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

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.

Fabry disease is due to a mutation on the X chromosome (Xq22)4

Chromosome X

Xp Xq

Gene

From Beck M, Ries M, 2001.6

*Gb3 = Globotriaosylceramide (sometimes abbreviated as GL-3, and also known as ceramide trihexoside [CTH]).

Diagnosis of Fabry Disease

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

Blood levels of α-galactosidase A DNA Analysis

Males Low or absent Confirmative

Females May be within normal range Diagnostic

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

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]

*Superficial endothelial dermal cells.

Clinical findings and Gb3 levels in 57 women with Fabry disease3

Elevated plasma Gb3

Elevated skin* Gb3

Cardiac, renal, or cerebrovascular abnormalities

Misdiagnosis% of Total Misdiagnoses

Rheumatological disease/rheumatic fever39

Arthritis 15

Fibromyalgia syndrome 7

Dermatomyositis 5

Erythromelalgia 5

Osler’s disease 5

Neuropsychological disease 13

Ménière’s disease 3

Other 49

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

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.

Different specialties involved in diagnosis.3

Other 51%Pediatricians 8%

Nephrologists 14%

Geneticists 10%

Dermatologists 7%

Family doctors 5%

Cardiologists 5%

Reproduced with permission from Mehta et al, 2004.

Kidneys

Brain

Heart

Ears

Eyes

GI tract

SkinPeripheral

nerves

Age (years: mean and SD)

Symptom Onset: Males• Fabry disease affects almost all organs1-4

• Onset of symptoms in 375 adult males from the Fabry Outcome Survey5

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.

• Females experience some of the same disease symptoms, and see a similar pattern of onset, but delayed by 10 years5

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

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.

Hands

Feet

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)

Orteu CH, et al. Br J Dermatol. 2007;157(2):331–337.

Umbilicus Lips TrunkAngiokeratomas

Reproduced with permission from Orteu CH, et al. 2007

Signs and Symptoms: Gastrointestinal

Occur in up to 55% of patients1

May be an early manifestationof Fabry disease2

Symptoms include1-3

Abdominal pain, bloating, constipation, and diarrhea Delayed gastric emptying Lack of appetite, early satiety Nausea and vomiting

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.

Adapted from Mehta, et al. 2004.1

Males

Females

Decade of life

Pa

tie

nts

(%

)

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)

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.

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

Signs and Symptoms: Cardiac

Up to 69% of male patients havecardiac 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)

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.

Reproduced with permission from Linhart et al, 2006.5

Short PR interval Voltage criteria for LVH

T-wave inversion

Reproduced with permission from Linhart, et al. 2006.5

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

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.

Reproduced courtesy of Dr R Manara.

Middle cerebral

artery

Reproduced with permission from Ginsberg, et al. 2005.4

Clinical Signs and Symptoms: Renal

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

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.

Adapted from Branton, et al. 2002.2

Proteinuria

CRI

Death

Age (years)

Pa

tient

s (c

um

ula

tive

%)

*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).

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)

1. Sachdev B, et al. Circulation. 2002;105:1407–1411.

Mehta A, Hughes DA. GeneReviews. 2002.

Clinical Manifestations in Fabry Children

Symptoms are reported from under 2 years of age1

Most frequent early manifestations are neurological and gastrointestinal1

Symptoms occur with similar frequency in boys and girls1

Quality of life scores are lower for Fabry children compared with published values for healthy controls2

1. Ramaswami U, et al. Acta Paediatr. 2006;95:86–92.2. Ries M, et al. Pediatrics. 2005;115:e344–55.

% with signs/symptoms

< 10 years old> 10 years old

Neurological

Gastrointestinal

Cardiac

General

Ear

Eye

Renal/urinary

Dermatological

Cerebrovascular

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 disease1

Parents should be careful not to expose young children to extremes of temperature1 Children and adolescents often experience

Episodes of pain and burning sensations in the hands and feetSpotted, dark red skin rash seen most densely between the belly button and the kneesChanges in the appearance of the cornea

Parents and teachers should considerEffects of physical exertion, exercise, and extremes of temperatureSocial-related issues to do with school or employment

AdultsFabry 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