Heterozygous Fabry Disease Females Are Not Just Carriers, But Suffer From
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1 Heterozygous Fabry Disease Females Are Not Just Carriers, But Suffer From Significant Burden of Disease And Impaired Quality of Life Raymond Wang, M.D. Children s Hospital of Orange County Division of Metabolic Disease
2 abry Disease Background Inheritance: X-linked recessive disorder that affects males; females unaffected Etiology: deficiency of α-galactosidase Function: degradation of glycosphingolipids Pathophysiology: glycosphingolipid accumulation in tissues, especially the vascular endothelium
3 linical Manifestations of Fabry Disease NS / PNS (Cognitive function reserved) Stroke Acroparesthesias ( Burning sensation of the hands and feet ) Anhidrosis / hypohidrosis with subsequent heat intolerance Decreased vibration sense ulmonary Small-airway infiltration Abnormal gas exchange ardiac Microvascular myocardial ischemia i Conduction abnormalities Valvular insufficiency Concentric, non-obstructive left ventricular hypertrophy enal Proteinuria / microalbuminuria Progressive loss of GFR renal failure From Warnock, 2005 From Seino, 2005 From Whybra, 2001
4 ignificance & Methods of Study Women with α-galactosidase mutations were, until recently, thought to be asymptomatic carriers Cedars-Sinai Medical Center is largest referral center for Fabry disease in the Southwestern United States Retrospective chart review was conducted to quantify the degree of involvement and severity of symptoms in women Categorical variables reported as percentages Categorical variables reported as percentages (proportions); continuous variables reported as mean (median) ± 95% C.I.
5 emographic Data of Cohort N: 44 women Age: 46.1 (48) ± 5.3 years Age of symptom onset: 13.8 (10) ± 3.7 years Age of diagnosis: 29.5 (27) ± 6.6 years Acroparesthesias as first symptom: 76% (16 / 21) Diagnosed because of family history: 76% (31 / 41) Diagnosed because of symptoms: 24% (10 / 41) All patients confirmed to be heterozygous for Fabry mutations
6 eurologic Involvement in Fabry Heterozygotes Stroke: 22% (8 / 36) Peripheral neuropathy Acroparesthesias: 65% (26 / 40) Anhidrosis: 60% (25 / 42) Heat intolerance: 49% (19 / 39) Decreased vibration sense: 79% (33 / 42)
7 ulmonary Involvement in Fabry Heterozygotes Spirometry indicates small-medium medium airway disease FEF : 71.8% (76) ± 13.2 predicted Abnormal noninvasive exercise testing maximum oxygen uptake: 78.5% (79.5) ± 9.8 predicted heart rate: 88.7% (88) ± 7.5 predicted diastolic blood pressure: 69% (18 / 26) 25.3 (19) ± 63mmHg 6.3
8 ardiac Involvement in Fabry Heterozygotes Angina: 28% (10 / 36) Hypertension: 43% (16 / 37) Resting bradycardia: 36% (14 / 39) Mitral and/or aortic insufficiency: 58% (18 / 31) Left ventricular hypertrophy: 24% (8 / 33)
9 enal Involvement in Fabry Heterozygotes End-stage Renal Disease: 12.5% (5 / 40) Reduced Creatinine Clearance: 90.4 (86.8) 8) ± 21.7 ml/min/1.73 m 2 CrCl < 90 ml/min/1.73 m 2 : 58% (21 / 36) CrCl < 60 ml/min/1.73 m 2 : 19% (7 / 36) Proteinuria / microalbuminuria 24-hr or random urine protein > 300 mg / 24 hr: 28% (5 / 18) 24-hr or random urine microalbumin > 30 mg / 24 hr: 80% (8 / 10)
10 paired Quality of Life in Fabry Heterozygotes Fatigue: 59% (24 / 41) Exercise intolerance: 83% (33 / 40) Depression: 62% (21 / 34) Anxiety: 39% (13 / 33) Physical Functionality Score on SF-36 survey: 62.2 ± 13.3 (normal ) BMI > 25 (overweight): 68% (28 / 41) BMI > 30 (obese): 44% (18 / 41)
11 paired Quality of Life
12 abry disease symptom comparison between and Sy ymptom Pre evalence (% %) Anhidrosis Acroparesth Stroke LVH Valvular dys Angina Fatigue Abnl VO2m ESRD Proteinuria Females (*) () Males (**) s thesia ysfunction max a * = data gathered from CSMC Fabry cohort ** = data gathered from MacDermot, JMG 2001 and from Bierer, Respiration 2005
13 onclusion I Heterozygous women with Fabry disease suffer from significant multisystem disease and reduction in quality of life Women were thought to be asymptomatic but clearly not the case from this cohort; other studies in heterozygotes corroborate our findings Symptomatology is greater than expected for random complete inactivation of the normal X-chromosome and α-galactosidase gene Symptomatology is comparable than men with Fabry disease, with a few exceptions Fatigue and exercise intolerance reduced physical functionality and well-being. Depression and anxiety were also common in this cohort, possibly due to effects of chronic pain.
