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By: Cory Sidelsky About Fabry • Fabry disease is a rare hereditary disorder caused by a faulty gene in the body. It affects more males than females: It is estimated that 1 in 40,000 males has Fabry disease, whereas the estimated prevalence in the general population is 1 in 117,000 people. • Hereditary (or genetic) disorders are those that are passed down from parents to their children through the genes. One or both parents may carry an abnormal gene that, when passed along to their children, can result in disease. Since the Fabry disease gene is located on the X chromosome, the disease primarily affects males (although some females can also experience symptoms). Location of Fabry Disease on the X Chromosome Start: 95,944,571 bp from pter End: 95,954,725 bp from pter Size: 10,154 bases Orientation: minus strand Punnett Squares for X-Linkage Clinical Symptoms • • • • • • • Sudden, intense episodes of burning Persistent pain in the hands or feet Recurrent fever Intolerance of heat or cold Impaired sweating Psychological and social issues A purple-red rash in the midriff area (angiokerotoma) • Corneal whorling Predicted Life Span Meet Dave • "I am 31, and Fabry disease affects me daily with burning pain in the hands. I had a kidney transplant three years ago when I was 28, and since then I have to take medication daily, and monitor blood pressure and so on. Before my surgery, going through dialysis had a big impact on my life. My inability to sweat affects me occasionally. It goes hand in hand with my body temperature. As my body temperature rises, pain increases in the hands." • "When I was a child, the most prevalent everyday symptom was burning of the feet. It started when I was about 8 years old with physical exercise and changes in body temperature. And then when I was about 13, it switched to the hands, and it's been in the hands ever since. Other members of my family have had it, and they always called it burning hands and feet." Meet Sara • "I am 43. I have different symptoms every day; my typical symptoms include difficulty breathing, appetite and sleeping problems, a lot of nausea. I have ringing in my ears, headaches, and just generally feel very ill, to different degrees, every day. I have pain throughout my body, sometimes incapacitating. I've read that as you get older, the pain decreases, but I do have pain every day, typically in my arms and legs, hands and feet. It varies from a stabbing, piercing type of pain to aching and throbbing. There are also times during a Fabry crisis [episodes of intense, burning pain] when I cannot get out of bed, when the pain feels like a dental drill or electrical shock going through my body." • "When I was a little girl, the school detected heart problems that doctors said I would outgrow, and that my pain was just an issue that I didn't want to go to school. In my twenties, I was told that I had arthritis, mono, bronchitis, many things. The only thing that was prescribed was aspirin. But no one took any tests to find out what I had." Meet Christopher • "I am 18, and my major symptoms are pains in my toes, and pretty bad pains in my chest. It's different every day. I have a definite problem with heat. If I can't stand the heat, I have to be in someplace cold or else I get heat exhaustion easily. I throw up every day, and I have diarrhea sometimes if I don't eat properly." • "When I was young, I would have diarrhea once in a while, and the doctors just assumed that it was lactose intolerance. I also had problems with heat as a child. I was told it was all in my head, or lactose intolerance. That was when I was about 4." Pictures of Fabry Victims Fabry on skin Fabry on leg and foot Fabry on skin X inactivation Women don’t get full blown Fabry’s. They get Corneal Opacity, this is where there is a fliming cloud over the eye. Cardiomyopathy Some victims of Fabry can get Cardiomyopathy which is inefficient pumping of the ventricles. Gene Sequence of Fabry • 946 bp upstream of BbvI recognition pattern; chromosome Xq21.33. 