Fabry disease in genetic counseling practice: recommendations of the National Society of Genetic...

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Journal of Genetic Counseling [jgc] ph105-jogc-368836 February 27, 2002 11:37 Style file version Nov. 19th, 1999

Journal of Genetic Counseling, Vol. 11, No. 2, April 2002 (C© 2002)

Fabry Disease in Genetic Counseling Practice:Recommendations of the National Societyof 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 recom-mendations for genetic counseling and testing of individuals with a suspected orconfirmed diagnosis of Fabry disease, with a family history of Fabry disease, andthose identified as female carriers of Fabry disease. These recommendations arethe opinions of a multicenter working group of genetic counselors, medical geneti-cists, 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 diseasepatient advocacy group in the United States. The recommendations are U.S. Pre-ventive Task Force Class III, and they are based on clinical experience, a review ofpertinent English-language articles, and reports of expert committees. This docu-ment reviews the genetics of Fabry disease, the indications for genetic testing andinterpretation of results, psychosocial considerations, and references for profes-sional and patient resources. These recommendations should not be construed as

1Department of Medicine, Division of Medical Genetics,University of Washington,Seattle,Washington.2Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco,California.

3Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh,Pittsburgh, Pennsylvania.

4Fabry Support and Information Group, Concordia, Missouri.5Department of Medicine, Addenbrooke’s Hospital, Cambridge, United Kingdom.6Department of Neurology and Pediatrics, New York University School of Medicine, New York,New York.

7Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilita-tion Center, Dorenbecher Children’s Hospital, Oregon Health & Science University, Portland, Oregon.

8Department of Medicine and Renal Unit, Massachusetts General Hospital, Harvard Medical School,Boston, Massachusetts.

9Correspondence should be directed to Robin L. Bennett, MS, CGC, University of Washington MedicalCenter, Box 357720, Seattle, Washington 98195-7720; e-mail: [email protected].

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1059-7700/02/0400-0121/1C© 2002 National Society of Genetic Counselors, Inc.

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122 Bennettet al.

dictating an exclusive course of management, nor does use of such recommenda-tions guarantee a particular outcome. The professional judgment of a healthcareprovider, familiar with the facts and circumstances of a specific case, will alwayssupersede these recommendations.

KEY WORDS: enzyme therapy; Fabry disease; genetic counseling; genetic testing; National Societyof Genetic Counselors; practice guidelines.

INTRODUCTION

The following case scenarios were collected from a support group for indi-viduals affected by Fabry disease.

Vignette 1—Eric

Growing pain was the diagnosis; I remember one of the visits when my son was 11 yearsold. A physician brought my son close to the lighted panel showing the side view of thex-ray of his foot. He pointed to the white ends of the bones near Eric’s heel and said “Seethis 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 thingskept happening to him during the following years. Hand pain was a problem along withthe 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 wouldpush him just a little more, in the hope that he would walk right out of the pain. “Ignore itand maybe it would go away” became my motto.

Eventually, Crohn disease was ruled-out as the cause of his abdominal problems, butwe still had no diagnosis. Fabry disease was known to be in the family. After learning moreabout Fabry disease we requested testing. Finally, a correct diagnosis was made. Eric was25 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 throbbingpain typically would be in my hands and feet most days, but also in my arms and legs duringsome days, and always during serious bouts, or attacks. About every three weeks I woulddevelop a fever, and then the very intense pain would begin. I’ll always remember how as achild I would look at my hands and feet and not understand how they could feel as thoughthey were on fire yet not show any signs of redness, or look any different than usual. With theburning came severe throbbing and aching, as well as stabbing (piercing) pains that wouldstart in my hands and feet, and then move throughout my arms and legs. The stabbingwould 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 cryingand wanting to scream from the pain. I would be bedridden during these attacks, whichwould last from 24 to 48 hours. I’d have other symptoms during these bouts that seemedflu-like, with nausea, vomiting, headache, and just a general feeling of illness. Shortly afterthe 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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Genetic Counseling: Fabry Disease 123

and went to my doctors as little as possible. I finally was correctly diagnosed with Fabrydisease at the age of 30 years.

These vignettes dramatically illustrate the need for increased awareness of Fabrydisease among health professionals to facilitate early diagnosis, as well as theimportance of recommendations for genetic counseling for Fabry disease to ed-ucate genetic counselors and other health professionals about this rare, and nowpotentially treatable inherited condition.

