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Monosodium urate (MSU) crystals increase gout associated coronary heart disease (CHD) risk through the activation of NLRP3 inflammasome
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Letters to the Editor
Monosodium urate (MSU) crystals increase gout associated coronary heart disease (CHD) risk through the activation of NLRP3 inflammasome Jia He, Yang Yang, Dao-Quan Peng ⁎ Department of Cardiology, The Second Xiangya Hospital, Central South University, #139 Middle Renmin Road, Changsha, Hunan 410011, PR China
a r t i c l e
i n f o
Article history: Received 10 May 2012 Accepted 27 May 2012 Available online 20 June 2012 Keywords: Gout Coronary heart disease (CHD) Monosodium urate (MSU) crystals NLRP3 inflammasome
Gout is a metabolic disease most often affecting middle-aged to elderly men and post-menopausal women. Many epidemiological researches have demonstrated that gout was an independent cardiac risk. One study concluded that the increased mortality risk of men without preexisting coronary heart disease (CHD) primarily resulted from an elevated risk of cardiovascular disease (CVD) death, particularly from CHD, and it also showed that men with gout had a higher risk of nonfatal myocardial infarction than men without gout [1]. It also suggested that the increase in cardiovascular risk could be related more to the presence of gout than to isolated hyperuricemia [2]. On the other hand, the association between uric acid and cardiac risk remains controversial. A meta-analysis including 26 eligible studies found that hyperuricemia may marginally increase the risk of CHD events, independently of traditional CHD risk factors, while in male subgroup no significant association between hyperuricemia and CHD incidence or mortality was showed [3]. Furthermore, a famous study from Framingham Heart Study group argued that uric acid is not a risk factor for cardiovascular disease [4]. There are several possible reasons for this controversy, the most important one is that studies indicating uric acid as an independent risk factor did not sufficiently control for other known risk factors. Actually the anti-oxidant capacity of uric acid should be beneficial to CHD other than detrimental to it [5]. In most cases, gout attack appears closely related to hyperuricemia: why gout but not hyperuricemia increases cardiac risk? In fact, their relationships may not link as tightly as what we thought. There are many reports of gout in patients with normouricemia [6–8]. In some large clinical studies, gout attacks still occurred despite serum uric acid levels being below 6.8 mg/dl, the saturation level for urate [9,10], so hyperuricemia might only be an indirect factor to predict gout attacks. But the presence of tophi [6], the number of involved joints [6] and increased body uric acid pool [11] were independently associated with acute attacks in normouricemic gout patients. Considering that tophi are the deposition of monosodium urate (MSU) crystals in connective tissue, we suspected that the MSU crystals may play a central role in gout attacks as well as increased CVD risk. What is the mechanism by which MSU crystals increase cardiac risk? Firstly, MSU crystals promote inflammation in arthritis. It was found that MSU crystals activated NLRP3 inflammasome in THP-1 cell and human monocytes in vitro [12]. The NLRP3 inflammasomes are molecular platforms activated upon pathogens as well as danger ⁎ Corresponding author. Tel.: +86 731 85295307; fax: +86 731 85295407. E-mail address: [email protected] (D.-Q. Peng).
