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About Fabry disease
Managing
Fabry disease
In Fabry disease, an enzyme deficiency of alphagalactosidase A leads to the abnormal function of
many cells and blood vessels throughout the body.
Although the mechanism of Fabry disease is not
well understood, this dysfunction contributes to a
wide variety of complications that affect the
nervous system, ears, eyes, gastrointestinal tract,
heart, kidneys, and skin.1,2
Although there is no cure for the gene mutation that
causes the enzyme deficiency in Fabry disease,
there are a number of considerations for managing
the various individual symptoms.
Symptom management
Once a diagnosis of Fabry disease has been made,
the patient may be referred to a specialist center for
coordinated care and ongoing treatment. A team
of doctors, nurses, therapists, and counselors may
be involved in the management of Fabry disease.
Patients should visit their doctor to discuss disease
management options.
• Primary care physicians. The patient’s usual
healthcare provider may have been the person
who made the initial referral for the patient to see
a specialist. He or she will also be responsible for
day-to-day healthcare and should be kept
informed about treatments received.
• Genetic counselors. Genetic counseling may
be offered, particularly if a person diagnosed with
Fabry disease is considering starting a family
or if there are concerns regarding other family
members who may also be affected.
About Fabry disease
• Geneticists. Geneticists specialize in inherited and
genetic diseases. They are often involved in confirming an
initial diagnosis and may be consulted during an ongoing
management program.
• Specialists in metabolic diseases and lysosomal
storage disorders (LSDs). Metabolic specialists and
specialists in LSDs focus on diseases that affect how
the body makes and breaks down substances. These
specialists will also have experience in genetics. They
may be the doctors who confirm the diagnosis and
coordinate management and treatment. The patient
may be assigned a specialist nurse who has expertise in
Fabry disease and other LSDs. The nurse will potentially
be the person with whom patients and their family have
the most contact. Nurses may also be responsible for
organizing and monitoring treatments.
Managing
Managing specific symptoms
For information on managing specific symptoms of Fabry
disease, please refer to the “Impact of Fabry Disease” set
of brochures in this series.
• Other specialists. Depending on the extent and severity
of the patient’s symptoms, a number of other specialists
often can be involved in treatment. These specialists
may include a nephrologist (kidneys), cardiologist (heart),
dermatologist (skin), ophthalmologist (eyes), neurologist
(nervous system), and psychiatrist (mental well-being).
Therapeutic approaches
Another treatment consideration, in addition to managing
individual symptoms, may be enzyme replacement
therapy. The rationale for enzyme replacement therapy,
as the name suggests, is to replenish the deficient
enzyme. Other specific therapeutic approaches are being
developed, including pharmacological chaperones. These
small-molecule drugs are under investigation to help
restore normal protein function and reduce the buildup and
toxic effects of misfolded proteins in Fabry disease. Other
proposed therapeutic approaches are substrate reduction
therapy and gene therapy.2
References
1. Desnick RJ, Ioannou YA, Eng CM. α-Galactosidase A deficiency: Fabry disease. In: The Metabolic and Molecular
Bases of Inherited Disease. New York, NY: McGraw-Hill; 2001:3733-3774.
2. Schiffmann R. Fabry disease. Pharmacol Ther. 2009;122(1):65-77.
©2011 Shire Human Genetic Therapies, Inc. US/FAB-00049-Nov11
About Fabry disease
Adolescents and
Fabry disease
For decades, it was generally believed that Fabry
disease symptoms would affect only adult men
and not women or children.1 In recent years,
however, with increasing attention, awareness,
and scientific research, it is now better recognized
that adolescent boys and girls have important
symptoms that warrant definitive diagnosis and
proper management.2
Common symptoms
Most patients with Fabry disease first notice
symptoms in childhood. However, diagnostic delay
is frequent, probably due both to the rarity of the
disease and to the fact that the first complaints
are of subjective symptoms that are not unique to
Fabry disease.1 Some symptoms may be difficult
for very young children to make sense of or clearly
describe.1
The most common early signs and symptoms of
Fabry disease include pain attacks, gastrointestinal
symptoms, abnormal sweating, skin lesions called
angiokeratomas, and a hazy, swirling appearance
of the cornea (cornea verticillata).2 The onset
of symptoms may be later in girls than in boys.2
Symptoms may impact quality of life and affect
daily activities at home and at school.3
The most severe complications of progressive
Fabry disease, including stroke, end-stage kidney
disease, and cardiac failure, are rarely seen in
childhood.2
Pain attacks2
67 45
%
%
of boys
of girls
About Fabry disease
Common signs and symptoms of Fabry disease
in children
Pain attacks
One of the first symptoms of Fabry disease may be a painful,
burning, or numb sensation in the hands and feet called
acroparesthesia.4 The pain can be severe and worsen with
physical activity, fever, illness, and abrupt changes in air
temperature.1,4
Gastrointestinal
problems
Some of the earliest signs of Fabry disease are gastrointestinal
symptoms, including episodes of diarrhea, abdominal pain,
bloating, and constipation.5,6 In a study of children and
adolescents with Fabry disease, approximately 60% of
patients had gastrointestinal symptoms.2
Abnormal
sweating
and fatigue
General fatigue, lethargy, and muscle pain are not uncommon
in children with Fabry disease, but may be mistaken for
problems with the joints, muscles, and bones (rheumatologic
conditions). Children with Fabry disease may have difficulty
keeping up with their peers during sporting activities because
of excessive tiredness and abnormal sweating.2
Angiokeratomas
A common sign of Fabry disease that can appear in late
childhood is the presence of small, benign, reddish blue
lesions on the skin.2 Angiokeratomas are composed of dilated
blood vessels (capillaries) under the surface of the skin.