PURPOSE

The following recommendations are intended to assist health care profes-sionals who provide genetic counseling for individuals and families in whom thediagnosis of Fabry disease is suspected or has been confirmed. We review the ge-netics 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/medicalgenetics (GMP, JAB, KDM, RDS), clinical molecular genetics (GMP), renaldisease (RT), pediatrics (GMP, RDS), and internal medicine (KDM, RT). Inputwas also sought from a patient advocacy group for Fabry disease (JJ). A litera-ture search for relevant English-language medical articles published betweenJanuary 1985 and June 2001 was performed using the MEDLINE and PUBMEDdatabases. Bibliographies of articles were also reviewed. Articles were reviewedwith particular attention to genetic counseling and diagnostic issues. The literaturereviewed was based on clinical experience, descriptive studies, and/or reports ofexpert committees.

The literature was reviewed and evaluated for quality according to the cate-gories outlined by the U.S. Preventive Services Task Force (1995):

I. Evidence obtained from at least one properly designed randomized controlledtrial.

II-1. Evidence obtained from well-designed controlled trials without randomiza-tion.

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 supportingliterature for genetic counseling practices in categories I and II was identified.

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124 Bennettet al.

The authoring committee sought expert review from specialists in Fabry dis-ease and genetic counseling in the United States. Opinions were sought from rep-resentatives of advocacy groups for Fabry disease. The full document was madeavailable for review on the Internet to all Full and Associate members of the Na-tional Society of Genetic Counselors (NSGC). At the time, 78% of the 1536 NSGCFull and Associate members were registered on the NSGC listserv. The NSGC Fulland Associate membership includes genetic counselors, physicians, nurses, attor-neys, PhD genetics professionals, and social workers. The NSGC Ethics Subcom-mittee (consisting of seven genetic counselors, and an ad hoc bioethicist/clergyrepresentative) and an attorney for the NSGC reviewed the revised document. Noconflicts with the NSGC Code of Ethics were identified in the final document. TheNSGC 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 glycosphingolipidcatabolism resulting from deficient or absent activity of the lysosomal enzymeα-galactosidase A (α-gal A). This enzyme helps to break down and remove gly-colipids (complex sugar–fat substances). The enzymatic defect leads to progressiveaccumulation of the glycolipid globotriaosylceramide (Gb3 or Gl3) or ceramide-trihexoside in the lysosomes in the cells of most organs. This accumulation leads toselective damage of the renal glomerular and tubular epithelial cells, the myocar-dial cells and valvular fibrocytes, neurons of the dorsal root ganglia and autonomicnervous system, as well as damage in the endothelial, perithelial, and smooth mus-cle cells of the vascular system.

Progressive renal insufficiency and cardiovascular disease are causes of sig-nificant morbidity and mortality in Fabry disease, but virtually any organ may beaffected (Desnicket al., 2001; MacDermotet al., 2001a,b). In the predialysis andprekidney transplant era, the average age of death in males was 41 years (Colombiet al., 1967; Wiseet al., 1962). Recently, MacDermotet al.obtained median age atdeath in Fabry disease from cumulative survival curves in a cohort of 51 affectedmales and 32 obligate carrier females. Fifty percent of males with Fabry diseasehad died by age 50 years, and 50% of obligate carrier females died by age 70. Whencompared with the general population, this represents an approximate reductionof 20 years and 15 years respectively in life span (MacDermotet 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% ofcarrier 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 Summaryof Medical Management (Brady and Schiffmann, 2000; Brownet al., 1997; Desnicket al., 2001;a

MacDermotet al., 2001a,b;b,c Rosenberget al., 1980; Stryker and Kreps, 2001; Sybert, 1997)

Clinical features Typical age of onset Management

Neuropathic pain/burning inextremities

Particularly the palms andsoles of the feet

May be constant or episodicSeen in 80%a,b of males and

70% of femalesc

Onset in childhood orearly adolescence

Analgesic medications; acombination of drugs such asDilantin, Carbamazepine, and/orNeurontin may be indicated tocontrol or minimize the intensity ofpain episodes

Avoid situations that may triggersymptoms (e.g., exercise, fatigue,emotional stress, extremetemperature or humidity, fever)

OphthalmologicCorneal dystrophy and opacity

(corneal verticillata)Lenticular abnormalities (Fabry

cataract)Seen in 100% of males and

70–80% of femalesRetinal changes associated with

hypertension and uremia

Usuallyasymptomatic, butmay be detected atany age

Slit-lamp examination is helpful indiagnosis but the cataracts andcorneal abnormalities do notrequire treatment as they rarelyimpair visual acuity

May also enable carrier detectionwhen positive in females withequivocal enzyme test results

AngiokeratomaIndividual punctate angiectases,

dark red to blue-black colorDistribution is most dense

between the umbilicus andknees, on the buttocks andpenis, and in the oral mucosaand underside of the tongue