associated molecular platforms (DAMPs) including MSU crystals and cholesterol crystals, then triggered activation of inflammatory caspases and pro IL-1β [13]. The mature IL-1β and other cytokine may be elevated in synovial fluid and thus contribute to local inflammation, which was confirmed in synovial fluid analyze in gout patients [14]. It has been well recognized that inflammation plays central roles in coronary arthrosclerosis. Recently, it is found that cholesterol crystals activated the NLRP3 inflammasome in phagocytes in vitro. Moreover, when mice deficient in low density lipoprotein receptor (LDLR) were bone-marrow transplanted with components of inflammasome deficient bone marrow and fed on a high-cholesterol diet, the atherosclerosis lesion obviously decreased [15], which means that NLRP3 inflammasome plays a critical role in the progress of atherosclerosis. So both gout and CHD share the same inflammation mechanism, more exactly, both diseases involve NLRP3 inflammasome activation. But how do the MSU crystals exert effect on remote coronary arteries? Based on the findings that cytokine elevated not only in synovial fluid but also in plasma concentrations [16], we suspect cytokines and macrophages activated by NLRP3 inflammasome released from the gout focus may effect on remote coronary arteries and aggravate the symptoms of CHD. In addition, considering that the NLRP3 inflammasome is not fully understood yet, other unknown up-stream or down-stream factors of NLRP3 inflammasome from local inflammation of gout may be also released to the serum and contribute to the aggravated CHD symptoms. Our clinical observation also supported our hypothesis. In clinical practice, we often found the symptoms of arthritis and chest pain aggravated almost simultaneously in patients who were previously diagnosed with gout and CHD; furthermore, both chest pain and the symptoms of arthritis did not respond well to drug treatment. The frequent chest pain indicated the ischemia of myocardium and unstable coronary plaque, while the prolonged chest pain might even be a warning of myocardial infarction, so the aggravated chest pain represented increased cardiac risk. We also noticed that not only a few of these patients have normouricemia. In summary, epidemiological researches confirmed that gout but not hyperuricemia increases cardiac risk. Based on the activation of NLRP3 inflammasome by MSU crystals in gout and by cholesterol crystals in CHD, we suspect the MSU crystals may contribute to the gout associated CHD risk. Our clinical observations also support the hypothesis. Considering this potential mechanism, drugs targeting NLRP3 inflammasome or IL-1β may have favorable effect on gout associated coronary heart disease, which may provide another broad perspective on the treatment of gout as well as CHD [17]. The authors of this manuscript have certified that they comply with the principles of ethical publishing in the International Journal of Cardiology (Shewan and Coats 2010; 144: 1–2).
References [1] Choi HK, Curhan G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation 2007;116:894–900. [2] Krishnan E, Svendsen K, Neaton JD, Grandits G, Kuller LH. Long-term cardiovascular mortality among middle-aged men with gout. Arch Intern Med 2008;168:1104–10. [3] Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA. Hyperuricemia and coronary heart disease: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) 2010;62:170–80. [4] Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999;131:7–13.
Letters to the Editor [5] Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811–21. [6] So MW, Lee SG, Kim YG, Lee CK, Yoo B. Factors associated with acute gout attacks in normouricaemic gout patients receiving allopurinol: a retrospective study. Scand J Rheumatol 2011;40:444–7. [7] McCarty DJ. Gout without hyperuricemia. JAMA 1994;271:302–3. [8] Schlesinger N, Baker DG, Schumacher Jr HR. Serum urate during bouts of acute gouty arthritis. J Rheumatol 1997;24:2265–6. [9] Schumacher Jr HR, Boice JA, Daikh DI, et al. Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis. BMJ 2002;324:1488–92. [10] Rubin BR, Burton R, Navarra S, et al. Efficacy and safety profile of treatment with etoricoxib 120 mg once daily compared with indomethacin 50 mg three times daily in acute gout: a randomized controlled trial. Arthritis Rheum 2004;50:598–606. [11] Schlesinger N, Norquist JM, Watson DJ. Serum urate during acute gout. J Rheumatol 2009;36:1287–9.
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[12] Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237–41. [13] Schroder K, Tschopp J. The inflammasomes. Cell 2010;140:821–32. [14] Bertazzo A, Punzi L, Bertazzolo N, et al. Tryptophan catabolism in synovial fluid of various arthropathies and its relationship with inflammatory cytokines. Adv Exp Med Biol 1999;467:565–70. [15] Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010;464:1357–61. [16] Inokuchi T, Moriwaki Y, Tsutsui H, et al. Plasma interleukin (IL)-18 (interferongamma-inducing factor) and other inflammatory cytokines in patients with gouty arthritis and monosodium urate monohydrate crystal-induced secretion of IL-18. Cytokine 2006;33:21–7. [17] Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011;162:597–605.
