consider a diagnosis of Fabry's disease

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1 CASE REPORT Unexplained left ventricular hypertrophy: consider a diagnosis of Fabry's disease G.E. Linthorst, A.C. Vedder, B.J. Bouma, L.RC. Dekker, C.E.M. Hollak Lysosomal storage disorders are a group of disorders characterised by the deficiency of a specific lysosomal hydrolase. These diseases are rare, with only a few hundred patients in the Netherlands. Fabry's disease, an X-linked lysosomal storage disorder, is caused by a deficiency ofthe lysosomal enzyme a-galactosidase A which results in, among other things, left ventricular hypertrophy, renal failure and cerebrovascular events. Patients with Fabry's disease, especially males, have a decreased life expectancy. Recent studies have shown that Fabry's disease may be much more common among patients with left ventricular hypertrophy (LVH) than previously thought. Up to 7% ofmale patients with left ventricular hypertrophy and up to 12% of female patients with unexplained LVH were found to suffer from Fabry's disease. Thus, Fabry's disease should be considered in patients with unexplained LVH. This case report summarises the main features ofthe disease. In addition recent developments concerning prevalence, diagnosis and the current available treatments are discussed and an algorithm on who and how to screen for Fabry's disease is presented. (NetkHeartJ2006;14:100-5.) Keywords: lysosomal storage disorders, left ventricular hypertrophy, diagnosis, treatment, Fabry's disease G.E. Unthorst A.C. Vedder C.E.M. Hollak Department of Intemal Medicine B.J. Bouma L.R.C. Dekker Department of Cardiology Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands Correspondence to: G.E. Linthorst Academic Medical Centre, Department of Internal Medicine, Clinical Haematology, F4-224, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands g.e.linthorst@amc.uva.nl Lysosomal storage disorders are a group ofdisorders characterised by the deficiency ofa specific lysosomal hydrolase, which results in the accumulation of substrates within the lysosome.' Due to the increase in the number and size of lysosomes, cell swelling occurs in various organs and this in turn causes organ malfunction and disease. The affected organs vary between the 60 different known lysosomal storage disorders, as do symptoms and complications. Examples oflysosomal storage disorders in which the heart plays a critical role are Pompe's disease (a-glucosidase deficiency), various forms of mucopolysaccharidoses (MPS) and Fabry's disease. Lysosomal storage disorders are rare, with a combined birth prevalence in the Netherlands during the period from 1970 to 1997 of 14 per 100,000 live births.2 Most ofthe lysosomal storage disorders follow a rapidly progressive course and often symptoms evolve during early childhood. As a result, a cardiologist will not often encounter a patient with a lysosomal storage disorder. However, recent developments have shown that one of the lysosomal storage disorders, Fabry's disease, may be much more common among patients with left ventricular hypertrophy than previously thought. This article describes the symptoms of the disease and reviews recently performed screening studies for Fabry's disease among patients with left ventricular hypertrophy. Fabry's disease Fabry's disease is an X-linked disorder caused by the deficiency ofthe lysosomal enzyme alpha galactosidase A (agal). Due to this deficiency specific glycolipids (mainly globotriaosylceramide or GL-3) accumulate in the entire body, but predominantly in the vascular endothelial cells, cardiac myocytes, renal tubular and glomerular interstitial cells.3 Males with this disorder classically suffer in childhood from severe pain in the hands and feet (acroparesthesias), hypohidrosis or anhidrosis and have specific skin lesions of the trunk and genitals, known as angiokeratoma. In most patients accumulation of glycosphingolipids in the cornea (cornea verticillata) can also be demonstrated. These are the classical 100 Netherlands Heart Journal, Volume 14, Number 3, March 2006 Clqpc

