant pulmonar bilateral terapia genica ar urma sa inlocuiasca gena mutanta cu una normala (uneori lipozomii /vectorii virali nu sunt preluati de celule, alteori gena normala nu se exprima)

Caracteristicile bolilor autozomal dominante


Ele se manifesta la persoanele homozigote dar si heterozigote

pentru mutatia cauzatoare a patologiei


Persoana afectata are cel putin unul dintre parinti bolnav;

acesta are gena specifica bolii in stare heterozigota sau homozigota


Cand o persoana este bolnava datorita unei mutatii ce se

transmite autozomal dominant riscul de a avea un copil afectat este de 50% daca este heterozigota si respectiv 100% daca este homozigota.
Transmisia este pe verticala, din generatie in generatie

Seneb, un pitic al dinastiei a 4a sau a5a, sef al garderobei regale si preot al cultului funerar Khufu impreuna cu familia sa: sotia si copii de statura normala

Acondroplazia este una din cauzele aparitiei


nanismului (piticismului) Caracteristicile sindromului includ:

Statura mica cu membre proportional de scurte Un cap mare (macrocefalie), O frunte prominenta (bose frontal ) Radacina nasului aplatizata.

Acondroplazia

Este o tulburare a cresterii osoase datorita unei mutatii specifice.


drept rezultat piticismul/nanismul.

Cartilajul prezinta dificultati in a fi convertit in os, avand

Desi nu se cunoaste un tratament genetic/genic, totusi pot fi ameliorate simptomele asociate frecvent cu boala precum problemele respiratorii.

Desi literal numele bolii inseamna fara formarea

cartilajului," totusi problema nu o reprezinta formarea acestuia, ci transformarea cartilajului in os, in mod special in cazul oaselor lungi ale bratelor si picioarelor.

Inaltimea medie a adultilor este de

131 cm pentru barbati


si 123 cm pentru femei

Gena responsabila
FGFR3 este acronimul pentru fibroblast growth factor receptor 3, care este proteina pe care o codifica, adica receptorul 3 pentru factorul de crestere fibroblastic
Localizarea citogenetica a genei FGFR3 :

4p16.3 Localizarea moleculara pe cromozomul 4: de la perechea de baze 1,762,853 la perechea 1,777,828 (14kb) Proteina are rol in dezvoltarea si conservarea tesutului osos si cerebral.

Functia Genei FGFR3


Cercetatorii cred ca receptorul pe care il codifica regleaza osificarea si aceasta in mod particular la nivelul oaselor lungi. Mutatii ale genei FGFR3 determina activarea exagerata a receptorului, ceea ce interfera cu osificarea si conduce la tulburari ale cresterii oaselor, fenomen caracteristic acondroplaziei. Aceasta teorie este sustinuta de catre modelul soarecilor knockout, care nu au receptorul, reglarea negativa a formarii oaselor fiind deci pierduta. Rezultatul consta intrun soarece cu oase excesiv de lungi si vertebre elongate, respectiv o coada lunga.

Acondroplazia
Acondroplazia poate fi mostenita sau poate fi

rezultatul unei noi mutatii a genei FGFR3; In majoritatea cazurilor (80%), boala se datoreaza unei noi mutatii, deoarece parintii celor avand acondroplazie au talie medie (normala), dar inca nu se stie cauza aparitiei acestor mutatii Copii cu acondroplazie pot avea probleme auditive, de vorbire si de respiratie, toate putand fi tratate. Tratmentul implica prevenirea sau tratarea semnelor, simptomelor, sau altor manifestari asociate care apar ca rezultat al bolii. Totodata sprijinul social si familial este o parte importanta a tratmentului.

Acondroplazia
Acondroplazia poate fi detectata inainte de nastere

prin ecografie
Diagnosticul ecografic se face pe baza discordantei

progresive dintre lungimea femurului si diametrul biparietal in functie de varsta. Mana cu aspect de trident poate fi de asemenea vizualizata daca degetele sunt in intregime extinse.
Aditional testarea ADN inainte de nastere poate

detecta homozigozitatea, atunci cand sunt mostenite doua copii ale genei mutante boala este letala ceea ce conduce la avort.