Angiokeratomas usually appear in the area between the belly
button and the knees, but can also appear on other parts of the
body such as the lips, tongue, hands, and toes. They may be
confined to a small area of the body or may affect a larger area.7
Cornea
verticillata
Cornea verticillata—a hazy, swirling appearance in the
cornea—is common and can be seen by slit-lamp examination
by an eye specialist, even in children under the age of 5 years.2
Hearing problems
Hearing impairment and tinnitus were reported in >40% of
children ages 18 and below in the Fabry Outcome Survey.2
Adolescents
Fabry disease background
In Fabry disease, an enzyme deficiency
of alpha-galactosidase A leads not only
to buildup of the fatty substance
globotriaosylceramide (Gb3) but also to
damage to cells and blood vessels throughout
the body. This damage contributes to a wide
variety of complications that affect the nervous
system, ears, eyes, gastrointestinal tract, heart,
kidneys, and skin.4,8
Suspecting Fabry disease in children
Fabry disease in children should be suspected on the basis of a cluster of
symptoms, including general pain, nonspecific gastrointestinal complaints,
and hearing problems. When Fabry disease is a possible diagnosis, an eye
examination for cornea verticillata is useful, even in patients younger than 5 years
of age. In females, it is essential to confirm the diagnosis by DNA analysis. Family
history, especially concerning early deaths and kidney, heart, and neurologic
disease, is also important when Fabry disease is suspected.2
For more information about how Fabry disease is diagnosed, see the “Testing
and Diagnosis” brochure in this series.
References
1. Ries M, Ramaswami U, Parini R, et al. The early clinical phenotype of Fabry disease: a study on 35 European
children and adolescents. Eur J Pediatr. 2003;162:767-772.
2. Ramaswami, U., Whybra, C., Parini, R., Pintos-Morell, G., Mehta, A., Sunder-Plassmann, G., Widmer, U., Beck, M.
and on behalf of the FOS european investigators (2006), Clinical manifestations of Fabry disease in children:
Data from the Fabry Outcome Survey. Acta Paediatrica ; 95: 86–92
3. Bouwman M, Maurice-Stam H, Linthorst G, Hollak C, Wijburg F, Grootenhuis M. Impact of growing up with Fabry
disease on achievement of psychosocial milestones and quality of life. Molecular Genetics and Metabolism
(November 2011), 104 (3), pg. 308-313.
4. Desnick RJ, Ioannou YA, Eng CM. α-Galactosidase A deficiency: Fabry disease. In: The Metabolic and
Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2001:3733-3774.
5. Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical manifestations of 366 patients
in the Fabry Outcome Survey. Eur J Clin Invest. 2004;34(3):236-242.
6. Argoff CE, Barton NW, Brady RO, Ziessman HA. Gastrointestinal symptoms and delayed gastric emptying
in Fabry’s disease: response to metoclopramide. Nucl Med Commun. 1998;19(9):887-891.
7. Orteu CH, Jansen T, Lidove O, et al. Fabry disease and the skin: data from FOS, the Fabry Outcome Survey.
Br J Dermatol. 2007;157(2):331-337.