Not painful and do not itch orblanch with pressure

Seen in 70% of males by age 17,30a–35%c of females (breast,back, trunk, inner thighs)

Usually increase innumber over time

May be seen inchildhood (by age10–20 years)

Argon laser therapy for cosmeticimprovement

Hypohidrosis (acquired)Seen in 56b–66%a of males and

up to 33%c of females

Childhood Avoid extremes of heat, humidity, andphysical exertion

Increase water intakeCardiac disease

Left ventricular enlargement(88%b of males, 19% offemalesc)

Valvular involvement (mostcommonly mitralinsufficiency)

20s and 30s in males;later in females

Monitor with EKG and 2-dimensionaland M-mode echocardiography

Medications for control ofhypertension, conductionabnormalities, angina (as needed)

Conduction defects may necessitatethe use of a pacemaker

Conduction abnormalitiesLater manifestations include

angina pectoris, myocardialischemia and infarction,congestive heart failure

TIA or CVA (24%b of males,22%cof females)

Severe cardiac disease maynecessitate heart transplant

(Continued)

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126 Bennettet al.

Table I. (Continued)

Clinical features Typical age of onset Management

Cerebrovascular diseaseThrombosesTransient ischemic attacksBasilar artery ischemiaAneurysmSeizuresStrokesVascular dementiaWhite matter changesOccurs in <1% of females

Mid-30s Brain MRIPsychometric testingAnticoagulants may be

indicated in patients at riskof stroke/aneurysm

Seizure medications, asappropriate

Renal diseaseProteinuriaHypertensionChronic renal insufficiencyEnd stage renal failure in∼31%b of males and 1–4%a,c

of females

Appears most oftenbetween age 30 and40 years in males

Urinalysis24-h urine collection for total protein

and creatinineGlomerular filtration rateBUNMedications for hypertension (e.g.,

ACE inhibitors)Hemo- or peritoneal dialysis (as

appropriate) and possible renaltransplantation

PsychologicalDepressionDiminished quality of life

May become manifestat any time, butusually evident inadolescence oradulthood

Quality of Life measurement toolsSupportive counseling and

medication, as appropriate

Auditory problemsHearing loss (bilateral,

sensorineural). Seen in∼41%b of males, 23%c offemales. In a cohort of23 males, 78% had abnormalaudiogramsb

Tinnitus (38%b of males, 23%c

of females)Vertigo


AudiogramsHearing aides

Gastrointestinal problemsAcute intermittent abdominal

pain, vomiting, crampsDiarrhea (postprandial)Seen in 33a–69%b of males,

58%cof females


Medication (antidiarrheals, fatabsorption supplements)

Dietary modifications (high fiber diet,avoid fatty foods)

Male infertilityErectile dysfunction

30s or 40s Urological consultation andmedication, as appropriate

Pulmonary involvementAirway obstruction

May be clinicallysilent, althoughoften evident inadulthood

Pulmonary function testingBronchodilators, inhalantsDiscontinue smoking

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due to skewed X-inactivation (nonrandom lyonization). Discordance in expressionof the disease in monozygotic female heterozygotes has been described (Desnicket al., 2001; Levadeet al., 1991). Among males, the clinical manifestations of Fabrydisease usually begin in childhood or adolescence, with recurrent severe pain inthe extremities, angiokeratomas, corneal dystrophy, and episodic fevers. Fabrydisease often causes renal failure, requiring renal dialysis and kidney transplant, amajor cause of morbidity and mortality in this patient population. Cardiac manifes-tations, usually cardiomyopathy and/or premature coronary artery disease, is an-other leading source of morbidity and mortality for individuals with Fabry disease.Cerebrovascular accidents are common in Fabry disease. Premature death usuallyoccurs from renal failure, or from cardiac or cerebrovascular disease. Table I pro-vides a summary of the medical features and management of Fabry disease.

Neuropathic pain is the most common and debilitating symptom of Fabrydisease. 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). Individualswith Fabry disease use terms such as burning, piercing, sharp, appalling, andagonizing to describe their pain. The pain is often present in the palms and solesof the feet (acroparesthesias), and often radiates to the arms and legs. Neuropathicabdominal pain is also common, and is often accompanied by nausea, diarrhea, andvomiting. A painful crisis can be precipitated by fever, exercise, fatigue, emotionalstress, or rapid changes in the environmental temperature or humidity, or the crisiscan have no precipitating cause (Desnicket al., 2001).

