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2. disease

Fabry disease: clinical manifestations,
diagnosis and therapy
Second edition
by Michael Beck
Slides based on the book
Beck M. Fabry disease: clinical manifestations,
diagnosis and therapy. 2nd edition.
Sponsored by Shire HGT
The abbreviated PI can be found on slide 45
Overview of contents
• The cause and discovery of Fabry disease
• The genetic basis of Fabry disease
• Signs and symptoms of Fabry disease
• Enzyme trafficking and glycosylation
• Clinical improvements following enzyme
replacement therapy
Defects in a single metabolic pathway lead
to different lysosomal storage diseases
Gal, galactose; GalNAc,
N-acetyl-D-galactosamine;
Glc, glucose; NeuAc,
N-acetylneuraminic acid
Reproduced from Beck & Ries, Fabry disease: clinical manifestations, diagnosis and therapy. Oxford: OCC Europe Ltd;
2001 with permission
Globotriaosylceramide (Gb3) – the major lipid
that accumulates in Fabry disease
Gb3 is broken down into galactose and lactosylceramide
by the enzyme α-galactosidase A
Gal, galactose; Glc, glucose
Reproduced from Beck & Ries, Fabry disease: clinical manifestations, diagnosis and therapy. Oxford: OCC Europe Ltd;
2001 with permission
Structure of Gb3
Reproduced from Beck & Ries, Fabry disease: clinical manifestations, diagnosis and therapy. Oxford: OCC Europe Ltd;
2001 with permission
Fabry disease was first described
independently in 1898 by two physicians
Johannes Fabry (1860–1930)
William Anderson (1842–1900)
Anderson, Br J Dermatol 1898;18:113–17; Fabry, Arch Derm Syph 1898;43:187–200
Angiokeratoma corporis diffusum in
Johannes Fabry’s patient
From Fabry, Arch Derm Syph 1916;123:294–307
Distribution of angiokeratoma corporis
diffusum in William Anderson’s patient
From Anderson, Br J Dermatol 1898;18:113–17
Inheritance of Fabry disease:
the Lyon hypothesis
Females inherit one X chromosome
from each parent. In each cell, one
of the X chromosomes is randomly
inactivated, and the remaining X
chromosome provides the genetic
information.
Reproduced from Beck & Ries, Fabry disease: clinical manifestations, diagnosis and therapy. Oxford: OCC Europe Ltd;
2001 with permission
Location of the GLA gene that encodes the
lysosomal enzyme α-galactosidase A
Position of band Xq22 in
the X chromosome
Fabry disease is caused by
a mutation in the GLA gene
found in the Xq22 region of
the X chromosome
Exon structure of the
GLA gene
Adapted from Bishop et al., Proc Natl Acad Sci USA 1988;85:3903–7 with permission
Signs and symptoms of Fabry disease
• Fabry disease is a progressive multisystemic condition
affecting both males and females
• Many of the signs and symptoms begin during childhood
or adolescence. In general, men are more severely affected
than women, although some women may show severe
manifestations of the disease
• Typically, women develop signs and symptoms
approximately 5–10 years later than men, although
this is not invariably the case [1]
• Patients with Fabry disease have an increased risk of death
from renal, cardiovascular or cerebrovascular disease [2–3]
1. Mehta & Ginsberg, Acta Paediatr 2005;94 (Suppl 447);24–7
2. Colombi et al., Helv Med Acta 1967;34:67–83
3. MacDermot et al., J Med Genet 2001;38:750–60
4. MacDermot et al., J Med Genet 2001;38:769–75
Fabry disease has widespread effects
throughout the body
Proportion of patients with symptoms (%)
Signs and symptoms of Fabry disease according to
age at entry in FOS – the Fabry Outcome Survey
Decade of life
Reproduced from Mehta et al., Eur J Clin Invest 2004;34:236–42 with permission from Blackwell Publishing
Neurological features of Fabry disease
Peripheral nervous system
• Peripheral neuropathy
– Typically small fibre, painful
– Impaired sweating
– Temperature insensitivity
Central nervous system
• Cerebrovascular manifestations
– Stroke
– Transient ischaemic attacks
• Epilepsy
• Magnetic resonance imaging
abnormalities – white matter
lesions
• Psychiatric/cognitive changes
Sensory organs
• Ear manifestations
– Vertigo
– Hearing loss
– Tinnitus
• Eye manifestations
– Cornea verticillata
– Subcapsular cataract
– Tortuous vessels
Reproduced from Mehta & Ginsberg, Acta Paediatr 2005;94 (Suppl 447):24–7 with permission from Blackwell Publishing
Areas of the body affected by
acroparaesthesiae in Fabry disease
Pain begins in the
hands and feet and
radiates proximally
to the shaded
areas
Magnetic resonance image showing the
characteristic symmetrical high signal in the
posterior thalamus in a patient with Fabry disease
Reproduced from Ginsberg et al., Acta Paediatr 2006;95 (Suppl 451):57–62 with permission from Blackwell Publishing
Lipid deposition in the kidneys
begins in the glomerulus
Lipid deposition
in glomerular
epithelium (blue
arrows) and distal
tubules (yellow
arrow) with limited
vascular endothelial
involvement (orange
arrow)
Toluidine blue stain,
original magnification
x 100
Reproduced from Brady & Schiffmann, JAMA 2000;284:2771–5 © 2000 American Medical Association.