0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2012.05.083
Acquired, familial noncompaction and eccentric hypertrophic cardiomyopathy associated with metabolic myopathy and epilepsy Josef Finsterer a,b,⁎, Claudia Stöllberger c a b c
Danube University Krems, Krems, Austria Krankenanstalt Rudolfstiftung, Vienna, Austria Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria
a r t i c l e
i n f o
Article history: Received 4 May 2012 Accepted 27 May 2012 Available online 15 June 2012 Keywords: Cardiomyopathy Non-compaction Arrhythmia Metabolic myopathy Epilepsy Seizures
Left ventricular hypertrabeculation (LVHT) is generally believed to be congenital [1]. However, single cases have been reported, in which LVHT unambiguously developed during adulthood (acquired LVHT) [2–6]. Acquired LVHT has been also found in the right ventricle [7]. In most of these cases LVHT was associated with a neuromuscular disorder (NMD) [8]. Here we report another patient with NMD who developed LVHT within 6 years. The patient is a 45‐year‐old (April 2012) Caucasian female, height 163 cm, weight 52 kg, with a history of jaundice (age 12 years), recurrent syncopes since age 16 years, arterial hypotension, palpitations and trepidation, exertional dyspnoea, renal insufficiency, visual impairment, and conisation for carcinoma and right-sided ovarectomy (age 31 years). Despite her strong wish, she never became pregnant. Her sister had a history of palpitations, exertional dyspnoea, focal right atrial hypertrophy, left ventricular hypertrophy, patent foramen ovale, retrospectively diagnosed LVHT, sinus-bradycardia, left anterior hemiblock, two syncopes, slight renal insufficiency and renal cysts, short stature, hyperlidpidemia, several miscarriages,
⁎ Corresponding author at: Postfach 20, 1180 Vienna, Austria, Europe. Tel.: + 43 1 71165 92085; fax: + 43 1 4781711. E-mail address: fifi[email protected] (J. Finsterer).
and sudden cardiac death (age 49 years). General hypotonia from suspected hypothyroidism was reported in the sister's son and pacemaker implantation and heart transplantation for hypertrophic cardiomyopathy in her father. At age 39 years (August 2006) she was admitted for fatigue, recurrent syncopes, and visual impairment. Blood tests revealed slight renal insufficiency, hyperuricemia, and hyperlipidemia. Blood pressure decreased to a minimal of 85/60 mmHg. ECG showed high and sharp P-waves. Holter-ECG was indicative of a sick-sinus syndrome with sinus-bradycardia down to 27 bpm. Echocardiography revealed a thickened right atrial and right ventricular wall, and slightly reduced systolic function (Table 1). These abnormalities were also seen on cardiac MRI (Table 1). Ultrasonography of the kidneys revealed diffuse echo-rich parenchyma. Ophthalmologic investigations revealed a cornea verticillata and sicca syndrome. Diagnostic work-up for suspected Fabry's disease, including myocardial biopsy and genetic investigations [9], was non-informative. She was heterozygote for the polymorphism GLA 5′UTR,-10c/t. Re-admission at age 45 years for anginal chest pain revealed sinus-bradycardia down to 23 bpm and intermittent AV-dissociation on telemetric ECG-recordings, latent hypothyroidism, incipient cataract, and LVHT in addition to the previously diagnosed abnormalities (Fig. 1). Stress-testing was discontinued because of muscular fatigue, without coronary insufficiency or arrhythmias. Coronary angiography showed a 50% proximal LAD stenosis exclusively. Routine referral for neurological investigations revealed a history of previous migraine, occasional double vision, spontaneous and postexercise muscle aching, muscle cramping since adolescence, recurrent myocloni, loss of words, impaired memory, right-sided tinnitus, and depression. At age 41 years epilepsy was diagnosed upon recurrent syncopes, cloni and secessus during an observed syncope, and their disappearance after initiation of antiepileptic treatment. Clinical exam revealed cervicalgia, reduced biceps and patella tendon reflexes, and diffuse wasting. Routine blood tests revealed slight renal insufficiency, elevated alpha-amylase, hyperuricemia, latent hypothyroidism, and hyperlipidemia. Nerve conduction studies were normal. Electromyography was myogenic. Cerebral CT, cerebral MRI, and MRI of the
