RESEARCH REPORT

Social-adaptive and psychological functioning of patientsaffected by Fabry disease

Dawn Alyssia Laney & Daniel J. Gruskin &

Paul M. Fernhoff & Joseph F. Cubells & Opal Y. Ousley &

Heather Hipp & Ami J. Mehta

Received: 25 August 2009 /Revised: 9 November 2009 /Accepted: 26 November 2009# SSIEM and Springer 2010

Summary Fabry disease (FD) is an X-linked lysosomalstorage disorder caused by the deficiency of alpha-galactosidase A. In addition to the debilitating physicalsymptoms of FD, there are also under-recognized andpoorly characterized psychiatric features. As a first steptoward characterizing psychiatric features of FD, weadministered the Achenbach adult self report question-naire to 30 FD patients and the Achenbach adultbehavior checklist questionnaire to 28 partners/parents/friends of FD patients. Data from at least one of thequestionnaires were available on 33 subjects. Analysisfocused on social-adaptive functioning in variousaspects of daily life and on criteria related to theDiagnostic and statistical manual of mental disorders IV(DSM-IV). Adaptive functioning scale values, which pri-marily measure social and relationship functioning and

occupational success, showed that eight FD patients (sixfemale and two male) had mean adaptive functioningdeficits as compared to population norms. Greater rates ofdepression (P<0.01), anxiety (P=0.05), depression andanxiety (P= 0.03), antisocial personality (P<0.001),attention-deficit/hyperactivity (AD/H; P<0.01), hyperac-tivity–impulsivity (P<0.01), and aggressive behavior (P=0.03) were associated with poorer adaptive functioning.Decreased social-adaptive functioning in this study wasnot statistically significantly associated to disease severity,pain, or level of vitality. This study shows for the first timethat FD patients, particularly women, are affected bydecreased social-adaptive functioning. Comprehensivetreatment plans for FD should consider assessments andinterventions to evaluate and improve social, occupational,and psychological functioning. Attention to the behavioralaspects of FD could lead to improved treatment outcomeand improved quality of life. Individuals affected by Fabrydisease exhibited social-adaptive functioning deficits thatwere significantly correlated with anxiety, depression,antisocial behavior, and AD/H problems in a sampling ofour male and female patients aged between 18 years and59 years.

AbbreviationsABCL adult behavior checklistAD/H attention-deficit/hyperactivityASEBA Achenbach system of empirically based

assessmentASR adult self reportBPI brief pain inventoryDSM-IV Diagnostic and statistical manual of mental

disorders IVERT Enzyme Replacement TherapyFD Fabry disease

Communicated by: Alberto B. Burlina

References to electronic databases: OMIM: Fabry disease: OMIM301500, α-galactosidase A, EC 3.2.1.22

D. A. Laney (*) : P. M. Fernhoff : J. F. Cubells :H. Hipp :A. J. MehtaDepartment of Human Genetics, Emory University,2165 North Decatur Road,Decatur, GA 30033, USAe-mail: dawn.laney@emory.edu

D. J. GruskinGenzyme Corporation,500 Kendall Street,Cambridge, MA 02421, USA

O. Y. OusleyDepartment of Psychology, Emory University,2165 North Decatur Road,Decatur, GA 30033, USA

DOI 10.1007/s10545-009-9025-6J Inherit Metab Dis (201 ) 3 (Suppl 3):S73–0 3 S81

/Published online: 20 January 2010

α-gal A α-galactosidase AGL3 globotriaosylceramideMSS Mainz severity scoreSAFD social-adaptive functioning deficiency

Introduction

Fabry disease (FD) is an X-linked genetic lysosomal storagedisorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (α-gal A; EC 3.2.1.22). (Kampmann et al.2002; Desnick et al. 2003). The lack of α-gal A enzymeresults in the storage of globotriaosylceramide (GL3), a fattysubstance, in the lysosomes of cells throughout the body.Symptoms and complications of FD include severe pain inthe hands and feet, the inability to sweat, fatigue, a pinkish-purple skin rash, frequent diarrhea and constipation, kidneyfailure, cardiovascular problems, hearing loss, strokes, andearly death (Brady et al. 2001; MacDermot et al. 2001;Desnick et al. 2003). Although elevated levels of GL3 arepresent from childhood, the rate and scope of diseaseprogression and overall phenotype in adults vary widelyfrom individual to individual.