The most common ophthalmologic findings in Fabry disease are corneal dys-trophy and opacity (haziness) with a whorl-like pattern (corneal verticillata). Twotypes of lenticular abnormalities may be seen—a posterior opacity (the “Fabrycataract”) with a spoke-like appearance, and a granular, anterior capsular, or sub-capsular wedge-shaped lipid deposit. The cataracts and corneal anomalies do notimpair visual acuity. Retinal vascular changes associated with hypertension anduremia may occur, including retinal artery thrombosis resulting in blindness. Theconjunctival and retinal vessels may be tortuous (a nonspecific finding), even in theabsence of hypertension, with venous changes being more common than arteriallesions.

Acquired hypohidrosis (decreased sweating, saliva, and tear production fromautonomic nervous system dysfunction) develops in adolescence. This problem isexacerbated by extremes of heat, humidity, and physical exertion.

Because Fabry disease affects multiple organ systems, a multidisciplinaryteam approach is useful (Peterset al., 1997). Referrals to multiple subspecialistsmay be necessary to achieve optimal patient care. Case management can includespecialists in medical genetics, pediatrics, or internal medicine, nephrology, oph-thalmology, cardiology, dermatology, neurology, pain management, organ trans-plant, OT/PT, social work, and psychology/psychiatry. A sample form for clinicalevaluation of an individual with Fabry disease is shown in Fig. 1.

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128 Bennettet al.

Intravenous enzyme replacement therapy is currently in extended clinicalresearch trials awaiting FDA approval. Several reports demonstrate this treat-ment to be a promising approach to the management of the manifestations ofFabry disease (Brady and Schiffmann, 2000; Enget al., 2001a,b; Gahl, 2001;Schiffmannet al., 2000, 2001). These studies revealed reduction in plasma andtissue globotriaosylceramide levels in the vascular endothelium of the kidney,skin, and heart as surrogate markers of clinical benefit. There are also indicationsof decreased pain and improvement in quality of life. Other genetic therapies arealso being considered for Fabry disease, such as substrate deprivation, chaperone-mediated enzyme enhancement, and gene therapy (Abeet al., 2000; Desnick,2001).

Genetic Diagnosis and Genotype/Phenotype Correlations

Fabry disease is considered highly penetrant in males although variable inits expression. In affected males, the clinical diagnosis is confirmed byα-gal Adeficiency. The majority of males with Fabry disease have absent or very lowenzyme activity (1–2% of normal) and classical phenotype with multiple diseasemanifestations. Some males with clinical features of Fabry disease have residualα-gal-A enzyme activity (level of enzyme activity 1–10%) (Desnicket al., 2001).Several males were described with higher residual enzyme activity, approximately3–10% 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 cardiomyopathyof unknown etiology was discovered (Desnicket al., 2001).

About 60–70% of females heterozygous for a Fabry disease mutation havesome disease manifestations, and approximately 10% of these heterozygous fe-males have severe manifestations, similar to the phenotype in males (Desnicket al.,

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130 Bennettet al.

Fig. 1. (Continued)

2001; MacDermotet al., 2001b). Enzyme activity is not reliable for determiningfemale carrier status because women who are obligate carriers have variable levelsof alpha-gal A that can overlap with enzyme levels found in healthy controls.

Theα-gal A locus is on Xq22.1. The gene is 12 kb in length and contains sevenexons. More than 200 mutations have been identified in theα-gal Agene (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 (Ashleyet al., 2001; Enget al., 1997; Topalogluet al., 1999). Therefore it is necessary tosequence the entireα-gal Agene and flanking regions to identify the Fabry diseasemutation in a family. The limitations of gene sequencing include limited clinicalavailability from CLIA-approved laboratories, labor intensity, the possibility thatnot all mutations will be identified, and the possible identification of sequencevariations of uncertain significance. Several laboratories offer enzymatic testingfor Fabry disease (refer to http://biochemgen.ucsd.edu/). Currently, the availabilityof direct DNA sequencing for diagnostic testing in the United States is limited toa few CLIA-approved laboratories (refer to www.genetests. org).

A suggested flow diagram for genetic testing for Fabry disease is shown inFig. 2. De novo mutations have been documented, and therefore the absence offamily history suggestive of Fabry disease does not rule out the diagnosis of Fabrydisease (Germainet al., 2001). The rate of new mutations is unknown. In a recentsurvey of 67 families with Fabry disease in the United Kingdom, 20 males had nofamily history of the disease (MacDermotet al., 2001a).