All rights reserved
Electron micrographs showing podocytes
in the kidney in Fabry disease
Glomerular podocytes appear
enlarged and vacuolated
Original magnification x 2200
Courtesy of Dr Jarl Ahlmén, Skövde, Sweden
Lamellar myeloid bodies are
evident in different regions of
the glomerulus
Original magnification x 10 500
Cardiac signs and symptoms and
their cause in Fabry disease
Symptom
Leading cause
Dyspnoea
Diastolic LV dysfunction
Pulmonary involvement
Arrhythmias
Systolic LV dysfunction (late, infrequent)
Valvular regurgitation
Palpitations
Arrhythmias
Anginal chest pain
LV hypertrophy (increased oxygen demand)
Impaired coronary supply (functional hypoperfusion
versus fixed stenosis)
LV outflow obstruction
Syncope
Arrhythmias
Third-degree AV blocks
LV outflow obstruction
AV, atrioventricular; LV, left ventricular
Reproduced from Linhart et al., Acta Paediatr 2002;91 (Suppl 439):15–20 with permission from Blackwell Publishing
Typical electrocardiogram from
a patient with Fabry disease
PR intervals are short, there is marked left ventricular hypertrophy
and prominent ST depressions and T-wave inversions
Adapted from Linhart et al., In Mehta, Beck and Sunder-Plassmann, editors. Fabry disease: perspectives from 5 years
of FOS. Oxford: Oxford PharmaGenesis Ltd; 2006: p. 189–201 with permission
Hypertrophic cardiomyopathy
in a patient with Fabry disease
Short-axis cine
magnetic resonance
image showing that
the ventricular cavity
is virtually absent in
systole because
of concentric
hypertrophy of
myocardial fibres
From Lidove et al., Am J Roentgenol 2006;186:1184–91. Reprinted with permission from the American Journal
of Roentgenology
Typical distribution of angiokeratomas on
the skin of a patient with Fabry disease
Courtesy of Dr Thomas Jansen, Bochum, Germany
Cornea verticillata: the most
typical ocular sign in Fabry disease
Reproduced from Sodi et al., In Mehta, Beck and Sunder-Plassmann, editors. Fabry disease: perspectives from 5 years
of FOS. Oxford: Oxford PharmaGenesis Ltd; 2006: p. 249–61 with permission.
Fabry cataract: a posterior subcapsular
‘spoke-like’ cataract specific to Fabry disease
Reproduced from Sodi et al., In Mehta, Beck and Sunder-Plassmann, editors. Fabry disease: perspectives from 5 years
of FOS. Oxford: Oxford PharmaGenesis Ltd; 2006: p. 249–61 with permission
Increased vessel tortuosity in the
conjunctiva and retina of the eye
Conjunctiva
Retina
Reproduced from Sodi et al., In Mehta, Beck and Sunder-Plassmann, editors. Fabry disease: perspectives from 5 years
of FOS. Oxford: Oxford PharmaGenesis Ltd; 2006: p. 249–61 with permission
Ear manifestations associated
with Fabry disease
• Most patients with Fabry disease experience hearing loss
at some time during their life. The majority suffer from
sensorineural hearing loss, with a minority experiencing
mixed or conductive hearing losses [1]
• The frequency of sudden hearing loss is elevated compared
with the general population [2]
• About 85% of male patients over 50 years of age and 75%
of female patients over 60 years of age suffer from hearing
loss severe enough to justify the use of a hearing aid
• Tinnitus is much more frequent in patients with Fabry
disease than in the normal population and has also been
observed in children [3]. Vertigo has also been reported
1. Hajioff et al., Acta Paediatr 2003;92 (Suppl 443):28–30
2. Germain et al., BMJ Med Genet 2002;3:10
3. Keilmann, Acta Paediatr 2003;92 (Suppl 443): 31–2
Gastrointestinal symptoms of Fabry disease
•
Gastrointestinal symptoms have been reported in 50–70%
of patients with Fabry disease [1, 2]
•
These include postprandial symptoms such as diarrhoea,
abdominal bloating, urgency, flatulence, nausea and vomiting.