2 symptoms ofthe disease. Later in life, patients develop complications due to the chronic ongoing accumulation ofglycosphingolipids in endothelial cells: renal failure, hearing loss, cardiomyopathy (cardiac hypertrophy and rhythm disturbances) and cerebrovascular accidents.3'4 Originally, female carriers were believed to be asymptomatic, but recent data show that females can be affected as well, although they generally develop less severe symptoms compared with male patients. More than 100 different mutations that result in agal deficiency have already been described and currently 22 different mutations are known in the Netherlands. These mutations are often family specific. The disease has a very heterogeneous presentation: even within one family, where affected family members express the same agal A mutation, the disease can show considerable variability.4 The many different mutations and the variability in expression of disease symptoms hamper the identification ofa clear geno-phenotype correlation. Patient A PatientA is a female, now 46 years ofage. She was seen in the outpatient clinic at our hospital for evaluation and treatment offabry's disease. She had had an unremarkable youth, although when asked, she confirmed of having severe pain in her hands and feet during exercise (sports at school) and fever, which started at the age of 10, decreased after puberty and had abated by the age of 20. She had experienced venous thrombosis of the leg and a lung embolism at the age of 30 and 31, respectively, for which no identifiable cause was found (such as hyperhomocysteinaemia, or resistance to activated protein C). At the age of40 she developed hemiparesis and diplopia that lasted for a few hours. Brain MRI showed a vascular lesion ofthe brainstem. A transoesophageal echocardiography performed at that time to exclude a cardiac thrombotic process demonstrated mild hypertrophy (dimensions not specified) and mild mitral regurgitation. Ever since, she has felt tired, and experienced a reduced exercise tolerance. At the age of 45 she reported difficulty in hearing and evaluation showed hearing loss, most predominant in the left ear, which was thought to be due reduced blood flow in the cochlea. A year before being seen in the outpatient clinic one ofher nephews (her sister's son) was found to have Fabry's disease. She went to her local hospital where a diagnosis of Fabry's disease was confirmed. When seen in our outpatient clinic, she recalled that her father had died at the age of 33 of an unknown cause, although she remembered that he had suffered from a renal disease. On physical examination she had numerous angiokeratomas on her abdomen and back. She was slightly overweight, with normal blood pressure (while taking an ACE inhibitor). Additional investigations revealed a severe left ventricular hypertrophy (left ventricular septum 16 mm, left ventricular posterior wall 18 mm) with systolic ventricular obliteration, without outflow. Her creatinine level was 78 pmol/l, with a glomerular filtration fraction of 96 ml/min (near-normal), but with a reduced renal blood flow of 322 ml/min (normal >500 ml/min), suggesting glomerular hyperfiltration. Microalbuminuria was present. Hearing evaluation confirmed the previously determined sensoric hearing loss in both ears in the upper frequencies. In summary, this patient showed the classical unrecognised symptoms offabry's disease, which abated over time. Apart from the episodes ofrecurrent thrombosis, all other symptoms and organ complications are consistent with a diagnosis offabry's disease. Because of the multiorgan involvement (brain, heart, ear, kidney) she is currently being treated with human recombinant (rh) agal A infusions once every two weeks. Cardiac features of Fabry's disease Apart from angiokeratoma, which is present in 60% of male and 40% of female patients, physical examination is often unremarkable. The ECG may show bradycardia and evidence of left ventricular hypertrophy (figure 1). In some patients an atrioventricular conduction block is found, requiring pacemaker implantation. There is evidence that this is due to GL-3 accumulation within the conduction system.5 Echocardiography may indicate cardiac hypertrophy, which is usually concentric and does not affect the right ventricle (figure 2). Coronary angiography is almost always normal. Whether this is due to the fact that patients are protected from atherosclerotic lesions, or whether they die prematurely because of other causes is as yet unknown. A study on the natural history of the Dutch Fabry patients, before the availability of treatment, revealed that eight out of 16 male patients died because ofa cardiac cause, at a mean age of49 (range 31 to 65).6 Studies