Historically, the focus of FD assessment, monitoring,and treatment has been on somatic manifestations of thedisease, with very little attention being paid to psychiatricmanifestations in patients. Miners et al. and Gold et al. haveboth reported that men affected by FD tend to have a poorhealth-related quality of life, and Street et al. reportedsimilar results for women (Gold et al. 2002; Miners et al.2002; Street et al. 2006). Several small-scale case serieshave described associations between FD and psychiatricsymptoms such as generalized anxiety, depression, andpanic attacks. One study of 33 male patients affected by FDfound that 18% (six patients) developed psychiatricdisorders, primarily depression (Grewal 1993). Anothercase series found that four women with FD met the criteriain the Diagnostic and statistical manual of mentaldisorders IV (DSM-IV) for major depressive disorder(Sadek et al. 2004). Following a literature review ofpsychiatric studies on Fabry disease in the literature, Mulleret al. concluded that there have been no systematic,prospective studies made of the neuropsychological andpsychiatric manifestations of FD or of the etiology of suchdifficulties (Muller et al. 2005). In 2007 a systematic surveyof female Fabry patients by Wang et al. found a globallyreduced quality of life, with a large proportion (62%; 21/33) reporting either symptoms of depression or treatmentwith antidepressants, and 39% reporting generalized anxi-ety (Wang et al. 2007). In 2008 Wilcox et al. found adecreased quality of life in the Fabry disease population ascompared with that of the general population, particularlyin men aged between 18 and 25 years of age and women

aged 25 to 35 years (Wilcox et al. 2008). In the largestpsychiatric study of FD to date, Cole et al. assessed 296 FDpatients with the Center for Epidemiological Studiesdepression scale (CES-D), a well-validated and widelyused questionnaire that assesses current depressive symp-toms. They found that 83 (46%) of 296 FD patients metcriteria for clinically significant depressive symptoms, with50 of those patients (28%) exhibiting severe depressivesymptoms (Cole et al. 2007). Those data strongly suggestthat FD patients are at high risk for developing depression.To date, however, little work has focused on the impact ofFD-related psychiatric symptoms on adaptive functioning.

Adaptive functioning refers to the effectiveness withwhich an individual copes with the daily demands ofeveryday tasks and responsibilities as parents, children,students, caregivers, and employees. Two fundamentalaspects of adaptive functioning are personal independenceand social responsibility. Adaptive function can be mea-sured through questionnaires and evaluations focused on anindividual’s relationships, job, education, substance use,psychological issues, and coping skills. Previous studies ofpatients with disorders such as attention deficit andhyperactivity disorder (ADHD) suggest that individualswith identical intelligence quotients (IQs) might have verydifferent levels of skills in completing everyday tasks and,accordingly, will require different treatment plans toimprove adaptive functioning (Stavro et al. 2007). Anec-dotal evidence in FD points towards a high prevalence ofdifficulties in performing the daily tasks of living, keeping afull time job, and adhering to medical advice. Many FDpatients have difficulty completing tasks and paperwork(even with significant assistance) that could provide themwith financial and emotional help. Standard-of-care treat-ment for FD requires bi-weekly infusions of replacementenzyme. Anecdotal reports suggest that some FD patientsdo not adhere well to such treatment, despite the adversehealth effects of their missing infusions (West and LeMoine2007). Extensive evidence suggests that depressive symp-toms are associated with poor treatment adherence incommon chronic disorders such as diabetes mellitus,(Katon et al. 2009) and coronary artery disease (Khawajaet al. 2009). Those data, together with the evidence that FDis associated with substantially elevated risk for depression,suggests that poor treatment adherence, and, more general-ly, poor adaptive functioning associated with depression,might be important barriers to the optimization of care forpatients with FD. We therefore undertook a cross-sectional,descriptive study of social-adaptive functioning in a clinicalsample of FD patients. We hypothesized that FD wouldassociate with poor adaptive functioning, and, furthermore,that such functioning would be poorest in those exhibitingclinically significant evidence of depression, anxiety, orpanic disorders.

