Download Fabry Disease in Genetic Counseling Practice: Recommendations

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Journal of Genetic Counseling, Vol. 11, No. 2, April 2002 (°
Fabry Disease in Genetic Counseling Practice:
Recommendations of the National Society
of Genetic Counselors
Robin L. Bennett,1,9 Kimberly A. Hart,2 Erin O’Rourke,3 John A. Barranger,3
Jack Johnson,4 Kay D. MacDermot,5 Gregory M. Pastores,6
Robert D. Steiner,7 and Ravi Thadhani8
The objective of this document is to provide health care professionals with recommendations for genetic counseling and testing of individuals with a suspected or
confirmed diagnosis of Fabry disease, with a family history of Fabry disease, and
those identified as female carriers of Fabry disease. These recommendations are
the opinions of a multicenter working group of genetic counselors, medical geneticists, and other health professionals with expertise in Fabry disease counseling,
as well as an individual with Fabry disease who is a founder of a Fabry disease
patient advocacy group in the United States. The recommendations are U.S. Preventive Task Force Class III, and they are based on clinical experience, a review of
pertinent English-language articles, and reports of expert committees. This document reviews the genetics of Fabry disease, the indications for genetic testing and
interpretation of results, psychosocial considerations, and references for professional and patient resources. These recommendations should not be construed as
1 Department of Medicine, Division of Medical Genetics,University of Washington,Seattle,Washington.
2 Department
of Pediatrics, Division of Medical Genetics, University of California, San Francisco,
California.
3 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh,
Pittsburgh, Pennsylvania.
4 Fabry Support and Information Group, Concordia, Missouri.
5 Department of Medicine, Addenbrooke’s Hospital, Cambridge, United Kingdom.
6 Department of Neurology and Pediatrics, New York University School of Medicine, New York,
New York.
7 Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Dorenbecher Children’s Hospital, Oregon Health & Science University, Portland, Oregon.
8 Department of Medicine and Renal Unit, Massachusetts General Hospital, Harvard Medical School,
Boston, Massachusetts.
9 Correspondence should be directed to Robin L. Bennett, MS, CGC, University of Washington Medical
Center, Box 357720, Seattle, Washington 98195-7720; e-mail: [email protected].
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C 2002 National Society of Genetic Counselors, Inc.
1059-7700/02/0400-0121/1 °
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dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. The professional judgment of a healthcare
provider, familiar with the facts and circumstances of a specific case, will always
supersede these recommendations.
KEY WORDS: enzyme therapy; Fabry disease; genetic counseling; genetic testing; National Society
of Genetic Counselors; practice guidelines.
INTRODUCTION
The following case scenarios were collected from a support group for individuals affected by Fabry disease.
Vignette 1—Eric
Growing pain was the diagnosis; I remember one of the visits when my son was 11 years
old. A physician brought my son close to the lighted panel showing the side view of the
x-ray of his foot. He pointed to the white ends of the bones near Eric’s heel and said “See
this bone growth right here? This is definitely what’s causing the pain.” Made sense to him,
and he was the expert. Made sense to me. Made sense to my son. But from that point on,
making sense was not a logical way of thinking. Not only did the pain continue, other things
kept happening to him during the following years. Hand pain was a problem along with
the foot pain. When he was ill or ran a fever, the pain was so much worse—but of course,
doesn’t everyone suffer this with a fever? When he would sit because his feet hurt, I would
push him just a little more, in the hope that he would walk right out of the pain. “Ignore it
and maybe it would go away” became my motto.
Eventually, Crohn disease was ruled-out as the cause of his abdominal problems, but
we still had no diagnosis. Fabry disease was known to be in the family. After learning more
about Fabry disease we requested testing. Finally, a correct diagnosis was made. Eric was
25 years old. At last he began to talk about the suffering he had endured all those years.
Vignette 2—Jill
My earliest memories of severe pain go back to about age 11. The aching and throbbing
pain typically would be in my hands and feet most days, but also in my arms and legs during
some days, and always during serious bouts, or attacks. About every three weeks I would
develop a fever, and then the very intense pain would begin. I’ll always remember how as a
child I would look at my hands and feet and not understand how they could feel as though
they were on fire yet not show any signs of redness, or look any different than usual. With the
burning came severe throbbing and aching, as well as stabbing (piercing) pains that would
start in my hands and feet, and then move throughout my arms and legs. The stabbing
would start at a low intensity and then, within a second, build to an unbearable intensity,
and this type of pain would happen continually throughout the attack. I remember crying
and wanting to scream from the pain. I would be bedridden during these attacks, which
would last from 24 to 48 hours. I’d have other symptoms during these bouts that seemed
flu-like, with nausea, vomiting, headache, and just a general feeling of illness. Shortly after
the attack, I would resume my normal activities.
Over the years there were many diagnoses: chronic mononucleosis, adult Still disease,
lupus, arthritis, bronchitis and pneumonia. The usual treatment was aspirin or antibiotics.
With many years of frustration, and physicians who provided no real relief, I was frustrated
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and went to my doctors as little as possible. I finally was correctly diagnosed with Fabry
disease at the age of 30 years.
These vignettes dramatically illustrate the need for increased awareness of Fabry
disease among health professionals to facilitate early diagnosis, as well as the
importance of recommendations for genetic counseling for Fabry disease to educate genetic counselors and other health professionals about this rare, and now
potentially treatable inherited condition.
PURPOSE
The following recommendations are intended to assist health care professionals who provide genetic counseling for individuals and families in whom the
diagnosis of Fabry disease is suspected or has been confirmed. We review the genetics of Fabry disease, indications for genetic testing and interpretation of results,
psychosocial considerations, and references for professional and patient resources.