on screening for Fabry's disease among patits with LVH Initially the diagnosis offabry's disease was only made in patients who developed the dassical symptoms ofthe disease. In 1990, Elleder described a patient who exhibited severe cardiomyopathy on autopsy due to GL-3 accumulation, whereas other organs (brain, kidney, skin and liver) were free from storage material.7 A similar observation was made by Ogawa and coworkers, who demonstrated two Fabry patients with cardiac hypertrophy without other 'dassical' symptoms.8 Nagao reported in 1991 on two brothers with Fabry's disease who developed cardiac hypertrophy after the age of 50 and demonstrated that these patients had significant residual enzyme activity in cultured fibroblasts, compared with classical Fabry's disease patients.9 He speculated that the residual enzyme activity protected these patients from developing dassical symptoms such as renal failure, and acroparesthesias (which were Netherlands Heart Journal, Volume 14, Number 3, March

3 f.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ !. "...r Unexplained left ventricular hypertrophy: consider a diagnosis of Fabry's disease ~~~~Technician: ll _ 2 RefeEredby XHTOVEDDER CotmeoBy: C.A.!Ii~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~Rfefe b: HT VDDRD y:ca I.#H..Mt..~~~~~~~~~~~~~ ts..tt...g :,T 10H00 Hi { FX H0i d 0H0HiEW~~~~~~~:4I 7i1 _~~~~~~~~~~~~ V_4 L X_ -->1- ILEES E; t:l~~~~~~~~~~... E E ust S tetptttx 11;1 It:;4iI l: 5i11hi ItH i i r HHi iheheeehx I~~~~~~~~~... 11l;l0::l:;:l :L3.. I@He StetSCHE MEMEtEEE i...(t e<f.1.,1~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~... Figure 1. ECG ofpatienta, showing sinus rhythm with a rate of70 beats/min and severe left ventricular hypertrophy. lacking in the two studied patients) and named these 'cardiac variants'. Apparently this amount of residual activity was not high enough to prevent accumulation in the heart, causing hypertrophic cardiomyopathy. Similar cases have been reported.'0 Apparently, not all Fabry patients will demonstrate the classical symptoms such as excruciating pain in hands and feet and lack of sweating, but may still have localised symptoms ofthe disease. Figure 2. Echocardiography ofa Fabry patient (not patient A) showing marked hlertropby ofthe septum and theposterior wall of the left ventricle. This observation prompted Nakao and colleagues to study the prevalence offabry's disease in an unselected population of 230 male patients in whom LVH was noted on echocardiography (table 1). Ofthese patients, seven (3%) had low agal A activities (4 to 14% of normal values). Five of them were subsequently biopsied and showed characteristic lysosomal inclusions of glycosphingolipids in the myocardium, consistent with a diagnosis of Fabry's disease. Two of these patients had missense mutations in the agal A gene but in the other five patients no mutations were found, although the amounts ofagal A mrna were markedly lower compared with controls." In an attempt to confirm these results in a European population, Sachdev et al. studied men who were referred with an unexplained hypertrophic cardiomyopathy (HCM), diagnosed before (n=74) or after the age of4o (n=79). Five patients in the late-onset group (5/79, 6.8%) and one patient from the early-onset group (1/74, 1.4%) had low agal A activities and all had mutations in the agal A gene. Following the publication of this study, Ommen and colleagues at the Mayo clinics studied the prevalence of Fabry's disease in cardiac tissue specimens taken from 100 male patients during ventricular septal myotomy because ofsevere HCM.12 They failed to identify Fabry's disease among these patients. However, as they point out in their discussion, all of their patients showed asymmetrical hypertrophy leading to outflow obstruction, whereas 102 Netherlands Heart Joumnal, Volume 14, Number 3, March 2006 cqq)t