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Methods

Patients and recruitment

The Emory Lysosomal Storage Disease Center regularlyfollows approximately 100 patients affected by Fabry disease.Approximately 40 of these patients are between the ages of18 years and 59 years. The inclusion criteria required patientsto have a confirmed and documented diagnosis of Fabrydisease, a willingness to provide informed consent andcomplete the study questionnaires, and an age between18 years and 59 years. Anyone who was aged under 18 yearsor over 59 years was excluded from the study, because thescales used were validated for ages 18–59 years. Afterobtaining approval from the Emory Institutional ReviewBoard, every eligible adult patient and his or her accompa-nying family member or friend were invited to participate inthe study. The subjects were approached at the end of theirannual genetics appointment and had the option tocomplete the questionnaire on site or at a later time. Ifsubjects chose to complete the questionnaire on site, theywere given unlimited time and a private room to fill out theassessment after their clinical appointment. If subjectschose to complete the questionnaire off site, they wereprovided with a postage-paid, addressed envelope in whichto return the questionnaire via mail. A reminder telephonecall was placed approximately 4 weeks later to those whohad not returned a questionnaire. One individual, who washospitalized for the treatment of severe depression soonafter her appointment, was excluded, as the investigatorsfelt that the severity of her symptoms might preclude trueinformed consent.

Primary questionnaire

Adult levels of social-adaptive functioning and psychiatricconditions were measured on the Achenbach system ofempirically based assessment (ASEBA), adult self report(ASR) and adult behavior checklist (ABCL) questionnaires(Achenbach and Rescorla 2003; Achenbach et al. 2005).These instruments use self-report (ASR) or report of aninformant who knows the patient well (ABCL) to assess avariety of domains of psychiatric symptoms and adaptivefunctioning. The decision to use the Achenbach question-naires was derived from the investigators’ experience withthe Achenbach system in other disorders and the validated,comprehensive, quantitative approach to assessing adaptiveand maladaptive functioning in Fabry disease that thequestionnaires offer to researchers. The Achenbach ques-tionnaire set has been used to evaluate adaptive functioningand psychiatric problems in individuals affected by a widevariety of conditions, such as cystic fibrosis, Duchennemuscular dystrophy, inflammatory bowel disease, 22q11.2

deletion syndrome, attention deficit and hyperactivity disor-der, chronic pain, chronic fatigue syndrome, rheumatoidarthritis, congenital adrenal hyperplasia, and autism/autisticspectrum disorders (Howe et al. 1993; Hinton et al. 2006;Väistö et al. 2009; Carpenter et al. 2009; Compas et al. 2006;Gothelf et al. 2007; Gray et al. 2001; Berenbaum et al. 2004;Cubells 2007). Published studies of the ASR and ABCLhave reported findings on ADHD, epilepsy, adults who havebeen operated on for congenital heart disease, adultsfollowing hypospadias surgery, adults who had been of verylow birth weight, survivors of meningococcal septic shock inchildhood, offspring of bipolar parents, obsessive–compul-sive disorder, and Turner syndrome (Todd et al. 2008; Sbarraet al. 2002; van Rijen et al. 2004; Mureau et al. 1997; Hacket al. 2004; Buysse et al. 2007, Roza et al. 2003; vanGrootheest et al. 2007; van Pareren et al. 2005).

The ASEBA forms for adults are designed to assesssocial-adaptive and maladaptive functioning using DSMIV-oriented scales for subjects aged between 18 years and59 years. The norms are designed to be collectivelyrepresentative of the U.S. population’s mix of ethnicities,socio-economic status, urban–rural–suburban residences,and geographic areas. Demographic data, including infor-mation on occupational and educational status, is includedas part of the questionnaire. The scales are scored usingspecialized software. The reliability of the ASR and ABCLquestionnaires is very high in terms of statisticallysignificant test–retest correlations at P<0.1 and changes inthe DSM-oriented mean scores over periods of 1–2 weeksat 0.83 on the ASR and 0.85 on the ABCL (Achenbach andRescorla 2003). The validity of the DSM-oriented andadaptive function scales on the ASR and ABCL issupported by the questionnaires’ ability to discriminatesignificantly between referred and nonreferred samples andtheir identification by experts as being very consistent withDSM-IV diagnostic categories. The manuals for theASEBA instruments provide detailed data that support thecontent validity, criterion-related validity, and constructvalidity of the instruments (Achenbach and Rescorla 2003).Scale scores are normed by gender and age group. Thescores are then categorized as normal (below the 93rdpercentile), borderline clinical (93rd to 97th percentiles), orclinical (above the 97th percentile) for the DSM-IVdiagnostic categories. Scores in the borderline clinical andclinical range suggest that subjects’ conditions should beevaluated to determine if they meet diagnostic criteria.