Imaginea este o radiografie a mainii unui tanar cu acondroplazie. Forma caracteristica de "trident apare datorita separarii policelui de degetul al doilea, cat si a degetelor trei si patru. Se pot observa oasele tubulare

scurtate ale mainii, in mod particular falangele proximale.

Imaginea din dreapta: mana unui adult, cu oase scurte tubulare, cu ulna subtiata, specific acondroplaziei.

CUM SE MOSTENESTE ACONDROPLAZIA

Boala se poate transmite din generatie in generatie

Persoanele cu acondroplazie pot transmite boala


descendentilor Riscul este de 1/2

Cum se mosteneste acondroplazia?


Daca ambii parinti au acondroplazie, copii au un risc de 1 din 4 de a mosteni gena de la ambii parinti, devenind homozigoti pentru gena mutanta. Noii nascuti care mostenesc ambele gene
sunt considerati ca avand o forma severa de acondroplazie, supravietuirea lor nu

depaseste 12 luni.

Boala Huntington (HD)


Este o tulburare neurodegenerativa

progresiva caracterizata prin:


Miscari choreiforme (necoordonate desi ele

pot parea coordonate - involuntare ale corpului)


Chorea era sugestiv imaginata a fi un dans grotesc. Cuvantul "chorea" provine din lb. greaca insemnand dans; Probleme psichiatrice, si dementa ( declinul unor capacitati mentale)

Boala Huntington
In jurul varstei de 35 - 40 de ani apar simptome usoare:

neindemanare, uitare si modificarea perosnalitatii. In urmatorii 10-20 de ani de la debut, o persoana cu HD isi pierde gradual intregul control mental si fizic.
Astazi

nu

exista o terapie pentru HD unele medicamente putand insa ameliora simptomele.

HD
Este o boala neurologica caracterizata prin tulburarea

functiei motorii
Alela mutanta determina aparitia unei proteine anormale,

ce contine un numar mare de repetitii ale a.a glutamina.


Proteina anormala este toxica pentru tesutul nervos

conducand la aparitia semnelor si simptomelor

caracteristice bolii .
O singura copie a genei anormale este suficienta pentru a

conferi boala.

Boala Huntington (HD)

Este cauzata de repetitia unei expansiuni anormale trinucleotidice (CAG) sa fie intre 7 si 35 de repetitii

In mod normal repetitia CAG trebuie

Gena HTT codifica proteina

huntingtina si daca este anormala ea contine o expansiune poliglutaminica


Huntingtina este prezenta in

numeroase tesuturi; nivelurile cele mai ridicate se gasesc intracerebral.

Boala Huntington (HD)


Gena Huntingtin (HTT), numita si gena HD

(Huntington disease) sau gena IT15 ("interesting transcript 15") este localizata pe bratul scurt al cromozomului 4 (4p16.3). HTT contine o secventa de baze azotate citozina adenina-guanina (CAG)repetata de multiple ori (i.e. ...CAGCAGCAG...) la capatul 5, avand denumirea de repetitii trinucleotidice.
Codonul CAG codifica amino acidul glutamina, a.i. se

va sintetiza un lant de glutamine cunoscut astazi sub


denumirea de tract poliglutaminic sau polyQ iar partea repetata a genei, se numeste PolyQ region

Localizarea genei HTT


Cytogenetic: 4p16.3 Molecular pe cz. 4: Perechile de baze de la 3,046,205 to 3,215,484

Cum se mosteneste HD?


HD este monogenica si transmisa din generatie in

generatie.
Avand un parinte afectat, fiecare copil are un risc de

1:2 sa mosteneasca HD.


Copii care nu au gena cu certitudine nu vor face boala si nici nu o vor transmite mai departe descendentilor

Boala Huntington(HD)
De obicei numarul de repetitii CAG este

corelat cu gradul de afectare, cu varsta de debut si cu rata de progresie a simptomelor. De exemplu, 3639 de repetitii determina un debut mai tardiv si o progresie cu mult mai redusa a simptomelor decat media populationala a persoanelor bolnave, a.i. unii indivizi pot deceda din alte cauze inainte ca simptomele de HD sa se manifeste, aceasta numindu-se " penetranta redusa/incompleta