4 Table 1. Summary of published studies on the prevalence of Fabry's disease in patients with LVH. Authors, country Patients Studied patients Analysis Outcome Age of Identifled Fabry patients Nakao, Japan, All subsequent male patients seen at the cardiac outpatient clinic in whom an cardiac ultrasound was performed (n=1603) Male patients with hypertrophy on cardiac ultrasound (septal or left ventricular thickness of 13 mm) Enzyme and DNA mutation analysis, endomyocardial biopsy in some patients 7/220 (3%) had low agal A activities, Fabry's disease confirmed in 5/5 biopsied patients >54 years Sachdev, UK, Referral population of apparently unexplained hypertrophic cardiomyopathy Diagnosis of HCM at <40 years in 74 men and >40 in 79 men Enzyme and DNA mutation analysis, endomyocardial biopsy in some patients Fabry's disease was seen in 1/74 (1.4%) men found to have HCM <40 and 5/79 (6.3%) men >40 years All but one >40 (one was 34 years) Chimenti, Italy, 2004'3 475 consecutive female patients with LVH Female patients, n=34 (7%), in whom no cause could be found for LVH (defined as hypertension, aortic stenosis or severe regurgitation) Enzyme and DNA mutation analysis, endomyocardial biopsy in all patients EM=electron microscopy, HCM=hypertrophic cardiomyopathy, LVH=left ventrcular hypertrophy. On endomyocardial biopsy, histology and EM confirmed Fabry's disease in 4/34 (12%) patients with unexplained LVH. All had DNA mutations in the agal A gene. Two patients had normal agal A activity, 1 nearly normal and 1 reduced All >40 years in Fabry's disease cardiac hypertrophy is usually concentric. Chimenti and colleagues studied the prevalence of Fabry's disease in female patients (table 1 ).13 They studied a cohort of 475 female patients with HCM referred to a tertiary cinical centre. Ofthe 34 patients for whom no identifiable cause was found (thus excluding patients with hypertension, aortic stenosis, or severe aortic regurgitation), four (12%) had typical lysosomal inclusions in myocardial biopsies suggesting a diagnosis offabry's disease. In all patients a mutation in the agal A gene could be identified. Only one patient had clearly decreased agal A activity in leucocytes, the other patients had (near) normal levels. Following the identification of these patients, other family members, expressing classical symptoms ofthe disease, were subsequently diagnosed. These results show that Fabry's disease may be much more common than previously thought. Whether the 'cardiac' or 'atypical' variant is truly a different phenotype of the disease, or just part of the wide clinical spectrum, remains to be seen. The fact that Chimenti found patients with LVH as a sole manifestation ofthe disease in her cohort, whereas this mutation caused the classical phenotype in other patients, seems to favour the latter theory. Treatment of Fabry's disease Until recently only symptomatic treatment such as pain management, dialysis or renal transplantation was available. There is one report ofcardiac transplantation performed because of severe ventricular hypertrophy in a female patient with one year offollow-up.14 Treating the cause involves decreasing the accumulated glycosphingolipids by either supplementing the missing enzyme, or by gene therapy. Since the latter is still in the preclinical phase this will not be discussed. Trials with infusion of recombinant human a- galactosidase A once every two weeks have shown a significant reduction in accumulated glycosphingolipids in skin, kidney and heart after six months. These effects were sustained or improved further after an additional six months (total of 12 months) of treat- #c Netherlands Heart Journal, Volume 14, Number 3, March

5 Figure 3. An algorithm on when to screenfor Fabty's disease. ment.'5",6 It is believed that reducing or clearing the amount ofaccumulated lipid can halt disease progression. Weideman and colleagues showed that 12 months of treatment with rhagal A infusions once every two weeks reduced MRI-estimated myocardial mass and improved strain rate imaging on echocardiography.'7 These results suggest that enzyme therapy may reduce LVH and improve regional myocardial function. The long-term effects (that is >3 years) of treatment on cardiac symptoms are unclear. A disadvantage of enzyme supplementation therapy is that it has to be administered once every two weeks on a lifelong basis, thus creating a significant burden for patients and it is hugely expensive. Whether treatment with ACE inhibitors has a beneficial effect in Fabry's cardiomyopathy has not been studied. In the Netherlands, the Academic Medical Centre in Amsterdam is the allocated treatment centre for Fabry's disease. Who should be screened? A relatively high prevalence of Fabry's disease among patients with left ventricular hypertrophy in males and females above the age of 40 has only recently been shown. This implies that Fabry's disease should be considered in all patients aged 40 years or older with unexplained left ventricular hypertrophy. Every patient deserves a proper diagnosis, but in Fabry's disease this may be even more essential since the identification of Fabry's disease in a subject may lead to a similar diagnosis in family members already affected, so that treatment can be started to alleviate symptoms or prevent complications ofthe disease. We propose that F A3 B R Y familial history angiokeratoma anhydrosis acroparesthesieen brain imaging abnormalities renal insufficiency hypertrophy, left ventricular Figure 4. Acronym ofthe classical symptoms offabty's disease. 104 Netherlands Heart Journal, Volume 14, Number 3, March 2006 q

