Skeletal muscle involvement in cardiomyopathies.

Invited article

Skeletal muscle involvement in cardiomyopathies Giuseppe Limongellia, Raffaella D’Alessandroa, Valeria Maddalonia, Alessandra Reaa, Anna Sarkozyc and William J. McKennab The link between heart and skeletal muscle disorders is based on similar molecular, anatomical and clinical features, which are shared by the ‘primary’ cardiomyopathies and ‘primary’ neuromuscular disorders. There are, however, some peculiarities that are typical of cardiac and skeletal muscle disorders. Skeletal muscle weakness presenting at any age may indicate a primary neuromuscular disorder (associated with creatine kinase elevation as in dystrophinopathies), a mitochondrial disease (particularly if encephalopathy, ocular myopathy, retinitis, neurosensorineural deafness, lactic acidosis are present), a storage disorder (progressive exercise intolerance, cognitive impairment and retinitis pigmentosa, as in Danon disease), or metabolic disorders (hypoglycaemia, metabolic acidosis, hyperammonaemia or other specific biochemical abnormalities). In such patients, skeletal muscle weakness usually precedes the cardiomyopathy and dominates the clinical picture. Nevertheless, skeletal involvement may be subtle, and the first clinical manifestation of a neuromuscular disorder may be the occurrence of heart failure, conduction disorders or ventricular arrhythmias due to cardiomyopathy. ECG and echocardiogram, and eventually, a more detailed

Introduction Skeletal muscle is composed of fascicles of myofibres (i.e. elongated multinucleate cells), whereas cardiac myocytes are singly nucleated (or binucleate cells) with a rectangular shape. Although cardiomyocytes and skeletal myofibres share the same sarcomeric structure, the general architecture of the cell, the calcium handling and, also, their regenerative capacity varies significantly. Structural and functional gene abnormalities producing degeneration of the heart muscle can similarly produce degeneration of the skeletal muscle, and vice versa.1 An acquired and/or genetically determined injury of the skeletal muscle is counterbalanced by an active and ready regeneration process regulated by the additional fusion of mononucleated myoblasts to the syncytium of the skeletal myofibre.2 The regeneration process of the myocytes, however, is limited compared with the skeletal muscle, and the result is generally an activation of the extracellular matrix with increased and generalized myocardial fibrosis and/or localized scar, depending on the type (genetic/acquired) and duration of injury. A mixed clinical presentation is frequently encountered by cardiologists and neurologists, particularly in children 1558-2027 ß 2013 Italian Federation of Cardiology

cardiovascular evaluation may be required to identify early cardiac involvement. Paediatric and adult cardiologists should be proactive in screening for neuromuscular and related disorders to enable diagnosis in probands and evaluation of families with a focus on the identification of those at risk of cardiac arrhythmia and emboli who may require specific prophylactic treatments, for example, pacemaker, implantable cardioverter-defibrillator and anticoagulation. J Cardiovasc Med 2013, 14:837–861 Keywords: cardiomyopathies, neuromuscular disorders, subclinical skeletal muscle involvement a

Monaldi Hospital, Second University of Naples, Naples, Italy, bInstitute of Cardiovascular Science, University College London and The Heart Hospital, University College London Hospitals Trust, London and cInstitute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK Correspondence to Giuseppe Limongelli, MD, PhD, FAHA, FESC, Monaldi Hospital, Second University of Naples, 80100 Naples, Italy Fax: +39 0817062683; e-mail: [email protected] Received 2 September 2012 Revised 6 May 2013 Accepted 6 June 2013

and adolescents. In one study examining the cause of paediatric dilated cardiomyopathy (DCM), 26% of the patients had associated neuromuscular disease.2 Cardiac symptoms can sometimes precede muscle weakness.3 Recent reports also suggest that 25% of the genes that have been associated with cardiomyopathies are also causative of neuromuscular disorders as allelic forms.4 In these cases, patients who initially presented with advanced cardiomyopathy are later diagnosed with a specific muscle disease. Katzberg et al.5 reported five children who initially presented with cardiomyopathies without neuromuscular signs or symptoms. The severity of cardiac presentation required cardiac transplantation in four, while one died prior to transplantation; a review of the muscle pathology revealed the diagnoses of five different neuromuscular disorders (Becker muscular dystrophy (BMD), myofibrillar myopathy (MFM), mitochondrial myopathy with cytochrome oxidase deficiency, Danon disease and glycogen storage disease). Moreover, cardiomyopathy may complicate an already severe picture of myopathy of varying origin (neuromuscular, metabolic, mitochondrial). Although dilated and DOI:10.2459/JCM.0b013e3283641c69

Copyright © Italian Federation of Cardiology. Unauthorized reproduction of this article is prohibited.

838 Journal of Cardiovascular Medicine 2013, Vol 14 No 12

hypertrophic cardiomyopathy (HCM) have been most frequently reported, all the cardiomyopathy phenotypes may be observed, including left ventricular noncompaction and restrictive cardiomyopathy (RCM), and some specific association may sometimes be recognized (clinical hallmarks or disease ‘red flags’).

associated with cardiac involvement.79,80 Rarely, heart muscle diseases may represent an early, and occasionally as the only, manifestation of primary neuromuscular or mitochondrial diseases. The cause, pathogenesis, and cardiac phenotypes associated with neuromuscular disease are presented in Table 1.

In this review, we present an overview of the molecular basis and clinical features of the principal skeletal muscle disorders associated with heart muscle disorders.

Skeletal muscle involvement in hypertrophic cardiomyopathy

Skeletal muscle involvement in dilated cardiomyopathy DCM (OMIM #115200) is a disease affecting the heart muscle characterized by progressive ventricular dilation and impaired systolic function. The familial form of DCM (familial dilated cardiomyopathy, FDC) can be found in up to 50% of those with idiopathic dilated cardiomyopathy (IDC). The genes involved in DCM show allelic heterogeneity and encode for a variety of proteins expressed within the cardiomyocyte, and localized in the nuclear envelope, the cardiac sarcomere, the dystrophin-associated cytoskeletal complex, ion channels, calcium-homeostasis regulators and transcription factors. Abnormal mitochondrial function (due to nuclear or mitochondrial DNA gene variations) may also cause DCM.6 The pattern of inheritance is heterogeneous (Table 1).1,7–75 Mutations in genes encoding components of the cytoskeleton, as well as sarcomeric proteins, suggest that DCM is both a disease of force transmission and force production.76,77 There is a strong link between neuromuscular disorders and DCM. A mutation in the dystrophin gene was the first gene discovered as an underlying cause of familial (X-linked) DCM.77 The dystrophin– glycoprotein complex (DGC), embodying dystrophin, the sarcoglycans, dystroglycan, dystrobrevins, syntrophins, sarcospan, caveolin-3 and nitric oxide synthase, is an oligomeric complex of protein found on the sarcolemma. First identified for its role in maintaining muscle membrane stability, the genes encoding this complex lead to muscular dystrophy and cardiomyopathy, suggesting that the link between cytoskeleton, plasma membrane (sarcolemma) and extracellular matrix is fundamental for both skeletal and heart muscle cells.78 The DGC is divided into different subunits: the dystrophin (Duchenne muscular dystrophy, DMD) and the syntrophin (SNTA1) in the cytoplasm, and the dystroglycans and the sarcoglycans (sarcoglycan complex, SGC) on the membrane (Fig. 1). Mutations in other genes involved in the development and maintenance of the cardiac cytoskeleton and nuclear membrane (emerin, lamin A/C, fukutin and components of the SGC) similarly result in primary neuromuscular disorders, such as Emery–Dreifuss muscular dystrophy and some types of limb girdle muscular dystrophies, often

HCM (OMIM #192600) is diagnosed when there is unexplained hypertrophy of the left ventricle (LV). The prevalence of HCM is 1 in 500 in young adults.81 It is a familial (FHCM), genetic disorder, with a high degree of genetic (sarcomeric and nonsarcomeric genes) and clinical (age and mode of presentation, severity of the phenotype and outcome) heterogeneity.82 To date, 10 sarcomeric genes, more than 20 causal genes and more than 600 disease-causing mutations (often private) have been characterized, but knowledge is still partial, explaining only 2/3 of the overall HCM cases.76 Mutations in myosin heavy chain and myosin binding protein C are the commonest disease-causing genes. Rare cases are related to mutations in MYL3, MYL2, TNNC1, TTN (myosin light chain-3, myosin light chain-2, troponin C and titin); in the genes of the Z-disk, MYOZ2 and TCAP, coding respectively for Myozenin 2 and Titin-cap; LIM protein and alpha-myosin (CSRP3, MYH6, respectively).79 In the remaining 30–40%, a genetic cause is not recognized, though comprehensive genetic evaluation with conventional Sanger sequencing is rarely feasible even in the major reported series. Possible explanations for this ‘gap’ are as follows: some of the genes are very large (e.g. titin), and difficult to analyse; mutations in intronic regions (splicing, regulatory regions) may be ‘invisible’ to the molecular screening; ‘overlapping phenotypes’, such as genetic syndromes, neuromuscular, mitochondrial and metabolic diseases mimicking the original phenotype of FHCM may not be distinguished on a clinical basis; and comprehensive mutation analysis involving known genocopies-phenocopies is not generally performed. To date, knowledge regarding the functional effects of sarcomeric mutations is incomplete.76,82,83 It has been reported that b-myosin mutations Arg719Trp and Arg723Gly both cause an overall reduction in calcium sensitivity of the soleus muscle fibres but with a large variability among individual fibres, which seems to be due to large differences in intrinsic properties of the fibres. Both the varying levels of force generation and the incomplete relaxation of some fibres under normally relaxing conditions could also cause large variability in force generation from fibre to fibre.76 In-vitro studies, mainly using recombinant proteins, showed that sarcomeric gene mutation may cause an hypercontractile phenotype (‘gain of function’), with a higher Ca2þ-sensitivity of the contractile apparatus (and,


Skeletal: Increased lordosis, Scoliosis joint contractures; Muscle: progressive muscle weakness; Calf muscle pseudohypertrophy, Respiratory impairment; Central nervous system: variable cognitive impairment1,11–13

Dystrophin (DMD, Xp21.2)

Dystrophin (DMD, Xp21.2)

Delta-sarcoglycan (SGCD, 5q33–34)

Titin-cap; telethonin (TCAP, 17q12)

Duchenne muscular dystrophy (DMD)11

Becker muscular dystrophy (BMD)14

Limb-girdle muscular dystrophy 2C-D-E-F (LGMD 2C-D-E-F)17

Limb-girdle muscular dystrophy 2G LGMD2G18

High serum CK; Absent dystrophin on muscle biopsy1,11–13

DCM, LVNC1,11–13

DCM, HCM1,15,17

Muscle: Proximal and distal HCM, DCM1,15,18 muscle weakness and atrophy in lower limbs, Proximal muscle weakness and atrophy in upper limbs18

LGMD2C-D-E-F; Muscle: usually childhood onset muscle weakness and wasting, mainly involving hip, thigh and shoulder muscles. Prominent scapular winging. Calf muscle pseudohypertrophy; Variable progression; Joint contractures; Respiratory impairment1,15,17

Q-waves > R-waves (V1, V2), AVBs, RBBB, LBBB, AF15

Serum CK elevated18

As myofilament CMPs15

Follow-up

Management (drugs/devices)

(continued overleaf )