METHOD AND CONSENSUS PROCESS
The authoring subcommittee consisted of experts in genetic counseling (EO,
KAH, RLB), biochemical genetics (GMP, JAB, KDM, RDS), clinical/medical
genetics (GMP, JAB, KDM, RDS), clinical molecular genetics (GMP), renal
disease (RT), pediatrics (GMP, RDS), and internal medicine (KDM, RT). Input
was also sought from a patient advocacy group for Fabry disease (JJ). A literature search for relevant English-language medical articles published between
January 1985 and June 2001 was performed using the MEDLINE and PUBMED
databases. Bibliographies of articles were also reviewed. Articles were reviewed
with particular attention to genetic counseling and diagnostic issues. The literature
reviewed was based on clinical experience, descriptive studies, and/or reports of
expert committees.
The literature was reviewed and evaluated for quality according to the categories outlined by the U.S. Preventive Services Task Force (1995):
I. Evidence obtained from at least one properly designed randomized controlled
trial.
II-1. Evidence obtained from well-designed controlled trials without randomization.
II-2. Evidence obtained from well-designed cohort or case-control analytic studies,
preferably from more than one center or research group.
II-3. Evidence obtained from multiple time series, with or without the intervention.
III. The opinions of respected authorities, based on clinical experience, descriptive
studies, or reports of expert committees.
The rating of supporting literature for this document is class III. No supporting
literature for genetic counseling practices in categories I and II was identified.
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Bennett et al.
The authoring committee sought expert review from specialists in Fabry disease and genetic counseling in the United States. Opinions were sought from representatives of advocacy groups for Fabry disease. The full document was made
available for review on the Internet to all Full and Associate members of the National Society of Genetic Counselors (NSGC). At the time, 78% of the 1536 NSGC
Full and Associate members were registered on the NSGC listserv. The NSGC Full
and Associate membership includes genetic counselors, physicians, nurses, attorneys, PhD genetics professionals, and social workers. The NSGC Ethics Subcommittee (consisting of seven genetic counselors, and an ad hoc bioethicist/clergy
representative) and an attorney for the NSGC reviewed the revised document. No
conflicts with the NSGC Code of Ethics were identified in the final document. The
NSGC Board of Directors approved the final document in August 2001.
OVERVIEW OF FABRY DISEASE
Fabry disease (Online Mendelian Inheritance in Man, 2000, Catalogue
#301500) is an X-linked inherited lysosomal storage disorder of glycosphingolipid
catabolism resulting from deficient or absent activity of the lysosomal enzyme
α-galactosidase A (α-gal A). This enzyme helps to break down and remove glycolipids (complex sugar–fat substances). The enzymatic defect leads to progressive
accumulation of the glycolipid globotriaosylceramide (Gb3 or Gl3) or ceramidetrihexoside in the lysosomes in the cells of most organs. This accumulation leads to
selective damage of the renal glomerular and tubular epithelial cells, the myocardial cells and valvular fibrocytes, neurons of the dorsal root ganglia and autonomic
nervous system, as well as damage in the endothelial, perithelial, and smooth muscle cells of the vascular system.
Progressive renal insufficiency and cardiovascular disease are causes of significant morbidity and mortality in Fabry disease, but virtually any organ may be
affected (Desnick et al., 2001; MacDermot et al., 2001a,b). In the predialysis and
prekidney transplant era, the average age of death in males was 41 years (Colombi
et al., 1967; Wise et al., 1962). Recently, MacDermot et al. obtained median age at
death in Fabry disease from cumulative survival curves in a cohort of 51 affected
males and 32 obligate carrier females. Fifty percent of males with Fabry disease
had died by age 50 years, and 50% of obligate carrier females died by age 70. When
compared with the general population, this represents an approximate reduction
of 20 years and 15 years respectively in life span (MacDermot et al., 2001a,b).
Clinical Condition and Medical Management
Table I provides a summary of the major medical features of Fabry disease.