Of the 150 mutations identified by Desnick and colleagues, 71.6% of themutations were coding region missense or nonsense mutations, 6.5% were mRNAprocessing defects, and 21.9% were large or small gene rearrangements (Desnicket al., 2001). Identification of a gene mutation is diagnostic but does not predict theseverity of disease. Mutations inR112H, R301Q, andG328Rhave been describedin individuals with primarily cardiac manifestations, although they also have beenreported in patients with classical disease symptoms (Ashton-Prollaet al., 2000;Desnicket al., 2001).

Differential Diagnosis

Although the individual features of Fabry disease may not be specific, theyshould lead to a high index of suspicion particularly in the presence of a familyhistory of Fabry disease. Table II lists some of the conditions to consider in thedifferential diagnosis of Fabry disease.

Many conditions have symptoms similar to Fabry disease. Angiokeratomasare not pathognomonic of Fabry disease. Neuropathic pain (pain associated with thecranial nerves, or the peripheral or autonomic nervous system) is associated withmany different acquired and inherited conditions including diabetes mellitus andtrigeminal neuralgia. Some individuals with Fabry disease pain crises have beenmisdiagnosed with erythromelalgia. There are also multiple causes of prematurecardiovascular disease and cardiomyopathy.

Kanzaki disease is a rare autosomal recessive condition caused by deficiencyof α-N-acetylgalactosaminidase (α-NAGA). The disease manifestations begin inpuberty with clinical findings of angiokeratoma corporis diffusum, peripheral

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Table II. Conditions to Consider in the Differential Diagnosis of Fabry Disease (Desnicket al., 2001;Dinc et al., 2000; Kodomaet al., 2001; Sybert, 1997)

Symptom Condition Inheritance

Angiokeratoma Fucosidosis ARAspartylglucosaminuria ARGM1 gangliosidosis ARGM2 gangliosidosis ARSialidosis ARGalactosialidosis ARLate infantile gangliosidosis ARBeta-mannosidosis ARKanzaki disease ARPetechiae Multiple causesAngiokeratoma of Fordyce AcquiredAngiokeratoma of Mibelli AcquiredAngiokeratoma circumscripta Acquired

Hypohidrosis Hypohidrotic ectodermaldysplasias

Several, AD

Numbness/tingling/pain Kanzaki disease ARFamilial Mediterranean fever ARAcute intermittent porphyria ADMultiple sclerosis (especially

in females)Multifactorial

Rheumatic fever MultifactorialErythromelalgia

(erythermalgia)?AD, or secondary

erythromelalgiadue tothrombocythemia

Arthritis, rheumatoid andjuvenile

Multifactorial

Raynaud’s syndrome MultifactorialNeuropathy Many acquired and

genetic causes, withdiabetes mellitusbeing one of themost common

Corneal dystrophy Phenocopy from long-termchloroquine or amiodaronetherapy

Drug induced

Proteinuria, lipiduria, and lamellarinclusions in the lysosomes ofglomerular epithelial cells

Phenocopy from silica dust 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 primarydisease manifestation in Schindler disease is severe central nervous system in-volvement evidenced in the first year of life.) Interestingly, theα-NAGAgene andtheα-gal Agene in Fabry disease have greater than 50% homology, and are thoughtto have evolved from the same gene (Kodomaet al., 2001).

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Incidence

The incidence of Fabry disease is estimated to be 1:117,000 live births inCaucasian males (Meikleet al., 1999). Fabry disease has been identified in allracial groups, and there is no known racial or ethnic predilection.

Fabry disease was diagnosed (by measuringα-gal A activity) in 3% of un-selected male patients with left ventricular hypertrophy (Nakaoet al., 1995), and9% of patients with a diagnosis of nonobstructive hypertrophic cardiomyopathy(Kuhnet al., 1982).

PRIMARY GENETIC COUNSELING CONSIDERATIONS:FABRY DISEASE

Assessment

Ascertain the client’s primary questions and concerns and mutually developa plan to address these concerns.

Medical Family History

A. Using standardized pedigree symbols, obtain at least a three generationpedigree from the consultand or proband (Bennett, 1999; Bennettet 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 relativesof a male proband (i.e., his mother’s siblings and their children, both ofher parents and their siblings and children, and the mother’s maternaland paternal grandparents). Family history of maternal relatives of afemale proband is also important, as is the history of her father andhis relatives.

iii. Note any consanguinity, documenting the exact relationship of unionsbetween relatives on the pedigree (i.e., consanguinity could put femalerelatives at risk for being homozygotes).

B. Verify positive family history with medical records, if possible. Documentresults of enzyme analysis and/or DNA mutation analysis.

C. For female carriers, obtain pregnancy history (gravidity, parity, termi-nation of pregnancy, spontaneous abortion), and potential exposure topossible teratogenic agents (see under Teratogenesis).