8. Schiffmann R. Fabry disease. Pharmacol Ther. 2009;122(1):65-77.
©2011 Shire Human Genetic Therapies, Inc. US/FAB-00047-Nov11
About Fabry disease
Women and
Fabry disease
For decades, symptoms of the rare genetic
condition known as Fabry disease were
thought to affect only men. As a rare condition,
little was known about its progression. Women
were considered to be only genetic carriers;
they inherited and passed Fabry disease
from generation to generation but did not
experience symptoms.1
In recent years, however, with increasing
attention, awareness, and scientific research,
it is now recognized that most women who fit
the genetic profile for Fabry disease are not
simply carriers but have specific symptoms
that warrant definitive diagnosis and proper
management.1,2 Women are known to
experience a wide range of Fabry symptoms,
many of which appear later than in men, and
which may vary widely in severity from patient
to patient.2
Onset and burden of symptoms
The onset of many signs and symptoms of
Fabry disease occurs during childhood and
adolescence in girls, just as it does in boys.3
Although the onset of major organ involvement
(heart, brain, and kidneys) generally appears
later in women than in men, leading to delays
in diagnosis,2 many women will experience
most signs and symptoms of Fabry disease by
their 20s and 30s.2
Neurological symptoms2
77
%
of women
Kidney problems2
40
%
of women
Cardiac symptoms2
59
%
of women
About Fabry disease
In a study of 248 women with Fabry disease, 77% of the women were reported
to have neurological symptoms, including chronic pain, and pain attacks;
59% were reported as experiencing cardiac signs and symptoms, including
chest pain, palpitations, and thickening of the heart muscle; and 40% were
reported as having kidney problems. Other commonly reported symptoms were
gastrointestinal complaints (eg, diarrhea and constipation), skin lesions (eg,
angiokeratomas), and eye and ear symptoms.2
The burden of Fabry disease in women increases with age and can be substantial.
Quality of life in women with Fabry disease is greatly affected by fatigue, exercise
intolerance, and poor self-perception of health.1 Chronic pain interferes with
mood and enjoyment of life. Not surprisingly, these factors can also influence
mental health and contribute to depression.1
Diagnosis of Fabry disease in women
In women as well as in men, the diverse signs and symptoms of Fabry
disease, different ages of onset, and variable timing and severity of disease
progression often delay diagnosis by several years.2,4 In one study, the
average delay from the onset of symptoms to a correct diagnosis was
16 years in women and 14 years in men.5
In women, laboratory testing for Fabry disease may involve a blood test to check
the level of the enzyme alpha-galactosidase A. A diagnosis of Fabry disease may
be made when there is a very low level of enzyme detected—but a laboratory
DNA analysis is the definitive test. This is especially true when there is a family
history of Fabry disease.6
Prenatal diagnosis is possible by measuring the enzyme activity or doing a DNA
analysis from tissue or fluid around the fetus. This testing may be offered to
expectant mothers who have Fabry disease.7
Women
X-inactivation
The severity of symptoms of Fabry disease
varies widely from woman to woman.2 Some
women may not experience any symptoms
and live a healthy life. Others may have some
of the symptoms. Still others may experience
every symptom.
One possible reason for symptom
variability in women is a genetics concept
called X-inactivation. Females have two
X chromosomes. When X-inactivation
occurs in a female embryo, one of the two
X chromosomes is randomly switched off
(inactivated). As the embryo develops, two cell
populations are produced from this random
X-inactivation pattern—one with the normal
X chromosome and one with the abnormal
(inactivated) X chromosome. As organs
develop from these two cell populations, each
organ will have its own X-inactivation pattern.10
Some organs may function normally, while
others may be affected.
So X-inactivation within each organ may
explain why a woman with Fabry disease
may experience some symptoms to a greater
degree than others, and why some symptoms
may not appear at all. It may also explain the
greater variability of symptoms in women
than in men.10
For more information about the genetics
and inheritance of Fabry disease, please see
the “Genetics of Fabry Disease” brochure in
this series.
References
Fabry disease background
In Fabry disease, an enzyme deficiency of alpha-galactosidase A leads not
only to the buildup of the fatty substance globotriaosylceramide (Gb3) but
also to the damage of cells and blood vessels throughout the body. This
damage contributes to a wide variety of complications that affect the nervous
system, ears, eyes, gastrointestinal tract, heart, kidneys, and skin.8,9
1. Wang RY, Lelis A, Mirocha J, Wilcox WR. Heterozygous Fabry women are not just carriers, but have a significant
burden of disease and impaired quality of life. Genet Med. 2007;9(1):34-45.
2. Deegan PB, Baehner AF, Barba Romero MA, et al. Natural history of Fabry disease in females in the Fabry
Outcome Survey. J Med Genet. 2006;43(4):347-352.
3. Ries M, Ramaswami U, Parini R, et al. The early clinical phenotype of Fabry disease: a study on 35 European
children and adolescents. Eur J Pediatr. 2003;162:767-772.