Echo: initial at diagnosis; ECG, echo; ACE-i; BB; frequency 1–2 years till Female carrier: as age of 10 years; Holter needed with decrease ECG: initial age in ejection fraction13 6 years; frequency 1–2 years; Cardiac investigations before any surgery and every 2 years up to age 10; every year after age 10 assessment and treatment of respiratory dysfunction in parallel with cardiac investigations; Female carrier: Echo and ECG at diagnosis or after age 16 and every 5 years thereafter; more frequent evaluations with test abnormalities or symptoms1,13 DCM, LVNC, WMA, RV Echo: initial at diagnosis or ECG, echo, diuretics; dilatation/dysfunction by the age 10 years; ACE-i; BB with MVP14,15 frequency 1–2 years; decrease in ejection Holter ECG: initial age fraction (if progressive 10 years; frequency abnormalities found, 1–2 years. Echo and consideration of cardiac ECG at diagnosis. transplantation)1,13,15,16 Screening for cardiomyopathy at least every 5 years1,13,15,16 DCM, WMA, RV dilatation/ Regular ECG and echo As for DMD and BMD; dysfunction, HCM15 (case by case)1,15 ACE-i and BB once cardiac involvement is identified. Also for preventive therapy to slow progression of cardiomyopathy, although it has not been proved in clinical trials. Consideration of calcium antagonist medications to improve coronary artery flow; PMK; AICD; Consideration of cardiac transplantation1,13,15 15 HCM, DCM ECG, echo, Holter at As myofilament CMPs1,15 baseline and during follow-up (as myofilament CMPs)

Cardiac phenotype (Imaging)

R-waves (V1> V2) DCM, LVNC; WMA1,13 > Q-waves (most commonly in the lateral leads and less commonly in the inferior and anterior leads) AVBs, RBBB, LBBB, AF1,13

Cardiac phenotype (ECG)

Serum CK high or extremely Q-waves, R-waves elevated. Variable loss of (V1, V2), AVBs, RBBB, sarcoglycans on muscle AF, VT15 15,17 biopsy

High serum CK abnormal dystrophin on muscle biopsy14

Clinical investigations

Cardiac phenotype

Muscle: progressive muscle DCM, LVNC14–16 weakness; Calf muscle pseudohypertrophy, Calf pain and cramps; Joint contractures; Central nervous system: variable cognitive impairment;14,15 Respiratory impairment

Noncardiac phenotype

Gene (symbol, locus)

Neuromuscular, metabolic and mitochondrial disorders associated with heart muscle diseases

Disease

Table 1

Myopathies and cardiomyopathies Limongelli et al. 839


Muscle: Shoulder and hip girdle DCM1,15,19 muscle weakness, variably progressive. Joint contractures. Calf muscle pseudohypertrophy; Diaphragmatic involvement leading to respiratory insufficiency (’restrictive’) in ambulant phase19 Ears: Sensorineural hearing Presyncope, Syncope, loss; Eyes: Retinal SCD1,15,17,21 vasculopathy, Peripheral retinal telangiectasia; Skeletal: Scapular winging; Muscle: variably progressive facial, shoulder girdle, upper arm muscle weakness and atrophy; later, involvement of pelvic girdle, abdominal wall muscle and foot extensor muscles. Respiratory impairment21 Eyes: Cataract; Abdomen: DCM, LVNC1,7,15 cholelithiasis, recurrent intestinal pseudo-obstruction, dysphagia, poor feeding (congenital form); Genitourinary: hypogonadism, testicular atrophy (male), uncoordinated uterine contraction (female); Hair: frontal balding (male pattern baldness); Muscle: myotonia (delayed muscle relaxation after contraction), weakness, wasting, especially temporal, neck, and facial muscles, Respiratory distress (congenital form), Bilateral facial weakness (congenital form), Absence of myotonia in infancy (congenital form); Central nervous system: Mild cognitive deterioration in adults, Speech disability, Excessive daytime sleepiness, Reduced sleep latency, Sleep-onset REM, Hypotonia (congenital form), Severe mental retardation (congenital form), Poor feeding (congenital form); Prenatal manifestation: Reduced fetal movements (congenital form), Polyhydramnios (congenital form)22

FKRP

- (-, 4q35)

Dystrophia myotonicaprotein kinase gene (DMPK, 19q13.32)

Limb-girdle muscular dystrophy 2I (LGMD2I, MDDGC5)‘19

Facioscapulohumeral muscular dystrophy (FSHD)20

Myotonic muscular dystrophy (DM1)22

Cardiac phenotype



Disease

Table 1 (continued ) Cardiac phenotype (ECG)

AVBs, RBBB, AF, VT15,21

Decreased gamma globulin AVBs, LBBB, AF, VT, concentration on serum SND, Q-waves1,7,15,23 electrophoresis may be present. Myotonic discharges on EMG; Muscle biopsy: fibre size variability, ring fibres, increased number of central nuclei, with nuclear chains, sarcoplasmic masses, type 1 fibre predominance and atrophy, fibrosis and fatty infiltration. CK: normal22

Serum CK normal-elevated nonspecific chronic myopathic changes and mononuclear inflammatory reaction.20

Serum CK high or extremely As myofilament CMPs15 elevated; Variable loss of alpha dystroglycan and laminin alpha 2 on muscle biopsy19

Clinical investigations ECG, echo, Holter at baseline and during follow-up (as myofilament CMPs)1,15

Follow-up

DCM, WMA, RV dilatation, MVP, HCM, Perfusion abnormalities1,7,15

PMK; AICD1,15

As myofilament CMPs1,15


Echo: initial age ECG; Pacemaker as 10–20 years; frequency needed; AICD; 2–3 years; Annual ECG Consider ACE-i and starting at diagnosis; b-adrenergic blockade Holter ECG: initial age (progressive rhythm 10–20 years; frequency abnormalities detected); 2–3 years; If Holter Consideration of drugs ECG shows increased to treat overly fast heart risk of abnormally slow rate in atria (upper heart rate; consideration cardiac chambers) but of invasive measurement with caveat that these of cardiac may worsen rate 1,15,23 conduction. irregularities in ventricles (lower chambers)1,15,23

Normal echo; RV dilatation; ECG and echo at Perfusion diagnosis, with followabnormalities15,21 up dictated by clinical picture; Holter ECG1,15

DCM15




Emery–Dreifuss muscular dystrophy26–32

Four and a half LIM domain protein (FHL1, Xq)31

Emerin (EMD, Xq28)30

Lamin A/C (LMNA, 1q21.2-.3)

Proximal myotonic CCHC-type zinc finger, myopathy (PROMM); nucleic acid binding Myotonic dystrophy 2 protein (ZNF9, 3q21) 24 (DM2)

Eyes: Cataracts, posterior, subcapsular, iridescent; Genitourinary: Hypogonadism, Oligospermia (male); Skin, Hair, Nails: Hyperhydrosis, Frontal balding (male pattern baldness); Muscle: Muscle pain, Myotonia, Proximal muscle weakness, Deep finger muscle weakness, Neck flexor weakness, Myotonic discharges on EMG Endocrine features: Insulin insensitivity, Low testosterone, Elevated follicle stimulating hormone; CK: normal24 Muscle: scapulo-humeroperoneal weakness, preceding joint contractures, later also involving pelvic girdle; Skeletal: cervical, spinal rigidity, scapular winging, Elbow and ankle contractures; Limb-girdle muscle weakness, proximal, upper greater than lower, Pelvic muscle involvement occurs later;26 Respiratory impairment; LGMD1B; Muscle: Hip girdle muscle weakness (usually presenting symptom), Shoulder girdle muscle weakness;27 Skeletal: Mild joint contractures with sparing of the elbows; Respiratory impairment; CK normal Neck, elbows, Achilles tendon contracture;30 Muscle: Slowly progressive muscle wasting and weakness with humeroperoneal and scapuloperoneal distribution; Respiratory impairment Spinal rigidity, scapular winging pelvic, peroneal or pelviperoneal weakness; Respiratory impairment31

Elevated serum GGT IgG AVBs, RBBB, AF, VT1,15 and IgM; Muscle biopsy: atrophic fibres, increased numbers of central nuclei.24,25

Serum CK normal-elevated; Absence of emerin on muscle biopsy30

Serum CK increased31

DCM1,15,30

HCM1,15,31,32

As myofilament CMPs1,15,32

AVBs, Atrial standstill, AF, SVT, VT1,15

LVNC, DCM, HCM1,15,28 Serum CK normalAVBs, AF, SVT, VT1,15 moderately elevated; Muscle biopsy: nonspecific myopathic or dystrophic changes; Muscle biopsy is now rarely performed for diagnostic purposes because of the lack of specificity of the dystrophic changes observed27,28

Cardiac conduction abnormalities; Palpitations; Tachycardia1,15,25

HCM1,15,31,32

DCM1,15

LVNC, DCM, HCM1,15,28

Normal echo1,15

PMK; AICD1,15

ECG, echo, Holter at baseline and during follow-up (as myofilament CMPs)1,15,32


As myofilament CMPs1,15,32

ECG, Holter ECG, echo: PMK and/or ICD: primary at diagnosis or by the prevention1,15 age 10 years; frequency 1–3 years1,15

ECG, Holter ECG, echo: PMK and/or ICD: primary at diagnosis or by the prevention, to be age 10 years; frequency considered in carriers; 1,15 1–3 years consider ACE-i and BB; consideration of warfarin to prevent stroke1,15

ECG at diagnosis, with follow-up dictated by clinical picture; Holter ECG1,15



Myotilin (TTID 5q31.2)39 Muscle: progressive weakness39

DCM39

Muscle: Proximal and distal HCM, DCM, RCM, (often at onset) muscle ARVC; Conduction weakness usually at onset, abnormalities and facial and neck muscle Arrhythmias8,37 weakness; Bulbar weakness; Respiratory impairment37 Muscle: late onset and HCM, DCM38 progressive weakness; Eyes: cataracts38

Desmin (DES, 2q35)37

Myofibrillar myopathy37–40

Alpha-B crystallin (CRYAB 11q23.1)38

Skeletal: Kyphoscoliosis may LVNC36 occur, Claw hand deformities (in severe cases), Pes cavus, Hammer toes, Foot deformities; Peripheral nervous system: Distal limb muscle weakness due to peripheral neuropathy, Distal limb muscle atrophy due to peripheral neuropathy, ’Steppage’ gait, Foot drop, cold-induced muscle cramps, Distal sensory impairment, Hyporeflexia, areflexia, decreased motor nerve conduction velocity (NCV) (less than 38 m/s), Hypertrophic nerve changes, ’Onion bulb’ formations on nerve biopsy, Segmental demyelination/remyelination on nerve biopsy, Decreased number of myelinated fibres, Myelin outfoldings may occur in a subset of patients

CMT1 peripheral myelin protein 22 (PMP22, 17p11.2–24)

Charcot–Marie– Tooth33–35

Cardiac phenotype



Disease


CMT1: Electrophysiological AVBs, SVT, VT1,15 examination: nerve conduction velocity is slowed and motor conduction velocity is below 38 m/s. ‘Onion bulb’ formations and segmental demyelination/ remyelination on nerve biopsy. Hypertrophic nerve changes.33 CMT2: Electrophysiological examination: motor conduction velocity is preserved or only mildly decreased. Absent nerve conduction velocities. Axonal atrophy on nerve biopsy. Axonal degeneration/ regeneration on nerve biopsy; Small ’onion bulbs’ may be present; Decreased number of myelinated fibres may be found; Mitochondrial abnormalities in nerve biopsy.34 CMTX: Electrophysiological examination: nerve conduction velocity may vary widely, in males nerve conduction velocities are often intermediate between those of CMT1 and CMT2 (30–45 m/s in upper limbs), whereas in females, they are normal to mildly slowed; Loss of myelinated fibres on nerve biopsy. Axonal degeneration. Regenerative nerve sprouting.35 Serum CK normalAVBs, SVT, AF, VT1,15,37 moderately elevated. Myofibrillar changes and protein aggregates are often observed on muscle biopsy.37 Three-fold to five-fold AV block, arrhythmias38 increase in serum CK levels38


