Fabry Disease. What is Fabry Disease? One of the most common lysosomal storage disorders 1,2 ...
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Transcript of Fabry Disease. What is Fabry Disease? One of the most common lysosomal storage disorders 1,2 ...
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