Page Hemophilia by Aronova-Tiuntseva and HerreidNATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCEHemophilia: The Royal DiseaseHemophilia is an X-linked recessive disorder characterized by the inability to properly form blood clots.Until recently, hemophilia was untreatable, and only a few hemophiliacs survived to reproductive age because any small cut or internal hemorrhaging after even a minor bruise were fatal.Now hemophilia is treated with blood transfusions and infusions of a blood derived substance known as antihemophilic factor.However, such treatment is very expensive and involves the risk of contracting AIDS.Hemophilia a ects males much more frequently (1 in 10,000) than females (1 in 100,000,000).
is occurs because a critical blood clotting gene is carried on the X chromosome.Since males only carry one X chromosome, if that is defective, hemophilia will immediately show up.An early death is likely.Females, on the other hand, carry two X chromosomes.If only one is defective, the other normal X chromosome can compensate.
e woman will have normal blood clotting; she will simply be a carrier of the recessive defective gene.
is fact will be discovered if some of her children are hemophiliacs.Naturally, women hemophiliacs are rare because it takes two defective X chromosomes in order for the condition to be seen.Hemophilia has played an important role in Europes history, for it suddenly cropped up in the children of Great Britains Queen Victoria.
It became known as the Royal disease because it spread to the royal families of Europe through Victorias descendants.Queen Victoria had always been worried about the quality of the blood of the British royal family.Her feelings about the necessity of revitalizing what she called the lymphatic blood of their houses are re ected in her letter to her daughter Vicky: I do wish one could
nd some more black eyed Princes and Princesses for our children! I cant help thinking what dear Papa saidthat it was in fact when there was some little imperfection in the pure Royal descent that some fresh blood was infused For that constant fair hair and blue eyes makes the blood so lymphatic it is not as trivial as you may think, for darling Papaoften with vehemence said: We must have some strong blood.It is doubtful that at the time of writing this letter, the Queen knew exactly what was wrong with her familys blood.
rst appeared in Victorias family in her eighth child, Prince Leopold, Duke of Albany.
roughout his short life, Leopold had su ered severe hemorrhages, and always was described as very delicate.Leading the life of a normal child was impossible for Leopold because any cut or bump could lead to death and it was necessary to keep him always under strict surveillance.However, in spite of all the protection, Prince Leopold died at the age of thirty-one as the result of a minor fall.e appearance of hemophilia in one of Victorias sons upset and confused the Queen, who could only protest that the disease did not originate in her side of the family.
Yet, a whisper about the curse of the Coburgs was spread
is curse was supposed to have dated from the early nineteenth century, when a Coburg prince had married a Hungarian princess named Antoinette de Kohary.A monk, a member of the Kohary family, envied the wealth inher-ited by the happy couple from the brides father, and cursed future generations of Coburgs with the disease.
ecting Victorias o spring had nothing to do with the curse.
e traditional view is that there was a mutation in either her or in a sperm of her father, Edward Augustus, Duke of Kent.From there it spread through the Royal Houses of Europe as monarchs arranged marriages to consolidate political alliances.
We can trace the appear-ance of hemophilia as it popped up in Spain, Russia, and Prussia by looking at the family tree (Figure 1 next page).PageHemophilia by Aronova-Tiuntseva and HerreidATINAL CENTER FOR CASE STUDY TEACHING IN of 1.
Royal Houses of EuropeNATIONAL CENTER FOR CASE STUDY TEACHING IN SCIENCEPage Hemophilia by Aronova-Tiuntseva and Herreid1.First, lets take a look at Queen Victorias son Leopolds family (see Figure 2).His daughter, Alice of Athlone, had one hemophilic son (Rupert) and two other childrena boy and a girlwhose status is unknown.(a) What is the probability that her other son was hemophilic?(b) What is the probability that her daughter was a carrier? Hemophilic?(c) What is the probability that both children were normal? Fortunately, Leopold was the only one of Victorias sons who su ered from hemophilia.
Her other three sons, Edward, Alfred, and Arthur, were una ected.
Since the present royal family of England descended from Edward VII, the
rst son, it is free from hemophilia.Louise, Queen Victorias fourth daughter and sixth child, did not have children and her status as a carrier cannot be assessed.
rst child, and Helena,
fth child, had children, none of whom was hemophilic, indicating that the mothers probably were not carriers.2.
Now for the Spanish connection: Victorias youngest child, Beatrice, gave birth to one daughter, one normal son, and two hemophilic sons (see Figure 3).(a) Looking at the pedigree of the royal family, identify which of Beatrices children received the hemophilic gene; why can you make this conclusion? (b) Notice that Beatrices daughter, Eugenie, married King Alfonso XIII of Spain and had six children, one of whom was the father of Juan Carlos, the current King of Spain.
Would you predict that Juan Carlos was normal, a carrier, or 3.Queen Victorias third child, Alice, passed hemophilia to the German and Russian imperial families (see Figure 4, next page).Of Alices six children, three were a
icted with hemophilia
At the age of three, her son Frederick bled for t
Ihtc genetics hemophilia training module
HemophiliaHemophiliaSheffield Molecular Genetics Service hemophiliaand its inhethen describes the mutations responsible for hemophiliaAanalysis by mutation screening or DNA sequencing.The use of linkage genetic analysis is also described.An algorithm for genetic testing is given, plus & Royalty& RoyaltyPedigree of the most famous hemophiliafaUK.The X-chromosome linked inheritance pattern of hemophiliais clearly seen, with females carrying the disorder, and males affected by hemophilia.Queen Victoria was the first known carrier in the family.The mutation responsible may have arisen in her father, Edward, Duke of defective gene in hemophiliaA is The defective gene in hemophiliaB is This pedigree shows the ined (orange) andnormal (green) X chromosomes.