Numar de repetitii <27 2735 3639 >39

Clasificare Normal Intermediar Penetranta Redusa Penetranta totala/completa

Statusul bolii Neafectat Neafectat +/- Afectat Afectat

Varsta de debut variaza pt. o lungime data

de repetitii CAG, in mod particular in cazul valorilor intermediare (4050 CAG). De exemplu, o repetitie de 40 de codoni CAG conduce la un debut situat intre 40 si 70 de ani intr-un studiu. Aceasta variatie inseamna ca, desi s-au propus o serie de algoritmi, in practica medicala nu se poate prevedea cu certitudine instalarea bolii

Pana aici de invatat pt examen

1983 Scientists discover a gene marker linked to HD on the short arm of chromosome 4, which indicates that the Huntington gene is also located on chromosome 4. Predictive linkage testing is introduced to assess the

likelihood of contracting HD.

1993 The location of the Huntington gene is discovered at the 4p16.3 gene site on chromosome 4. The gene is found to contain codon C-A-G in varying numbers. An abnormal number of CAG repeats turns out to be a highly reliable way to tell whether someone has the allele for HD.

Huntington disease (HD)


Huntington's disease is one of several

trinucleotide repeat disorders, caused by the length of a repeated section of a gene exceeding the normal range. The huntingtin gene (HTT) normally provides the information to produce Huntingtin protein, but when affected, produces mutant Huntingtin (mHTT) instead.

Huntington disease (HD)


Huntington disease (HD) is a disorder affecting

nerve cells in the brain.

Huntington disease (HD)


This genetic neurological disorder itself isn't fatal, but as

symptoms progress, complications reducing life expectancy increase.


Although research of HD has increased greatly in the last few

decades, the exact mechanism is unknown, so symptoms are managed individually.


Abnormal movements are initially exhibited as general lack of

coordination, an unsteady gait and slurring of speech, but, as the disease progresses, any function that requires muscle control is affected, causing physical instability, abnormal facial expression, but the most characteristic physical symptoms are jerky, random, and uncontrollable movements called chorea.

Huntington disease (HD)


Cystic fibrosis is one of the most common life-

shortening, genetic diseases. In the United States, 1 in 4,000 children are born with CF.[ Huntington disease is a more common hereditary disorder than phenylketonuria, which occurs in one of about 10,000

newborns in the United States. By contrast, about one


in 2,000 persons is at risk for Huntington disease.
Globally, up to 7 people in 100,000 have the disorder,

although there are localized regions with a higher


incidence.

Huntington disease (Huntington chorea)


The advances in molecular genetics make

it possible to detect Huntington disease in a preclinical stage at or even before birth.


The molecular approach does not replace

prior approaches to Huntington disease but is synergistic and provides a model of the new genetics.

Huntingtin
The exact function of this protein

is yet not known, but it plays an important role in nerve cells. Within cells, huntingtin may be involved in
o signaling,
o transporting materials, o binding proteins and other structures, and o protecting against programmed cell death (apoptosis).

Huntingtin protein is required for normal

development before birth.

Huntington disease (HD)


The pathophysiology of HD is not fully

understood, although it is thought to be related to toxicity of the mutant huntingtin protein.


However, pathology appears to be limited

to the central nervous system, with atrophy of the caudate and putamen (the neostriatum) being most prominent.
At the cellular level, protein aggregates

are seen both in the cytoplasm and nucleus.

Huntingtin
It regularly interacts with proteins found only in the

brain. Thus, altered huntingtin is most disruptive to nerve cells, even though it is found throughout the body. The altered form of huntingtin protein has been found in the autopsied brains of patients who have died of HD; altered huntingtin protein, contains 40 or more glutamine repeats, resulting from the genetic mutation discussed above. The extended number of glutamine repeats in Htt characterizes HD as one of nine polyglutamine expansion disorders.

Huntington disease (HD)


Although most cases start clinically

in midadulthood, usually between 35 and 42 years of age, there is great variability in age of onset.
About 3% of cases are diagnosed as

juvenile Huntington disease before the age of 15 years. Late onset is well known after 50 years of age.