6 all patients (male or female) with unexplained left ventricular hypertrophy (that is not associated with aortic stenosis, or longstanding hypertension), at an onset above the age of4o, especially those with a family history of renal, cardiac or cerebrovascular disease, should be screened for a-galactosidase A deficiency (for an algorithm see figure 3). An acronym for remembering the classical symptoms of Fabry's disease is shown in figure 4. How to screen Male patients can be reliably diagnosed by measuring agal A activity in leucocytes. This is routinely performed at Dutch genetic centres. Not all female Fabry patients have a decreased enzyme activity (varying from 25 to 75% in different cohorts) and as such this is not a reliable assay. Alpha-galactosidase A DNA mutation analysis is the only reliable diagnostic procedure in females. Conclusion In patients older than 40 years ofage with unexplained hypertrophy, especially those with a family history of renal or cardiac disease, Fabry's disease should be considered. U References 1 Reuser AJ. Cel en ziekte: V. Pathologie van het lysosoom. Ned Tijdschr Geneeskd 1993;137: Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in the Netherlands. Hum Genet 1999;105: Linthorst GE, Hollak CEM, Bosman DK, Heymans HSA, Aerts JM. De ziekte van Fabry: op weg naar een behandeling. Ned Tijdschr Geneeskd 2000;144: Verovnik F, Benko D, Vujkovac B, Linthorst GE. Remarkable variability in renal disease in a large Slovenian family with Fabry's disease. EurJHum Genet2004;12(8): Ikari Y, Kuwako K, Yamaguchi T. Fabry's disease with complete atrioventricular block: histological evidence ofinvolvement ofthe conduction system. Br Heart j 1992;68: Vedder AC, Linthorst GE, Aerts JM, Hollak CE. Clinical characteristics ofthe Dutch Fabry patients. Medicine (Baltimore). 7 Elleder M, Bradova V, Smid F, et al. Cardiocyte storage and hypertrophy as a sole manifestation of Fabry's disease. Report on a case simulating hypertrophic non-obstructive cardiomyopathy. VirchowsArchA Pathol Anat Histopathol 1990;417: Ogawa K, Sugamata K, Funamoto N, et al. Restricted accumulation of globotriaosylceramide in the hearts of atypical cases of Fabry's disease. Hum Pathol 1990;21: Nagao Y, Nakashima H, Fukuhara Y, et al. Hypertrophic cardiomyopathy in late-onset variant offabry's disease with high residual activity of alpha-galactosidase A. Clin Genet 1991;39: Von Scheidt W, Eng CM, Fitzmaurice TF, et al. An atypical variant offabry's disease with manifestations confined to the myocardium. NEnglJMed 1991;324: Nakao S, Takenaka T, Macda M, et al. An atypical variant offabry's disease in men with left ventricular hypertrophy. NEnglJMed 1995;333: Ommen SR, Nishimura RA, Edwards VVD. Fabry's disease: a mimic for obstructive hypertrophic cardiomyopathy? Heart2003;89: Chimenti C, Pieroni M, Morgante E, et al. Prevalence of Fabry's disease in female patients with late-onset hypertrophic cardiomyopathy. Circulation 2004;110: Cantor WJ, Butany J, Iwanochko M, Liu P. Restrictive Cardiomyopathy Secondary to Fabry's Disease. Circulation 1998;98: Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human a-galactosidase A replacement therapy in Fabry's disease. NEnglJMed 2001;345: Wilcox WR, Banikazemi M, Guffon N, et al. Long-Term Safety and Efficacy ofenzyme Replacement Therapyfor Fabry's disease. AmJHum Genet2004;55(1): Weidemann F, Breunig F, Beer M, et al. Improvement ofcardiac function during enzyme replacement therapy in patients with Fabry's disease: a prospective straini rate imaging study. Circulation 2003;108: Sachdev B, Takenaka T, Teraguchi H, et al. Prevalence of Anderson-Fabry's disease in male patients with late onset hypertrophic cardiomyopathy. Circulation 2002;105: Dp Netherlands Heart Journal, Volume 14, Number 3, March