Males have a single X, plus a Y chromosome, females have two Xs.Males with hemophiliain the first and chromosome.They have the same mutation and thus tsimilar hemophiliaseverity.
Daughters of a male with hemophiliaare all obligate carriers; they can only inherit a copy of the affected X chromosome from their father.The third generation of he four possible outcomes for children of the obligate carrier; unaffected or affected male, non-carrier or carrier female.Genetic analysis can be used to determine which X chromosome possible carriers have inherited.HemophiliaA 50% normal activity FVIII:CHemophiliaB 50% normal activity FIX:CSevere 1%40% of patientsModerate 1-5%10% of patientsMild 5%50% of patientsmophiliaB Leiden (later), hemophiliais a lifelong disorder of the same severity.In a family with hemophilia, the same mutation is inherited by all affected males, and the hemophiliaseverity inBleeding -prolonged, internalspontaneous joint and muscle bleedsThere is a strong correlation between residual clotting factor level and severity of bleeding symptoms.
Spontaneous bleeding is only seenin severe disease.Affected males with severe diere there is no prior family history of hemophilia.In males with mild disease, it is diagnosed until middle age, possibly following prolonged bleeding at surgery.Painful target jointCrippling arthropathySymptoms of hemophiliainclude bleeding into joints and muscles.Knees, ankles and elbows particularly are affected.
Target joints develop when bleeding occurs recurrently into thWorld Federation of Hemophilia Hemophiliain Pictures with synovialfluid.Excessive bleeding can swell the joint.Resorptionof blood can be associated with cartilage damage and eventually lead to cartilage loss.Arthritis due to progressive joint damage results in limited andpainful joint movement.
HemophiliaHemophiliaSevere disease -replacement clotting factor therapy required to Immune tolerance therapy (ITT) for hemophiliainhibitory Mild disease -DDAVP provokes stimulated release of DDAVP 100Treatment available varies widely in different parts of the world.Current UK costs are worldwide at very similar prevalence rates, as the mutations responsible recur due to intrinsiHemophiliaA is five-fold more prevalent than hemophiliaB.IIIIaXaFibrin MonomerFibrin PolymerStable FibresXIIIXIIIaVIIIVIIIaThe Coagulation Cascade Von Willebrandfactor (vWF) carries and protects factor VIII (FVIII) from proteolyticdegradation.Thrombin (FII) cleavage activates FVIII to FVIIIa.FVIIIathen acts as a co-factor for activated FIXa, which activates FX to FXa.de is to form stable cross-linked fibres of fibrin in blood clots.
Insufficient FVIII or FIX results in less stable ive fibrin formation.Insufficient FVIII or FIX due to hemophiliaA or B will result in the same symptoms of bleeding as the two coagulation factors are involvedin the Fibrin CrossFibrin Cross--Linked Blood ClotLinked Blood ClotRed blood cells trapped in a fibrin mesh of a normal blood clot are shown in this electron micrograph.result in the same symptoms as they Treatment of hemophiliaA and B patients differs.
The Coagulation testing is sufficient in almost all cases to diagnose hemophiliain affected males.Occasionally, cord blood from a new male baby from a hemophiliafamily is not suitable for coagulation factor level analysis due to clotting, so genetic testing is used to determine affected status.In a small proportion of cases, mild hemophiliaA is not readily discriminated from type 2N von Willebranddisease by coagulation tests and genetic analysis is required instead.Hemophiliacarrier status in females is not readily determined by clottingfactor levels.
Genetic testing is necessary for accurate carrierstatus determination.: The factor VIII and IX genesFactor VIII and IX: The coagulation factor proteinsand Factor IX:C (FIX:C): Coagulant activityFVIII Protein020406080100120140160180 kb1 2
4 5 6
7 8 9 10
11 > A2 a2 B chainConnecting regionLight chainThe upper panel shows the 125 introns.These encode an 8.8kb mRNA.The all, being at most a few hundred nucleotides in rather larger, particularly exon 14,which is 3kb in length.Exon 14 encodes the B domain of the FVIII protein.
Introns1 and 22 are notable for their sequences, of which copies are prThese repeated regions are involved in the two intrachromosomalinversion mutations (below).The FVIII protein has a repeated domain structure, with repeatedA, a (acidic) and C dongle large B domain.F8F8Intron22 Inversion22 on a figure by TuddenhamEGD in Lancet 1994;343:307-8Panel 1 shows the location of the gene at Xq28, towards the telomere (tel) of the long arm Panel 2 shows an expansion of this region.The Intron22 of the gene contains a region of 9.5kb (black bar), which is repeated twice approx 500kb 5and telomericto the gene.These regions are referred to as intron22 homologous regions (int-2d of the X chromosome, which occurs particularly at male meiosis.Two copies of int22h line up and homolocan occur between them, as the sequences are 99% identical; only 5 nucleotides differ in 9.5kb between the three copies int22h copies, but is stal
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