Fabry Disease
What is Fabry Disease?
 One of the most common lysosomal storage
disorders1,2
 Caused by α-galactosidase A deficiency3
 Due to a mutation on the X chromosome (Xq22)4
 Leads to pathological accumulation of
sphingolipid Gb3*2,5
 Results in organ failure and premature death in
males and females2,5
*Gb3 = Globotriaosylceramide (sometimes abbreviated as GL-3, and
also known as ceramide trihexoside [CTH]).
Fabry disease is due to a mutation on
the X chromosome (Xq22)4
Chromosome X
Xp
Gene
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.
Xq
Diagnosis of Fabry Disease
Males
Females
Blood levels of α-galactosidase A
DNA Analysis
Low or absent
Confirmative
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
Geneticists 10%
Other 51%
Pediatricians 8%
Dermatologists 7%
Family doctors 5%
Cardiologists 5%
Arthritis
15
Fibromyalgia syndrome
7
Dermatomyositis
5
Erythromelalgia
5
Osler’s disease
5
Neuropsychological disease
13
Ménière’s disease
3
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.
39
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
contributes to poor exercise and heat tolerance4
Hands
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)
Umbilicus
Angiokeratomas
Lips
Reproduced with permission from Orteu CH, et al. 2007
Orteu CH, et al. Br J Dermatol. 2007;157(2):331–337.
Trunk
Signs and Symptoms: Gastrointestinal




Abdominal pain, bloating, constipation, and diarrhea
Delayed gastric emptying
Lack of appetite, early satiety
Nausea and vomiting
Males
Females
Patients (%)
 Occur in up to 55% of patients1
 May be an early manifestation
of Fabry disease2
 Symptoms include1-3
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
Short PR interval Voltage criteria
for LVH
T-wave inversion




Left ventricular dysfunction (systolic and diastolic)
Conduction abnormalities
Left ventricular hypertrophy (mainly concentric)
Valve dysfunction (mainly mitral)
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
 Vertebrobasilar vascular changes4
 Non-specific white matter lesions4
Reproduced with permission from Ginsberg, et al. 2005.4
Middle
cerebral
artery
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.
 Accumulation of Gb3 occurs in renal glomeruli
and tubules1
 Glomerular injury leads to mesangial
widening, ultimately leading to
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
Patients (cumulative %)
Clinical Signs and Symptoms: Renal
Proteinuria
CRI
Death
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
activity
Time of
presentation
Symptom triad
Classic
< 1%
Early
Yes
Cardiac
late-onset
> 1%
Later
No (single organ)
Renal
late-onset
> 1%
Later
No (single organ)
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
Neurological
under 2 years of age1
 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
Dermatological
published values for healthy
Cerebrovascular
controls2
< 10 years old
> 10 years old
% 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 45 2
 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