Patients may also experience a sense of early satiety and
epigastric discomfort.
•
The most commonly reported gastrointestinal symptoms are
diarrhoea, with frequent loose bowel motions, and cramping
abdominal pain [3]
•
In many patients, there is an alternating pattern of episodes
of diarrhoea and normal or reduced bowel activity/constipation.
This alternating pattern is reminiscent of irritable bowel syndrome,
as are the symptoms of abdominal discomfort and bloating
associated with meals [4]
1. MacDermot et al., J Med Genet 2001;38:750–60
2. MacDermot et al., J Med Genet 2001;38:769–75
3. Dehout et al., J Inherit Metab Dis 2004;27:499–505
4. Cremonini & Talley, Gastroenterol Clin North Am 2005;34:189–204
Impact of Fabry disease on quality of life
• The symptoms of Fabry disease may clearly have
a significant impact upon quality of life
• Hoffmann et al. [1] found that quality of life in 120 patients
with Fabry disease enrolled in FOS was significantly lower
than in age- and sex-matched normal population
• The impact of Fabry disease on quality of life has also been
shown to be of comparable severity to that reported by
patients with AIDS, and more severe than that reported
by patients with Gaucher disease [2]
• Psychiatric problems have also been reported, with a high
incidence of suicide and depression [3, 4]
• The frequency of psychiatric complaints may by as high
as 18% [3]
1. Hoffmann et al., J Med Genet 2005;42:247–52
2. Gold et al., Qual Life Res 2002;11:317–27
3. Grewal, Int J Psychiatry Med 1993;23:307–12
4. Wendrich et al., J inherit Metab Dis 2001;24 (Suppl 2):139
Other manifestations of Fabry disease
•
Obstructive airway disease is a relatively late finding in Fabry
disease and can be severe [1]
•
Many male patients show retarded growth or delayed puberty and
sparse, fine facial and body hair. In some families, affected males
have a characteristic facial appearance similar to that seen in
patients with acromegaly
•
Many patients have some evidence of musculoskeletal defects
•
A high prevalence of anaemia has been reported among patients
with Fabry disease [2]. This may be of clinical relevance as
anaemia is a major risk factor for patients with kidney disease,
heart failure or stroke, which are important manifestations of
Fabry disease
•
Hypothyroidism [3], osteopenia [4] and oral–dental abnormalities
[5] have also been reported
1. Kariman et al., Am J Med 1978;64:911–12
2. Kleinert et al., Kidney Int 2005;67:1955–60
3. Hauser et al., J Inherit Metab Dis 2005;28:715-22
4. Germain et al., Clin Genet 2005;68:93–5
5. Baccaglini et al., Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 2001;92:415–19
Fabry disease with predominant
manifestations in a single major organ system
• Several cases have been reported of patients with Fabry
disease with signs and symptoms mostly confined to the
heart or kidney [e.g. 1, 2]
• These patients generally have relatively high residual levels
of α-galactosidase A activity
• In some such cases, however, other organ manifestations
have not been excluded [3, 4]
1. Nakao et al., N Engl Med J 1995;333:288–93
2. Ogawa et al., Hum Pathol 1990;21:1067–73
3. Cybulla et al., Am J Kidney Dis 2005;45:e82–9
4. Nakao et al., Kidney Int 2003;64:801–7
Fabry disease in children
•
In recent years there has been a growing awareness that children
show signs and symptoms of Fabry disease. Even at an early age,
these manifestations may be severe [1]. Nevertheless, the
diagnosis may often be missed
•
Some of the most common early signs and symptoms of Fabry
disease in children are acroparaesthesiae, pain, angiokeratomas
and gastrointestinal manifestations [1]. These may be seen in both
boys and girls, although the onset is generally 2–5 years later in
girls
•
Other signs and symptoms, such as hypohidrosis, fever, ocular
manifestations and tinnitus, may also be observed in young
patients. Children may report a reduced tolerance for physical
activity
•