D. Maintain family history with respect to the confidentiality of the consul-tand/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 theproblem or event occurred)

Has anyone had an eye exam (called a slit-lamp examination) to look for the nonharmful eyefindings that can be seen in Fabry disease?

Does anyone have any unusual skin findings (such as a rash or birthmark)? If so, describe themand their location on the body.

Does anyone have problems with sweating (not sweating enough), or problems with toleratingextremely hot or cold temperatures?

Does anyone have major gastrointestinal problems such as chronic diarrhea, vomiting, orrecurrent 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 historyof chest pain (angina)? Has anyone died of heart disease? Does anyone have a history ofirregular 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, whathas 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 alcoholor 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 havingaffected offspring.

i. All daughters of an affected male are obligate gene carriers, whereasnone of the affected male’s sons will have Fabry disease. If there isconsanguinity, 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 ofskewed 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 analysisfor potential carrier females.

Psychosocial Issues

A. The rate of depression, alcoholism, marital problems, unemployment,and suicide is high among men with Fabry disease (Abreoet al., 1984;Grewal, 1993). In a cohort of 46 men with Fabry disease, MacDermotet al.(2001b) found that only 57% were currently employed and 17% hadnever had a job because of the diagnosis of Fabry disease.

B. Assess/identify family, peer, and community resources for appropriateservices and/or support, and consider referrals as needed.

C. Assess support services and accommodations in settings for school and/oremployment, particularly because rapid changes in environmental tem-perature and humidity, physical exertion, emotional stress, and fatiguecan exacerbate painful crises (Desnicket al., 2001).

D. Address psychological issues related to genetic diagnosis such as denial,anxiety, anger, grief, survivor and parental guilt, blame, depression, iso-lation, inability to cope, hopelessness, damage to self-esteem, changedrelationship with family of origin, and change in sense of identity, asindicated (Bakeret al., 1998; Weil, 2000; Williamset al., 2000).

E. For an individual affected with Fabry disease, explore the client’s no-tions of sexuality. The angiokeratomas may be a significant source ofembarrassment and psychological stress. A patient in a study at the Na-tional Institute of Health summarized his distress by stating, “I haveangiokeratomas on my genitalia. When you are planning to lose your

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virginity, the last thing you want is something that looks like a venerealdisease” (Stryker and Kreps, 2001). MacDermotet al.(2001a) also founda significant proportion of individuals with angiokeratomas feared initi-ating sexual relationships. Chronic pain and fatigue may also contributeto sexual difficulties (Stryker and Kreps, 2001).

F. Assess patient’s and family’s preconceived notion of affected or carrierstatus. Family members may have an incorrect understanding of the in-heritance, and therefore they may not be aware of their chances to have achild with Fabry disease (Sørensen and Hasholt, 1983). An individual withdiagnostic results that are opposite of his or her preconceived affected sta-tus may be at higher risk for adverse psychological consequences (Resta,2000).

G. For individuals/couples at risk to have a child with Fabry disease, assesstheir feelings about childbearing, prenatal diagnosis, and subsequent op-tions (e.g., pregnancy termination or continuation upon diagnosis of anaffected male fetus, feelings about termination of pregnancy given po-tential treatment options). Assess self-concept as it relates to threatenedparental role (McConkie-Rosell and DeVellis, 2000).

H. Individuals diagnosed with Fabry disease may have seen many healthcare professionals before receiving a confirmative diagnosis. The averagetime to diagnosis is 10 years, with affected individuals typically see-ing 10 specialists before diagnosis (Morgan and d’A Crawford, 1988).There may be an inherent distrust of health professionals because of thisexperience.

I. Address psychological issues arising from the uncertainty of the variableclinical phenotype.

J. Individuals with a tentative diagnosis of Fabry disease who are subse-quently found to not have this condition may have mixed feelings onreceipt of a normal (negative) genetic test result (Williamset al., 2000).For example, siblings of individuals diagnosed with Fabry disease mayhave always thought they would develop the condition, and they may takesome time to absorb the information that they are unaffected. The “sickrole” may have been unconsciously “assigned” to the family member (pre-selection) thereby creating the illusion of control over the randomness ofgene transmission (Resta, 2000). Unaffected siblings may also experiencesurvivor guilt.

K. Make referrals for further psychological counseling as necessary.

PRENATAL DIAGNOSIS

Prenatal diagnosis for determining fetal sex is the first step in prenatal diag-nosis 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 diag-nosis. Because of this, prenatal diagnosis for female fetuses is usually not availablefrom the laboratories offering testing. For male fetuses at-risk for Fabry disease,subsequent enzyme analysis, or DNA mutation analysis (if the mutation has beenidentified in the family) can be performed on chorionic villi (CVS) or culturedamniocytes.