Although Fabry disease predominantly affects males, approximately 60–70% of
carrier females show clinical expression of the disease, which is assumed to be
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Table I. Clinical Features of Fabry Disease, the Typical Age of Symptom Onset, and Summary
of Medical Management (Brady and Schiffmann, 2000; Brown et al., 1997; Desnick et al., 2001;a
MacDermot et al., 2001a,b;b,c Rosenberg et al., 1980; Stryker and Kreps, 2001; Sybert, 1997)
Clinical features
Neuropathic pain/burning in
extremities
Particularly the palms and
soles of the feet
May be constant or episodic
Seen in 80%a,b of males and
70% of femalesc
Ophthalmologic
Corneal dystrophy and opacity
(corneal verticillata)
Lenticular abnormalities (Fabry
cataract)
Seen in 100% of males and
70–80% of females
Retinal changes associated with
hypertension and uremia
Angiokeratoma
Individual punctate angiectases,
dark red to blue-black color
Distribution is most dense
between the umbilicus and
knees, on the buttocks and
penis, and in the oral mucosa
and underside of the tongue
Not painful and do not itch or
blanch with pressure
Seen in 70% of males by age 17,
30a –35%c of females (breast,
back, trunk, inner thighs)
Hypohidrosis (acquired)
Seen in 56b –66%a of males and
up to 33%c of females
Cardiac disease
Left ventricular enlargement
(88%b of males, 19% of
femalesc )
Valvular involvement (most
commonly mitral
insufficiency)
Conduction abnormalities
Later manifestations include
angina pectoris, myocardial
ischemia and infarction,
congestive heart failure
TIA or CVA (24%b of males,
22%c of females)
Typical age of onset
Management
Onset in childhood or Analgesic medications; a
early adolescence
combination of drugs such as
Dilantin, Carbamazepine, and/or
Neurontin may be indicated to
control or minimize the intensity of
pain episodes
Avoid situations that may trigger
symptoms (e.g., exercise, fatigue,
emotional stress, extreme
temperature or humidity, fever)
Usually
Slit-lamp examination is helpful in
asymptomatic, but
diagnosis but the cataracts and
may be detected at
corneal abnormalities do not
any age
require treatment as they rarely
impair visual acuity
May also enable carrier detection
when positive in females with
equivocal enzyme test results
Usually increase in
number over time
May be seen in
childhood (by age
10–20 years)
Argon laser therapy for cosmetic
improvement
Childhood
Avoid extremes of heat, humidity, and
physical exertion
Increase water intake
20s and 30s in males; Monitor with EKG and 2-dimensional
later in females
and M-mode echocardiography
Medications for control of
hypertension, conduction
abnormalities, angina (as needed)
Conduction defects may necessitate
the use of a pacemaker
Severe cardiac disease may
necessitate heart transplant
(Continued )
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Table I. (Continued )
Clinical features
Cerebrovascular disease
Thromboses
Transient ischemic attacks
Basilar artery ischemia
Aneurysm
Seizures
Strokes
Vascular dementia
White matter changes
Occurs in <1% of females
Renal disease
Proteinuria
Hypertension
Chronic renal insufficiency
End stage renal failure in
∼31%b of males and 1–4%a,c
of females
Psychological
Depression
Diminished quality of life
Auditory problems
Hearing loss (bilateral,
sensorineural). Seen in
∼41%b of males, 23%c of
females. In a cohort of
23 males, 78% had abnormal
audiogramsb
Tinnitus (38%b of males, 23%c
of females)
Vertigo
Gastrointestinal problems
Acute intermittent abdominal
pain, vomiting, cramps
Diarrhea (postprandial)
Seen in 33a –69%b of males,
58%c of females
Male infertility
Erectile dysfunction
Pulmonary involvement
Airway obstruction
Typical age of onset
Mid-30s
Management
Brain MRI
Psychometric testing
Anticoagulants may be
indicated in patients at risk
of stroke/aneurysm
Seizure medications, as
appropriate
Appears most often
Urinalysis
between age 30 and 24-h urine collection for total protein
40 years in males
and creatinine
Glomerular filtration rate
BUN
Medications for hypertension (e.g.,
ACE inhibitors)
Hemo- or peritoneal dialysis (as
appropriate) and possible renal
transplantation
May become manifest Quality of Life measurement tools
at any time, but
Supportive counseling and
usually evident in
medication, as appropriate
adolescence or
adulthood
May become manifest Audiograms
at any time, but
Hearing aides
usually evident in
adolescence or
adulthood
May become manifest Medication (antidiarrheals, fat
at any time, but
absorption supplements)
usually evident in Dietary modifications (high fiber diet,
adolescence or
avoid fatty foods)
adulthood
30s or 40s
May be clinically
silent, although
often evident in
adulthood
Urological consultation and
medication, as appropriate
Pulmonary function testing
Bronchodilators, inhalants
Discontinue smoking
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due to skewed X-inactivation (nonrandom lyonization). Discordance in expression
of the disease in monozygotic female heterozygotes has been described (Desnick
et al., 2001; Levade et al., 1991). Among males, the clinical manifestations of Fabry
disease usually begin in childhood or adolescence, with recurrent severe pain in
the extremities, angiokeratomas, corneal dystrophy, and episodic fevers. Fabry
disease often causes renal failure, requiring renal dialysis and kidney transplant, a
major cause of morbidity and mortality in this patient population. Cardiac manifestations, usually cardiomyopathy and/or premature coronary artery disease, is another leading source of morbidity and mortality for individuals with Fabry disease.
Cerebrovascular accidents are common in Fabry disease. Premature death usually
occurs from renal failure, or from cardiac or cerebrovascular disease. Table I provides a summary of the medical features and management of Fabry disease.
Neuropathic pain is the most common and debilitating symptom of Fabry
disease. Pain occurs in the form of severe acute attacks (referred to as Fabry crisis),
or as a chronic background pain (e.g., aching, tingling, tenderness). Individuals
with Fabry disease use terms such as burning, piercing, sharp, appalling, and
agonizing to describe their pain. The pain is often present in the palms and soles
of the feet (acroparesthesias), and often radiates to the arms and legs. Neuropathic
abdominal pain is also common, and is often accompanied by nausea, diarrhea, and
vomiting. A painful crisis can be precipitated by fever, exercise, fatigue, emotional
stress, or rapid changes in the environmental temperature or humidity, or the crisis
can have no precipitating cause (Desnick et al., 2001).
The most common ophthalmologic findings in Fabry disease are corneal dystrophy and opacity (haziness) with a whorl-like pattern (corneal verticillata). Two
types of lenticular abnormalities may be seen—a posterior opacity (the “Fabry
cataract”) with a spoke-like appearance, and a granular, anterior capsular, or subcapsular wedge-shaped lipid deposit. The cataracts and corneal anomalies do not
impair visual acuity. Retinal vascular changes associated with hypertension and
uremia may occur, including retinal artery thrombosis resulting in blindness. The
conjunctival and retinal vessels may be tortuous (a nonspecific finding), even in the
absence of hypertension, with venous changes being more common than arterial
lesions.