Comparisons between an adult’s self-reported adaptiveand psychological functioning provide the opportunity forpatient data to be examined from two perspectives. Themean cross-informant agreement between the ASR asreported by the subject and the ABCL reported byfriends/family members is 0.38 for the DSM-oriented scales(P<0.001) (Achenbach and Rescorla 2003). This is the

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same median r as that found by Klonsky in 2002 for tenstudies of r values between self reports and other reports ofDSM personality disorders (Klonsky 2002). Of note, in theAchenbach system, adaptive functioning is only calculatedfrom the ASR, as such correlations are not available foradaptive functioning (Achenbach and Rescorla 2003).

The ASR includes 208 self-assessed questions which arecompleted by the primary subject. The ABCL has 152questions, which are completed by a close family memberor friend, about the patient’s functioning. Through theseASEBA questionnaires, information can be collected onseveral psychiatric conditions from the perspectives ofmultiple informants, including the patient themselves. Thedata can then be combined into a single report.

Supplemental questionnaires

The brief pain inventory (BPI) questionnaire is used toquantify the degree of pain and the interference by pain inthe patient’s life over a specified period of time (Cleelandand Ryan 1994) The BPI also asks patients to quantify theirpain relief, pain quality, and perception of the cause of painusing a numeric rating scale. On a scale from 0 to 10, 0indicates ‘no pain’ and 10 indicates ‘pain as bad as can beimagined’. The questionnaire has demonstrated respectablereliability over short intervals of time and is the standard-of-care instrument of pain assessment for Fabry disease (Cleeland2002; Schiffmann and Scott 2002; Hoffman et al. 2005,2007) This questionnaire is routinely given to the Emorypatient population annually as part of the Emory InstitutionalReview Board (IRB)-approved Fabry registry protocol tocomplete as they wait to be checked in and seen in clinic.

We used the short-form 36-item health survey (SF-36)questionnaire to quantify the patient’s vitality specificallyas an ad hoc measurement of fatigue levels over a specificperiod of time. The SF-36 questionnaire is a 36-item surveythat measures a patient’s self-reported quality of life. Thescores from the questionnaire provide summary measure-ments of physical and mental health/well being. It alsoprovides eight subcomponent scores, which include phys-ical functioning, role-physical, bodily pain, general health,vitality, social functioning, role-emotional, and mentalhealth. The SF-36 is a reliable, validated questionnaireand is used routinely for patients affected by Fabry disease(Hoffman et al. 2005).

Disease severity

In this study we utilized the Fabry-specific Mainz diseaseseverity score (MSS) as an objective measurement ofdisease severity. The MSS was designed in 2004 to providea general estimate of disease severity at one point in time,and it has been used in several peer-reviewed, published

studies of Fabry disease (Whybra et al. 2004; Beck 2006)The MSS has items which are scored by body system andthen added to give a total Fabry disease severity score. Thescore is then divided into mildly affected (less than 20),moderately affected (20 to 40), and severely affected (above40). Although the MSS cannot capture all aspects of thedisease’s severity and change in status over time, the scorehas been effective in the measurement of disease severity atone point in time in our patient population. Chart review ofour patient population’s disease status as determined by theclinical lysosomal storage disease (LSD) team agreed withtheir overall classification by the MSS. In other words, forpatients who were classified as severely affected, the MSScaptured all subjects with end organ damage, such as renalfailure, significant cardiac disease, and/or severe andcontinued pain. The moderately affected subjects werecharacterized by chronic mid-level pain, proteinuria, anxi-ety, mild to moderate cardiac arrhythmias, moderategastrointestinal issues, and chronic fatigue. The mildlyaffected subjects were characterized by fatigue, mildergastrointestinal issues, and mild chronic pain.

Treatment status

Detailed chart review provided information related todemographic data and information about any treatmentwith enzyme replacement therapy, antidepressants, and anti-anxiety medications. Review of the annual patient visitsalso provided the patients’ subjective impressions of theirlevels of depression, anxiety, fatigue, and pain.