ECG and echo at diagnosis, with follow-up dictated by clinical picture; Holter ECG1,15 ECG and echo at diagnosis, with follow-up dictated by clinical picture; Holter ECG ECG and echo at diagnosis, with follow-up dictated by clinical picture; Holter ECG39

HCM, DCM38

ECG and echo at diagnosis, with follow-up dictated by clinical picture1,15

Follow-up

HCM, DCM, RCM1,15

LVNC, DCM1,15,36


Management of cardiomyopathy and arrhythmias39

Management of cardiomyopathy and arrhythmias

Management of cardiomyopathy; PMK; AICD; Transplant1,15

Management of arrhythmias and/or cardiomyopathy1,15




Myofibrillar degeneration and reduced muscle function in patients with HIBM (Nonaka myopathy)48

Udd distal myopathy44

Laing distal myopathy42

BCL2-associated Muscle: early-onset rapidly athanogene 3 (BAG3 progressive myofibrillar 10q26.11)40 myopathy, scoliosis, contractures of the Achilles tendons40 Cardiac b-myosin heavy Muscle: Weakness of ankle and chain (MYH7, toe extensor (dorsiflexor) 14q12)42,43 muscles, atrophy of ankle and toe extensor (dorsiflexor) muscles, weakness of anterior compartment tibial muscles, atrophy of anterior compartment tibial muscles, ’Hanging’ big toe, Gait difficulties, Weakness of long finger extensor muscles (occurs later), Weakness of neck muscles may occur later, Atrophy of neck muscles may occur later, Proximal muscle weakness (occasional)42,43 44,45,47 Titin (TTN, 2q31) Muscle: Weakness of the muscles in the anterior compartment of the lower leg (particularly the tibialis anterior muscle), Atrophy of the muscles in the anterior compartment of the lower leg, ’Steppage’ gait, Reduced ankle dorsiflexion, Cardiomyopathy is not a common feature.44,46 UDP-NMuscle: Distal muscle acetylglucosamine weakness, Distal muscle 2-epimerase/Natrophy, Hamstring muscle acetylmannosamine affected, Tibialis anterior kinase (GNE, muscle affected, Quadriceps 48 9p1-q1) muscle spared, EMG shows myopathic changes, ’Rimmed’ vacuoles on biopsy, Tubulofilamentous nuclear or cytoplasmic inclusions on biopsy, Deposits immunoreactive to beta-amyloid protein, Congophilic amyloid material, Inflammatory cells absent; Central nervous system: gait abnormalities49 Cardiomyopathy is rare (HCM)48,49

DCM, HCM.44,46

HCM, DCM42,43

DCM40,41

Increased serum CK (CPK)50

Serum CK normal or slightly elevated.44,46

Serum CK normal to mildly increased42,43

High serum CK40

HCM, DCM42,43

DCM40,41

ECG: normal or no specific Echo: normal or rare findings cardiomyopathy (HCM)48,49

As myofilament CMPs.44,46 DCM, HCM44,46

Prolonged QT interval40

ECG and echo at diagnosis, with follow-up dictated by clinical picture

ECG, echo, Holter at baseline and during follow-up (as myofilament CMPs)1,15

ECG and echo at diagnosis, with follow-up dictated by clinical picture; Holter ECG ECG and echo at diagnosis, with followup dictated by clinical picture1,15


Management of cardiomyopathy

As myofilament CMPs1,15

Management of cardiomyopathy and arrhythmias1,15




Glycogen storage disease54,56,58

Frataxin (FXN, 9q13)50

Friedreich’s ataxia50


Cardiac phenotype

Eyes: Nystagmus, Optic HCM51–53 atrophy, Reduced visual acuity (less common), Visual field defects, Reduced retinal nerve fibre layer thickness, Abnormal visual evoked potentials; Skeletal: scoliosis, pes cavus; central nervous system: Gait and limb ataxia, dysarthria, nystagmus, impaired proprioception, impaired vibratory sense; peripheral nervous system: peripheral sensory neuropathy, Abnormal motor and sensory nerve conduction, Absent lower limb tendon reflexes, Extensor plantar responses; Endocrine features: Diabetes mellitus50,51 Alpha-glucosidase (GAA, Ears: Hearing loss; Mouth: HCM54,55 17q25.2-q25.3)54 Macroglossia; Vascular: Cerebral artery aneurysm; Chest: Diaphragmatic paralysis; Abdomen: Hepatomegaly, Splenomegaly; Muscle: Weakness, Proximal muscle weakness, Myopathic pattern on EMG, Firm muscles; Central nervous system: Hypotonia, Abnormal brain myelination; Peripheral nervous system: Absent deep tendon reflexes; METABOLIC: Fever of central origin.54,55 g 2 subunit of AMPGrowth: Growth retardation in HCM56,57 activated protein childhood, Normal final adult kinase height; Abdomen: Liver (PRKAG2,7q36.1)56 (hepatomegaly, fibrosis, bile duct proliferation, cirrhosis, hepatic glycogen accumulation), Splenomegaly; Muscle: Hypotonia; Central nervous system: Mildly delayed motor development56


Disease

Table 1 (continued )

HCM56,57

WPW, AVBs, AF, VT56,57

Fasting hypoglycaemia; Lactic acidosis; Fasting ketosis; Abnormal liver enzymes; Increased serum triglycerides; Decreased PHK activity in liver; Moderately decreased to normal PHK activity in skeletal muscle56

Enzyme replacement therapy55

No specific data on common medications (ACE-i, BB, diuretics); ventricular arrhythmias should be managed with medical therapy of device implantation (as in familial HCM). Idebenone has been shown to ameliorate cardiac status (cardiomyopathy remodelling) in an animal model and in roughly half the patients with Friedreich ataxia1,15,51 –53


ECG and echo at Management of diagnosis (generally, cardiomyopathy adolescence) with (as myofilament CMPs); follow-up dictated by PMK AICD56,57 clinical picture (as myofilament CMPs)56,57

ECG and echo at diagnosis, with followup dictated by clinical picture55

HCM55

ECG and echocardiogram starting at an early age.1,15,51–53

Follow-up

HCM51–53


WPW, Conduction defects, LVH55

LVH, T-wave inversion Q-waves > R-waves (V1, V2)51–53


Elevated serum creatine kinase; Elevated AST and LDH, especially infantile-onset; Presence of vacuoles on muscle biopsy; Deficiency of alpha-1,4-glucosidase (acid maltase).55

Abnormal spinocerebellar tracts, dorsal columns, pyramidal tracts, cerebellum and brainstem; Abnormal ECG; Abnormal echocardiogram; Low pyruvate carboxylase activity in liver and cultured fibroblasts; Decreased mitochondrial malic enzyme50,51




Danon disease60

Lysosome-associated membrane protein-2 (LAMP-2, Xq24)60

Glycogen debranching enzyme (GDE, 1p21)58

Growth: Short stature, Growth HCM58,59 retardation; Face: Midface hypoplasia; Eyes: Deep-set eyes; Nose: Depressed nasal bridge, Broad upturned nasal tip; Mouth: Bow-shaped lips, Thin vermilion border; Abdomen: Hepatomegaly, Hepatic fibrosis; Muscle: Muscle weakness (increases with age), Distal muscle wasting, Myopathy, Muscle biopsy shows vacuoles containing PAS-positive glycogen; Metabolic features: Hypoglycaemia58 Eyes: Moderate central loss of HCM, DCM60,61 visual acuity in males (20/ 60), Normal to near-normal visual acuity in carrier females (20/30–20/20), Fine lamellar white opacities on slit lamp examination in carrier females, Near complete loss of peripheral retinal pigment in males, Peppered pigmentary mottling of peripheral retinal pigment in carrier females, Nonspecific changes on electroretinogram in carrier females. Feet: Pes cavus (uncommon); Muscle: proximal muscle weakness (85% of patients), Diffuse muscle atrophy, Exercise intolerance, Muscle cramps with exercise, EMG shows myopathic changes, Muscle biopsy shows sarcoplasmic PAS-positive vacuoles, Muscle biopsy shows glycogen accumulation in myofibrils and lysosomes, Indentations or folds of the sarcolemma are connected to the membranes enclosing the vacuoles, Vacuoles are autophagocytic, Vacuolar membranes immunostain with sarcolemmal proteins, Severely decreased or absent LAMP2 protein, Positive staining for complement C5b-9 membrane attack complex proteins within vacuoles, but not on muscle fibre membrane, Normal alphaglucosidase or acid maltase activity; Central nervous system: Mental retardation (70%); Cognitive impairment, mild; Delayed development61 Increased serum creatine kinase60

WPW, conduction defects60–62

Amylo-1,6-glucosidase LVH, repolarization deficiency; abnormalities58,59 Hypoglycaemia; Hyperlipidaemia; Normal blood lactate; Normal uric acid; Elevated transaminases; Increased serum creatine kinase58,59

HCM, DCM62

HCM58,59


ECG and echo at Early cardiac diagnosis (generally, transplantation62 adolescence) with follow-up dictated by clinical picture; high risk of sudden death and heart failure (before the age of 25 years)1,15,61,62

ECG and echo at Management of the severe, diagnosis with follow-up progressive dictated by clinical cardiomyopathy58,59 58,59 picture



Barth syndrome66

Solute carrier family 25 Growth: Failure to thrive; HCM, DCM63 (carnitine/acylcarnitine Muscle: Muscle weakness, translocase), member Hypotonia, Muscle biopsy 20 (SLC25A20, shows lipid deposition. 63 3p21.31), ; Carnitine Central nervous system: palmitoyltransferase II Lethargy associated with 64 (CPT2, 1p32) hypoglycaemia, Encephalopathy associated with hypoglycaemia, Coma associated with hypoglycaemia, Reye syndrome, delay in gross motor development due to weakness, Seizures, Ventriculomegaly, Intracerebral periventricular calcifications, Antenatal intracerebral haemorrhage, Dysplastic or absent corpus callosum, Polymicrogyria, Neuronal migration disorder, Paraventricular cysts, Basal ganglia cysts. Head and neck: Microcephaly, High, sloping forehead, Prominent forehead, Overfolded helices, Low-set ears, Posteriorly rotated ears, Cataracts, Bulbous nose, High-arched palate, Narrow palate. Abdomen: Hepatomegaly, Macrovesicular steatosis, Lipid accumulation in hepatocytes, Liver calcifications. Genitourinary: Enlarged polycystic kidneys, Dysplastic renal parenchyma, Hydronephrosis, Lipid accumulation in kidney, especially in proximal convoluted tubules, Renal insufficiency, Double ureters. Skeletal: Contractures of knees and of elbows. Long, tapering fingers (extra digital creases in digits 2–4) and toes.63,64 Tafazzin (TAZ/G4.5, Growth: Growth retardation; LVNC, DCM66–68 Xq28)66 Muscle: Skeletal myopathy; Metabolic features: Intermittent lactic acidaemia; Haematology: Granulocytopenia; Immunology: Recurrent infections in infancy and early childhood.66

Cardiac phenotype

Carnitine deficiency63,64



Disease


Ultrastructural abnormalities in mitochondria on electron microscopy; Endomyocardial fibroelastosis on light microscopi; Elevated urinary 3methylglutaconate; Elevated urinary 3-methylglutarate; Elevated urinary 2-ethylhydracrylate; Neutropenia; Hypocholesterolaemia (total, LDL); Low prealbumin66