Acquired hypohidrosis (decreased sweating, saliva, and tear production from
autonomic nervous system dysfunction) develops in adolescence. This problem is
exacerbated by extremes of heat, humidity, and physical exertion.
Because Fabry disease affects multiple organ systems, a multidisciplinary
team approach is useful (Peters et al., 1997). Referrals to multiple subspecialists
may be necessary to achieve optimal patient care. Case management can include
specialists in medical genetics, pediatrics, or internal medicine, nephrology, ophthalmology, cardiology, dermatology, neurology, pain management, organ transplant, OT/PT, social work, and psychology/psychiatry. A sample form for clinical
evaluation of an individual with Fabry disease is shown in Fig. 1.
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Intravenous enzyme replacement therapy is currently in extended clinical
research trials awaiting FDA approval. Several reports demonstrate this treatment to be a promising approach to the management of the manifestations of
Fabry disease (Brady and Schiffmann, 2000; Eng et al., 2001a,b; Gahl, 2001;
Schiffmann et al., 2000, 2001). These studies revealed reduction in plasma and
tissue globotriaosylceramide levels in the vascular endothelium of the kidney,
skin, and heart as surrogate markers of clinical benefit. There are also indications
of decreased pain and improvement in quality of life. Other genetic therapies are
also being considered for Fabry disease, such as substrate deprivation, chaperonemediated enzyme enhancement, and gene therapy (Abe et al., 2000; Desnick,
2001).
Genetic Diagnosis and Genotype/Phenotype Correlations
Fabry disease is considered highly penetrant in males although variable in
its expression. In affected males, the clinical diagnosis is confirmed by α-gal A
deficiency. The majority of males with Fabry disease have absent or very low
enzyme activity (1–2% of normal) and classical phenotype with multiple disease
manifestations. Some males with clinical features of Fabry disease have residual
α-gal-A enzyme activity (level of enzyme activity 1–10%) (Desnick et al., 2001).
Several males were described with higher residual enzyme activity, approximately
3–10% of normal, and appeared to have milder expression of Fabry disease. These
Fig. 1. Sample clinic evaluation for Fabry disease.
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Fig. 1. (Continued )
individuals were diagnosed with Fabry disease later in life after cardiomyopathy
of unknown etiology was discovered (Desnick et al., 2001).
About 60–70% of females heterozygous for a Fabry disease mutation have
some disease manifestations, and approximately 10% of these heterozygous females have severe manifestations, similar to the phenotype in males (Desnick et al.,
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Fig. 1. (Continued )
2001; MacDermot et al., 2001b). Enzyme activity is not reliable for determining
female carrier status because women who are obligate carriers have variable levels
of alpha-gal A that can overlap with enzyme levels found in healthy controls.
The α-gal A locus is on Xq22.1. The gene is 12 kb in length and contains seven
exons. More than 200 mutations have been identified in the α-gal A gene (Human
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Gene Mutation Database, http://archive.uwcm.ac.uk/uwcm/mg/hgmd0.html);
most of the mutations are unique (“private mutations”) in each family (Ashley
et al., 2001; Eng et al., 1997; Topaloglu et al., 1999). Therefore it is necessary to
sequence the entire α-gal A gene and flanking regions to identify the Fabry disease
mutation in a family. The limitations of gene sequencing include limited clinical
availability from CLIA-approved laboratories, labor intensity, the possibility that
not all mutations will be identified, and the possible identification of sequence
variations of uncertain significance. Several laboratories offer enzymatic testing
for Fabry disease (refer to http://biochemgen.ucsd.edu/). Currently, the availability
of direct DNA sequencing for diagnostic testing in the United States is limited to
a few CLIA-approved laboratories (refer to www.genetests. org).
A suggested flow diagram for genetic testing for Fabry disease is shown in
Fig. 2. De novo mutations have been documented, and therefore the absence of
family history suggestive of Fabry disease does not rule out the diagnosis of Fabry
disease (Germain et al., 2001). The rate of new mutations is unknown. In a recent
survey of 67 families with Fabry disease in the United Kingdom, 20 males had no
family history of the disease (MacDermot et al., 2001a).
Of the 150 mutations identified by Desnick and colleagues, 71.6% of the
mutations were coding region missense or nonsense mutations, 6.5% were mRNA
processing defects, and 21.9% were large or small gene rearrangements (Desnick
et al., 2001). Identification of a gene mutation is diagnostic but does not predict the
severity of disease. Mutations in R112H, R301Q, and G328R have been described
in individuals with primarily cardiac manifestations, although they also have been
reported in patients with classical disease symptoms (Ashton-Prolla et al., 2000;
Desnick et al., 2001).
Differential Diagnosis
Although the individual features of Fabry disease may not be specific, they
should lead to a high index of suspicion particularly in the presence of a family
history of Fabry disease. Table II lists some of the conditions to consider in the
differential diagnosis of Fabry disease.
Many conditions have symptoms similar to Fabry disease. Angiokeratomas
are not pathognomonic of Fabry disease. Neuropathic pain (pain associated with the
cranial nerves, or the peripheral or autonomic nervous system) is associated with
many different acquired and inherited conditions including diabetes mellitus and
trigeminal neuralgia. Some individuals with Fabry disease pain crises have been
misdiagnosed with erythromelalgia. There are also multiple causes of premature
cardiovascular disease and cardiomyopathy.