Letters to the Editor
Monosodium urate (MSU) crystals increase gout associated coronary heart disease (CHD) risk through the activation of NLRP3 inflammasome Jia He, Yang Yang, Dao-Quan Peng ⁎ Department of Cardiology, The Second Xiangya Hospital, Central South University, #139 Middle Renmin Road, Changsha, Hunan 410011, PR China
a r t i c l e
i n f o
Article history: Received 10 May 2012 Accepted 27 May 2012 Available online 20 June 2012 Keywords: Gout Coronary heart disease (CHD) Monosodium urate (MSU) crystals NLRP3 inflammasome
Gout is a metabolic disease most often affecting middle-aged to elderly men and post-menopausal women. Many epidemiological researches have demonstrated that gout was an independent cardiac risk. One study concluded that the increased mortality risk of men without preexisting coronary heart disease (CHD) primarily resulted from an elevated risk of cardiovascular disease (CVD) death, particularly from CHD, and it also showed that men with gout had a higher risk of nonfatal myocardial infarction than men without gout [1]. It also suggested that the increase in cardiovascular risk could be related more to the presence of gout than to isolated hyperuricemia [2]. On the other hand, the association between uric acid and cardiac risk remains controversial. A meta-analysis including 26 eligible studies found that hyperuricemia may marginally increase the risk of CHD events, independently of traditional CHD risk factors, while in male subgroup no significant association between hyperuricemia and CHD incidence or mortality was showed [3]. Furthermore, a famous study from Framingham Heart Study group argued that uric acid is not a risk factor for cardiovascular disease [4]. There are several possible reasons for this controversy, the most important one is that studies indicating uric acid as an independent risk factor did not sufficiently control for other known risk factors. Actually the anti-oxidant capacity of uric acid should be beneficial to CHD other than detrimental to it [5]. In most cases, gout attack appears closely related to hyperuricemia: why gout but not hyperuricemia increases cardiac risk? In fact, their relationships may not link as tightly as what we thought. There are many reports of gout in patients with normouricemia [6–8]. In some large clinical studies, gout attacks still occurred despite serum uric acid levels being below 6.8 mg/dl, the saturation level for urate [9,10], so hyperuricemia might only be an indirect factor to predict gout attacks. But the presence of tophi [6], the number of involved joints [6] and increased body uric acid pool [11] were independently associated with acute attacks in normouricemic gout patients. Considering that tophi are the deposition of monosodium urate (MSU) crystals in connective tissue, we suspected that the MSU crystals may play a central role in gout attacks as well as increased CVD risk. What is the mechanism by which MSU crystals increase cardiac risk? Firstly, MSU crystals promote inflammation in arthritis. It was found that MSU crystals activated NLRP3 inflammasome in THP-1 cell and human monocytes in vitro [12]. The NLRP3 inflammasomes are molecular platforms activated upon pathogens as well as danger ⁎ Corresponding author. Tel.: +86 731 85295307; fax: +86 731 85295407. E-mail address: [email protected] (D.-Q. Peng).
