What is Fabry Disease?
One of the most common lysosomal storage Fabry disease is due to a mutation on
the X chromosome (Xq22)4
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
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
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
*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
Nephrologists 14% Misdiagnosis
% of Total Misdiagnoses
Rheumatological disease/rheumatic fever
Fibromyalgia syndrome 7
Pediatricians 8% Dermatomyositis 5
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
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
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:
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
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
Dermatological symptoms (telangiectases and angiokeratomas) are frequent (up to 78%) early signs of
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,
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
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)
Left ventricular hypertrophy (mainly concentric)
Valve dysfunction (mainly mitral)
Short PR interval Voltage criteria T-wave inversion
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
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
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
> 1% Later No (single organ)
> 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
under 2 years of age1 Neurological
Most frequent early manifestations Gastrointestinal
are neurological and Cardiac
Symptoms occur with similar Ear
frequency in boys and girls1
Quality of life scores are lower for
Fabry children compared with < 10 years old
Dermatological > 10 years old
published values for healthy
% 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
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
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
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