Kanzaki disease is a rare autosomal recessive condition caused by deficiency
of α-N -acetylgalactosaminidase (α-NAGA). The disease manifestations begin in
puberty with clinical findings of angiokeratoma corporis diffusum, peripheral
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Fig. 2. Suggested diagnostic testing flow-chart—Fabry disease. All of the five testing pathways include obtaining medical history, family history,
performing a physical examination, and genetic counseling prior to and following testing. -gal A = -galactosidase A; = suggested pathway;
⊕ eye examination = ophthalmologic finding consistent with Fabry disease; ª eye examination = normal ophthalmologic examination.
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Table II. Conditions to Consider in the Differential Diagnosis of Fabry Disease (Desnick et al., 2001;
Dinc et al., 2000; Kodoma et al., 2001; Sybert, 1997)
Symptom
Angiokeratoma
Hypohidrosis
Numbness/tingling/pain
Condition
Fucosidosis
Aspartylglucosaminuria
GM1 gangliosidosis
GM2 gangliosidosis
Sialidosis
Galactosialidosis
Late infantile gangliosidosis
Beta-mannosidosis
Kanzaki disease
Petechiae
Angiokeratoma of Fordyce
Angiokeratoma of Mibelli
Angiokeratoma circumscripta
Hypohidrotic ectodermal
dysplasias
Kanzaki disease
Familial Mediterranean fever
Acute intermittent porphyria
Multiple sclerosis (especially
in females)
Rheumatic fever
Erythromelalgia
(erythermalgia)
Arthritis, rheumatoid and
juvenile
Raynaud’s syndrome
Neuropathy
Corneal dystrophy
Proteinuria, lipiduria, and lamellar
inclusions in the lysosomes of
glomerular epithelial cells
Phenocopy from long-term
chloroquine or amiodarone
therapy
Phenocopy from silica dust
Inheritance
AR
AR
AR
AR
AR
AR
AR
AR
AR
Multiple causes
Acquired
Acquired
Acquired
Several, AD
AR
AR
AD
Multifactorial
Multifactorial
?AD, or secondary
erythromelalgia
due to
thrombocythemia
Multifactorial
Multifactorial
Many acquired and
genetic causes, with
diabetes mellitus
being one of the
most common
Drug induced
Environmental
Note. AR: autosomal recessive; AD: autosomal dominant.
sensory neuropathy, hearing loss, Meniere syndrome, and cardiac hypertrophy.
(This is the same enzyme deficiency found in Schindler disease, but the primary
disease manifestation in Schindler disease is severe central nervous system involvement evidenced in the first year of life.) Interestingly, the α-NAGA gene and
the α-gal A gene in Fabry disease have greater than 50% homology, and are thought
to have evolved from the same gene (Kodoma et al., 2001).
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Incidence
The incidence of Fabry disease is estimated to be 1:117,000 live births in
Caucasian males (Meikle et al., 1999). Fabry disease has been identified in all
racial groups, and there is no known racial or ethnic predilection.
Fabry disease was diagnosed (by measuring α-gal A activity) in 3% of unselected male patients with left ventricular hypertrophy (Nakao et al., 1995), and
9% of patients with a diagnosis of nonobstructive hypertrophic cardiomyopathy
(Kuhn et al., 1982).
PRIMARY GENETIC COUNSELING CONSIDERATIONS:
FABRY DISEASE
Assessment
Ascertain the client’s primary questions and concerns and mutually develop
a plan to address these concerns.
Medical Family History
A. Using standardized pedigree symbols, obtain at least a three generation
pedigree from the consultand or proband (Bennett, 1999; Bennett et al.,
1995).
i. Targeted medical family history questions are included in Table III.
ii. Because Fabry disease is inherited in an X-linked pattern, special
attention should be paid to the medical history of maternal relatives
of a male proband (i.e., his mother’s siblings and their children, both of
her parents and their siblings and children, and the mother’s maternal
and paternal grandparents). Family history of maternal relatives of a
female proband is also important, as is the history of her father and
his relatives.
iii. Note any consanguinity, documenting the exact relationship of unions
between relatives on the pedigree (i.e., consanguinity could put female
relatives at risk for being homozygotes).
B. Verify positive family history with medical records, if possible. Document
results of enzyme analysis and/or DNA mutation analysis.
C. For female carriers, obtain pregnancy history (gravidity, parity, termination of pregnancy, spontaneous abortion), and potential exposure to
possible teratogenic agents (see under Teratogenesis).
D. Maintain family history with respect to the confidentiality of the consultand/proband and extended family members.
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Table III. Suggestions for Targeted Family History Questions for Fabry Disease
Answer the following questions about yourself, or any of your blood relatives (note the age that the
problem or event occurred)
Has anyone had an eye exam (called a slit-lamp examination) to look for the nonharmful eye
findings that can be seen in Fabry disease?
Does anyone have any unusual skin findings (such as a rash or birthmark)? If so, describe them
and their location on the body.
Does anyone have problems with sweating (not sweating enough), or problems with tolerating
extremely hot or cold temperatures?
Does anyone have major gastrointestinal problems such as chronic diarrhea, vomiting, or
recurrent abdominal pain?
Has anyone experienced problems with hearing loss or ringing in the ears?
Do you or your relatives have a history of heart disease? Specifically, has anyone been told
they have heart murmurs or problems with their heart valve(s)? Does anyone have a history
of chest pain (angina)? Has anyone died of heart disease? Does anyone have a history of
irregular heart rhythm? A pacemaker? Has anyone received a heart transplant?
Is there a history of high blood pressure (hypertension)?
Does anyone have a history of kidney problems? Is anyone on dialysis? Has anyone had a
kidney transplant?
Has anyone had a stroke, particularly at a young age?
Does anyone have problems with memory or thinking?
Have you or your relatives had a seizure? If so, how many? Do they take medications for this?
