Transcript Fabry

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
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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.”