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					Fabry Disease
       What is Fabry Disease?
        One of the most common lysosomal storage                                                                            Fabry disease is due to a mutation on
                                                                                                                                  the X chromosome (Xq22)4
         disorders1,2
        Caused by α-galactosidase A deficiency3                                                                             Chromosome X
        Due to a mutation on the X chromosome (Xq22)4
        Leads to pathological accumulation of                                                                                        Xp                               Xq

         sphingolipid Gb3*2,5
        Results in organ failure and premature death in
         males and females2,5


        *Gb3 = Globotriaosylceramide (sometimes abbreviated as GL-3, and                                                          Gene
         also known as ceramide trihexoside [CTH]).                                                                        From Beck M, Ries M, 2001.6




1. Fuller M, et al. In: Mehta A, et al (eds). Fabry disease: perspectives from five years of FOS. 2006. 2. Barbey F, et al. Curr Med Chem Cardiovasc Hematol Agents.
2004;2:277–286. 3. Kint JA. Science. 1970;167:1268–1269. 4. Bishop DF, et al. Proc Natl Acad Sci USA 1988;85:3903–3907. 5. Mehta A, et al. Eur J Clin Invest.
2004;34:236–242. 6. Beck M, Ries M. Fabry disease: clinical manifestations, diagnosis and therapy. 2001.
Diagnosis of Fabry Disease
                            Blood levels of α-galactosidase A                          DNA Analysis
   Males                                Low or absent                                  Confirmative
   Females                      May be within normal range                              Diagnostic


 Pedigree analysis should be carried out whenever possible
 Enzyme activity in females
   Can be low, absent, or normal in affected females
   Fabry disease should not be ruled out in females based on normal enzyme analysis
 Prenatal diagnosis
   α-galactosidase A activity present in fetal tissue
   May be requested if mother is heterozygous for Fabry disease
     Assessing Disease Severity
      α-galactosidase A deficiency leads to deposition of lipid – mainly Gb3
       (globotriaosylceramide) – in cells throughout the body1,2
      Nevertheless, Gb3 has not been established as an ideal marker in females3
      Urinary Gb3 is a better marker of Fabry disease than plasma Gb33
      Disease severity assessment
           Mainz Severity Score Index (MSSI)4
           Fabry disease severity scoring system (DS3)5
           Fabry age-adjusted score6
                                              Clinical findings and Gb3 levels in 57 women with Fabry disease3
                                                                         Elevated plasma Gb3

                                                                            Elevated skin* Gb3
                                                        Cardiac, renal, or cerebrovascular
                                                                             abnormalities
                                                                                                       *Superficial endothelial dermal cells.


1. Barbey F, et al. Curr Med Chem Cardiovasc Hematol Agents. 2004;2:277–286. 2. Mehta A, et al. Eur J Clin Invest. 2004;34:236–242. 3. Gupta S, et al. Medicine.
2005;84:261–268. 4. Whybra C, et al. Clin Genet. 2004;65:299–307. 5. Giannini EH, et al. Mol Genet Metab. 2010;99(3):283–290.
6. Hughes DA, et al. Mol Genet Metab. 2010 Jun 22. [Epub ahead of print]
      Fabry Disease May Be Initially Misdiagnosed
       Fabry patients may be seen by many different specialists before a diagnosis is
        made1,2                                      Patients may receive a wide range of initial
                                                                                                   diagnoses1-3

                                                         Nephrologists 14%                       Misdiagnosis
                                                                                                                                                % of Total Misdiagnoses


                                                                                                 Rheumatological disease/rheumatic fever
                                                                                                                                                          39
                                                         Geneticists 10%
                                                                                                 Arthritis                                                15

                                                                                                 Fibromyalgia syndrome                                    7
          Other 51%
                                                         Pediatricians 8%                        Dermatomyositis                                          5

                                                                                                 Erythromelalgia                                          5
                                                         Dermatologists 7%
                                                                                                 Osler’s disease                                          5

                                                                                                 Neuropsychological disease                               13
                                                         Family doctors 5%
                                                                                                 Ménière’s disease                                        3

                                                         Cardiologists 5%                        Other                                                    49

                                                                                                 Reproduced with permission from Mehta et al, 2004.
               Different specialties involved in
               diagnosis.3


1. Mehta A. Hosp Med. 2002;63:347–350.
2. Mehta A, et al. Eur J Clin Invest. 2004;34:236–242.
3. Beck M. In: Mehta A, et al (eds). Fabry disease: perspectives from five years of FOS. 2006.
     Symptom Onset: Males
       • Fabry disease affects almost all organs1-4
       • Onset of symptoms in 375 adult males from the Fabry Outcome Survey5