Has anyone had a history of chronic high fevers?
Do you or your relatives have a problem with chronic pain? Do you or your relatives
experience burning sensations in the palms of the hands or the soles of the feet? If so, what
has been done to treat this?
Do you or your relatives have a history of feeling tired all the time or experiencing weakness?
Have you (if male) or the men in your family experienced infertility (problems having
children) and/or erectile dysfunction?
Has anyone in the family been treated for depression? Is there a history of suicide or suicide
attempts in the family?
For female patients who are pregnant or planning a pregnancy
What medications are you taking?
Psychosocial History of the Consultand/Proband
Attempt to build a relationship with the consultand/proband by validating,
empathizing, and listening. Assess, record, and address the consultand’s/proband’s
A. Level of comprehension and communication.
B. Level of education, employment, and social functioning, as appropriate.
C. History of depression (e.g., disturbance in sleep pattern, anxiety, changes
in appetite, weight gain or weight loss, fatigue, feelings of hopelessness,
loss of libido, suicidal ideation).
D. History of alcohol or other drug use (especially a history of using alcohol
or other drugs to self-medicate for depression and/or pain control).
E. Perceived burden of Fabry disease.
F. Perceived notions of Fabry disease occurrence/recurrence risks.
G. Coping skills.
H. Family and community support systems.
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Risk Assessment
A. Analyze the pedigree. Using principles of X-linked recessive inheritance,
provide genetic risk assessment for carrier status and the chance of having
affected offspring.
i. All daughters of an affected male are obligate gene carriers, whereas
none of the affected male’s sons will have Fabry disease. If there is
consanguinity, females are also potentially at risk for homozygosity.
ii. Sons of female carriers have a 50% risk of inheriting Fabry disease,
and daughters of female carriers have a 50% risk of being carriers.
iii. Females can have manifestations of Fabry disease because of
skewed X-inactivation.
B. Offer genetic testing for family members, as appropriate (Fig. 2).
i. Offer DNA mutation analysis for diagnostic or carrier testing if the
mutation is known in affected family member(s).
ii. Offer enzyme analysis for at-risk males.
iii. Offer ophthalmologic evaluation, enzyme and DNA mutation analysis
for potential carrier females.
Psychosocial Issues
A. The rate of depression, alcoholism, marital problems, unemployment,
and suicide is high among men with Fabry disease (Abreo et al., 1984;
Grewal, 1993). In a cohort of 46 men with Fabry disease, MacDermot
et al. (2001b) found that only 57% were currently employed and 17% had
never had a job because of the diagnosis of Fabry disease.
B. Assess/identify family, peer, and community resources for appropriate
services and/or support, and consider referrals as needed.
C. Assess support services and accommodations in settings for school and/or
employment, particularly because rapid changes in environmental temperature and humidity, physical exertion, emotional stress, and fatigue
can exacerbate painful crises (Desnick et al., 2001).
D. Address psychological issues related to genetic diagnosis such as denial,
anxiety, anger, grief, survivor and parental guilt, blame, depression, isolation, inability to cope, hopelessness, damage to self-esteem, changed
relationship with family of origin, and change in sense of identity, as
indicated (Baker et al., 1998; Weil, 2000; Williams et al., 2000).
E. For an individual affected with Fabry disease, explore the client’s notions of sexuality. The angiokeratomas may be a significant source of
embarrassment and psychological stress. A patient in a study at the National Institute of Health summarized his distress by stating, “I have
angiokeratomas on my genitalia. When you are planning to lose your
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F.
G.
H.
I.
J.
K.
virginity, the last thing you want is something that looks like a venereal
disease” (Stryker and Kreps, 2001). MacDermot et al. (2001a) also found
a significant proportion of individuals with angiokeratomas feared initiating sexual relationships. Chronic pain and fatigue may also contribute
to sexual difficulties (Stryker and Kreps, 2001).
Assess patient’s and family’s preconceived notion of affected or carrier
status. Family members may have an incorrect understanding of the inheritance, and therefore they may not be aware of their chances to have a
child with Fabry disease (Sørensen and Hasholt, 1983). An individual with
diagnostic results that are opposite of his or her preconceived affected status may be at higher risk for adverse psychological consequences (Resta,
2000).
For individuals/couples at risk to have a child with Fabry disease, assess
their feelings about childbearing, prenatal diagnosis, and subsequent options (e.g., pregnancy termination or continuation upon diagnosis of an
affected male fetus, feelings about termination of pregnancy given potential treatment options). Assess self-concept as it relates to threatened
parental role (McConkie-Rosell and DeVellis, 2000).
Individuals diagnosed with Fabry disease may have seen many health
care professionals before receiving a confirmative diagnosis. The average
time to diagnosis is 10 years, with affected individuals typically seeing 10 specialists before diagnosis (Morgan and d’A Crawford, 1988).
There may be an inherent distrust of health professionals because of this
experience.
Address psychological issues arising from the uncertainty of the variable
clinical phenotype.
Individuals with a tentative diagnosis of Fabry disease who are subsequently found to not have this condition may have mixed feelings on
receipt of a normal (negative) genetic test result (Williams et al., 2000).
For example, siblings of individuals diagnosed with Fabry disease may
have always thought they would develop the condition, and they may take
some time to absorb the information that they are unaffected. The “sick
role” may have been unconsciously “assigned” to the family member (preselection) thereby creating the illusion of control over the randomness of
gene transmission (Resta, 2000). Unaffected siblings may also experience
survivor guilt.
Make referrals for further psychological counseling as necessary.