To read
As HD is autosomal dominant, and does not usually affect reproduction, areas of

increased prevalence occur according to historical migration of carriers, some of which can be traced back thousands of years using genetic haplotypes.[82] Since the discovery of a genetic test that can also be used pre-symptomatically, estimates of the incidence of the disorder are likely to increase. Without the test, only individuals displaying physical symptoms or neurologically examined cases were diagnosed, excluding any who died of other causes before symptoms or diagnosis occurred. These cases can now be included in statistics as the test becomes more widely available and estimates have shown the incidence of HD could be two to three times higher when these results are included.[83] The prevalence varies greatly according to geographical location, both by ethnicity and local migration; The highest occurrence is in peoples of Western Europe descent, averaging between 3 to 7 per 100,000 people, but is relatively lower in the rest of the world, e.g. 1 per 1,000,000 of Asian and African descent.[4] Some localised areas have a much higher prevalence than their geographical average, for example the isolated populations of the Lake Maracaibo region of Venezuela (where the marker for the gene was discovered), have an extremely high prevalence of up to 700 per 100,000,[84] leading to the conclusion that one of their initial founders must have been a carrier of the gene. This is known as the local founder effect.[7]

Understanding HD
The symptoms of Huntington disease

(HD) appear when an abnormal protein builds up in nerve cells in certain areas of the brain, causing the cells to die. One of the brain areas affected is the area that controls movement. Cells in the outer layer of the brain also die, affecting mental abilities.

Brain scan from a patient with

Huntington disease (right) showing a larger cavity where brain cells have died, compared with a normal brain (left). (arrows)

Department of Neurogenetics, Institute of Neurology, London

Testing for HD
As the symptoms of Huntington disease (HD) do not usually appear until middle age, some people only discover they are at risk when one of their parents or grandparents is diagnosed. A genetic test is available to HD families that can tell people whether or not they have inherited the altered gene, but not the age at which they will start to develop symptoms. Although there is no cure available at the moment, genetic tests can help people at risk of HD make decisions about their future. However most decide not to take the test.

DNA analysis of Huntingtons disease. Each lane shows a different person's DNA: two bands in the normal (N) range show someone is unaffected. One band in the H range predicts the person will get Huntington disease.
Department of Neurogenetics, Institute of Neurology, London

Testing for HD
Genetic testing may infer information about relatives who do not

want it. Testing a descendant of an undiagnosed parent has implications to other family members, since a positive result automatically reveals the parent as carrying the affected gene, and siblings (and especially identical twins) as being 'at risk' of also inheriting it. This emphasizes the importance of disclosure, as individuals have to decide when and how to reveal the information to their children and other family members. For those at risk, or known to carry a mutant allele, there can be the consideration of prenatal genetic testing and preimplantation genetic diagnosis in order to ensure that the disorder is not passed on.

Testing for HD
Embryonic screening is also possible, giving

affected or at-risk individuals the option of ensuring their children will not inherit the disease. It is possible for women who would consider abortion of an affected fetus to test an embryo in the womb (prenatal diagnosis). Other techniques, such as preimplantation genetic diagnosis in the setting of in vitro fertilisation, can be used to ensure that the newborn is unaffected

NEURONAL INCLUSIONS

In a process similar to the formation of aggregates, the excess glutamines in Htt can lead to a type of protein bundling known as neuronal inclusions (NI), or inclusion bodies.

(NI) - Clumps of protein formed by aggregation of mutant proteins. These mutant proteins have abnormally expanded polyglutamine tracts in hereditary tri-nucleotide repeat disorders. Also referred to as neuronal intranuclear inclusions, nuclear inclusions, or inclusion bodies.
NIs initially form at the axons and dendrites of nerve cells in specific areas of the

human brain, producing the damaged neurons characteristic of HD. Subsequently, an enzyme cuts Htt into smaller fragments which enter the nerve cell nuclei, forming more clumps at the centrosomes. (See Figure P-2.)

www.stanford.edu

NEURONAL INCLUSIONS
They can cause significant changes in cell structure, trap and

interfere with the normal production of other proteins, and ultimately become toxic to the nerve cell. Thus, the formation of NIs and the neurodegenerative symptoms of HD are clearly linked.
In fact, Htt indirectly leads to nerve cell damage and toxicity

through the formation of protein aggregates and NIs. Researchers have explored a number of hypotheses regarding the mechanisms by which huntingtin aggregates cause cell dysfunction in HD.