Statistical analysis

The raw data obtained from the ASR and ABCL wereentered into the assessment data manager (ADM) ASEBAscoring software (version 7.0) which scores the forms,displays individual profiles, and produces narrative reports,including scores for critical items, plus cross-informants.The report included scores from the DSM-oriented scalesfor depressive problems and anxiety problems as well asfrom an adaptive functioning scale, which assesses socialfunctioning (ASR, ABCL), and occupational functioning(ASR only). The mean scores for adaptive functioning werecalculated for all patients who had completed an ASR andthen classified as normal, borderline clinical, or clinical. Thepatients with borderline clinical or clinical adaptive function-ing deficit were considered to have social-adaptive function-ing deficiency (SAFD). The relationships between SAFD andseveral concomitant psychiatric symptom clusters wereanalyzed. Continuous variables were analyzed using samplet-tests for equality of means, and categorical variables wereanalyzed using the Fisher’s exact test (two-sided). P valuesless than 0.05 were considered to be statistically significant.

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P values were reported exactly, or as <0.01 or <0.001. Noadjustments were made for multiple comparisons.

Results

A total of 30 patients affected by FD completed the ASRquestionnaire, a response rate of 81% (30/37). Two patientsdeclined to participate, and four consenting patients didnot complete the questionnaire. One individual, who washospitalized to treat severe depression soon after herappointment, was excluded, as the investigators felt thatthe severity of her psychiatric symptoms could have com-promised true informed consent. Twenty-seven friends/family members completed the ABCL. Of the 27 ABCLquestionnaires completed, three were on patients who didnot complete the ASR questionnaire themselves.

Demographic characteristics

Fifteen men with FD (45%) and 18 women with FD (55%)completed the survey. All patients were from the South-eastern region of the USA. A slight majority 20/33 (61%)were married or living with a partner. Twenty one of the 33(64%) patients were being treated with enzyme replacementtherapy (ERT) at the time of evaluation. Twenty five of the33 patients (76%) were employed or in school full time. Ofthe 33 FD subjects, 29 were Caucasian and four wereAfrican–American. The 33 subjects represented 24 differentfamilies with Fabry disease. The mean age of theparticipants was 40 years (range 18–59 years). This wasin line with the mean age of the 3,030 participants that arereported in the Fabry registry: 38.222±15.31 years for menand 42.2±17.50 years for women [Registry Aggregate DataAnnual Report (RADAR) 2009].

Of the 27 friends/family members who completed theABCL questionnaires, three were children, four were parents,two were friends, 12 were spouses, and six were siblings ofthe affected individual. Twelve of these 27 were relatives ofthe subjects who were also affected by Fabry disease.Answers to the self-reported section on race and ethnicityshowed that 24 respondents were Caucasian and threewere African–American. The majority (19) of friend/family respondents were working, although four werestudents and four were on disability benefits. Three of thefour friend/family member respondents on disability bene-fits were affected by Fabry disease.

Prevalence of social adaptive function deficienciesand other psychiatric conditions

Analysis of ASEBA data determined that 8/30 FD patients(26.7%) had mean adaptive functioning scores within the

clinical range of SAFDs on the ASR. When the scoreswere analyzed by gender, it was found that 6/18 (33%)women and 2/12 (17%) men had had mean adaptivefunctioning scores within the clinical range on the ASRand/or ABCL. The age range of women affected by aSAFD was 18–51 years, with a mean of 37 years and amedian of 36 years. The majority of women with anSAFD were moderately affected by Fabry disease (4/6);the remaining two were mildly affected at the time ofthe MSS calculation. The men affected by an SAFDwere aged 23 years and 53 years. One of the men wasconsidered to be severely affected by Fabry disease, andthe other was moderately affected, according to the MSScalculation.

Prevalence of depression, anxiety and otherpsychiatric conditions

Analysis of the DSM-oriented criteria also determined that19/33 FD patients (58%) fell into the borderline to clinicalrange of depression and 13/33 FD patients (39%) fell intothe borderline to clinical range of a generalized anxietydisorder on ASR and/or ABCL. These numbers did notinclude the four patients treated with anti-depressant oranti-anxiety medications who were not found to be withinthe clinical range for depression or generalized anxiety onthe ASR and/or ABCL, as their psychiatric treatment hadbeen optimized. Other psychiatric conditions with a highprevalence in the Fabry patients included avoidant person-ality (12/33, 36%); antisocial personality (8/33, 24%);AD/H (8/33, 24%); inattention (7/33, 21%); hyperactivity–impulsivity (7/33, 21%), and aggressive behavior (7/33,21%). Cross-informant analysis of agreement found that,out of the 15 depressed individuals for whom both the ASRand ABCL had been completed, eight had borderline/clinicaldepression reported by both themselves and friends/relatives(53%). In a similar manner, five out of the nine (56%)individuals for whom both the ASR and ABCL had beencompleted fell into the borderline to clinical range of ageneralized anxiety disorder. This correlation was somewhatbetter than the expected 0.38 reported by Achenbach andRescorla (2003). The presence of depression and generalizedanxiety did not always coincide with the presence of SAFD(Tables 1, 2 and 3).

