A 30 year-old male was referred to our hospital for screening as his brother was found to have otherwise unexplained borderline left ventricular hypertrophy (LVH).
On presentation, he appeared completely asymptomatic from a cardiovascular point of view, denying anginal pain or palpitations. He was classified as NYHA functional class I.
No history of presyncope or syncope was reported. However, he complained of tightness at his Achilles tendon from a young age, a feature that was also evident in his brother who had undergone surgery to relieve contractures to his Achilles tendons.
On review of his family history, a maternal uncle was reported to have been diagnosed with hypertrophic cardiomyopathy. In his late forties, he suffered a stroke and subsequently died at the age of 50.
His maternal grandmother’s brother died suddenly aged 28 of unknown cause. The family’s pedigree is demonstrated in Figure 1.
Figure 1. Family pedigree. The patient presented is noted with an arrow. The proband (noted in red) is his brother, an asymptomatic male, diagnosed with otherwise unexplained borderline LVH and contractures. A maternal uncle was diagnosed with HCM in his 20’s and died subsequent to a stroke aged 40. The brother of the maternal grandmother died suddenly, aged 28 from an undetermined heart condition
On examination, the patient was normotensive (120/70mmHg), his heart sounds were normal with no additional sounds or murmurs. Chest auscultation was normal. Jugular venous pressure was normal and there was no peripheral oedema. Neurological examination revealed bilateral Achilles tendon contractures. There were no features of proximal myopathy.
The patient’s ECG demonstrated normal sinus rhythm (Figure 2). P waves were biphasic in V1 and V2 suggestive of left atrium enlargement. LVH by voltage criteria and deep S waves in the precordial leads were evident. Q waves were noted inferiorly with T-wave inversion in the lateral leads.
Figure 2. ECG. Biphasic p-waves in V1 and V2 suggestive of left atrium enlargement. LVH by voltage criteria and deep S waves in the precordial leads were evident. Q waves were noted inferiorly with T-wave inversion in the lateral leads.
Echocardiography showed asymmetrical left ventricular hypertrophy with anteroseptal distribution (Figure 3). Maximal wall thickness was 14mm at the mid septal segment. No LVOT or midventricular obstruction was present. Systolic and diastolic function were within normal limits. All other findings were unremarkable.
Figure 3. Echocardiography. Asymmetrical LVH with a maximal wall thickness of 14 mm at the mid-anterior septum.
The patient underwent a cardiac magnetic resonance (CMR) study which demonstrated a small LV cavity and asymmetric LV hypertrophy in a spiral pattern with maximal wall thickness of 16mm at mid infero-septum (Figure 4). Mild biatrial dilatation with LA and RA areas of 21 and 24 cm2 respectively was also present. On tissue characterization, trivial focal RV insertion point LGE was detected.
Figure 4. CMR. Asymmetric LVH with maximal wall thickness of 16mm (top row). LGE was trivial, localized at the RV insertion points (bottom row).
Holter monitoring showed sinus rhythm throughout, with no significant ectopic burden or complex arrhythmias recorded.
During cardiopulmonary exercise testing, he exercised without any symptoms achieving a VO2 of 25.5 mL/min/kg (64% of predicted) with an RQ of 1.11. His heart rate and blood pressure response were normal (120/80 mmHg, 82bpm at rest, increasing to 160/80 mmHg, 170 bpm at peak exercise). No arrhythmias were detected during the test.
1. What is the differential diagnosis in this patient? 2. What further investigations would you perform in this patient?
This patient clearly fulfils current diagnostic criteria for hypertrophic cardiomyopathy. The presence of Achilles tendon contractures from an early age in the patient and his brother raised the clinical suspicion of an inherited neuromuscular disorder. The initial neurological assessment suggested mildly expressed Emery Dreifuss muscular dystrophy (EDMD).
Emery Dreifuss muscular dystrophy is a hereditary muscular disorder inherited in most patients as an autosomal dominant trait caused by mutations in the LMNA gene encoding lamin A/C or an X-linked disease caused by mutations in the STA gene encoding another nuclear envelope protein, emerin (1;2). Analysis of the LMNA and STA genes in phenotypically EDMD affected populations identifies mutations in about half of all patients, indicating the presence of additional causative genes (3).
In this case, the family pedigree was consistent with either autosomal dominant or X-linked recessive inheritance. The early onset contractures are typical of EDMD but the cardiac phenotype was not. Patients with LMNA and STA related EDMD usually develop conduction defects (4), atrial arrhythmias (fibrillation or flutter) and atrial standstill. The latter appears to be a hallmark in this subset of cardiomyopathy (5). In the majority of cases, cardiac structural involvement comes in the form of dilated cardiomyopathy rather than HCM as in this patient (6). A recently reported exception to this is EDMD caused by mutations in a lamin associated protein, FHL1 (four and a half LIM protein 1). FHL1 is a protein with 3 distinct isoforms (FHL1A, FHL1B, and FHL1C). FHL1A is the isoform mainly expressed in striated and cardiac muscle and has been recognised to play a role in sarcomere synthesis and preservation by binding with myosin binding protein C (MYBPC)(7). The nature of its interactions within the myofilament is not fully understood but data suggest that it is also implicated in intracellular signaling and genetic transcription pathways (8). Around 25 distinct mutations in FHL1 have been described in association with four myopathic conditions; reducing body myopathy (RBM), X-linked myopathy with postural muscle atrophy (XMPMA), scapuloperoneal myopathy (SMP) and Emery-Dreifuss myotonic dystrophy (9-11).