LVH, Prolonged QTc, repolarization abnormalities, VT68

Carnitine-acylcarnitine LVH63 translocase deficiency: Hypoketosis; Hypoglycaemia; Hyperammonaemia; Carnitine-acylcarnitine translocase deficiency.63 Carnitine palmitoyltransferase II deficiency: Increased liver function tests Increased plasma long-chain acylcarnitines; Increased tissue longchain acylcarnitines; Decreased plasma total and free carnitine Decreased tissue total and free carnitine; Increased serum longchain fatty acids; Increased tissue longchain fatty acids; Longchain dicarboxylic aciduria; Hyperammonaemia; Increased total bilirubin; Increased tissue levels of triglycerides; Increased tissue levels of free fatty acids; Severely decreased palmitate oxidation; Severely decreased carnitine palmitoyltransferase II (CPT II) activity (less than 10% of normal) in multiple tissues.64


LVNC, DCM68

HCM, DCM63



ECG and echo at diagnosis (generally, childhood) with followup dictated by clinical picture15,66–68

Management of cardiomyopathy15,66–68

Cardiac presentation with Management of skeletal myopathy is cardiomyopathy.63,64,65 more frequent in older patients; Metabolic presentation (hypoketotic hypoglycaemia, hepatomegaly, Reye syndrome) is common before the age of 2, and may be complicated by syncopal episodes, after periods of fasting, and sudden death.65

Follow-up



MERRF, MELAS, ocular myopathy71–73

Mitochondrial genes; MERRF: MTTK, MTTL1, MTTH, MTTS1, MTTS2, MTTF, MTND5;71 MELAS: MTTL1, MTTQ, MTTH, MTTK, MTTC, MTTS1, MTND1,MTND5, MTND6, MTTS2;72 Ocular myopathy: MTND1, MTND2, MTND4, MTND4L, MTND5, MTND6, MTCYB, MTCO1, MTCO3, MTAP6,73 Mitochondrial DNA)

Myoadenylate deaminase AMP deaminase deficiency (MADA)69 (AMPD1, 1p13)69,70

Muscle: exercise-induced HCM, LVNC69,70 myopathy; Postexertional muscle weakness or cramping; Prolonged fatigue after exertion; Neurological: Limp infant; Benign congenital hypotonia70 MERFF: Muscle: Muscle HCM, DCM, LVNC9,10 weakness. Myopathy. Neurology: Myoclonus epilepsy. Ataxia. Spasticity. Ears: Sensorineural hearing loss.71 MELAS: Growth: Thin; Ears: Hearing loss, progressive bilateral sensorineural; Eyes: Bilateral cataracts, Hemianopsia, Cortical blindness; Gastrointestinal: Episodic vomiting; Muscle: Myopathy, Reduced muscle mass, Ragged-red fibres on muscle biopsy; Central Nervous System: Episodic sudden headache, Intermittent migraine headaches, Grand mal seizures, Hemiparesis, Stroke-like episodes, Dementia, Encephalopathy; Metabolic features: Lactic acidosis;72 Ocular Myopathy: Visual blurring/clouding (acute phase), Centrocecal scotoma (acute phase), Central retinal vessel vascular tortuosity (acute phase), Circumpapillary telangiectatic microangiopathy (acute phase), Swelling of retinal nerve fibre layer (acute phase), Optic atrophy (chronic phase), Visual loss (chronic phase); Muscle: Nonspecific myopathy; Central Nervous System: Postural tremor, Movement disorders, Multiple sclerosislike illness, Spastic dystonia, Ataxia, Peripheral Nervous System: Peripheral neuropathy73 No specific findings

HCM, LVNC69,70

Ragged-red muscle fibres. WPW, ST abnormalities, T- HCM, DCM, LVNC, Serum pyruvate or wave inversion, VPD QNormal echo9,10 pyruvate and lactate waves9,10 elevated. Defect in translation of all mtDNAencoded genes;72 MELAS: Elevated resting serum lactate, increased with exercise; Subsarcolemmal pleomorphic mitochondria on EM10,71–73

Decreased purine release after exercise70



ECG and echo at Management of diagnosis with follow-up cardiomyopathy; PMKdictated by clinical AICD9,10 picture9,10

ECG and echo at diagnosis, with followup dictated by clinical picture



Increased cerebrospinal fluid (CSF) protein (>100 mg/dl); Lactic acidosis; Decreased cerebrospinal fluid folic acid; Decreased serum and muscle coenzyme Q.9,10

No histochemical evidence of mitochondrial myopathy.74


Normal echo, rare DCM9,10 ECG and echo at Management of diagnosis with follow-up cardiomyopathy and/or dictated by clinical arrhythmias; PMK9,10 picture; ECG Holter (baseline, follow-up)9,10

AVBs, AF9,10


ECG and echo at Management of diagnosis with follow-up cardiomyopathy and dictated by clinical arrhythmias9,10 9,10 picture

Follow-up

HCM9,10


Conduction defects9,10


ACE-Is, angiotensin converting enzyme inhibitors; AF, atrial fibrillation; AICD, automated implantable cardioverter-defibrillator; ARVD, arrhythmogenic right ventricular dysplasia; AVBs, atrioventricular blocks; BB, b adrenergic blocker; CK, creatine kinase; CMPs, cardiomyopathies; DCM, dilated cardiomyopathy; EMG, electromyography; HCM, hypertrophic cardiomyopathy; LBBB, left bundle branch block; LVH, left ventricular hypertrophy; LVNC, Left ventricular noncompaction; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes; MERRF, myoclonic epilepsy associated with ragged-red fibres; MVP, mitral valve prolapsed; NARP, neuropathy, ataxia, and retinitis pigmentosa; PMK, pacemaker; RBBB, right bundle branch block; RCM, restrictive cardiomyopathy; RV, right ventricle; SCD, sudden cardiac death; SND, sinus node dysfunction; SVT, supraventricular tachycardia; VT, ventricular tachycardia; WMA, wall motion abnormalities; WPW, Wolff–Parkinson–White.

Kearns–Sayre syndrome75

ATP synthase F0 subunit Eyes: Salt and pepper HCM9,10,74 6 (MT-ATP6, retinopathy, early, Retinitis 74 Mitochondrial DNA) pigmentosa, Nystagmus, Sluggish pupils, Blindness; Muscle: Proximal muscle weakness, Muscle mitochondria normal by histochemical analysis Central Nervous System: Corticospinal tract atrophy, Developmental delay, Dementia, Seizures, Ataxia, Peripheral Nervous System: Sensory neuropathy, Proximal neurogenic muscle weakness.74 NADH dehydrogenase Growth: Short stature; Head: DCM9,10 subunit; 3, 4, & 5; Microcephaly; Ears: Cytochrome coxidase Sensorineural hearing loss; subunit 3 (MTND5, Eyes: Progressive external MTND4,MTND3, ophthalmoplegia, Pigmentary MTCO3, mtDNA retinopathy, Ptosis; multigene 5 kb Genitourinary: Renal tubular deletion75 acidosis, Fanconi syndrome; Muscle: Muscle weakness, Ragged-red fibres seen on muscle biopsy; Central Nervous System: Cerebellar ataxia, Basal ganglia calcifications, Diffuse signal abnormality of central white matter, Dementia, Seizures, Sensory neuropathy, Motor neuropathy; Metabolic features: Lactic acidosis; Endocrine features: Diabetes mellitus, Hypoparathyroidism, Addison disease; Haematology: Sideroblastic anaemia.75

Cardiac phenotype

NARP syndrome74



Disease

Table 1 (continued )




Fig. 1

DSP

GLA

HFE

LA MP

TAZ

2

mtDNA

CA V

MYH7

SCO2

TCAP ST

TTN

DE

S

RBM20

ACTC

RP

D M

FK

MYPN MYBPC3

DAG

D

MYL2, MYL3

1 NA

PDLIM3 ACTN2 LDB3

SGC

LAMA4

TPM1 TNNT2

TNNC1 TNNI3

VCL α β

EM D

ILK RyR2

TMPO

PSEN1

LM

/2

NA PLN

The principal proteins involved in cardiomyopathies and neuromuscular disorders. ACTC, actin, alpha cardiac muscle; ACTN2, actinin alpha 2; CAV, caveolin; DAG, dystroglycan; DES, desmin; DMD, dystrophin; DSP, desmoplakin; EMD, emerin; FKRP, fukutin-related protein; GLA, alpha galactosidase; HFE, human haemochromatosis protein; ILK, integrin-linked kinase; LAMA4, laminin alpha 4; LAMP2, lysosomal-associated membrane protein 2; LDB3, LIM domain binding 3 (Cypher/ZASP); LMNA, lamin A/C; MYBPC3, myosin binding protein C cardiac; MYH7, myosin heavy chain 7 cardiac muscle b; MYL2, myosin light chain 2 regulatory cardiac, slow; MYL3, myosin light chain 3 alkali ventricular skeletal slow; MYPN, myopalladin; PDLIM3, alpha actinin-associated LIM protein; PLN, phospholamban; PSEN1/2, presenilin; RBM20, RNA binding motif protein 20; RYR2, ryanodine receptor 2 (cardiac); SGC, sarcoglycan; SNTA1, syntrophin alpha 1; TAZ, tafazzin; TCAP, telethonin; TMPO, thymopoietin; TNNC1, troponin C type 1; TNNI3, troponin I type 3 (cardiac); TNNT2, troponin T type 2 (cardiac); TPM1, tropomyosin 1 (alpha); TTN, titin; VCL, vinculin.

particularly, a higher Ca2þ/troponin C affinity), a faster crossbridge turnover rate and incomplete relaxation.82 A hypothesis by Watkins et al.83 proposes that the effect of heterogeneous force/Ca sensitivity relationships on contractile performance determines an inefficient contraction at rest, burning more ATP and compromising the ‘energy balance’ of the cardiomyocyte. Several skeletal myopathies have been associated with the HCM phenotype (Table 1). These conditions represent primary neuromuscular disorders with heart muscle involvement, and they need to be distinguished from FHCM.

Skeletal muscle involvement in left ventricular noncompaction Left ventricular noncompaction cardiomyopathy (LVNC; OMIM#604169), formerly referred to as ‘spongiform

myocardium’, represents a rare myocardial disease characterized by noncompaction of the trabecular network of the ventricular myocardium.84,85 LVNC can be associated with congenital cardiovascular diseases, such as Ebstein’s anomaly, bicuspid aortic valve, transposition of great vessels, ventricular septal defects and also with metabolic diseases and genetic syndromes.86 Mild forms of LVNC frequently overlap with other cardiomyopathy phenotypes, including dilated, hypertrophic, restrictive and arrhythmogenic cardiomyopathy.87 Recently, LVNC was classified as a primary genetic cardiomyopathy by the American Heart Association.88 The prevalence of LVNC ranges from 4.5 to 26 per 10 000 adult patients referred for echocardiography.89 LVNC has been defined as a spontaneous intrauterine arrest of the process of myocardial compaction during



cardiogenesis.84–86 During in-utero ventriculogenesis, myocardial blood supply is initially linked to the presence of sinusoids, in which blood penetrates and diffuses nutrients and oxygen to myocardial cells. An intrauterine arrest of myocardial compaction is possibly the cause of typical intratrabecular recesses in LVNC patients. The genetic background is heterogeneous. Genetic studies have shown that mutations in different sarcomeric genes are implicated in HCM, DCM and LVNC.87 Within families with LVNC, affected individuals sharing the same genetic aetiology may have different clinical phenotypes, for example, HCM, DCM and RCM, suggesting a role of sarcomere proteins in myocardial morphogenesis,88,90 and the role of gene–gene interaction and gene– environment interaction in the determination of different cardiomyopathy phenotypes. In addition, it has been recognized that multiple (two or more) sarcomeric mutations may lead to a more severe phenotype, if compared with the association of a sarcomeric mutation and a nonsarcomeric mutation.91 LVNC has been associated with a number of neuromuscular disorders, including myotonic dystrophy type 1 (DM1), dystrophinopathy, dystrobrevinopathy, myotonic dystrophy, zaspopathy, myoadenylate-deaminase deficiency, Charcot–Marie–Tooth disease, mitochondrial disorder, Barth syndrome, Friedreich’s ataxia or Pompe’s disease7,92 (Table 1).