4. Beck M. Demographics of FOS—the Fabry Outcome Survey. In: Mehta A, Beck M, Sunder-Plassmann G, eds.
Fabry Disease: Perspectives From 5 Years of FOS. Oxford, England: Oxford PharmaGenesis Ltd; 2006:155-161.
5. Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the
Fabry Outcome Survey. Eur J Clin Invest. 2004;34(3):236-242.
6. Hughes DA, Ramaswam U, Elliott P, et al. Guidelines for the diagnosis and management of Anderson-Fabry
disease. London, England: Department of Health; 2005. http://www.dh.gov.uk/en/Publicationsandstatistics/
Publications/PublicationsPolicyAndGuidance/DH_4118404. Accessed June 1, 2010.
7. Desnick RJ. Prenatal diagnosis of Fabry disease. Prenat Diagn. 2007;27(8):693-694.
8. Desnick RJ, Ioannou YA, Eng CM. α-Galactosidase A deficiency: Fabry disease. In: The Metabolic and Molecular
Bases of Inherited Disease. New York, NY: McGraw-Hill; 2001:3733-3774.
9. Schiffmann R. Fabry disease. Pharmacol Ther. 2009;122(1):65-77.
10. Germain DP. General aspects of X-linked diseases. In: Mehta A, Beck M, Sunder-Plassmann G, eds.
Fabry Disease: Perspectives From 5 Years of FOS. Oxford, England: Oxford PharmaGenesis Ltd; 2006:63-68.
©2011 Shire Human Genetic Therapies, Inc. US/FAB-00048-Nov11
Impact of Fabry disease
Well-being
Coping with the variety of medical and
physical challenges of a chronic condition
such as Fabry disease can be demanding.
Managing the disease can put a strain on
everyday living, affect relationships, and alter
your outlook and well-being.
Patients have a number of medical issues to
attend to, so social and psychological issues
often get overlooked in Fabry disease.
Studies show that depression, for example,
is underdiagnosed and undertreated in
Fabry disease.1 Therefore, it is well worth
recognizing the connection between medical
symptoms and mood.
Fabry disease and mood
The more that your Fabry symptoms interfere
with everyday living, the greater the chance
that the disease will affect your mood.1
Understandably, the daily routine of coping
with serious symptoms in Fabry disease—
such as pain, heart disease, kidney disease,
and sweating abnormalities—can greatly
influence your quality of life and frame of
mind.
It is not surprising that these symptoms
can have a negative impact on mood. In
the largest study of depression in people
with Fabry disease, the rate of depression
was 46%—higher than that of the general
population.1 In the study, the biggest
predictor of depression was the extent to
which symptoms disrupted daily living.
Depression1
46
%
of men and women
Impact of Fabry disease
Well-being
Managing well-being
If the symptoms of Fabry disease limit or interfere with your everyday activities, it
is important to have a discussion with your doctor about them.1
Your doctor can help make sure your pain is being adequately managed, which
can help improve mood.1,2 Research shows that patients who have chronic
medical conditions can cope more effectively with their illness and symptoms if
their depression is treated.3 If depression is left untreated, it can complicate other
symptoms, such as making pain intensity worse.1,4-6
Even if you suffer no signs of depression, it is important to take good care of
yourself. Find ways to reduce sources of stress that you can control. Spend your
time and energy in ways that help your general well-being. Physical activity can
help reduce stress. Work with your doctor to identify activities or exercises that
you can tolerate.
Talk to others about your symptoms. Fabry disease is rare, so very few people
know what it is like to live with the disease. Educating others—including friends,
family, and colleagues—about your symptoms can go a long way toward
dispelling misconceptions and enriching relationships.
References
1. Cole AL, Lee PJ, Hughes DA, Deegan PB, Waldek S, Lachmann RH. Depression in adults with Fabry
disease: a common and under-diagnosed problem. J Inherit Metab Dis. 2007;30(6):943-951.
2. Leo RJ. Chronic pain and comorbid depression. Curr Treat Options Neurol. 2005;7(5):403-412.
3. Katon W, Ciechanowski P. Impact of major depression on chronic medical illness. J Psychosom Res.
2002;53(4):859-863.
4. Katon WJ. Clinical and health services relationships between major depression, depressive symptoms,
and general medical illness. Biol Psychiatry. 2003;54(3):216-226.
5. Polsky D, Doshi JA, Marcus S, et al. Long-term risk for depressive symptoms after a medical diagnosis.
Arch Intern Med. 2005;165(11):1260-1266.
6. Dersh J, Polatin PB, Gatchel RJ. Chronic pain and psychopathology: research findings and theoretical
considerations. Psychosom Med. 2002;64(5):773-786.
©2011 Shire Human Genetic Therapies, Inc. US/FAB-00044-Nov11