associated molecular platforms (DAMPs) including MSU crystals and cholesterol crystals, then triggered activation of inflammatory caspases and pro IL-1β [13]. The mature IL-1β and other cytokine may be elevated in synovial fluid and thus contribute to local inflammation, which was confirmed in synovial fluid analyze in gout patients [14]. It has been well recognized that inflammation plays central roles in coronary arthrosclerosis. Recently, it is found that cholesterol crystals activated the NLRP3 inflammasome in phagocytes in vitro. Moreover, when mice deficient in low density lipoprotein receptor (LDLR) were bone-marrow transplanted with components of inflammasome deficient bone marrow and fed on a high-cholesterol diet, the atherosclerosis lesion obviously decreased [15], which means that NLRP3 inflammasome plays a critical role in the progress of atherosclerosis. So both gout and CHD share the same inflammation mechanism, more exactly, both diseases involve NLRP3 inflammasome activation. But how do the MSU crystals exert effect on remote coronary arteries? Based on the findings that cytokine elevated not only in synovial fluid but also in plasma concentrations [16], we suspect cytokines and macrophages activated by NLRP3 inflammasome released from the gout focus may effect on remote coronary arteries and aggravate the symptoms of CHD. In addition, considering that the NLRP3 inflammasome is not fully understood yet, other unknown up-stream or down-stream factors of NLRP3 inflammasome from local inflammation of gout may be also released to the serum and contribute to the aggravated CHD symptoms. Our clinical observation also supported our hypothesis. In clinical practice, we often found the symptoms of arthritis and chest pain aggravated almost simultaneously in patients who were previously diagnosed with gout and CHD; furthermore, both chest pain and the symptoms of arthritis did not respond well to drug treatment. The frequent chest pain indicated the ischemia of myocardium and unstable coronary plaque, while the prolonged chest pain might even be a warning of myocardial infarction, so the aggravated chest pain represented increased cardiac risk. We also noticed that not only a few of these patients have normouricemia. In summary, epidemiological researches confirmed that gout but not hyperuricemia increases cardiac risk. Based on the activation of NLRP3 inflammasome by MSU crystals in gout and by cholesterol crystals in CHD, we suspect the MSU crystals may contribute to the gout associated CHD risk. Our clinical observations also support the hypothesis. Considering this potential mechanism, drugs targeting NLRP3 inflammasome or IL-1β may have favorable effect on gout associated coronary heart disease, which may provide another broad perspective on the treatment of gout as well as CHD [17]. The authors of this manuscript have certified that they comply with the principles of ethical publishing in the International Journal of Cardiology (Shewan and Coats 2010; 144: 1–2).
References [1] Choi HK, Curhan G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation 2007;116:894–900. [2] Krishnan E, Svendsen K, Neaton JD, Grandits G, Kuller LH. Long-term cardiovascular mortality among middle-aged men with gout. Arch Intern Med 2008;168:1104–10. [3] Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA. Hyperuricemia and coronary heart disease: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) 2010;62:170–80. [4] Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999;131:7–13.
Letters to the Editor [5] Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811–21. [6] So MW, Lee SG, Kim YG, Lee CK, Yoo B. Factors associated with acute gout attacks in normouricaemic gout patients receiving allopurinol: a retrospective study. Scand J Rheumatol 2011;40:444–7. [7] McCarty DJ. Gout without hyperuricemia. JAMA 1994;271:302–3. [8] Schlesinger N, Baker DG, Schumacher Jr HR. Serum urate during bouts of acute gouty arthritis. J Rheumatol 1997;24:2265–6. [9] Schumacher Jr HR, Boice JA, Daikh DI, et al. Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis. BMJ 2002;324:1488–92. [10] Rubin BR, Burton R, Navarra S, et al. Efficacy and safety profile of treatment with etoricoxib 120 mg once daily compared with indomethacin 50 mg three times daily in acute gout: a randomized controlled trial. Arthritis Rheum 2004;50:598–606. [11] Schlesinger N, Norquist JM, Watson DJ. Serum urate during acute gout. J Rheumatol 2009;36:1287–9.
73
[12] Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237–41. [13] Schroder K, Tschopp J. The inflammasomes. Cell 2010;140:821–32. [14] Bertazzo A, Punzi L, Bertazzolo N, et al. Tryptophan catabolism in synovial fluid of various arthropathies and its relationship with inflammatory cytokines. Adv Exp Med Biol 1999;467:565–70. [15] Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010;464:1357–61. [16] Inokuchi T, Moriwaki Y, Tsutsui H, et al. Plasma interleukin (IL)-18 (interferongamma-inducing factor) and other inflammatory cytokines in patients with gouty arthritis and monosodium urate monohydrate crystal-induced secretion of IL-18. Cytokine 2006;33:21–7. [17] Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011;162:597–605.