Recent studies have shown that altered huntingtin can

kidnap smaller proteins from their usual locations, preventing them from functioning normally within nerve cells. A recent Johns Hopkins University study showed that Htt entangles and inhibits CREB-binding protein (also known as CBP), a smaller regulatory protein that is key for cell survival. CREB = acronym for cAMP cyclic adenosine monophosphate - response element binding; it is a protein that is a transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE) and thereby increases or decreases the transcription, and thus the expression, of certain genes

CREB
Genes whose transcription is regulated by CREB include: c-fos, the neurotrophin

BDNF (Brain-derived neurotrophic factor), tyrosine hydroxylase, and many neuropeptides (such as somatostatin, enkephalin, and corticotropin releasing hormone).
Mechanism of action A typical (simplified) sequence of events is as follows: a signal arrives at the cell

surface, activates the corresponding receptor, which leads to the production of a second messenger such as cAMP or Ca2+, which in turn activates a protein kinase. This protein kinase translocates to the cell nucleus, where it activates a CREB protein. The activated CREB protein then binds to a CRE region, and is then bound to by a CBP (CREB binding protein) which coactivates it, allowing it to switch certain genes on or off.
The DNA binding of CREB is mediated via its basic leucine zipper domain (bZIP domain) as

depicted in the picture. The cAMP response element is the response element for CREB. Since the effects of protein kinase A on the synthesis of proteins work by activating CREB, the cAMP response element is responsible for modulating the effects of protein kinase A that work by protein synthesis.

CREB a protein that is a transcription factor.

Insides
CBP has its own tract of 18 glutamines, and these glutamines interact directly with the

expanded Htt glutamine chain. Huntingtin aggregates pull CBP away from its normal position alongside the DNA in the nucleus.
Live mouse models with altered huntingtin and autopsied brains of patients who have

died of HD show very reduced amounts of CBP, suggesting that it has been pulled away from the DNA and sequestered by the altered huntingtin.
Once seized, CBP is out of service. It can no longer accomplish its normal function of

activating transcription or turning on genes for survival pathways. Fewer proteins are produced, ultimately leading to nerve cell death. the laboratory. This reversal was accomplished by inserting

However, researchers were able to fully halt and reverse this degenerative process in

an engineered form of CBP that did not have glutamine repeats. Since Htt interacts

directly with the CBPs glutamines, the modified CBP was not recognized by Htt. The modified CBP was not sequestered in huntingtin inclusion bodies, and the nerve cells survived.

Insides
In addition, other compounds known as histone-

deacetylase inhibitors (HDAC inhibitors) have been shown to compensate for the negative effects of CBP. It has been shown in fruit flies that HDAC inhibitors reduce the lethal effects of the altered huntingtin. These developments indicate potential targets for new drug treatments, but further research is still needed

Neurofibromatosis type I (NF-1), commonly


known as von Recklinghausen disease
Neurofibromatosis (NF) is one of the

A girl with neurofibromatosis (left).


The Neurofibromatosis Association (www.nfa.zetnet.co.uk

most common genetic conditions. There are several different types: about one in 2500 people have neurofibromatosis type 1 (NF1). This causes many benign nerve tumours, which can occur anywhere in the body. They first appear during childhood as coffee-coloured spots on the skin. Later in life, more nerve tumours appear as lumps under the skin. NF1 sometimes causes mild learning difficulties. ) Symptoms of NF1 vary a lot, even between affected people in the same family

How is NF1 inherited?


About half the people with

NF1 are born to unaffected parents, following a genetic change in the egg or sperm. (New mutation) People with NF1 may pass the condition on to their children: with one affected parent, each child has a onein-two chance of being born with NF1, and a one-in-two chance of being unaffected. Those born with NF1 may pass the condition on to their own children, while those unaffected will not.

Inheritance of neurofibromatosis

Understanding NF1
The cells that make up our bodies grow

and multiply in a carefully controlled way. Nerve tumours appear in people with NF1 because some of their nerve cells start to grow unchecked. In 1990, researchers discovered that people with NF1 have an altered version of a gene that usually helps to keep cell growth under control. A genetic test may be able to detect this altered gene before symptoms appear, usually during the first year of life.

A girl with neurofibromatosis (right).


The Neurofibromatosis Association (www.nfa.zetnet.co.uk)

Neurofibromatosis type I
NF-1 is a tumor disease that is caused by the malfunction of a gene on chromosome 17,

that is responsible for control of cell division.


