This document provides an update on research into Fabry disease. Some key points: - Fabry disease is an X-linked lysosomal storage disease caused by a deficiency in the enzyme alpha-galactosidase A. Symptoms typically appear in childhood and include pain, fatigue, and kidney, heart, and neurological problems. - Current treatments include enzyme replacement therapies which require intravenous infusions. Research is exploring oral treatments, biomarkers to monitor treatment effectiveness, and ways to target tissues not reached by current therapies. - Studies show symptoms often appear earlier than previously thought, and early initiation of treatment may help prevent organ damage. However, most patients still start treatment after significant disease progression. - Research is

1. Fabry disease
Up date on research
Robert J. Hopkin
February 14, 2014
Division of Human Genetics Cincinnati Children’s
Hospital Medical Center
Rob.hopkin@cchmc.org

2. Background
 Described separately in 1898 by Anderson
and Fabry
 X-linked lysosomal storage disease
 1/40,000 for classical disease
 Both men and women symptomatic

3. Physical signs

5. Symptoms (Males)
 First symptoms in males average age 6
years

Most common first complaint Pain
 Other common problems in childhood
include fatigue, heat intolerance,
anhydrosis, recurrent / chronic diarrhea
 Adults: Kidney disease, Heart disease,
Stroke, Lymphedema, Hearing loss,
shortness of breath with exercise, early
death

6. Symptoms (Females)
 First symptoms in females age 9 years
 Most common initial symptom fatigue and
pain
 Other common pediatric complaints include
diarrhea and other GI complaints
 Adult: Heart disease, Stroke, Kidney
disease, Hearing loss, decreasing QOL,
early death

7. Treatment
 Enzyme infusions
 Fabrazyme
 Replagal
 Other
 Takes several hours and requires an IV to
be placed.
 Storage and preparation of the enzyme is
difficult

8. Needs
 Pain management, Lymphedema, Stroke,
GI, Hearing loss
 Early diagnosis/management guidelines
 Easier treatment (oral medication)
 Markers that can be monitored for early
treatment
 Hard to reach tissues or cell types.
 Natural history and treatment data on
females

9. Tools
 New mouse model that actually develops
progressive renal disease
 A symptomatic Fabry disease mouse model generated by
inducing globotriaosylceramide synthesis.
 Taguchi A, Maruyama H, Nameta M, Yamamoto T, Matsuda J,
Kulkarni AB, Yoshioka H, Ishii S. Biochem J. 2013 Dec
15;456(3):373-83.
 IPS (stem) cells developed in culture
 Induced pluripotent stem cells derived from mouse models of
lysosomal storage disorders.
 Meng XL, Shen JS, Kawagoe S, Ohashi T, Brady RO, Eto Y. Proc
Natl Acad Sci U S A. 2010 Apr 27;107(17):7886-91

10. Tools
 Improved genotyping
 Improved activity estimation
 Improved classification of mutations
 (note this is critical for new born screening
and prognosis. It is also helpful for
evaluation of interventions)

11. Innovations
 Many biomarkers tested
 Lyso GL3
 tetrahydrobiopterine
 Cytokine profiles
 Many other biochemical assays
 Better measures of tissue level response to
treatment (semi-quantative measures as
opposed to scoring)
 I WILL LEAVE DETAILS OF THIS TO OTHER
SPEAKERS

12. Innovations
 New forms of ERT
 Using a modified version of a different enzyme
 Alpha-N-acetylgalactoseaminidase
 PEGylation of enzyme
 Modified glycoslyation
 Coformulation with chaperones
 Coformulation with substrate inhibition

13. Innovations
 Re-assessment of chaperon therapy
 Had miss classified several mutations
 Measures of impact not done in best fassion
 The revised analysis of the data indicated
that a smaller number of mutations did
have a significant benefit from oral
chaperone therapy. P=.002

14. Innovations
 Substrate inhibition is now in clinical trials.

15. Age in Fabry disease
 At least 3 studies identified “young”
patients or “early features” in their 30s and
40s.
 Treatment success and value of ERT has
been studied in several papers with a
conclusion that ERT has minimal impact on
Fabry disease
 These studies all had average age of
patients >40.
 Rombach SM, Smid BE, Bouwman MG, Linthorst GE, Dijkgraaf
MG, Hollak CE. Orphanet J Rare Dis. 2013 Mar 25;8:47
 Weidemann F, Niemann M, Störk S, Breunig F, Beer M, Sommer
C, Herrmann S, Ertl G, Wanner C.J Intern Med. 2013
Oct;274(4):331-41.