In small series of patients with EDMD due to FHL1 mutations already described, cardiac involvement predominantly in the form of LVH was evident, in contrast to the dilated cardiomyopathy phenotype imposed by lamin A/C and emerin mutations. Interestingly, mild disease expression was described in female carriers as well. It should also be noted that isolated cardiac phenotypes have been described in those series, establishing FHL1 mutations as potentially disease-causing, even in patients with apparently typical HCM features (9;10).
Genetic analysis for EDMD in the patient and his brother identified a missense mutation at exon 6 of the FHL1 gene in the X chromosome of both siblings. Their mother was a mutation carrier and had a normal phenotype. LMNA and STA gene mutations were absent in all screened members of this family.
In summary, our patients were diagnosed with Emery Dreifuss myotonic dystrophy due to a novel FHL1 mutation. Sudden cardiac death is well recognized in EDMD patients, especially in LMNA mutation carriers (12;13). Current knowledge on risk stratification of patients with FHL1 mutations is only just emerging. For the moment, the patient is undergoing frequent monitoring for arrhythmia and changes in ventricular function; growing knowledge on prognosis and outcome of such patients will determine the threshold for a more active treatment approach.
(1) Brown CA, Lanning RW, McKinney KQ, Salvino AR, Cherniske E, Crowe CA et al. Novel and recurrent mutations in lamin A/C in patients with Emery-Dreifuss muscular dystrophy. Am J Med Genet 2001; 102(4):359-367. (2) Bione S, Maestrini E, Rivella S, Mancini M, Regis S, Romeo G et al. Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat Genet 1994; 8(4):323-327. (3) Bonne G, Yaou RB, Beroud C, Boriani G, Brown S, de Visser M et al. 108th ENMC International Workshop, 3rd Workshop of the MYO-CLUSTER project: EUROMEN, 7th International Emery-Dreifuss Muscular Dystrophy (EDMD) Workshop, 13-15 September 2002, Naarden, The Netherlands. Neuromuscul Disord 2003; 13(6):508-515. (4) Emery AE. Emery-Dreifuss muscular dystrophy - a 40 year retrospective. Neuromuscul Disord 2000; 10(4-5):228-232. (5) Boriani G, Gallina M, Merlini L, Bonne G, Toniolo D, Amati S et al. Clinical relevance of atrial fibrillation/flutter, stroke, pacemaker implant, and heart failure in Emery-Dreifuss muscular dystrophy: a long-term longitudinal study. Stroke 2003; 34(4):901-908. (6) Sachdev B, Elliott PM, McKenna WJ. Cardiovascular Complications of Neuromuscular Disorders. Curr Treat Options Cardiovasc Med 2002; 4(2):171-179. (7) McGrath MJ, Cottle DL, Nguyen MA, Dyson JM, Coghill ID, Robinson PA et al. Four and a half LIM protein 1 binds myosin-binding protein C and regulates myosin filament formation and sarcomere assembly. J Biol Chem 2006; 281(11):7666-7683. (8) Shathasivam T, Kislinger T, Gramolini AO. Genes, proteins and complexes: the multifaceted nature of FHL family proteins in diverse tissues. J Cell Mol Med 2010; 14(12):2702-2720. (9) Gueneau L, Bertrand AT, Jais JP, Salih MA, Stojkovic T, Wehnert M et al. Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy. Am J Hum Genet 2009; 85(3):338-353. (10) Windpassinger C, Schoser B, Straub V, Hochmeister S, Noor A, Lohberger B et al. An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1. Am J Hum Genet 2008; 82(1):88-99. (11) Cowling BS, Cottle DL, Wilding BR, D'Arcy CE, Mitchell CA, McGrath MJ. Four and a half LIM protein 1 gene mutations cause four distinct human myopathies: a comprehensive review of the clinical, histological and pathological features. Neuromuscul Disord 2011; 21(4):237-251. (12) Meune C, Van Berlo JH, Anselme F, Bonne G, Pinto YM, Duboc D. Primary prevention of sudden death in patients with lamin A/C gene mutations. N Engl J Med 2006; 354(2):209-210. (13) Becane HM, Bonne G, Varnous S, Muchir A, Ortega V, Hammouda EH et al. High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation. Pacing Clin Electrophysiol 2000; 23(11 Pt 1):1661-1666.
Thomas D. Gossios, MD1, Margherita Calcagnino, MD1,2, Perry M. Elliott, MD1 1. Heart Hospital, University College London Hospitals Trust, London, UK. 2. University of Pavia, Pavia, Italy.
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