Cardiac abnormalities in McLeod syndrome

130

Letters to the Editor

Cardiac abnormalities in McLeod syndrome Erwin Oechslin a,c , Daniela Kaup b , Rolf Jenni c , Hans H. Jung d,⁎ a

Congenital Cardiac Centre for Adults, University Health Network, Toronto General Hospital, University of Toronto, Canada b Institute of Clinical Pathology, Department of Pathology, University Hospital Zürich, Switzerland c CardioVascular Center, Clinic for Cardiology, Department of Internal Medicine, University Hospital Zurich, Switzerland d Department of Neurology, University Hospital Zürich, 8091 Zürich, Switzerland Received 25 June 2007; accepted 7 July 2007 Available online 28 November 2007

Abstract We report the cardiac features of seven patients with X-linked McLeod neuroacanthocytosis syndrome, a multi-system disorder resembling Huntington's disease and cardiac manifestations in about half of the patients reported to date. One patient presented with a cardiomyopathy (normal size of the left ventricle with concentric remodeling and mildly impaired ejection fraction, 43%). This patient died from sudden cardiac death in the absence of any cardiovascular risk factors. Autopsy demonstrated eccentric hypertrophy and mild left ventricular dilatation. Histopathology was not specific and revealed focal myocyte hypertrophy, slight variation of myofiber size and patchy interstitial fibrosis. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: McLeod syndrome; Cardiomyopathy; Neuroacanthocytosis; Chorea; XK gene

The McLeod neuroacanthocytosis syndrome is an Xlinked multi-system disorder with hematological, cardiac, neuromuscular, and central nervous system (CNS) involvement [1–3]. CNS manifestations resemble Huntington's disease, and comprise choreatic movement disorder, psychiatric symptoms, subcortical cognitive decline, and generalized epileptic seizures [2,3]. About half of the McLeod patients have additional neuromuscular symptoms as well as electrocardio- or echocardiographic abnormalities [3]. We assessed seven McLeod patients from 2 families. Six patients (IV-4, IV-5, IV-6, IV-7, IV-13, V-3) carried the Q299X nonsense mutation in the XK gene responsible for the McLeod syndrome [2]. One patient carried the E327 K missense mutation (II-2) [4]. The clinical findings are summarized in the Table 1. Assessment included clinical cardiologic examination, 12-lead electrocardiogram, bicycle exercise test, Holtermonitoring, and a complete two-dimensional and Dopplerechocardiographic examination echocardiography (Table 1). A bicycle exercise test was performed in five patients and a treadmill exercise test in one who was too disabled to perform a bicycle exercise test. One patient refused an exercise test. Two patients refused a Holter ECG. Left ventricular hypertrophy was calculated according to Devereux [5]. Calculation of relative wall thickness (rTh) by

⁎ Corresponding author. Tel.: +41 44 255 55 45; fax: +41 44 255 45 07. E-mail address: [email protected] (H.H. Jung).

the formula (2 × thickness of the posterior wall divided by left ventricular enddiastolic diameter) permitted categorization of an increase in left ventricular muscle mass as either concentric (rTh ≤ 0.42) or eccentric (rTh N 0.42) hypertrophy and indicated concentric remodeling in the presence of normal LV mass. Left ventricular diastolic function was assessed by measuring the left ventricular inflow pattern at the tip of the mitral valve leaflets and the pulmonary venous flow pattern in the right lower pulmonary vein. In all patients, Doppler tissue imaging was performed at the lateral mitral annulus. Diastolic function was graded as follows: normal, abnormal relaxation, pseudonormal or restrictive pattern. Left ventricular biplane ejection fraction was measured using the area–length method [6]. Mitral valve prolapse was defined as systolic displacement of the mitral valve leaflets (≥ 3 mm beyond mitral annular plane) visualized in two planes. The cardiovascular history was uneventful in all 7 patients and there was no systemic arterial hypertension or other cardiovascular risk factors. Results of the cardiac assessment are summarized in the Table 1. Clinical examination revealed a mesosystolic click in 2 patients (IV-5 and V-3). All patients were in sinus rhythm without atrioventricular conduction delay and no tachycardias were registered on Holtermonitoring. Doppler-echocardiography revealed concentric remodeling of the left ventricle and mildly impaired left ventricular systolic function in one patient (IV-5; Fig. 1, panel A and B). Therapy with an ACE inhibitor was recommended but refused by the patient. He had no complaints of cardiovascular symptoms during follow up. He died suddenly