Skeletal muscle involvement in restrictive cardiomyopathy Familial RCM (OMIM #115210) is a disorder of the heart muscle characterized by restrictive ventricular filling with normal or near normal wall thickness and systolic function.93 Restrictive physiology may dominate the clinical presentation in patients who have HCM, but it is rare to find a family with isolated familial RCM. Evaluation of families of probands with RCM will usually reveal evidence of HCM. Mogensen et al.94 described the association of RCM and HCM within a large Colombian family with a disease-causing mutation in TNNI3 (OMIM 191044). Kubo et al.95 showed that ‘restrictive phenotype’ is an uncommon presentation of the clinical spectrum of HCM; it is frequently associated with b-myosin and troponin I mutations and a poor prognosis. A locus for a different form of the disorder (RCM2; OMIM 609578) has been mapped to chromosome 10q23. An overlap with other cardiomyopathies is also recognized. RCM may be an evolution of DCM or HCM, or may represent a different expression of the disease in family members (‘intrafamilial heterogeneity’), due to the ‘sarcomeric plasticity’ or the presence of modifier genes.6,91,94,95 In children with RCM, Kaski et al.96 found sarcomere protein gene mutations in four of 12 patients (33%), including two in TNNI3 and one each in the TNNT2 and a-cardiac actin (ACTC) genes.

RCM associated with atrioventricular block and skeletal myopathy is usually caused by mutations in desmin or lamin A/C. Moreover, several infiltrative diseases may present with restrictive physiology, including familial amyloidosis, haemochromatosis, Gaucher’s disease and glycogen storage disease (Table 1). Desmin mutations have been recently associated to transformation of related cardiomyopathy. A case report describes the transition from hypertrophic to restrictive, and DCM.97

Skeletal muscle involvement in arrhythmogenic cardiomyopathy Arrhythmogenic right ventricular cardiomyopathy (ARVC; OMIM #107970) is an inherited heart muscle disease that predominantly affects the right ventricle (RV). It is characterized pathologically by RV myocardial atrophy with progressive fibrous or fibrofatty replacement.98 Life-threatening ventricular arrhythmias may occur either during the ‘hot phase’ of myocyte death as abrupt ventricular fibrillation or later in the form of scar-related macro-reentrant ventricular tachycardia, primarily in young people and athletes. The estimated prevalence of ARVC in the general population ranges from 1/2000 to 1/5000. A familial background has been demonstrated in 40–50% of ARVC/arrhythmogenic right ventricular dysplasia (ARVD) cases.98,99 The disease is usually inherited as an autosomal dominant trait with incomplete penetrance and variable expression. Autosomal recessive cardiocutaneous variants of ARVC (Naxos disease, Carvajal syndrome),100,101 in which there is a cosegregation of cardiac (ARVC/D), skin (palmoplantar keratosis), and hair (woolly hair) abnormalities were mapped to chromosome 17 (locus 17q21) and chromosome 6 (locus 6p23–p24; 7901delG mutation in desmoplakin). The first disease-causing gene, the JUP gene, was identified by McKoy et al.100 in patients with Naxos disease. The gene encodes the desmosomal protein plakoglobin, a major constituent of the cell adhesion junction. Its discovery suggested that ARVC is a cellto-cell junction disease and stimulated the research in other related genes. A recessive mutation of desmoplakin was identified in another cardiocutaneous syndrome, that is, Carvajal disease (#605676), characterized by keratoderma, woolly hair and a biventricular form of ARVC, with distinct ultrastructural abnormalities of intercalated discs and decreased immunoreactive signals for desmoplakin, plakoglobin and connexin.101 ARVC was found to be a cell junction disease also in the dominant form, with plakophilin-2 as the most frequent disease gene.98 It has been hypothesized that the lack of normal protein or the incorporation of mutant protein into cardiac desmosomes may provoke detachment of myocytes at the intercalated discs, particularly under conditions of mechanical stress (like that occurring during competitive sports activity), with progressive myocyte death and subsequent



repair by fibrofatty replacement.102 The RV appears to become affected initially, ventricular arrhythmias develop before or after the development of overt RV disease and the LV also becomes affected, usually later in the clinical course. An alternative hypothesis deriving from animal models (desmoplakin-deficient mice)103 suggests Wnt/b-catenin signalling defects, implicating a role for cell adhesion proteins as regulators in cardiac development and in cellular differentiation (e.g. fibrocytes vs. adipocytes). An association between ARVC and skeletal myopathy is recognized. In 1999, Melberg et al.104 described an autosomal dominant form of MFM in combination with ARVC (ARVC7) in a large Swedish family in which 12 members were affected; authors reviewed also the medical records of two affected deceased members. All the patients, including, the two deceased individuals, had myopathy, three male patients in addition developed cardiomyopathy, with (left, but prevalent right) dilatation, atrial flutter and nonsustained ventricular arrhythmias, in conjunction with atrioventricular block or a sick sinus syndrome, requiring pacemaker implantation in two cases. Moreover, autopsy findings from one patient showed dilatation of the RV, with fibrofatty replacement of the myocardium, extending from the epicardium to the endocardium. Similar, but less extensive, changes were present in the LV. Although a potential linkage to chromosome 10q22.3 has been suggested, a comprehensive follow-up study by Kuhl et al.105 did not reveal any pathogenic changes in 17 candidate genes mapped in the region, including ZASP. Recently, a study from the same group by exome sequencing in the Swedish family with MFM and ARVC, identified a heterozygous mutation in the DES gene (P419S) in affected members.8

severity.111 It has been noted that the MYH7 gene, encoding for the b (or slow) heavy chain subunit of cardiac myosin, is expressed predominantly in normal human ventricles, but it is also expressed in skeletal muscle tissues (e.g. soleus). Any change in the relative abundance of this protein and the a (or fast) heavy subunit of cardiac myosin has an impact on the contractile velocity of cardiac muscle. Mutant cardiac myosin purified from skeletal muscle of patients with the R403Q and L908V mutations has abnormal function in an in-vitro motility assay.111 The mutant b-myosin present in skeletal muscle has a demonstrable effect on the structure, and, in particular, the mitochondria, of myofibres. This effect appears to be absent in skeletal muscle of HCM patients in whom the disease is not a consequence of a MYH7 gene mutation. Anastasakis et al.112 found myopathic EMG findings in 1/4 of patients with HCM; they noted a higher prevalence of family history of sudden death in patients with normal EMG. As sarcomeric gene proteins other than b-myosin (e.g. Troponin T, which is often associated with a high risk of sudden death) are not expressed in skeletal muscle, they speculated that EMG findings may reflect the result of genetic heterogeneity in patients with HCM. Allelic variants of the MYH7 gene can also cause ‘pure’ muscle diseases, such as the Laing distal myopathy, a myosin storage myopathy,113 scapuloperoneal myopathy114 and congenital fibre type disproportion.115 In addition, rare MYH7 variants have also been identified in patients affected by a combination of skeletal and cardiac muscles disorders, further confirming the role of this protein in both cardiac and skeletal muscle diseases.113–116

Clinical implications Diagnosis and management

Subclinical skeletal muscle involvement in familial cardiomyopathies Subclinical skeletal involvement with exercise intolerance, increased cardiac enzymes and subtle skeletal muscle abnormalities is recognized in both familial HCM and DCM.106–112 Although FHCM is a primary disorder of the heart muscle, subclinical skeletal muscle abnormalities have been reported in affected patients.106–112 Using EMG and muscle biopsy, Caforio et al.109 found skeletal myopathic abnormalities in both patients with HCM and DCM, suggesting that the observed abnormalities in type I fibres were likely of myogenic origin and not related to the severity of heart failure. It has been shown that some b-myosin heavy chain mutations are expressed in skeletal muscle, and patients with different b-myosin heavy chain gene mutations showed various degrees of myopathic alterations in muscle biopsies, in the absence of muscle weakness related to disease

Diagnosis of inherited cardiac and neuromuscular disease may be straightforward when there is full disease expression. This is more common in autosomal recessive disorders, whereas in dominant conditions expression is often incomplete and age related. Diagnosis then relies on both the cardiologist and neurologist having a high index of suspicion when evaluating minor cardiac or neuromuscular complaints in the young. Baseline cardiovascular evaluation may include 12-lead ECG and twodimensional echocardiography. If abnormalities are detected, a more sophisticated cardiovascular evaluation is required to better evaluate arrhythmic risk (e.g. 24-h ECG) and exercise capacity (6-min walking test, metabolic stress test). Cardiac magnetic resonance (CMR) imaging may be useful when echo images are suboptimal, and in addition, provides an evaluation of tissue substrate with the use of gadolinium late enhancement. Electrophysiological testing may be appropriate in patients at risk of sudden death due to progressive atrioventricular block [i.e. KearnsSayre syndrome or limb-girdle muscular



dystrophy (LGMD)] and/or ventricular arrhythmias (i.e. laminopathies or DM1).1,117 Occasionally, a heart muscle or rhythm abnormality may represent the first manifestation of neuromuscular disease. When the neurological features are mild and/or not recognized, age at presentation is an important indicator to underlying aetiology. Neuromuscular disorders typically present within specific age ranges (i.e. Pompe diseases in neonates; BMD during childhood; familial cardiomyopathies related to sarcomeric gene diseases during adolescence; Fig. 2; see algorithms).118 The pedigree may also reveal a typical pattern of inheritance (female-to-male in X-linked disorders; matrilinear in mitochondrial disorders; multiple affected siblings and consanguinity in autosomal recessive disorders). The low penetrance and different expression of disease makes the clinical diagnosis of some autosomal dominant disorders difficult (particularly, familial DCM). A history of progressive exercise limitation may be present but, in some cases, the phenotype at presentation is mild, and an abnormal ECG (conduction abnormalities, e.g. short or long PR interval; incomplete or complete bundle branch block; prolonged QT; supraventricular or ventricular arrhythmias) may be the only sign of the disease. In the absence of other cardiac or extracardiac markers (clinical signs of myopathy and/or laboratory data), the diagnosis is difficult and often is delayed (‘age-dependent phenotype’).118 In such patients, family evaluation may provide the diagnostic clue; indeed, family members may manifest more advanced disease, with features that may help to reach the final diagnosis. This is particularly relevant with the laminopathies in which a single abnormal protein may cause many different phenotypes (‘one gene, many different diseases’).118 The aim is always to make a definitive diagnosis to enable specific clinical management of the disease. Cardiomyopathy may be of different type and aetiology, with some forms of neuromuscular disorders associated with DCM (e.g. dystrophinopathies), HCM (storage disorders) or restriction (desminopathies). Left ventricular noncompaction/ hypertrabeculation is a phenotype spanning the entire spectrum of neuromuscular and mitochondrial disorders, and it has been found associated with all the cardiomyopathy phenotypes. The presence of unexplained cardiac abnormalities on ECG or echo in association with extracardiac symptoms or signs suggests complex systemic disease. This is typical of some adult mitochondrial disorders, in which the disease is highly dependent on the ‘load of genetic protein abnormalities’, which may vary and accumulate with age (‘mutation load’ or ‘threshold effect’ dependent phenotype).9,10,118 Extracardiac features (exercise