                                                  Kidneys
                                                     Brain
                                                     Heart
                                                      Ears
                                                      Eyes
                                                   GI tract
                                                    Skin
                                               Peripheral
                                                  nerves


                                                                                      Age (years: mean and SD)
      • Females experience some of the same disease symptoms, and see a similar
        pattern of onset, but delayed by 10 years5
1. MacDermot KD, et al. J Med Genet. 2001;38:769–775. 2. MacDermot KD, et al. J Med Genet. 2001;38:750–760. 3. Mehta A, et al. Eur J Clin Invest. 2004;34:236–242. 4. Brady RO,
et al. N Engl J Med. 1967;276:1163–1167. 5. Beck M. In: Mehta A, et al (eds). Fabry disease: perspectives from five years of FOS. 2006.
      Clinical Signs and Symptoms:
      Peripheral Neuropathy
       Pain is an early, often debilitating symptom, seen
        in up to 77% of patients1
       Patients experience acroparesthesia and crisis of
        burning or lancinating pain1,2
       Exercise, temperature change, or stress may
        trigger a pain crisis1,3
       Reduced ability to sweat is common1 and                                                                     Hands

        contributes to poor exercise and heat tolerance4


                                                                                                                        Feet




1. MacDermot KD, et al. J Med Genet. 2001;38:750–760. 2. Mehta A, et al. Eur J Clin Invest. 2004;34:236–242. 3. Barbey F, et al.
Curr Med Chem Cardiovasc Hematol Agents. 2004;2:277–286. 4. Schiffmann R, et al. Muscle Nerve. 2003;28:703–710.
     Signs and Symptoms: Dermatological
     Manifestations
      Dermatological symptoms (telangiectases and angiokeratomas) are frequent (up to 78%) early signs of
       Fabry disease
      Angiokeratomas are typically, but not exclusively, distributed within the bathing trunk area
      May appear mild (few in number), moderate (dispersed, few in clusters) or severe (multiple, many,
       extensive)


                                                                            Angiokeratomas
                                   Umbilicus                                   Lips          Trunk




                          Reproduced with permission from Orteu CH, et al. 2007


Orteu CH, et al. Br J Dermatol. 2007;157(2):331–337.
      Signs and Symptoms: Gastrointestinal
       Occur in up to 55% of patients1
       May be an early manifestation                                                          Males
        of Fabry disease2                                                                      Females




                                                                       Patients (%)
       Symptoms include1-3
             Abdominal pain, bloating, constipation, and diarrhea
             Delayed gastric emptying
             Lack of appetite, early satiety
             Nausea and vomiting



                                                                                                  Decade of life

                                                                      Adapted from Mehta, et al. 2004.1




1. Mehta A, et al. Eur J Clin Invest. 2004;34:236–242.
2. Dehout F, et al. J Inherit Metab Dis. 2004;27:499–505.
3. Hoffmann B, et al. Eur J Gastroenterol Hepatol. 2004;16:106–109.
     Signs and Symptoms: Ocular
      Found in up to 62% of patients1
      Most specific manifestations are2,3
           Corneal opacities (cornea verticillata)
           Retinal vascular abnormalities (vessel tortuosity)
           Lens opacities (anterior or
            posterior subcapsular cataract)
                                                                                                                         Reproduced with permission from Sodi, et al. 2006.2




                 Reproduced with permission from Sodi, et al. 2006.2                                                     Reproduced with permission from Sodi, et al. 2006.2




1. Mehta A, et al. Eur J Clin Invest 2004; 34: 236–242.
2. Sodi A, Ioannidis AS, Mehta A, et al. Ocular manifestations of Fabry’s disease: data from the Fabry Outcome Survey. Br J Ophthalmol. 2007;91:210–214.
3. Brady RO, Schiffmann R. JAMA. 2000;284:2771–2775.
      Signs and Symptoms: Cardiac
                                                                                                    Up to 69% of male patients have
                                                                                                     cardiac symptoms (chest pain,
                                                                                                     palpitations, dyspnea, and syncope)1
                                                                                                    Cardiac abnormalities include2-4
                                                                                                           Left ventricular dysfunction (systolic and diastolic)
                                                                                                           Conduction abnormalities
                                                                                                           Left ventricular hypertrophy (mainly concentric)
                                                                                                           Valve dysfunction (mainly mitral)
                     Short PR interval Voltage criteria         T-wave inversion
                                       for LVH
        Reproduced with permission from Linhart et al, 2006.5