0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2012.05.083
Acquired, familial noncompaction and eccentric hypertrophic cardiomyopathy associated with metabolic myopathy and epilepsy Josef Finsterer a,b,⁎, Claudia Stöllberger c a b c
Danube University Krems, Krems, Austria Krankenanstalt Rudolfstiftung, Vienna, Austria Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria
a r t i c l e
i n f o
Article history: Received 4 May 2012 Accepted 27 May 2012 Available online 15 June 2012 Keywords: Cardiomyopathy Non-compaction Arrhythmia Metabolic myopathy Epilepsy Seizures
Left ventricular hypertrabeculation (LVHT) is generally believed to be congenital [1]. However, single cases have been reported, in which LVHT unambiguously developed during adulthood (acquired LVHT) [2–6]. Acquired LVHT has been also found in the right ventricle [7]. In most of these cases LVHT was associated with a neuromuscular disorder (NMD) [8]. Here we report another patient with NMD who developed LVHT within 6 years. The patient is a 45‐year‐old (April 2012) Caucasian female, height 163 cm, weight 52 kg, with a history of jaundice (age 12 years), recurrent syncopes since age 16 years, arterial hypotension, palpitations and trepidation, exertional dyspnoea, renal insufficiency, visual impairment, and conisation for carcinoma and right-sided ovarectomy (age 31 years). Despite her strong wish, she never became pregnant. Her sister had a history of palpitations, exertional dyspnoea, focal right atrial hypertrophy, left ventricular hypertrophy, patent foramen ovale, retrospectively diagnosed LVHT, sinus-bradycardia, left anterior hemiblock, two syncopes, slight renal insufficiency and renal cysts, short stature, hyperlidpidemia, several miscarriages,
⁎ Corresponding author at: Postfach 20, 1180 Vienna, Austria, Europe. Tel.: + 43 1 71165 92085; fax: + 43 1 4781711. E-mail address: fifi[email protected] (J. Finsterer).
and sudden cardiac death (age 49 years). General hypotonia from suspected hypothyroidism was reported in the sister's son and pacemaker implantation and heart transplantation for hypertrophic cardiomyopathy in her father. At age 39 years (August 2006) she was admitted for fatigue, recurrent syncopes, and visual impairment. Blood tests revealed slight renal insufficiency, hyperuricemia, and hyperlipidemia. Blood pressure decreased to a minimal of 85/60 mmHg. ECG showed high and sharp P-waves. Holter-ECG was indicative of a sick-sinus syndrome with sinus-bradycardia down to 27 bpm. Echocardiography revealed a thickened right atrial and right ventricular wall, and slightly reduced systolic function (Table 1). These abnormalities were also seen on cardiac MRI (Table 1). Ultrasonography of the kidneys revealed diffuse echo-rich parenchyma. Ophthalmologic investigations revealed a cornea verticillata and sicca syndrome. Diagnostic work-up for suspected Fabry's disease, including myocardial biopsy and genetic investigations [9], was non-informative. She was heterozygote for the polymorphism GLA 5′UTR,-10c/t. Re-admission at age 45 years for anginal chest pain revealed sinus-bradycardia down to 23 bpm and intermittent AV-dissociation on telemetric ECG-recordings, latent hypothyroidism, incipient cataract, and LVHT in addition to the previously diagnosed abnormalities (Fig. 1). Stress-testing was discontinued because of muscular fatigue, without coronary insufficiency or arrhythmias. Coronary angiography showed a 50% proximal LAD stenosis exclusively. Routine referral for neurological investigations revealed a history of previous migraine, occasional double vision, spontaneous and postexercise muscle aching, muscle cramping since adolescence, recurrent myocloni, loss of words, impaired memory, right-sided tinnitus, and depression. At age 41 years epilepsy was diagnosed upon recurrent syncopes, cloni and secessus during an observed syncope, and their disappearance after initiation of antiepileptic treatment. Clinical exam revealed cervicalgia, reduced biceps and patella tendon reflexes, and diffuse wasting. Routine blood tests revealed slight renal insufficiency, elevated alpha-amylase, hyperuricemia, latent hypothyroidism, and hyperlipidemia. Nerve conduction studies were normal. Electromyography was myogenic. Cerebral CT, cerebral MRI, and MRI of the