limitation, stroke-like episodes, ocular abnormalities, neurosensorineural deafness, hypoglycaemia and diabetes) may be associated with a mitochondrial disorder, which may become more evident with age. Symptomatic assessment is important when assessing neuromuscular disorders.119 Relevant information includes the type of exercise which provokes symptoms, the type of symptoms the patient experiences; and associated ‘triggering’ factors. In DMD, symptomatic muscle involvement typically presents with motor delays, gait abnormalities, frequent tripping or falling and/or difficulty climbing stairs.1 Patients manifest a characteristic waddling gait due to bilateral weakness in the proximal muscles of the hip girdle and legs, experiencing difficulties rising from the floor and toe walking due to shortening of the Achilles tendons. Affected males tend to use their hands to push off the floor and walk up the thighs into a standing position (‘Gower’s sign’), and they show muscle ‘pseudohypertrophy’ (an apparent enlargement of the muscles, typically calf, caused by infiltration of adipose and connective tissue into the degenerating muscle). Ultimately, without intervention, patients with DMD lose the ability to walk before the age of 13 years, and die at a mean age of 19 years, due to progressive respiratory or cardiac failure. With improved clinical care, mean age at death is now in the late 20s or 30s.120 The neuromuscular involvement is similar in BMD, but the symptoms are delayed and life expectancy is longer.1 Differential diagnosis should be guided principally by the pattern of skeletal muscle involvement, including proximal muscle weakness (DMD, BMD and LGMD), scapuloperoneal weakness (Emery–Dreifuss muscular dystrophy, in which neck and limb contractures precede muscle weakness) and generalized weakness (later onset forms of metabolic and congenital myopathies).1 Recently, mutations in the four and a half LIM domain 1 (FHL1) gene have been associated with a clinically and genetically heterogeneous group of diseases, characterized by variable cardiac and skeletal muscle involvement. This includes reducing body myopathy, X-linked myopathy with postural muscle atrophy, scapuloperoneal myopathy, a new subtype of Emery– Dreifuss muscular dystrophy and a rare form of cardiomyopathy with contractures and rigid spine.119 In particular, a recent study in patients with X-linked myopathy with postural muscle atrophy (FHL1 gene mutations), showed HCM associated with heavy hypertrabeculations and reduced systolic and diastolic function. This echocardiographic picture was also found in some of the unaffected female carriers.121 Indeed, the FHL1 protein has an important role in heart muscle cells, connecting the muscle stretch sensor machinery and the downstream hypertrophic response of the MAPK signalling pathway.119



Fig. 2

RCM and Myopathy AD

“subclinical” skeletal involvement

Sarcomeric LMNA A/C Amyloid Myopathy

Desmin Disease

AR

• ↑ CK • myopathy • ECG conduction defects • myopathy • neuropathy

After Infancy

• myopathy (lower limb muscle weakness, spreading to truncal, facial and respiratory muscles) • hepatomegalia •hypotonia • hypoglycemia*

Glycogen Storage

Infancy & after infancy

Infancy

• hepatomegalia • hypotonia • ↑ CK • hypoglycemia *

After Infancy

Matrilinear Mitochondrial

• lactic acidosis • encephalopathy • hypotonia

Infancy & After Infancy

Sporadic

• exclude AR diseases • exclude myocarditis • evaluate cardiac & noncardiac “red flags”

Infancy & After Infancy

* Absent in Pompe disease.

HCM and Myopathy AD Sarcomeric

“subclinical” skeletal involvement • myotonia

DM1

AR

Infancy & after infancy Infancy & after infancy

• muscular dystrophy •cataracts • hypogonadism • frontal balding • ECG changes

After Infancy

PRKAG2

• myopathy • WPW

After Infancy

Nemaline Myopathy

myopathy

After Infancy

• hepatomegalia • hypotonia • ↑ CK

Pompe

• ↑ CK • pelvic & shoulder myopathy

LGMD

Glycogen Storage Diseases

X-linked

Sporadic

After Infancy

After Infancy

Danon

• myopathy • mental retardation • WPW

After Infancy

Friedreich Ataxia

• limb & gait ataxia • areflexia • pyramidal sign

After Infancy

• muscle atrophy • flexion deformities of the elbows • pectus escavatum • mental retardation • ECG conduction abn

After Infancy

Emery -Dreifuss

Matrilinear

• hepatomegalia • hypotonia • ↑ CK • hypoglycemia (absent in Pompe)

Infancy

Mitochondrial



• exclude AR diseases • evaluate cardiac & noncardiac “red flags”


Algorithms for the diagnosis of cardiomyopathy and myopathy. DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular noncompaction; RCM, restrictive cardiomyopathy.



Fig. 2. (Continued).

DCM and Myopathy AD Sarcomeric

“subclinical” skeletal involvement • ↑ CK • myopathy • ECG conduction defects

LMNA A/C

• myotonia • muscular dystrophy • cataracts • hypogonadism • frontal balding • ECG changes

DM1

MYH7

AR Glycogen Storage

• distal & proximal myopathy

• hepatomegalia

Infancy & after infancy After Infancy


After Infancy

Infancy

• hypotonia

• hypoglycemia

LGMD

X-linked


Emery-Dreifuss

• muscle atrophy • flextion deformities of the elbows • pectus escavatum • mental retardation • ECG conduction abn

Barth Syndrome

• • • •

Dystrophinopathy

• ↑↑↑ CK • lower extremity myopathy

cyclic neutropenia hypocholesterolaemia myopathy recurrent stomatitis

After Infancy

Infancy & after Infancy

Infancy

After Infancy




Sporadic



If prolonged low-intensity exercise (hiking, playing soccer) provokes symptoms, such as muscle pain and pigmenturia without acute contractures, and they are triggered by different stressors (i.e. fever, dehydration, fasting, cold, etc.), a disorder of fatty acid metabolism should be suspected.119 Conversely, if short burst of high intensity exercise (weight lifting or sprinting) provokes symptoms, such as muscle cramps and pigmenturia, they may be related to glycogen storage disease. Exercise intolerance with premature fatigue, which is out of proportion to muscle strength (with activities as mild as walking up a flight of stairs) is typical of mitochondrial disorders.119 The type of exercise (e.g. dynamic and/or static) which provokes symptoms may vary. Clinical presentation of cardiac and neuromuscular disease in childhood is generally associated with more severe disease.3 In children, cardiomyopathies often present with a ‘mixed phenotype’, for example left ventricular hypertrophy with systolic dysfunction (mitochondrial and storage diseases), to a dilated and mildly hypokinetic heart with noncompaction areas throughout the apex and the body of the LV and RV (i.e. Barth syndrome). Typical clinical presentations that serve as useful starting points for the diagnostic algorithm for neuromuscular diseases

associated with cardiomyopathies include congenital hypotonia or weakness (floppy infant syndrome), weakness beginning after infancy (>1 year of age), ataxia (loss of motor control) and myotonia (decreased muscle relaxation; Fig. 2).3 Other findings suggesting the diagnosis of a neuromuscular disease include different patterns of muscle weakness, decreased muscle bulk, decreased or absent deep tendon reflexes, elevated serum creatine kinase levels and an abnormal nerve conduction velocity or EMG, although each sign on its own has a low diagnostic sensitivity. In newborns and older infants, when cardiomyopathies are associated with hypotonia, the most likely genetic cause is a metabolic or a congenital myopathy.9 When a heart muscle disorder is associated with a metabolic disorder, presentation generally occurs early in the clinical course and cardiac abnormalities may be the predominant clinical finding, whereas skeletal muscle weakness or hypotonia is often the predominant initial manifestation of the congenital myopathies. Cardiac and skeletal muscle involvement may both be severe, as in the typical ‘floppy babies’ with organomegaly and cardiomyopathy due to metabolic diseases (Pompe disease; b-oxidation defects; mitochondrial diseases). Again, the ECG may be important, with conduction abnormalities or a typical preexcitation pattern, typical features of both



Fig. 2. (Continued).

LVNC and Myopathy AD Sarcomeric

“subclinical” skeletal involvement • ↑ CK • myopathy • ECG conduction defects

LMNA A/C

• myotonia • muscular dystrophy • cataracts • hypogonadism • frontal balding • ECG changes

DM1

MYH7

AR

• distal & proximal myopathy • hepatomegaly • hypotonia • hypoglycemia*

Glycogen Storage

LGMD

X-linked

Infancy & after infancy After Infancy


After Infancy Infancy

• hepatomegaly • hypotonia • ↑ CK • hypoglycemia *

After Infancy


After Infancy

Emery-Dreifuss

• muscle atrophy • flexion deformities of the elbows • pectus escavatum • mental retardation • ECG conduction abn

Barth Syndrome

• • • •

Dystrophinopathy

• ↑↑↑ CK • lower extremity myopathy

After Infancy

Danon

• myopathy • mental retardation • WPW

After Infancy

cyclic neutropenia hypocholesterolaemia myopathy recurrent stomatitis


Infancy




Sporadic



* Absent in Pompe disease.

metabolic and storage diseases.3,118 Glycogen storage diseases involve not only cardiac myocytes, but also the special cells of the conduction system, particularly, the A-V node and the His-bundle cells and preexcitation (short PR, delta waves), atrio-ventricular block and bundle branch abnormalities are common. The pathogenesis of ventricular preexcitation (Wolf–Parkinson–White syndrome, WPW, when symptomatic) is unknown, though it is clear that the pattern does not reflect the presence of an accessory pathway (as in the classic WPW). The suggested hypotheses are as follows:3,118 a ‘direct insulating effect’ of the glycogen on the conduction system; an ‘indirect insulating effect’ of the glycogen on the conduction system, by the anatomic interruption of the annulus fibrosus (which acts as an ‘electric insulate’ between the atria and the ventricles). Cardiomyopathy is generally of the hypertrophic type, with severe thickening of the septum (‘asymmetric’ hypertrophy), or frequently of both the septum and other myocardial segments of the left and right heart (‘concentric’ hypertrophy). When the septal hypertrophy

is very pronounced, a left outflow tract obstruction [with systolic anterior motion of the mitral leaflet(s)] may be present. Both diastolic and systolic dysfunction can be observed. A metabolic or mitochondrial cardiomyopathy may mimic the presentation of Pompe disease.3,118 The presence of encephalomyopathy, metabolic acidosis (with or without hypoglycaemia), the increase of lactate and lactate/piruvate ratio (normal: 300 ms), or any fascicular block with or without symptoms, especially if there is evidence of progressive conduction disease, based on the unpredictable progression of heart conduction defects in neuromuscular and mitochondrial disorders.10,117 DCM associated with LMNA gene mutations is a highly penetrant, age-dependent disease characterized by a high risk of adverse cardiac events, including heart failure and sudden death (patients die suddenly even after pacing).1,118,127 In laminopathies, the current consensus recommendation is that when these patients require permanent pacing for bradycardia indications, an implantable cardioverter-defibrillator (ICD) should be recommended.117,118 Guidance on prophylactic ICD implantation in the absence of an indication for pacing is less certain, but should probably be considered in individuals with clear phenotypic expression. Competitive sports should be discouraged in these patients.118,128–130 In Friedreich’s ataxia, the cardiomyopathy is difficult to treat, and it is frequently associated with arrhythmias, heart failure and exercise intolerance. Idebenone, a synthetic form of CoQ10, has been used in therapeutic trials in patients with Friedreich’s ataxia, initially showing a significant reduction of cardiac hypertrophy preceded by an early and linear improvement in cardiac function.118,131 The clinical implications of these findings are that the cardiac output of affected patients in Friedreich’s ataxia may reflect the characteristics of a RCM with a greater dependence on heart rate to maintain adequate output. Thus, there will predictably be an increase in left ventricular filling pressures with resultant atrial arrhythmias, which are commonly seen in advanced Friedreich’s ataxia. Use of afterload reducing agents, such as losartan or angiotensin converting enzyme (ACE) inhibitors, may be beneficial in long-term treatment of this heart disease. The cardiomyopathy of Friedreich’s ataxia most often presents symptoms in