PRENATAL DIAGNOSIS
Prenatal diagnosis for determining fetal sex is the first step in prenatal diagnosis for Fabry disease. The inability to predict clinical outcome in carrier females,
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many of whom remain asymptomatic, complicates prenatal counseling and diagnosis. Because of this, prenatal diagnosis for female fetuses is usually not available
from the laboratories offering testing. For male fetuses at-risk for Fabry disease,
subsequent enzyme analysis, or DNA mutation analysis (if the mutation has been
identified in the family) can be performed on chorionic villi (CVS) or cultured
amniocytes.
If the family mutation is known, preimplantation diagnosis is feasible.
EDUCATION/HEALTH PROMOTION
A. Discuss the clinical manifestations of Fabry disease in males, and the
possibility that females can be affected.
B. Discuss follow-up recommendations (e.g., identification and testing of
at-risk family members, scheduling follow-up visits).
C. Discuss the genetics of Fabry disease and the approach to testing.
i. Review X-linked inheritance and recurrence risks.
ii. Review reproductive options and testing (e.g., adoption, donor egg or
donor sperm, prenatal diagnosis). Include ethical concerns raised by
such options, if appropriate.
iii. Review costs of genetic testing, and test limitations (e.g., enzyme
assay can be normal in carrier females; the percentage of residual
α-gal-A enzyme activity does not correlate with clinical severity; and
DNA testing may fail to identify a mutation).
iv. Answer questions regarding molecular genetic aspects of Fabry
disease.
D. Be able to answer general questions relating to potential therapy for Fabry
disease, including published trials of enzyme replacement (see under
Clinical Condition and Medical Management) (Brady and Schiffmann,
2000; Eng et al., 2001a,b; Gahl, 2001; Schiffmann et al., 2000, 2001).
E. Be prepared to make appropriate referrals for medical evaluations and further discussions that are beyond the scope of genetic counseling practice
(Fig. 1).
F. Provide contact information for support groups, as requested (Table V).
FOLLOW-UP
A. Arrange/facilitate additional appointments to complete the family history and genetic risk assessment, and arrangements to follow the medical
progress of the patient, as indicated.
B. Devise a plan for disclosing test results.
C. Offer posttesting support counseling (by office visit or telephone).
D. Facilitate referrals to appropriate professionals, as indicated (Fig. 1).
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E. Consider making available to the patient a letter to summarize major topics
discussed in the genetic counseling session(s), and to facilitate informing
their family members of their genetic risks (Baker et al., 1999; Hallowel
and Murton, 1998).
ETHICAL ISSUES AND SPECIAL CONSIDERATIONS
Testing Healthy At-Risk Minors
The age at which to test healthy at-risk minors is controversial, particularly if
no therapy or intervention is available, or if it is unknown at what age an intervention
should begin for the greatest health benefit for the child. Several position papers
(ASHG/ACMG Reports, 1995; NSGC, 1995) and printed discourses (Clarke, 1998;
Clarke and Flinter, 1996; Davis, 1997; Michie, 1996; Wertz et al., 1994) raise
multiple concerns about potential emotional damage to the child, as well as possible
discrimination. Some of the considerations of testing healthy at-risk children for
Fabry disease are summarized in Table IV.
Studies documenting the effect of genetic testing of children at risk for Fabry
disease have not been published. Testing of seemingly healthy minors for genetic
conditions is usually discouraged, unless testing allows for a health benefit due to
medical intervention. Testing for Fabry disease in seemingly healthy at-risk males
who are minors may be justified, given the subtle early manifestations of Fabry
disease and the high likelihood of disease progression. Early diagnosis allows for
closer medical monitoring and the opportunity for early intervention, especially
Table IV. Pros and Cons of Asymptomatic Testing for a Minor at Risk for Fabry Disease
Potential adverse consequences of
testing (focus on positive test results)
Damage to the minor’s self-esteem
Distortion of the family’s perception of
the child. Siblings may be treated
differently depending on genetic
status
Loss of future adult autonomy and
confidentiality for the tested child
Adverse effects on the child’s capacity
to form future relationships
Fear of rejection in forming long-term
relationships. Fear/guilt if person
wants biological children
Discrimination (insurance, employment,
education, choice of mate)
Increased medical surveillance for
“healthy” child (especially for
females). Child feels labeled
Potential benefits of testing
Resolution of the parent’s (and possibly the child’s)
concerns about carrier status
Allow child and family time to adjust to status if test is
positive. No anticipation of developing disease if
result is negative
Anticipatory guidance such as in choosing physical
activities and occupation for possibly affected child
Health status is normalized and Fabry disease becomes
part of that child’s sense of self
Ability to make informed reproductive decisions
Decreased premiums for insurance because risk factor
eliminated if test result is negative
Available at earliest opportunity for medical
intervention including enzyme replacement therapy
(when available)
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with the prospect of enzyme replacement therapy. Testing healthy at-risk minor
females may be more controversial because many female carriers of Fabry disease
will never have symptoms. It may be appropriate to time genetic testing for Fabry
disease before an adolescent (male or female) becomes sexually active, to assist
with discussions of reproductive risks and options.
Testing Siblings Before Kidney Transplant
Before considering a healthy sibling of a person with Fabry disease as an
organ donor for the affected male, unaffected status should be confirmed by enzyme
analysis or DNA testing. Enzyme analysis or DNA testing should not be initiated
solely to secure a matched donor. Female carrier siblings should not be used as
organ donors.