Cardiac and renal involvement can also begin in childhood [1–3];
thus early diagnosis and careful monitoring are necessary
1. Ramaswami et al., Acta Paediatr 2006;95:86–92
2. Meroni et al., Contrib Nephrol 1997;122:178–84
3. Ries et al., Eur J Paed 2003;162:767–72
Fabry disease in women
• Traditionally, it was believed that Fabry disease was
an X-linked recessive disorder; however, it is now clear
that females with this X-linked disease can be severely
affected [1–3]
• Females who are heterozygous for Fabry disease show
a wide range of clinical manifestations
• Although some individuals may remain completely
asymptomatic and have normal levels of α-galactosidase A,
others are as severely affected as hemizygous males [1, 2]
• Life expectancy is also reduced in women [1, 3, 4]
1. Mehta et al., Eur J Clin Invest 2004; 34:236–42
3. Deegan et al., J Med Genet 2006;43:347–52
2. Whybra et al., J Inherit Metab Dis 2001;24:715–24 4. MacDermot et al., J Med Genet 2001b;38:769–75
Clinical findings in young male and female
patients with Fabry disease
Adapted from Ries et al., Eur J Pediatr 2003;162:767–72 with permission. © Springer
Multiple hyperintensities in the white matter
of the brain in a woman with Fabry disease
Axial
Sagittal
T2-weighted magnetic resonance images of the brain of a 58-year-old
woman with Fabry disease showing multiple hyperintensities in the
central and subcortical white matter
Reproduced from Whybra et al., J Inherit Metab Dis 2001;24:715–24 © SSIEM and Kluwer Academic Publishers, with
kind permission from Springer Science and Business Media
Trafficking of the enzyme α-galactosidase A
to cellular lysosomes
ERT, enzyme replacement therapy; M6P, mannose-6-phosphate; TGN, trans-Golgi network
Reproduced from Beck & Ries, Fabry disease: clinical manifestations, diagnosis and therapy. Oxford: OCC Europe Ltd;
2001 with permission
Replagal PI
PRESCRIBING INFORMATION: Replagal (agalsidase alfa) 1 mg/ml concentrate for solution
for infusion. Please read Summary of Product Characteristics (SmPC) before prescribing.
Presentation: Concentrate solution for intravenous infusion: vials of 3 ml (containing 1 ml
of concentrate) and 5 ml (3.5 ml of concentrate). Indication: Replagal (agalsidase alfa) is
indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis
of Fabry disease (α-galactosidase A deficiency). Dose: Replagal is administered at a dose of
0.2 mg/kg body weight every other week by intravenous infusion over 40 minutes. No dosage
adjustment is necessary in patients with renal impairment. The presence of extensive renal
damage (eGFR < 60 ml/min) may limit the renal response to enzyme replacement therapy.
No dosage adjustment is recommended in patients on dialysis or postkidney transplantation.
Contraindications: Life-threatening hypersensitivity (anaphylactic reaction) to the active
substance or any of the excipients. Warnings and precautions: 13.7% of patients treated with
Replagal in clinical trials have experienced idiosyncratic infusion-related reactions. Overall, the
percentage of infusion-related reactions was significantly lower in females than males. The most
common symptoms have been rigors, headache, nausea, pyrexia, flushing and fatigue. Serious
infusion reactions have been reported uncommonly; symptoms reported include pyrexia, rigors,
tachycardia, urticaria, nausea/vomiting, angioneurotic oedema with throat tightness, stridor and
swollen tongue. The onset of infusion-related reactions has generally occurred within the first
2–4 months after initiation of treatment with Replagal although later onset (after 1 year) has
been reported as well. If mild or moderate acute infusion reactions occur, medical attention
must be sought immediately and appropriate actions instituted. The infusion can be temporarily
interrupted (5 to 10 minutes) until symptoms subside and the infusion may then be restarted.
Mild and transient effects may not require medical treatment or discontinuation of the infusion.