the second to third decade of life, although a significant range exists. Multiple authors have noted that the cardiac phenotype is quite variable and that cardiac MRI of left ventricular mass correlates with the GAA repeat number and longer duration of disease. Hypertrophy may progress to dilation in time. Earlier echocardiography and radionuclide studies demonstrated good systolic function of both ventricles, but impaired diastolic filling. These findings are consistent with the histologic appearance of fibrosis in the left ventricular wall and suggest that there may be diastolic dysfunction in the Friedreich’s ataxia heart. At the microscopic level, changes in the LV include cardiomyocyte hypertrophy, focal necrosis and diffuse fibrosis. Recent studies of patients with Friedreich’s ataxia using cardiac MRI and adenosine have shown that the heart has a significantly decreased myocardial perfusion reserve index, which parallels the onset of metabolic syndrome. Furthermore, the impaired perfusion reserve does not correlate with degree of hypertrophy or fibrosis, suggesting that this may be an important tool for identifying potential therapeutic targets to prevent the development or progression of heart failure.132–134 The most frequent cause of death is cardiac dysfunction, reflecting congestive heart failure, ventricular arrhythmias and cardioembolic stroke.135 More recent report showed no significant improvement of left ventricular mass and function in a paediatric population treated with idebenone.136 New therapeutic approaches, such as histone deacetylase inhibitors, and enzyme replacement with cell penetrant peptide fusion proteins, hold promise for Freidreich’s ataxia and other similar mitochondrial disorders.137 Evidence supporting the use of vitamins, cofactors and antioxidant supplements (such as ubiquinone, coenzyme Q10, ubidecarenone; CoQ10) aimed at reducing reactive oxygen species produced in increased amounts in patient with mitochondrial diseases is inconclusive.10 Patients with complex I and/or complex II deficiency may benefit from oral administration of riboflavin, a precursor of FADH2 and a cofactor for electron transport, though no clear evidence has been reported that these dietary supplements improve the symptoms or alter the course of disease in the majority of patients with OXPHOS defects. Of note, a recent Cochrane systematic review138 has shown that evidence supporting their use is lacking, and their use is effective only in very rare specific disorders such as primary carnitine deficiency or primary coenzyme Q10 deficiency. ACE inhibitors and b-blockers represent standard therapy for DCM and left ventricular dysfunction, and they are commonly indicated in neuromuscular and mitochondrial diseases, although evidence regarding their specific use is scant.1 A consensus multidisciplinary

group of experts recommended the use of ACE inhibitors in presymptomatic patients with dystrophinopathies and female carriers.139 The possible effect of combined ACE inhibitor and b-blocker therapy in preventing development and/or delaying onset of cardiomyopathy in DMD patients without echo-detectable left ventricular dysfunction is currently under investigation in the UK by means of a double-blind randomized multicentre, placebo-controlled trial (http://www.controlled-trials. com/ISRCTN50395346). Recently, some authors have demonstrated interesting effects of the angiotensin II type 1 receptor blocker on myopathy in Marfan syndrome. Many individuals with Marfan syndrome, caused by a deficiency of extracellular fibrillin-1, exhibit myopathy and evidence suggests that selected manifestations of Marfan syndrome reflect excessive signalling by transforming growth factor (TGF)-b. Cohn et al.140 showed that systemic antagonism of TGF-b through administration of TGF-b-neutralizing antibody or the angiotensin II type 1 receptor blocker losartan normalizes muscle architecture, repair and function in vivo. The use of steroid therapy to improve muscle strength in patients with dystrophinopathies and its potential negative effect on cardiomyopathy is contradictory, although many experts recommend continuing glucocorticoid therapy in nonambulant DMD patients in order to delay decline in cardiac function.141–143 Cardiac transplantation has been reported in selected cases of neuromuscular and mitochondrial disorders in the absence of severe systemic involvement.

Conclusion Adult and paediatric cardiologists should be aware of that skeletal muscle weakness may indicate a primary neuromuscular disorder (associated with creatine kinase elevation as in dystrophinopathies), a mitochondrial disease (particularly if encephalopathy, ocular myopathy, retinitis, neurosensorineural deafness, lactic acidosis are present), a storage disorder (progressive exercise intolerance, cognitive impairment and retinitis pigmentosa, as in Danon’s disease) or metabolic disorders (hypoglycaemia, metabolic acidosis, hyperammonaemia or other specific biochemical abnormalities). In such patients, skeletal muscle weakness usually precedes cardiomyopathies and dominates the clinical picture. On the other hand, skeletal involvement may be subtle, and the first symptom of a neuromuscular disorder may be the occurrence of heart failure, conduction disorders or ventricular arrhythmias due to cardiomyopathy. Symptoms secondary to cardiac dysfunction such as weight loss or gain, cough, increased fatigue and exercise intolerance should be evaluated. Early screening with ECG and echocardiogram, and eventually, a more detailed cardiovascular evaluation may be required to diagnose early cardiac involvement.



Potential therapeutic avenues for the treatment of skeletal muscle diseases include pharmacological therapy, gene therapy and cell therapy.144,145 Clinical trials using different pharmacological targets (anabolic agents and gentamicin) show unsatisfactory or negative results; others (upregulation of alternative therapeutic proteins) have been evaluated in animal models. Gene therapy has progressed by improving vectors for gene delivery (adenoviruses and adenoassociated viruses), understanding the factors needed for an efficient transfection of muscle, understanding of protein structure and function in muscular dystrophies, and finally allowing protein engineering as a way of gene therapy. Several molecular repair strategies are currently at the level of clinical testing for DMD. The main obstacle for gene replacement for DMD is the size of the protein, as this makes difficult to fit the protein in gene transfer vehicles, and immune responses in humans. PTC124 (Ataluren; PTC therapeutics, South Plainfield, New Jersey, USA), a 284 Da, 1,2,4-oxadiazole linked furobenzene and benzoic rings drug, has been designed to read through stop codon mutations in DMD and its therapeutic application has already been investigated in a phase IIb clinical trial. The results showed that a lower dose of the drug was more beneficial than the higher and in the United States, an open-label extension trial has been ongoing since November 2010. In DMD, it has been observed that spontaneous second mutations can cause exon skipping, restoration of the reading frame and production of shorter but functional dystrophin protein. Based on this concept, antisense oligonucleotides (AONs) have been chemically synthesized in order to alter RNA processing, skip one or more exons and restore the reading frame as observed in nature. Feasibility of exon skipping has been demonstrated in animal studies and proof-of-principle and safety studies have been already performed with two different backbones for exon 51 skipping (2-O-methylAONsPRO051 and morpholino AONs-AVI-4658). An openlabel, phase II, dose-escalation study of intravenously administered AONs-AVI-4658 showed that the drug was well tolerated and it induced exon 51 skipping in a significant dose-dependent but variable manner in boys on more than 2 mg/kg dose, confirming the potential disease-modifying effect of this drug. Phase I/II studies of subcutaneous administration of PRO051 also showed variable dose-dependent systemic restoration of dystrophin, as well as a modest improvement in functional tests. These results are promising, and they would be potentially applicable for up to 83% of all DMD mutations. Unfortunately, the cardiac muscle is not targeted by these approaches and further studies are warranted in this field. Following the initial failure of cell transplantation trials (hampered by poor survival and limited migratory ability of the cells), the development of new stem cell candidates, new molecular strategies for correction of gene expression and complementary approaches to improve transplantation success, may lead

to new preclinical researches and clinical trials based on these concepts.

Acknowledgements W.J.M. acknowledges the proportion of funding received by UCLH/UCL from the Department of Health’s NIHR Biomedical Research Centres funding scheme.

References 1 2 3 4

5

6

7

8

9

10

11

12 13

14

15

16

17 18

19

20

21

22

23

Dellefave LM, McNally EM. Cardiomyopathy in neuromuscular disorders. Prog Pediatr Cardiol 2007; 24:35–46. Towbin JA, Lowe AM, Colan SD, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 2006; 296:1867–1876. Schwartz ML, Cox GF, Lin AE, et al. Clinical approach to genetic cardiomyopathy in children. Circulation 1996; 94:2021–2038. Kostareva A, Sejersen T, Sjoberg G. Genetic spectrum of cardiomyopathies with neuromuscular phenotype. Front Biosci (Schol Ed) 2013; 5:325–340. Katzberg H, Karamchandani J, So YT, et al. End-stage cardiac disease as an initial presentation of systemic myopathies: case series and literature review. J Child Neurol 2010; 25:1382–1388. Hershberger RE, Siegfried JD. Update 2011: clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol 2011; 57:1641– 1649. Wahbi K, Meune C, Bassez G, et al. Left ventricular noncompaction in a patient with myotonic dystrophy type 2. Neuromuscul Disord 2008; 18:331–333. Hedberg C, Melberg A, Kuhl A, et al. Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation. Eur J Hum Genet 2012; 20:984–985. Limongelli G, Tome-Esteban M, Dejthevaporn C, et al. Prevalence and natural history of heart disease in adults with primary mitochondrial respiratory chain disease. Eur J Heart Fail 2010; 12:114–121. Limongelli G, Masarone D, D’Alessandro R, Elliott PM. Mitochondrial diseases and the heart: an overview of molecular basis, diagnosis, treatment and clinical course. Future Cardiol 2012; 8:71–88. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 310200: World Wide Web URL: http:// omim.org/. Bhakta D, Groh WJ. Cardiac function tests in neuromuscular diseases. Neurol Clin 2004; 22:591–617; vi. Bushby K, Muntoni F, Bourke JP. 107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy. 7th–9th June 2002, Naarden, The Netherlands. Neuromuscul Disord 2003; 13:166–172. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 300376. World Wide Web URL: http:// omim.org/ Bourke JP, Bushby K. Heart and neuromuscular disorders. In: Kumar D, Elliott P, editors. Principles and Practice of Clinical Cardiovascular Genetics. Oxford: Oxford University Press; 2010. Hershberger RE, Cowan J, Morales A, Siegfried JD. Progress with genetic cardiomyopathies: screening, counseling, and testing in dilated, hypertrophic, and arrhythmogenic right ventricular dysplasia/ cardiomyopathy. Circ Heart Fail 2009; 2:253–261. Orphanet: Autosomal recessive limb-girdle muscular dystrophy type 2F Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 601954. World Wide Web URL: http:// omim.org/ Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 607155. World Wide Web URL: http:// omim.org/ Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 158900. World Wide Web URL: http:// omim.org/ Laforeˆt P, de Toma C, Eymard B, et al. Cardiac involvement in genetically confirmed facioscapulohumeral muscular dystrophy. Neurology 1998; 51:1454–1456. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 160900. World Wide Web URL: http:// omim.org/ Colleran JA, Hawley RJ, Pinnow EE, et al. Value of the electrocardiogram in determining cardiac events and mortality in myotonic dystrophy. Am J Cardiol 1997; 80:1494–1497.