16. Age and Fabry disease
 Genzyme and Shire published data on age
of initiationof ERT
 Genzyme 37 years
 Shire 35 years
 Females are even older
 This is 2013 data
 Conclusion: We are not starting treatment
while there is still hope for prevention or
reversal of damage.

17. Pediatric Fabry
 Late on set mutations are rarely if ever
symptomatic in pediatric patients
 Null mutations are usually
(80%)symptomatic in pediatric males and
often in pediatric females
 There are subtle changes in heart function
in children and adolescents
 If there is overt renal disease (significant
proteinuria or low GFR) think of second hits

18. Proportion of Children with left
ventricular mass > 75th
centile
JIMD Rep. 2013;11:53-64. doi: 10.1007/8904_2013_222. Epub 2013
Apr 2.
Early cardiac changes in children with anderson-fabry disease.
Havranek S, Linhart A, Urbanova Z, Ramaswami U.

19. Pediatric Fabry
 Many symptomatic kids are not treated.
 There is a lot of debate about when
treatment should be started.
 As soon as the diagnosis is confirmed regardless
of age
 By age 10
 Only if there are symptoms of in males after age
20

20. Pediatric Fabry
 Pano et al.
 Study of 57 pediatric patients confirmed all
the previous studies remember that age of
first symptoms was 6 in boys and 9 in girls.

21. Other WORLD reported findings
 Pain is always accompanied by abnormal
renal findings if biopsies are done.
(Warnock)
 Patients prefer home infusions to center
infusions except those who are not
employed and live alone (Watkins)
 Most females with GI symptoms improve
when on ERT (Wilcox)
 Consensus recommendations were made
for when to test people with stroke, heart
disease and kidney disease for Fabry
disease

22.  It is safe to switch from Replagal to
Fabrazyme or Fabrazyme to Replagal
 There are several groups collecting
genotype phenotype data
 Eye findings are important
 Fabry disease is variable but there is a
trend toward consistency in families
(Kaminsky)
 Kids have lower lyso-GB3 levels than adults
(Auray-Blais)
Other WORLD reported findings

23. Surprises
 Decreased risk for cancer in patients with
Fabry disease (Hadjimichael)
 X-inactivation is random in Fabry disease
(this part not surprising) but there is a
strong correlation with outcome for women
with skewed inactivation.
 Active mutated X severe disease similar to men
 Active normal copy Little or no expression
 Random activation is in between with most
women having significant disease (Germain)

24. Surprises
 Women with Fabry disease are quite
worried about it and recognize that they
have a serious illness
 They rarely pursue monitoring or
intervention (Long)
 Androgen blockaid improved function in
male mice with fabry disease.(Shen)
 Systematic approach to treatment of pain
including some clinical trials (Sorgen)

25. Surprises
 1.5% of hypertrophic cardiomyopahty is
likely due to Fabry disease (Desnick)
 Oral ERT (NOT FOR FABRY DISEASE) by
encapsulation in carrot cells(Zimran)

26. Stuff that was not presented at
WORLD
 Use of Vitamin D as a biomarker and
treatment target
 Potential role of vitamin D deficiency on Fabry cardiomyopathy.
 Drechsler C, Schmiedeke B, Niemann M, Schmiedeke D, Krämer J,
Turkin I, Blouin K, Emmert A, Pilz S, Obermayer-Pietsch B,
Weidemann F, Breunig F, Wanner C. J Inherit Metab Dis. 2013
 1% of strokes under age 50 likely to be
from Fabry disease (multiple resources)

27. Primary motor cortex
hyperexcitability in Fabry's disease.
 CONCLUSIONS: Our data documented an
increased activity of motor cortex
glutamatergic excitatory circuits in FD,
evident also in patients without brain MRI
lesions. Following enzyme replacement
treatment, this abnormality was partly
reversed.
 Clin Neurophysiol. 2013 124:1381-9. Primary motor
cortex hyperexcitability in Fabry's disease.
 Ortu E, Fancellu L, Sau G, Falchi P, Traccis S, Pes GM,
Ganau A, Sechi G.

28. Inflammation
 Fabry disease peripheral blood immune cells
release inflammatory cytokines: role of
globotriaosylceramide.
 De Francesco PN, Mucci JM, Ceci R, Fossati CA, Rozenfeld PA. Mol
Genet Metab. 2013 May;109(1):93-9.

29. Questions