14 onclusion II Heterozygous women with Fabry disease suffer a significant delay in diagnosis Patient complaints consistent with disease (i.e. TIA, chest pain, palpitations, shortness of breath, or burning sensation of the hands and feet) should be fully evaluated, not disregarded Prompt recognition of symptoms results in earlier diagnosis, onset of treatment, and prevention of disease progression / irreversible damage
15
16 cknowledgements William Wilcox, M.D., Ph.D. Alicia Lelis, M.S. Dr. Wang was funded by the American College of Medical Genetics Foundation / Genzyme Corporation Fellowship in Biochemical Genetics CSMC General Clinical Research Center Grant #M01-RR00425 The families that volunteered their time and their stories to make this study possible
17 ymptom comparison between because f family history versus symptoms Neurologic Decreased vibration sense FH: 87% (27 / 31) Sx: 50% (5 / 10) p = 0.026, Fisher s exact test Cardiac Angina FH: 39% (10 / 26) Sx: 0% (0 / 10) p = 0.035, Fisher s exact test
18 ymptom comparison between because f family history versus symptoms Pulmonary % predicted FEF FH: 63 ± 15% Sx: 93 ± 13% p = 0.037, Wilcoxon rank-sum test Renal BUN FH: 14.2 ± 1.9 mg/dl Sx: 32 ± 15.8 mg/dl, p = 0.023, Wilcoxon rank-sum test Serum creatinine FH: 0.84 ± 0.16 mg/dl Sx: 265± mg/dl, p = 0.071, 071 Wilcoxon rank-sum test Creatinine clearance FH: 87.7 ± 10.3 ml/min/1.73 m 2 Sx: 60 ± 25 ml/min/1.73 m 2, p = 0.022, Wilcoxon rank-sum test
19 orrelation between subjective symptoms d abnormalities in exercise testing VO 2max, % of predicted + Fatigue: 70.1 ± 10.4% - Fatigue: 90.3 ± 16.3%, p = 0049(t-test) test) Maximum HR, % of predicted + Exercise intolerance: 83.5 ± 5.5% - Exercise intolerance: 113 ± 31% p = Exercise intolerance: 113 ± 31%, p (Wilcoxon rank-sum test)
20 ther Fabry disease manifestations Angiokeratoma: 22% (9 / 41) Abdominal Cramping: 39% (16 / 41) Postprandial Diarrhea: 43% (18 / 42) Vestibular nerve involvement Tinnitus: 58% (22 / 38) SHNL: 37% (14 / 38)
21 hy do females have significant mptomatology? Unlike all other sphingolipidoses, Fabry disease behaves as a dominant disorder Different organs have different thresholds for enzyme activity below which there is disease (less LVH, renal disease in women vs men) In organs where prevalence of disease is comparable in women and men, perhaps α- galactosidase activity is required in all cells.
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