30

53

V-3

II-2

Abbreviations: CNS: central nervous system; EF: ejection fraction; FS: fractional shortening; IAS: Interatrial septal aneurysm; LVEDDI: Left ventricular enddiastolic diameter indexed to body surface area (normal b 33 mm/m2); LVEDVI: Left ventricular enddiastolic volume indexed to body surface area; LVMMI: left ventricular myocardial mass index; MVP: mitral valve prolapse; rTh: relative wall thickness (2 × thickness of the posterior wall divided by left ventricular enddiastolic diameter; normal ≤ 0.42); SR: sinus rhythm; N/A: not applicable. a Treadmill exercise test.

66 39 51 71; 0.25 28 225 (145) N/A No SR None

39 52 IV-7 IV-13

200

SR

No

No

350 (171)

28

132; 0.34

81

31

58

Normal Subaortic septal hypertrophy MVP; apical LV Diverticulum Normal 58 68 40 47 45 41 105; 0.34 N/A 28 28 225 (136) N/A No No No No SR SR

44 IV-6

None 600 Myatrophy 3000 generalized weakness None 400

MVP 70 37 57 81; 0.33 30 160 (106) No No SR

76 43 33 15 52 39 60; 0.29 119; 0.47 27 26 100 (65) 95 a (66) No N/A No No SR SR

None 2300 Myatrophy 1500 generalized weakness None 1500

Chorea, depression Chorea, schizophrenia, cognitive decline Chorea personality disorder Chorea Chorea Cognitive decline None 53 53 IV-4 IV-5

CNS symptoms (years)

Patient Age

Table 1 Neurological and cardiovascular findings

Neuro-muscular symptoms

CK values Rhythm AV(U/L; normal block b200 U/L)

Holter Exercise test Echocardiography (Sustained (Watt; arrhythmia) % prediction) LVMMI LVEDVI (ml/ FS LVEDDI (g/m2); rTh m2) (%) (mm/m2)

EF (%)

MVP; IAS MVP; IAS

Morphology

Letters to the Editor

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two and a half years after the initial cardiologic assessment examination. Four patients (IV-4, IV-5, IV-6, and V-3) had a mitral valve prolapse by echocardiography with mild mitral regurgitation. None of the patients had a cardiovascular medication. Autopsy of patient IV-5 was performed 57 h after death. There was acute congestion of lungs, liver, spleen and kidneys. The heart was enlarged with a weight of 510 g before formalin fixation (expected weight 310 g). There was mild dilation of all four chambers and eccentric hypertrophy with increased thickness of the left and right ventricular walls, measuring 1.8 and 0.5 cm, respectively. The coronary arteries had focal atherosclerosis of less than 30% of crosssectional area. No old or recent myocardial infarcts were found. Microscopic analysis revealed focal myocyte hypertrophy, slight variation of myofiber size and patchy interstitial fibrosis (Fig. 1, panel C and D). All patients presented herein had a McLeod syndrome confirmed by molecular genetic analysis with variable neuromuscular and CNS involvement. In one patient, echocardiography documented a concentric remodeling of the left ventricle, mildly impaired left ventricular ejection fraction but normal Holter ECG. This patient died suddenly, most probably from sudden cardiac death. Autopsy demonstrated signs of a cardiomyopathy. Histological alterations, however, were not specific. The absence of cardiovascular risk factors, symptomatic coronary artery disease, and other disorders impacting the cardiovascular system suggests that this cardiomyopathy is a manifestation of the McLeod syndrome. The other patients had no clinical or echocardiographic manifestations of cardiomyopathy or heart failure. The frequency of discrete to mild mitral valve prolapse in our series (57%) is high compared to the reported frequency (b 3%) in a community based population. Unlike cardiomyopathy, arrhythmia, and sudden cardiac death, however, there are no other reports about mitral valve prolapse in McLeod syndrome in the literature and we do not to have an evidence for a direct relationship between mitral valve prolapse and McLeod syndrome. Available data suggest that cardiomyopathy might be more frequently associated with the McLeod syndrome in other families. In one large series, eleven out of 17 McLeod patients had cardiologic abnormalities [3]. The exact nature of the cardiac alterations, however, was not fully described in most patients, and no pathological examinations were available. In another study, however, cardiac biopsy demonstrated similar findings as ours [7]. Nine patients had an increased heart size on chest X-ray and six patients had atrial fibrillation or flutter. Four patients were diagnosed to have cardiomyopathy, but only two of them classified: one patient with dilated, the other with restrictive cardiomyopathy. Congestive heart failure was reported to be a major health problem in “some” of the patients, and a cardiac cause was suspected in four out of five deceased patients [3]. Noteworthy, a cardiomyopathy was the initial clinical manifestation in several McLeod patients [3].

