Published on March 16, 2014
Fabry disease Up date on research Robert J. Hopkin February 14, 2014 Division of Human Genetics Cincinnati Children’s Hospital Medical Center Rob.firstname.lastname@example.org
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
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
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
Treatment Enzyme infusions Fabrazyme Replagal Other Takes several hours and requires an IV to be placed. Storage and preparation of the enzyme is difficult
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
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
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)
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
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
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
Innovations Substrate inhibition is now in clinical trials.
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.
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.
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
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.
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
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.
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
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
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)
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)
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)
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)
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.
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.
Calcification Inhibitors in CKD and Dialysis Patients
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