Teratogenesis
A careful medication history should be taken for a symptomatic woman
who is planning a pregnancy or who is pregnant to determine if any medications she is taking are teratogenic. Dilantin and carbamazepine are commonly
used for pain symptoms; their potential teratogenic effects should be reviewed
with the client (Holmes et al., 2001). The patient can be referred to a regional
teratogen service for comprehensive information. Listings of such services can
be found through the Organization of Teratogen Information Services or OTIS
(http://ctispregnancy.org/home.html).
Confirming Parentage
All daughters of affected males with Fabry disease are obligate heterozygotes. Because of possible misattributed paternity, carrier status should not be
assumed. Confirmation with enzyme analysis or with DNA testing if the mutation is known is indicated to provide accurate genetic risk assessment and genetic
counseling. Enzyme analysis in females may not be definitive, and DNA testing
is preferred for diagnostic confirmation; ophthalmologic evaluation may also be
useful in establishing carrier status for females (see under Genetic Diagnosis and
Genotype/Phenotype Correlations and Fig. 2).
PATIENT RESOURCES
Table V contains a list of patient advocacy groups for Fabry disease.
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Table V. Advocacy Groups for Individuals and Their Families With Fabry Disease
Resource
Canadian Organization for
Rare Disorders (CORD)
Fabry’s Disease Support
Group
Fabry’s Support Group, Inc.
Fabry Support & Information
Group
Lysosomal Diseases,
Australia
Lysosomal Diseases,
New Zealand
Morbus Fabry
NORD—National
Organization for Rare
Disorders
Address
P. O. Box 814,
Coaldale, Alberta T1M 1M7,
Canada
10 Broadmeadow Road,
Wyke Regis,
Weymouth, Dorset DT4 9BS,
England
P. O. Box 174,
The Basin 3154,
Melbourne, Victoria,
Australia
P. O. Box 510,
Concordia, MO 64020,
USA
Dept. of Clinical Pathology,
Women’s & Children’s
Hospital,
72 King Road, North
Adelaide,
South Australia 5006,
Australia
1248 High Street,
Lower Hutt City 6009,
New Zealand
Bergstrasse 34,
Ransbach—Baumbach
56235
P. O. Box 8923,
New Fairfield,
CT 06812-8923, USA
Phone, Fax, Web site
Phone: (403) 345-4544
Fax: (403) 345-3948
http://www.cord.ca
Phone: 03 9762 3910
Fax: 03 9761 3503
Phone: (660) 463-1355
Fax: (660) 463-1356
http://www.fabry.org
http://www.lda.org.au
http://www.ldnz.org .nz
Phone: +49 2623-2710
Fax: +49 2623-9230 79
Phone: (203) 746-6518
Fax: (203) 746-6481
http://www.rarediseases.org
DISCLAIMER
Genetic counseling recommendations of the NSGC are meant to assist practitioners in making decisions about appropriate management of genetic concerns.
Each practice recommendation focuses on a clinical or practice issue, and is
based on a review and analysis of the professional literature. The information
and recommendations reflect scientific and clinical knowledge current as of the
publication date, and are subject to change as advances in diagnostic techniques,
treatments, and psychosocial understanding emerge. In addition, variations in
practice, taking into account the needs of the individual patient and the resources and limitations unique to the institution or type of practice, may warrant alternative approaches, treatments, or procedures to the recommendations
outlined in this document. Therefore, these recommendations should not be construed as dictating an exclusive course of management, nor does use of such
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recommendations guarantee a particular outcome. Genetic counseling recommendations are not intended to supersede a health care provider’s best medical judgment. The listing of patient and professional resources does not necessarily imply
NSGC endorsement.
SUMMARY
Without treatment, there is significant morbidity and mortality associated
with Fabry disease. Given the potential benefits of early medical and psychological interventions for Fabry disease, genetic counselors need to have increased
awareness about genetic testing, evaluation, and management for Fabry disease.
Specific genetic counseling issues in Fabry disease include phenotype and genotype variability; genetic testing of at-risk siblings before investigation for organ
donation; coping with a chronic and painful illness; increased rates of depression,
alcoholism, marital/relationship difficulties, unemployment, and suicide; anxiety
regarding sexual relationships because of angiokeratomas; mistrust of health professionals because of years of misdiagnosis; psychological consequences related
to uncertainty because of disease variability; issues related to presymptomatic
testing; issues of “preselection” especially for individuals who are not affected in
a family; and consideration of occupational therapy and anticipatory counseling
in view of the disease’s natural history. Ethical issues include testing healthy atrisk minors; prenatal diagnosis for a potentially treatable condition; and issues of
misattributed paternity.
Genetic counselors play a critical role in not only identifying individuals
and at-risk relatives with Fabry disease, but in providing genetic testing services
and counseling. Through on-going education and support, genetic counselors encourage families to enroll in Fabry disease registries, Quality of Life studies, and
clinical trials so that more can be learned about the clinical manifestations of
Fabry disease, appropriate modes of evaluation and therapy, and strategies for
psychological support of these families.
ACKNOWLEDGMENTS
The authors are grateful to the many reviewers of the NSGC for their helpful comments, particularly members of the Genetic Services Committee and the
Ethics Subcommittee. This work was initiated by the Fabry International Research
Exchange (FIRE) sponsored by Transkaryotic Therapies. Barranger, Bennett,
Pastores, Steiner, and Thadhani are paid advisors for FIRE. Barranger, Hart,
Steiner, and Pastores receive institutional support from Genzyme Corporation.
MacDermot has conducted clinical trials with Transkaryotic Therapies. The Fabry
Support and Information Group (FSIG) has received donations from Genzyme
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Coporation and Transkaryotic Therapies. The authors and reviewers of this paper
volunteered their time, and did not receive an honorarium.
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