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Fig. 1. Echocardiographic images (Panel A and B) of patient IV-5: Panel A (parasternal long-axis view) and panel B (parasternal short-axis view) are enddiastolic still frames showing normal size of the left ventricle with concentric remodeling. Microscopic examination of the left ventricle shows nonspecific myocyte hypertrophy (C; arrow) and variation of myocyte size (triangles; H&E stain; magnification bar 100 μm). Panel D demonstrates interstitial fibrosis (arrow; H&E stain; magnification bar 100 μm).

The XK gene shares important homologies with the ced8 gene of the nematode C. elegans where it is a cell death effector downstream of the caspase ced-3 [8]. Therefore, apoptosis dysregulation might represent a cause for the neurodegeneration in the McLeod syndrome [9]. Based on the findings of compensated hemolysis and erythrocyte acanthocytosis in McLeod patients, loss of cell membrane integrity and cytoskeletal changes have to be discussed as alternative pathogenetic pathways contributing to a novel cardiomyopathic mechanism. Patients with a cardiomyopathy associated with McLeod syndrome are at risk for sudden death. Therefore, a thorough cardiac evaluation is warranted and an appropriate treatment might offer a symptomatic and prognostic benefit to those with an obvious cardiomyopathy. References [1] Walker RH, Jung HH, Dobson-Stone C, et al. Neurologic phenotypes associated with acanthocytosis. Neurology 2007;68:92–8.

0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.07.167

[2] Jung HH, Hergersberg M, Kneifel S, et al. McLeod syndrome: a novel mutation, predominant psychiatric manifestations, and distinct striatal imaging findings. Ann Neurol 2001;49:384–92. [3] Danek A, Rubio JP, Rampoldi L, et al. McLeod neuroacanthocytosis: genotype and phenotype. Ann Neurol 2001;50:755–64. [4] Jung HH, Hergersberg M, Vogt M, et al. McLeod phenotype associated with a XK missense mutation without hematological, neuromuscular, or cerebral involvement. Transfusion 2003;43:928–38. [5] Devereux RB, Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57:450–8. [6] Jenni R, Vieli A, Hess O, Anliker M, Krayenbuehl HP. Estimation of left ventricular volume from apical orthogonal 2-D echocardiograms. Eur Heart J 1981;2:217–25. [7] Witt TN, Danek A, Reiter M, Heim MU, Dirschinger J, Olsen EG. McLeod syndrome: a distinct form of neuroacanthocytosis. Report of two cases and literature review with emphasis on neuromuscular manifestions. J Neurol 1992;239:302–6. [8] Stanfield GM, Horvitz HR. The ced-8 gene controls the timing of programmed cell deaths in C. elegans. Mol Cell 2000;5:423–33. [9] Jung HH, Russo D, Redman C, Brandner S. Kell and XK immunohistochemistry in McLeod myopathy. Muscle Nerve 2001;24:1346–51.