1 tcgaaattga tatgtagatt gttgttatca gcagaaaaat aaacattatt caaatactct 61 attcagttaa agtaatttat tgggcgcctt tgtcaagcac gcatttgcct agatgtgact 121 ctacagataa aattcacttg gggcctcccc ttacagacaa tcaggcagtg gagactgagt 181 gcctgaatgg atagaccagc actcagacca ctattttcag tatctgtttt tcttaactca 241 gggccgtggt tttcaaacgt ttttcgcctt acggtcaccc ttaggggtcc cccgagaccg 301 gcccagacag acagatatac aaaaacacat acacagtcat gagcgtccac catttcccca 361 ccaggcgcag acaggcggct tcccggcact gagatggggg ggaggaggga gagagcgcga 421 ggggggaggg gaaagcagag aacgaaagag gcggaggcgg cccccgaacc ccgctctggt 481 cttcatcatc accacccctg ggtccccagt tcccacccac acaccaacct ctaacgatac 541 cgggtaattt tcctccttct tccctcaaac ggctatagcg agacggtaga cgacgaccag 601 aactacttct gctcacgtaa gcgagtaatc acgtgagcgc ctacgtcatg tgagatctcg 661 gtcacgtgag caactctcgg cttaaactcg ggatcactaa ggtgccgcac ttccttctgg 721 tatggaaata gggcgggtca atatcaagaa aggaagaggg tgattggtta gcggaacgtc 781 ttacgtgact gattattggt ctacctctgg ggataaccgt cccagttgcc agagaaacaa 841 taacgtcatt atttaataag tcatcggtga ttggtccgcc cctgaggtta atcttaaaag 901 cccaggttac ccgcggaaat ttatgctgtc cggtcaccgt gacaatgcag ctgaggaacc 961 cagaactaca tctgggctgc gcgcttgcgc ttcgcttcct ggccctcgtt tcctgggaca 1021 tccctggggc tagagcactg gacaatggat tggcaaggac gcctaccatg ggctggctgc 1081 actgggagcg cttcatgtgc aaccttgact gccaggaaga gccagattcc tgcatcaggt 1141 atcagatatt gggtactccc ttccctttgc ttttccatgt gtttgggtgt gtttggggaa 1201 ctggagagtc tcaacgggaa cagttgagcc cgagggagag ctc // SEQUENCE 248 AA; 27774 MW; 7F4B44E3AA59ECE6 CRC64; MERASLIQKA KLAEQAERYE DMAAFMKGAV EKGEELSCEE RNLLSVAYKN VVGGQRAAWR VLSSIEQKSN EEGSEEKGPE VREYREKVE ELQGVCDTVL GLLDSHLIKE AGDAESRVFY LKMKGDYYRY LAEVATGDDK KRIIDSARSA YQEAMDISKK EMPPTNPIRL GLALNFSVF YEIANSPEEA ISLAKTTFDE AMADLHTLSE DSYKDSTLIM QLLRDNLTLW TADNAGEEGG EAPQEPQS Size: 429 amino acids; 48766 Da Catalytic activity: Melibiose + H(2)O = galactose + glucose. Subcellular location: Lysosomal. Pharmaceutical: Available under the name Replagal (Transkaryotic Therapies). Used as a long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry's disease. Similarity: BELONGS TO FAMILY 27 OF GLYCOSYL HYDROLASES. Distribution of Mutations in Fabry Summary of Mutation Types in Fabry Disease Nucleotide substitutions (missense / nonsense) 181 Nucleotide substitutions (splicing) 16 Nucleotide substitutions (regulatory) 0 Small deletions 42 Small insertions 13 Small indels 2 Gross deletions 8 Gross insertions & duplications 1 Complex rearrangements (including inversions) 3 Repeat variations 0 TOTAL 266 Accession Number Codon Nucleotide Amino acid Phenotype CM960756 1 ATGc-ATA Met-Ile Fabry disease 1 CM972793 1 ATG-ACG Met-Thr Fabry disease 2 CM950584 20 gGCC-CCC Ala-Pro Fabry disease 3 CM972763 31 GCA-GTA Ala-Val Fabry disease 2 Reference Treatment • The new treatment is termed “enzyme replacement therapy”--a deceptively simple phrase that represents the outcome of a lengthy series of clinical studies, in which NCRR’s GCRCs have played a major role. The partnership dates back to 1970, when Dr. Desnick and his colleagues, then working at the GCRC at the University of Minnesota, published a study in which two young men with Fabry’s disease showed a sharp drop in GL-3 after receiving an infusion containing alphagalactosidase A. At that time, long before the enzyme was available in purified form, the infusion came in the form of donated blood plasma, which contained normal amounts of the necessary enzyme. • In the Phase 1/2 trial, each of 15 Fabry patients received five infusions of recombinant human alpha-galactosidas A, at one of three dosage levels. “The higher the dose, the more rapid and complete” was the clearance of fatty GL-3 from the blood and affected tissues, says Dr. Eng. However, “with the highest dose, some patients experienced transient transfusion reactions, so a lower dose was chosen in subsequent studies.” • The Phase 3 trial, a multicenter study, tested the effects of recombinant alpha-galactosidase A in 58 Fabry patients, with half the study group receiving a placebo instead. All participants received biweekly infusions for 20 weeks. In addition, both before and after the treatment period, biopsies of the patients’ kidneys, heart tissue, and skin were each examined by nine independent pathologists who were experts in the pathologies of the respective tissues. Results • The results showed a clear effect in patients who had received the drug. More than two-thirds of this group--but none of the patients receiving placebo--achieved complete or nearly complete clearance of GL-3 deposits in the kidneys. Similar, or even better, results were observed in skin and heart tissue. • Perhaps the most telling result was that at the end of the designated 20 weeks, all patients who had been receiving enzyme replacement infusions elected to continue this therapy, and all those in the placebo group chose to switch to this therapy as well. “We now have an ongoing Phase 3 extension study, and we’re enrolling for Phase 4, which will look at clinical progression in a long-term study,” Dr. Eng says. “But we couldn’t have done these studies without the GCRC.”