Prevalence of treatment with anti-depressants/anti-anxiety medication

Eleven of the 33 FD patients (33%) were being treated withanti-depressants or anti-anxiety medications at the time ofevaluation. Four patients being treated with anti-depressantsor anti-anxiety medications were not found to be depressedor anxious on the ASR and/or ABCL.

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Prevalence of pain

Thirty one out of 33 patients (94%) completed the BPIshort form (Cleeland and Ryan 1994). The BPI data foraverage pain had a mean of 3.8, with a standard deviationof 2.3 (range 0–8). Only 4/31 (13%) reported no averagepain.

Associations with poorer social-adaptive function

Statistical analysis revealed that the demographic character-istics (age, gender, occupation, and relationship status) ofthe SAFD patients were not statistically significantlydifferent from those of the patients without SAFDs. Therewas a statistically significant relationship between pooreradaptive function and rates of depression (P<0.01), anxiety(P=0.05), depression and anxiety (P=0.03), antisocialpersonality (P<0.001), AD/H (P<0.01), inattention (P=0.03), hyperactivity–impulsivity (P<0.01), and aggressivebehavior (P=0.03) (Table 1).

Analysis of the data of patients not on anti-depression/anti-anxiety medication found that 20% showed pooreradaptive functioning, while 40% of patients on anti-depression/anti-anxiety medication showed an SAFD.However, Fisher’s exact test (two-sided) gave P=0.38, so

it could not be concluded that this trend was significant(Table 2).

Analysis of the data of patients not on ERT show anSAFD in 41.7%, while the data of those on ERT revealedthat only 16.7% exhibited an SAFD. However, Fisher’sexact test (two-sided) a P value of 0.21, so we could notconclude that this trend was significant (Table 2).

Fabry patients with an SAFD did have a mean averagepain score that was three-fourths of a point higher thanthat of patients without an SAFD; however, the standarderror of the difference was large, so we could not con-clude that this difference was statistically significant (P=0.47). Women with SAFDs reported a range of averagepain scores from 2–8, with an average pain score of 5 and amedian of 4. Men with SAFDs reported average pain scoresof 3 and 6. Concomitant conditions and social-adaptivefunction deficiency correlations by gender are shown inTable 3.

SF-36 scores ranged from extremely low levels ofvitality (0) to above normal vitality (>60). Similarly,patients spanned the spectrum of disease severity asmeasured by their Mainz severity score. Mean SF-36and Mainz severity score differences between patientswith SAFDs and those without SAFDs were notsignificant (P=0.84; P=0.45).

Table 1 Demographic characteristics, concomitant conditions, and SAFD correlations. Abbreviation: SEM, standard error of the mean

Factor Borderline of clinical mean social-adaptive functioningdeficit on ABCL or ASR

P

Yes 26.7% (n=8) No 73.3% (n=22)

Demographiccharacteristics

Age [mean (SEM)] 37 (4.3) 41 (2.9) 0.46

Gender [n (%)]

Male 2 (25%) 10 (45.5%) 0.42Female 6 (75%) 12 (54.5%)

Relationship status [n (%)]

Single 2 (25%) 6 (27.3%) 0.53Married 4 (50%) 14 (63.6%)

Divorced 2 (25%) 2 (9.1%)

Concomitant conditions(borderline or clinicalon ABCL or ASR)