If the family mutation is known, preimplantation diagnosis is feasible.

EDUCATION/HEALTH PROMOTION

A. Discuss the clinical manifestations of Fabry disease in males, and thepossibility that females can be affected.

B. Discuss follow-up recommendations (e.g., identification and testing ofat-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 ordonor sperm, prenatal diagnosis). Include ethical concerns raised bysuch options, if appropriate.

iii. Review costs of genetic testing, and test limitations (e.g., enzymeassay can be normal in carrier females; the percentage of residualα-gal-A enzyme activity does not correlate with clinical severity; andDNA testing may fail to identify a mutation).

iv. Answer questions regarding molecular genetic aspects of Fabrydisease.

D. Be able to answer general questions relating to potential therapy for Fabrydisease, including published trials of enzyme replacement (see underClinical Condition and Medical Management) (Brady and Schiffmann,2000; Enget al., 2001a,b; Gahl, 2001; Schiffmannet al., 2000, 2001).

E. Be prepared to make appropriate referrals for medical evaluations and fur-ther 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 his-tory and genetic risk assessment, and arrangements to follow the medicalprogress 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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140 Bennettet al.

E. Consider making available to the patient a letter to summarize major topicsdiscussed in the genetic counseling session(s), and to facilitate informingtheir family members of their genetic risks (Bakeret al., 1999; Halloweland 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 ifno therapy or intervention is available, or if it is unknown at what age an interventionshould 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; Wertzet al., 1994) raisemultiple concerns about potential emotional damage to the child, as well as possiblediscrimination. Some of the considerations of testing healthy at-risk children forFabry disease are summarized in Table IV.

Studies documenting the effect of genetic testing of children at risk for Fabrydisease have not been published. Testing of seemingly healthy minors for geneticconditions is usually discouraged, unless testing allows for a health benefit due tomedical intervention. Testing for Fabry disease in seemingly healthy at-risk maleswho are minors may be justified, given the subtle early manifestations of Fabrydisease and the high likelihood of disease progression. Early diagnosis allows forcloser 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 oftesting (focus on positive test results)

Potential benefits of testing

Damage to the minor’s self-esteem Resolution of the parent’s (and possibly the child’s)concerns about carrier status

Distortion of the family’s perception ofthe child. Siblings may be treateddifferently depending on geneticstatus

Allow child and family time to adjust to status if test ispositive. No anticipation of developing disease ifresult is negative

Loss of future adult autonomy andconfidentiality for the tested child

Anticipatory guidance such as in choosing physicalactivities and occupation for possibly affected child

Adverse effects on the child’s capacityto form future relationships

Health status is normalized and Fabry disease becomespart of that child’s sense of self

Fear of rejection in forming long-termrelationships. Fear/guilt if personwants biological children

Ability to make informed reproductive decisions

Discrimination (insurance, employment,education, choice of mate)

Decreased premiums for insurance because risk factoreliminated if test result is negative

Increased medical surveillance for“healthy” child (especially forfemales). Child feels labeled

Available at earliest opportunity for medicalintervention including enzyme replacement therapy(when available)

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with the prospect of enzyme replacement therapy. Testing healthy at-risk minorfemales may be more controversial because many female carriers of Fabry diseasewill never have symptoms. It may be appropriate to time genetic testing for Fabrydisease before an adolescent (male or female) becomes sexually active, to assistwith discussions of reproductive risks and options.

Testing Siblings Before Kidney Transplant

Before considering a healthy sibling of a person with Fabry disease as anorgan donor for the affected male, unaffected status should be confirmed by enzymeanalysis or DNA testing. Enzyme analysis or DNA testing should not be initiatedsolely to secure a matched donor. Female carrier siblings should not be used asorgan donors.

Teratogenesis

A careful medication history should be taken for a symptomatic womanwho is planning a pregnancy or who is pregnant to determine if any medica-tions she is taking are teratogenic. Dilantin and carbamazepine are commonlyused for pain symptoms; their potential teratogenic effects should be reviewedwith the client (Holmeset al., 2001). The patient can be referred to a regionalteratogen service for comprehensive information. Listings of such services canbe 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 heterozy-gotes. Because of possible misattributed paternity, carrier status should not beassumed. Confirmation with enzyme analysis or with DNA testing if the muta-tion is known is indicated to provide accurate genetic risk assessment and geneticcounseling. Enzyme analysis in females may not be definitive, and DNA testingis preferred for diagnostic confirmation; ophthalmologic evaluation may also beuseful in establishing carrier status for females (see under Genetic Diagnosis andGenotype/Phenotype Correlations and Fig. 2).