It often comes with scoliosis (bone disease) and eye problems. Neurofibromatosis is

not a deadly or contagious disease, however it has been shown to occasionally cause cancer.
NF-1 is inherited in an autosomal dominant fashion, although it can also arise due to

spontaneous mutation.
NF-1 is caused by a mutation of a gene on the long arm of chromosome 17 which encodes a

protein known as neurofibromin,. The neurofibromin is a negative regulator of the Ras oncogene.
The mutant gene is transmitted with an autosomal dominant pattern of inheritance, but up to 50%

of NF-1 cases arise due to spontaneous mutation.


The incidence of NF-1 is about 1 in 3500 live births

Do you feel wrapped in genetics?

Or are you just.floating?

Correlation Genotype Phenotype Environment Influences a single gene exerts an effect on many aspects of an Pleiotropy individual's phenotype.
The phenomenon whereby a single mutation affects several

apparently unrelated aspects of the phenotype The control by a single gene of several distinct and seemingly unrelated phenotypic effects.

Pleiotropism
For example in MARFAN SYNDROME, a

mutant gene is unable to code for production of a normal protein, fibrillin. This results in the inability to produce normal connective tissue. Individuals with Marfan syndrome tend to be tall and thin with long legs, arms, and fingers; are nearsighted; and the wall of their aorta is weak.
From his view Abraham Lincoln may have

had Marfan syndrome

What is Marfan syndrome?

Marfan syndrome is a disorder of the connective tissue. Connective tissue provides strength and flexibility to structures

throughout the body such as bones, ligaments, muscles, the walls of blood vessels, and heart valves. Marfan syndrome affects most organs and tissues, especially the skeleton, lungs, eyes, heart, and the large blood vessel that distributes blood from the heart to the rest of the body (the aorta). The signs and symptoms of Marfan syndrome vary widely in severity, timing of onset, and rate of progression.
Affected individuals often are tall and slender, have elongated fingers

and toes (arachnodactyly), and have an arm span that exceeds their body height.

Marfan syndrome
Other common features include unusually flexible

joints, a long and narrow face, a highly arched roof of the mouth, crowded teeth, an abnormal curvature of the spine (scoliosis), and either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum). About half of all people with Marfan syndrome have vision problems caused by a dislocated lens (ectopia lentis) in one or both eyes, and most have some degree of nearsightedness (myopia). Clouding of the lens (cataract) may occur in mid-adulthood, and increased pressure within the eye (glaucoma) occurs more frequently in people with Marfan syndrome than in those without the condition.

Marfan syndrome
Most people with Marfan syndrome have

abnormalities of the heart and the aorta. Leaks in valves that control blood flow through the heart can cause shortness of breath, fatigue, and an irregular heartbeat felt as skipped or extra beats (palpitations). If leakage occurs, it usually affects the mitral valve, which connects two chambers of the heart, or the aortic valve, which regulates blood flow from the heart into the aorta. The aorta can weaken and stretch, which may lead to a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may cause the aortic valve to leak, which can lead to a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can be life threatening.

How common is Marfan syndrome? Worldwide, the incidence of Marfan syndrome is approximately 1 in

5,000. What genes are related to Marfan syndrome? Mutations in the FBN1 gene cause Marfan syndrome. The FBN1 gene provides instructions for making a protein called fibrillin-1. Fibrillin-1 binds to itself and other proteins and molecules to form threadlike filaments called microfibrils. Microfibrils become part of the fibers that provide strength and flexibility to connective tissue. Additionally, microfibrils hold molecules called growth factors and release them at the appropriate time to control the growth and repair of tissues and organs throughout the body. A mutation in the FBN1 gene can reduce the amount and/or quality of fibrillin-1 that is available to form microfibrils. As a result, growth factors are released inappropriately, causing the characteristic features of Marfan syndrome.

Bone anomalies

dislocated lens

Heart valve anomaly

Aortic dissection death

Marfan syndrome
This condition is inherited in an autosomal

dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. At least 25 percent of classic Marfan syndrome cases result from a new mutation in the FBN1 gene. These cases occur in people with no history of the disorder in their family. Beside pleiotropy the syndrome also shows variable expressivity in families.