In addition, oral or intravenous pre-treatment with antihistamines and/or corticosteroids, from
1 to 24 hours prior to infusion may prevent subsequent reactions in those cases where
symptomatic treatment was required. As with any intravenous protein product, allergic-type
hypersensitivity reactions are possible. If severe allergic or anaphylactic-type reactions occur,
the administration of Replagal should be discontinued immediately and appropriate treatment
initiated. The current medical standards for emergency treatment are to be observed. As with all
protein pharmaceutical products, patients may develop IgG antibodies to the protein. A low titre
IgG antibody response has been observed in approximately 24% of the male patients treated
with Replagal. These IgG antibodies appeared to develop following approximately 3–12 months
of treatment. After 12 to 54 months of therapy, 17% of Replagal treated patients were still
antibody positive whereas 7% showed evidence for the development of immunologic tolerance,
based on the disappearance of IgG antibodies over time. The remaining 76% remained
antibody negative throughout. No IgE antibodies have been detected in any patient receiving
Replagal. The presence of extensive renal damage may limit the renal response to enzyme
replacement therapy, possibly due to underlying irreversible pathological changes. In such
cases, the loss of renal function remains within the expected range of the natural progression of
disease. Paediatrics: Experience in children is limited. Studies in children (0–6 years old) have
not been performed and no dosage regimen can presently be recommended. Limited clinical
data in children (7–18 years) do not permit recommendation of an optimal dosage regimen
Item code: Re-07-059
presently. As no unexpected safety issues were encountered in a six month study with Replagal
administered at 0.2 mg/kg, this dose is suggested for children between 7–18 years. Pregnancy
and lactation: Very limited data on pregnancies exposed to Replagal (n = 3) have shown no
adverse effects on the mother and newborn child. Animal studies do not indicate direct or
indirect harmful effects with respect to pregnancy or embryonal/foetal development when
exposed during organogenesis. It is not known whether Replagal is excreted in human milk.
Caution should be exercised when prescribing to pregnant or nursing women. Interactions:
Replagal should not be co-administered with chloroquine, amiodarone, benoquin or gentamicin
since these substances have the potential to inhibit intra-cellular α-galactosidase activity. As
α-galactosidase A is itself an enzyme, it would be an unlikely candidate for cytochrome P450
mediated drug–drug interactions. In clinical studies, neuropathic pain medicinal products (such
as carbamazepine, phenytoin and gabapentin) were administered concurrently to most patients
without any evidence of interaction. Side effects: The most commonly reported undesirable
effects were infusion associated reactions, which occurred in 13.7% of patients treated with
Replagal in clinical trials. Most undesirable effects were mild to moderate in severity. The
following AEs have been reported: peripheral oedema, headache, dizziness, dysgeusia,
neuropathic pain, tremor, hypersomnia, hypoesthesia, paraesthesia, parosmia, lacrimation
increased, tinnitus, tinnitus aggravated, tachycardia, palpitations, flushing, hypertension,
cough, hoarseness, throat tightness, dyspnoea, nasopharyngitis, pharyngitis, throat secretion
increased, rhinorrhoea, nausea, diarrhoea , vomiting, abdominal pain/discomfort, acne,
erythema, pruritus, rash, livedo reticularis, angioneurotic oedema, urticaria, musculoskeletal
discomfort, myalgia, back pain, limb pain, peripheral swelling, arthralgia, joint swelling,
sensation of heaviness, rigors pyrexia, pain and discomfort, fatigue, fatigue aggravated, feeling
hot, feeling cold, asthenia, chest pain, chest tightness, influenza like illness, injection site rash,
malaise, corneal reflex decreased, oxygen saturation decreased. Overdosage: No case of
overdose has been reported. Pharmaceutical Precautions: Store in a refrigerator (2°C–8°C).
Legal Category: POM. Pack Sizes, Product Licence Numbers and Cost: 1 ml of concentrate
for solution for infusion in a 3 ml vial. Pack sizes of 1, 4 or 10 vials. 3.5 ml of concentrate for
solution for infusion in a 5 ml vial. Pack sizes of 1, 4 or 10 vials. EU/1/01/189/001-006. Price
of £356.85 for 3 ml and £1161.57 for 5 ml vials. Further information available from
Product Licence Holder: Shire Human Genetic Therapies AB, Rinkebyvägen 11B, SE 182 36
Danderyd, Sweden.
Please read the Summary of Product Characteristics before prescribing.
Adverse events should be reported to the Yellow Card Scheme. Information about adverse
event reporting via this scheme can be found at www.yellowcard.gov.uk. Adverse events should
also be reported to Shire Human Genetic Therapies on +44 (0)1223 422707 or faxed on +44
(0)1223 424666.
Date of Preparation: 04 January 2007. Item Code: RePIv040107
Date of preparation: May 2007