Depression [n (%)] 8 (100%) 8 (36.4%) 0<.01

Anxiety [n (%)] 6 (75%) 7 (31.8%) 0.05

Depression Anxiety [n (%)] 6 (75%) 5 (22.7%) 0.03

Avoidant personality [n (%)] 4 (50%) 7 (31.8%) 0.42

Antisocial personality [n (%)] 6 (75%) 1 (4.5%) <0.001

AD/H problems [n (%)] 5 (62.5%) 2 (9.1%) <0.01

Somatic problems [n (%)] 6 (75%) 10 (45.5%) 0.23

Inattention subscale [n (%)] 4 (50%) 2 (9.1%) 0.03

Hyperactivity-impulsivity subscale [n (%)] 5 (62.5%) 1 (4.5%) <0.01

Aggressive Behavior [n (%)] 4 (50%) 2 (9.1%) 0.03

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Patients with poorer social-adaptive function spanned thespectrum of disease severity as measured by their Mainzseverity score. No correlation was found in the 31 subjectsbetween presence of poor social-adaptive function and theirMainz severity category of mild, moderate, or severe.(Spearman’s ρ=0.24 and P=0.19)

Discussion

This paper reports for the first time the presence of adaptivefunction deficits in patients with Fabry disease and theircorrelation with depression, anxiety, antisocial personality,AD/H, hyperactivity–impulsivity, and aggressive behavior.These findings suggest that the full neuropsychologicalimpact of Fabry disease on the day-to-day activities ofliving is underappreciated, or at least not yet wellunderstood. In addition, the increased representation ofwomen affected by Fabry disease with an SAFD suggeststhat women affected by Fabry disease may be particularlyat risk. Our results emphasize that defining and optimizingmanagement of psychiatric issues, with particular emphasis

on adaptive functioning, may be important elements indesigning the overall treatment of patients with FD.

In addition to the presence of SAFDs, 58% of thepatients examined exhibited scores in the clinical range ofdepression and 39% of patients in the borderline to clinicalrange of a generalized anxiety disorder on ASR and/orABCL. The rate of clinically significant depressive symp-toms was slightly higher than the 46% of FD patientsreported to have such symptoms by Cole et al. (2007).However, given the different methods used in our studycompared with those in the study by Cole et al., theagreement in rates of symptoms was more impressive thanthe difference. To the degree that our sample did show ahigher proportion of clinically significant depressive symp-toms, the difference may have been attributable, in part, tothe greater proportion of women in our sample.

As with any chronic disease, there are multiple factorscontributing to poorer adaptive functioning and psychiatricdisease in FD. The data from our study showed that theoften overlooked neuropsychiatric factors may play asubstantial role in poor adaptive function, as psychiatricsymptom scores correlated significantly with poor adaptive-

Table 2 Enzyme replacement therapy, anti-depressant and anti-anxiety medications, and SAFD correlations

Factor Borderline of clinical mean social-adaptive functioningdeficit on ABCL or ASR

P value(Fisher’s exact test)p-value

Yes 26.7% (n=8) No 73.3% (n=22)

On anti-depression/anti-anxietymedication [n (%)]

No 16 (80%) 4 (20%) 0.38Yes 6 (60%) 4 (40%)

On ERT [n (%)] No 7 (58.3%) 5 (41.7%) 0.21Yes 15 (83.3%) 3 (16.7%)

MAINZ score category [n (%)] Mild 6 (75%) 2 (25%) 0.25Moderate 11 (68.8%) 5 (31.3%)

Severe 4 (80%) 1 (20%)

Table 3 Concomitant conditions and social-adaptive function deficiency correlations by gender

Condition Women (n=18) Men (n=12)

Yes 33.3% (n=6) No 66.7% (n=12) P Yes 16.7% (n=2) No 83.3% (n=10) P

Depression [n (%)] 6 (100%) 5 (41.7%) 0.04 2 (100%) 3 (30%) 0.15

Anxiety [n (%)] 4 (66.7%) 4 (33.3%) 0.32 2 (100%) 3 (30%) 0.15

Depression/Anxiety [n (%)] 4 (66.7%) 3 (25%) 0.14 2 (100%) 2 (20%) 0.09

Avoidant personality [n (%)] 2 (33.3%) 5 (41.7%) 0.99 2 (100%) 2 (20%) 0.09

Antisocial personality [n (%)] 4 (66.7%) 1 (8.3%) 0.02 2 (100%) 0 (0%) 0.02

AD/H problems [n (%)] 3 (50%) 2 (16.7%) 0.27 2 (100%) 0 (0%) 0.02

Somatic problems [n (%)] 4 (66.7%) 1 (8.3%) 0.02 2 (100%) 9 (90%) 0.99

Inattention subscale [n (%)] 2 (33.3%) 1 (8.3%) 0.24 2 (100%) 1 (10%) 0.05

Hyperactivity-impulsivity subscale [n (%)] 4 (66.7%) 1 (8.3%) 0.02 1 (50%) 0 (0%) 0.17