                                                                                                                        Reproduced with permission from Linhart, et al. 2006.5


1. Mehta A, et al. Eur J Clin Invest. 2004;34:236–242. 2. Elliott P. Curr Med Lit. 2006;6:1–6. 3. Kampmann C, et al. J Am Coll Cardiol.
2002;40:1668–1674.4. Shah JS, Elliott PM. Acta Paediatrica. 2005;94(Suppl. 447):11–14. 5. Linhart A, et al, In: Mehta A, et al (eds). Fabry disease: perspectives from five
years of FOS. 2006.
      Signs and Symptoms: Cerebrovascular
       Early onset (mean age 33.5 in males and 41.4 in females)1
       13% of Fabry patients suffer stroke or TIA2
       Cerebrovascular abnormalities include
            Increased regional cerebral blood flow3                                                            Middle
            Vertebrobasilar vascular changes4                                                                 cerebral
            Non-specific white matter lesions4                                                                 artery




            Reproduced with permission from Ginsberg, et al. 2005.4                                                                  Reproduced courtesy of Dr R Manara.



1. Beck M. In: Mehta A, et al (eds). Fabry disease: perspectives from five years of FOS. 2006. 2. Mehta A, et al. Acta Paediatrica. 2003;94
(Suppl. 447):24–27. 3. Moore DF, et al. Stroke. 2002;33:525–531. 4. Ginsberg L, et al. Pract Neurol. 2005;5:110–113.
      Clinical Signs and Symptoms: Renal
       Accumulation of Gb3 occurs in renal glomeruli




                                                                       Patients (cumulative %)
        and tubules1                                                                               Proteinuria
       Glomerular injury leads to mesangial                                                       CRI

        widening, ultimately leading to                                                            Death

        glomerulosclerosis2
       By age 40, most patients have proteinuria*2
       By age 50, most patients have CRI2
       CKD** stage 3 is present in approximately 20%
        of patients and 15% progress to ESRD***3

                                                                                                            Age (years)
                                                                      Adapted from Branton, et al. 2002.2



  *Excess of serum proteins in the urine, as in renal disease.
  **Chronic Kidney Disease (eGFR < 60 ml/min/1.73 m2).
  ***End Stage Renal Disease (renal replacement therapy
    or serum creatinine > 6 mg/dL).
1. Brady RO, Schiffmann R. JAMA. 2000;284:2771–2775.
2. Branton MH, et al. Medicine. 2002;81:122–138.
3. Schiffmann R, et al. Nephrol Dial Transplant. 2009;24:2102-2111.
     Late-onset Variants of Fabry Disease
      At screening, 1–6% of patients have cardiac disease (typically LVH) but few or no
       other classic symptoms1


                                            α-galactosidase A     Time of
                                                 activity       presentation         Symptom triad

                Classic                                 < 1%       Early                     Yes

                Cardiac
                                                        > 1%       Later           No (single organ)
                late-onset
                Renal
                                                        > 1%       Later           No (single organ)
                late-onset
                                                                           Mehta A, Hughes DA. GeneReviews. 2002.




1. Sachdev B, et al. Circulation. 2002;105:1407–1411.
     Clinical Manifestations in Fabry Children
      Symptoms are reported from
       under 2 years of age1                   Neurological
      Most frequent early manifestations Gastrointestinal
       are neurological and                         Cardiac
       gastrointestinal1                            General
      Symptoms occur with similar                       Ear
       frequency in boys and girls1
                                                         Eye
      Quality of life scores are lower for
                                               Renal/urinary
       Fabry children compared with                                              < 10 years old
                                             Dermatological                      > 10 years old
       published values for healthy
                                            Cerebrovascular
       controls2
                                                               % with signs/symptoms

1. Ramaswami U, et al. Acta Paediatr. 2006;95:86–92.
2. Ries M, et al. Pediatrics. 2005;115:e344–55.
      Living With Fabry Disease
       Progression of Fabry disease varies from person to person
       It also means that symptoms appear at different ages and with differing severity
       Infants
         Pain and heat-related discomfort often appear first in young children with Fabry disease 1
         Parents should be careful not to expose young children to extremes of temperature 1
       Children and adolescents often experience
         Episodes of pain and burning sensations in the hands and feet
         Spotted, dark red skin rash seen most densely between the belly button and the knees
         Changes in the appearance of the cornea
       Parents and teachers should consider
         Effects of physical exertion, exercise, and extremes of temperature
         Social-related issues to do with school or employment
       Adults
         Fabry disease is slowly progressive and symptoms resulting from damage to the kidneys, heart, and
           central nervous system usually appear between the ages of 30 and 452
         Lifestyle considerations such as type of employment, choice of leisure activities, and diet are all
           important factors


1. Ramaswami U, et al. Acta Paediatrica. 2006;95:86–92.
2. Beck M. In: Mehta A, et al (eds). Fabry disease: perspectives from five years of FOS. 2006.
Fabry Disease Overview

				
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