PATIENT RESOURCES

Table V contains a list of patient advocacy groups for Fabry disease.

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142 Bennettet al.

Table V. Advocacy Groups for Individuals and Their Families With Fabry Disease

Resource Address Phone, Fax, Web site

Canadian Organization forRare Disorders (CORD)

P. O. Box 814,Coaldale, Alberta T1M 1M7,Canada

Phone: (403) 345-4544Fax: (403) 345-3948http://www.cord.ca

Fabry’s Disease SupportGroup

10 Broadmeadow Road,Wyke Regis,Weymouth, Dorset DT4 9BS,England

Fabry’s Support Group, Inc. P. O. Box 174,The Basin 3154,Melbourne, Victoria,Australia

Phone: 03 9762 3910Fax: 03 9761 3503

Fabry Support & InformationGroup

P. O. Box 510,Concordia, MO 64020,USA

Phone: (660) 463-1355Fax: (660) 463-1356http://www.fabry.org

Lysosomal Diseases,Australia

Dept. of Clinical Pathology,Women’s & Children’s

Hospital,72 King Road, North

Adelaide,South Australia 5006,

Australia

http://www.lda.org.au

Lysosomal Diseases,New Zealand

1248 High Street,Lower Hutt City 6009,New Zealand

http://www.ldnz.org .nz

Morbus Fabry Bergstrasse 34,Ransbach—Baumbach

56235

Phone:+49 2623-2710Fax:+49 2623-9230 79

NORD—NationalOrganization for RareDisorders

P. O. Box 8923,New Fairfield,CT 06812-8923, USA

Phone: (203) 746-6518Fax: (203) 746-6481http://www.rarediseases.org

DISCLAIMER

Genetic counseling recommendations of the NSGC are meant to assist prac-titioners in making decisions about appropriate management of genetic concerns.Each practice recommendation focuses on a clinical or practice issue, and isbased on a review and analysis of the professional literature. The informationand recommendations reflect scientific and clinical knowledge current as of thepublication date, and are subject to change as advances in diagnostic techniques,treatments, and psychosocial understanding emerge. In addition, variations inpractice, taking into account the needs of the individual patient and the re-sources and limitations unique to the institution or type of practice, may war-rant alternative approaches, treatments, or procedures to the recommendationsoutlined in this document. Therefore, these recommendations should not be con-strued as dictating an exclusive course of management, nor does use of such

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recommendations guarantee a particular outcome. Genetic counseling recommen-dations are not intended to supersede a health care provider’s best medical judg-ment. The listing of patient and professional resources does not necessarily implyNSGC endorsement.

SUMMARY

Without treatment, there is significant morbidity and mortality associatedwith Fabry disease. Given the potential benefits of early medical and psycholog-ical interventions for Fabry disease, genetic counselors need to have increasedawareness about genetic testing, evaluation, and management for Fabry disease.Specific genetic counseling issues in Fabry disease include phenotype and geno-type variability; genetic testing of at-risk siblings before investigation for organdonation; coping with a chronic and painful illness; increased rates of depression,alcoholism, marital/relationship difficulties, unemployment, and suicide; anxietyregarding sexual relationships because of angiokeratomas; mistrust of health pro-fessionals because of years of misdiagnosis; psychological consequences relatedto uncertainty because of disease variability; issues related to presymptomatictesting; issues of “preselection” especially for individuals who are not affected ina family; and consideration of occupational therapy and anticipatory counselingin view of the disease’s natural history. Ethical issues include testing healthy at-risk minors; prenatal diagnosis for a potentially treatable condition; and issues ofmisattributed paternity.

Genetic counselors play a critical role in not only identifying individualsand at-risk relatives with Fabry disease, but in providing genetic testing servicesand counseling. Through on-going education and support, genetic counselors en-courage families to enroll in Fabry disease registries, Quality of Life studies, andclinical trials so that more can be learned about the clinical manifestations ofFabry disease, appropriate modes of evaluation and therapy, and strategies forpsychological support of these families.

ACKNOWLEDGMENTS

The authors are grateful to the many reviewers of the NSGC for their help-ful comments, particularly members of the Genetic Services Committee and theEthics Subcommittee. This work was initiated by the Fabry International ResearchExchange (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 FabrySupport and Information Group (FSIG) has received donations from Genzyme

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144 Bennettet al.

Coporation and Transkaryotic Therapies. The authors and reviewers of this papervolunteered their time, and did not receive an honorarium.

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