Aggressive Behavior [n (%)] 2 (33.3%) 2 (16.7%) 0.57 2 (100%) 0 (0%) 0.02

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function scores. Somewhat surprisingly, our analysis ofpain, disease severity, and vitality did not find anystatistically significant correlations between these parame-ters and adaptive dysfunction; however, it should be notedthat only two out of the eight subjects with an SAFD weremildly affected and that the two affected men weremoderately and severely affected by Fabry disease basedon the MSS. An exploration into average pain as measuredby the BPI did find that subjects with SAFDs did haveaverage pain of between 2 and 8, but the FD subjects withoutSAFDs reported increased average pain as well. A larger,long-term study of these factors may reveal that aspects ofthese variables carry more weight than found here.

Our results emphasize the complexity of evaluatingpsychiatric symptoms and adaptive functioning in thecontext of FD. Other sets of measures are interwoven intothe complicated network of a chronic disease that involvespain, depression, anxiety, fatigue, numerous somatic healthissues, multiple affected family members, and lifetimeintravenous treatments.

Since this work suggests that many FD patientsexperience difficulty in tasks of daily living, it may helpexplain the challenges often faced when getting patientstested and treated, as well as the anecdotal high rate ofnoncompliance with treatment and assessments. As theadaptive functioning disorders had a greater likelihood ofoccurring in patients with depression and anxiety, perhapsconcentrated treatment of psychiatric conditions couldresult in increased quality of life and better adherence totreatment. These factors should be further explored in alarge-scale clinical trial.

There are several limitations to this study. The ASEBAquestionnaires only assess the patient at one point in timeand is based on patients’ self reports and/or reports byfamily members/friends. Other approaches, such as directinterview, might yield a more detailed picture of presentdifficulties, as well as lifetime history of psychiatricdifficulties. All the subjects were from a single site withina southeastern U.S. catchment area, and, although there wasa good urban/suburban/rural mix, most of the subjects wereCaucasian. Our clinical sample, therefore, might not havebeen representative of the overall population of FD patients.Despite our attempts to enroll all our adult patients, wewere unable to attain full ascertainment of our clinicsample. Our impression is that the incomplete ascertain-ment might have skewed the sample towards the moremildly affected subjects. For example, two male subjectswhom clinicians strongly felt exhibited difficulty withstandard daily tasks chose not to participate in our study,citing the length of the questionnaire as an obstacle. Anadditional patient, who was affected by depression to thepoint of needing hospitalization, was excluded for ethicalreasons. An additional limitation of the study was that some

individuals completed the questionnaires in the clinic andsome at home, which might have introduced biases into thedata. Although the subjects and their friends/family weregiven the option as to the timing of completing the survey,those who filled out the questionnaires in front of eachother might have responded differently from those who didso alone. There was also some overlap between severalsubjects who were representing the same family andmutations; this raises the possibility of confoundinghereditary and environmental factors for which our statis-tical analysis did not correct. Many of these biases can beeliminated by the creation of a larger scale, multi-centerclinical trial of SAFD and related psychiatric conditions.

The high prevalence of social-adaptive functioningdisorders in patients affected by Fabry disease in compar-ison with the unaffected population underscores the needfor regular psychological evaluation and treatment to beadded for all patients with Fabry disease, to increase theirmedical compliance and quality of life. Further comparisonstudies are needed to elucidate whether the high prevalenceis a manifestation of Fabry disease or due to the increasedburden of dealing with a chronic disease. Healthcarepractitioners should be aware of the psychiatric symptomsand their prevalence in FD patients and systematically offerpsychiatric therapy and/or medication to their Fabrypatients. Comprehensive treatment plans should considertherapies to improve social, occupational, and psycholog-ical functioning, which could lead to improved treatmentcompliance, daily functioning, and quality of life.

Acknowledgements The authors thank Andrea Knezevic in theEmory University Department of Biostatistics in the Rollins School ofPublic Health for her assistance with statistical analysis. They alsothank all the individuals who participated in this study for their candoron a difficult and personal subject.

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