24

25 26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46 47 48 49

50

Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 602668. World Wide Web URL: http:// omim.org/ Meola G, Moxley RT 3rd. Myotonic dystrophy type 2 and related myotonic disorders. J Neurol 2004; 251:1173–1182. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 181350. World Wide Web URL: http:// omim.org/ Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 159001. World Wide Web URL: http:// omim.org/ Fatkin D, MacRae C, Sasaki T, et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999; 341:1715–1724. Boriani G, Gallina M, Merlini L, 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; 34:901–908. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 300384. World Wide Web URL: http:// omim.org/ Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 300163. World Wide Web URL: http:// omim.org/ Bos JM, Poley RN, Ny M, et al. Genotype: phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin. Mol Genet Metab 2006; 88:78–85. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 118220. World Wide Web URL: http:// omim.org/ Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 118210. World Wide Web URL: http:// omim.org/ Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 302800. World Wide Web URL: http:// omim.org/ Corrado G, Checcarelli N, Santarone M, et al. Left ventricular hypertrabeculation/noncompaction with PMP22 duplication-based Charcot-Marie-Tooth disease type 1A. Cardiology 2006; 105:142–145. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 601419. World Wide Web URL: http:// omim.org/ Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 608810. World Wide Web URL: http:// omim.org/ Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 609200 . World Wide Web URL: http:// omim.org/ Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 612954. World Wide Web URL: http:// omim.org/ Arimura T, Ishikawa T, Nunoda S, et al. Dilated cardiomyopathyassociated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes. Hum Mutat 2011; 32:1481– 1491. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 160500 . World Wide Web URL: http:// omim.org/ Muelas N, Hackman P, Luque H, et al. MYH7 gene tail mutation causing myopathic profiles beyond Laing distal myopathy. Neurology 2010; 75:732–741. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 600334 . World Wide Web URL: http:// omim.org/ Gerull B, Gramlich M, Atherton J, et al. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet 2002; 30:201–204. Suominen T, Udd B, Hackman P. Gene reviews: udd distal myopathy PMID: 20301498. Hackman JP, Vihola AK, Udd AB. The role of titin in muscular disorders. Ann Med 2003; 35:434–441. OMIM: #605820 Nonaka Myopathy Malicdan MC, Nonaka I. Distal myopathies a review: highlights on distal myopathies with rimmed vacuoles. Neurol India 2008; 56:314– 324. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 229300 . World Wide Web URL: http:// omim.org/

51

52

53

54

55 56

57

58

59

60

61

62 63

64

65

66

67

68 69

70

71

72

73

74

75

76

Finsterer J, Sto¨llberger C, Blazek G. Neuromuscular implications in left ventricular hypertrabeculation/noncompaction. Int J Cardiol 2006; 110:288–300. Rustin P, Bonnet D, Rotig A, et al. Idebenone treatment in Friedreich patients: one-year-long randomized placebo-controlled trial. Neurology 2004; 62:524–525; [author reply 5; discussion 5]. Seznec H, Simon D, Monassier L, et al. Idebenone delays the onset of cardiac functional alteration without correction of Fe–S enzymes deficit in a mouse model for Friedreich ataxia. Hum Mol Genet 2004; 13:1017– 1024. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 232300. World Wide Web URL: http:// omim.org/ Parenti G, Di Iorio G, Sampaolo S, et al. Molecular basis and clinical management of Pompe disease. Cardiogenetics 2013; 3:e5. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 602743 . World Wide Web URL: http:// omim.org/ Murphy RT, Mogensen J, McGarry K, et al. Adenosine monophosphateactivated protein kinase disease mimicks hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome: natural history. J Am Coll Cardiol 2005; 45:922–930. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 232400 . World Wide Web URL: http:// omim.org/ Coleman RA, Winter HS, Wolf B, et al. Glycogen storage disease type III (glycogen debranching enzyme deficiency): correlation of biochemical defects with myopathy and cardiomyopathy. Ann Intern Med 1992; 116:896–900. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 300257 . World Wide Web URL: http:// omim.org/ Yang Z, McMahon CJ, Smith LR, et al. Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children. Circulation 2005; 112:1612–1617. Maron BJ, Roberts WC, Arad M, et al. Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA 2009; 301:1253–1259. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 212138. World Wide Web URL: http:// omim.org/ Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 608836. World Wide Web URL: http:// omim.org/ Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 2006; 142:77–85. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 302060. World Wide Web URL: http:// omim.org/ D’Adamo P, Fassone L, Gedeon A, et al. The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies. Am J Hum Genet 1997; 61:862–867. Spencer CT, Bryant RM, Day J, et al. Cardiac and clinical phenotype in Barth syndrome. Pediatrics 2006; 118:e337–e346. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 102770. World Wide Web URL: http:// omim.org/ Gross M. Clinical heterogeneity and molecular mechanisms in inborn muscle AMP deaminase deficiency. J Inherit Metab Dis 1997; 20:186– 192. Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 545000. World Wide Web URL: http:// omim.org/ Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 540000. World Wide Web URL: http:// omim.org/ Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 535000. World Wide Web URL: http:// omim.org/ Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 551500. World Wide Web URL: http:// omim.org/ Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 530000. World Wide Web URL: http:// omim.org/ Marston SB. How do mutations in contractile proteins cause the primary familial cardiomyopathies? J Cardiovasc Transl Res 2011; 4:245–255.



77

78

79 80 81

82

83 84 85 86 87

88

89

90

91

92

93 94

95

96

97

98

Vatta M, Mohapatra B, Jimenez S, et al. Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular noncompaction. J Am Coll Cardiol 2003; 42:2014–2027. Lapidos KA, Kakkar R, McNally EM. The dystrophin glycoprotein complex: signaling strength and integrity for the sarcolemma. Circ Res 2004; 94:1023–1031. Hsu DT. Cardiac manifestations of neuromuscular disorders in children. Paediatr Respir Rev 2010; 11:35–38. Marian AJ. Phenotypic spectrum of mutations in cardiolaminopathies. Cardiogenetics 2011; 1:e6. Maron BJ, McKenna WJ, Danielson GK, et al., Task Force on Clinical Expert Consensus Documents. American College of Cardiology; Committee for Practice Guidelines. European Society of Cardiology. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2003; 42:1687– 1713. Kirschner SE, Becker E, Antognozzi M, et al. Hypertrophic cardiomyopathy-related beta-myosin mutations cause highly variable calcium sensitivity with functional imbalances among individual muscle cells. Am J Physiol Heart Circ Physiol 2005; 288:H1242–H1251. Watkins H, Ashrafian H, Redwood C. Inherited cardiomyopathies. N Engl J Med 2011; 364:1643–1656. Ritter M, Oechslin E, Sutsch G, et al. Isolated noncompaction of the myocardium in adults. Mayo Clin Proc 1997; 72:26–31. Sarma RJ, Chana A, Elkayam U. Left ventricular noncompaction. Prog Cardiovasc Dis 2010; 52:264–273. Weisz SH, Limongelli G, Pacileo G, et al. Left ventricular non compaction in children. Congenit Heart Dis 2010; 5:384–397. Klaassen S, Probst S, Oechslin E, et al. Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation 2008; 117:2893– 2901. Maron BJ, Towbin JA, Thiene G, et al., American Heart Association; Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; Council on Epidemiology and Prevention. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006; 113:1807–1816. Habib G, Charron P, Eicher JC, et al., Working Groups ’Heart Failure and Cardiomyopathies’ and ’Echocardiography’ of the French Society of Cardiology. Isolated left ventricular noncompaction in adults: clinical and echocardiographic features in 105 patients. Results from a French registry. Eur J Heart Fail 2011; 13:177–185. Xia S, Wang H, Zhang X, et al. Clinical presentation and genetic analysis of a five generation Chinese family with isolated left ventricular noncompaction. Intern Med 2008; 47:577–583. Hoedemaekers YM, Caliskan K, Michels M, et al. The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. Circ Cardiovasc Genet 2010; 3:232–239. Finsterer J, Sto¨llberger C, Blazek G, Sehnal E. Familal left ventricular hypertrabeculation (noncompaction) is myopathic. Int J Cardiol 2013; 164:312–317. Sen-Chowdhry S, Syrris P, McKenna WJ. Genetics of restrictive cardiomyopathy. Heart Fail Clin 2010; 6:179–186. Mogensen J, Murphy RT, Kubo T, et al. Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy. J Am Coll Cardiol 2004; 44:2315– 2325. Kubo T, Gimeno JR, Bahl A, et al. Prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy with restrictive phenotype. J Am Coll Cardiol 2007; 49:2419–2426. Kaski JP, Syrris P, Burch M, et al. Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes. Heart 2008; 94:1478–1484. Gudkova A, Kostareva A, Sjoberg G, et al. Diagnostic challenge in desmin cardiomyopathy with transformation of clinical phenotypes. Pediatr Cardiol 2013; 34:467–470. Thiene G, Corrado D, Basso C. Arrhythmogenic right ventricular cardiomyopathy/dysplasia. Orphanet J Rare Dis 2007; 2:45.

99

100

101

102

103

104

105

106

107 108

109

110

111

112

113

114

115

116

117

118 119 120

121

Sen-Chowdhry S, Syrris P, McKenna WJ. Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/ cardiomyopathy. J Am Coll Cardiol 2007; 50:1813–1821. McKoy G, Protonotarios N, Crosby A, et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 2000; 355:2119–2124. Norgett EE, Hatsell SJ, Carvajal-Huerta L, et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet 2000; 9:2761–2766. Corrado D, Basso C, Pilichou K, Thiene G. Molecular biology and clinical management of arrhythmogenic right ventricular cardiomyopathy/ dysplasia. Heart 2011; 97:530–539. Garcia-Gras E, Lombardi R, Giocondo MJ, et al. Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Invest 2006; 116:2012–2021. Melberg A, Oldfors A, Blomstrom-Lundqvist C, et al. Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q. Ann Neurol 1999; 46:684– 692. Kuhl A, Melberg A, Meinl E, et al. Myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7: corroboration and narrowing of the critical region on 10q22.3. Eur J Hum Genet 2008; 16:367–373. Hootsmans WJM, Meerschwam IS. Electromyography in patients with hypertrophic obstructive cardiomyopathy. Neurology 1971; 21:810– 816. Shafig SA, Sande MA, Carruthers RR, et al. Skeletal muscle in idiopathic cardiomyopathy. J Neurol Sci 1972; 15:303–320. Smith ER, Heffernan LP, Sangalang VE, et al. Voluntary muscle involvement in hypertrophic cardiomyopathy. A study of eleven patients. Ann Intern Med 1976; 85:566–572. Caforio AL, Rossi B, Risaliti R, et al. Type 1 fiber abnormalities in skeletal muscle of patients with hypertrophic and dilated cardiomyopathy: evidence of subclinical myogenic myopathy. J Am Coll Cardiol 1989; 14:1464–1473. Karandreas N, Stathis P, Anastasakis A, et al. Electromyographic evidence of subclinical myopathy in hypertrophic cardiomyopathy. Muscle Nerve 2000; 23:1856–1861. Fananapazir L, Dalakas MC, Cyran F, et al. Missense mutations in the bmyosin heavy-chain gene causes central core disease in hypertrophic cardiomyopathy. Proc Natl Acad Sci U S A 1993; 90:3993–3997. Anastasakis A, Karandreas N, Stathis P, et al. Subclinical skeletal muscle abnormalities in patients with hypertrophic cardiomyopathy and their relation to clinical characteristics. Int J Cardiol 2003; 89:249–256. Onengu¨t S, Ug˘ur SA, Karasoy H, et al. Identification of a locus for an autosomal recessive hyaline body myopathy at chromosome 3p22.2p21.32. Neuromuscul Disord 2004; 14:4–9. Pegoraro E, Gavassini BF, Borsato C, et al. MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal myopathy. Neuromuscul Disord 2007; 17:321–329. Ortolano S, Tarrı´o R, Blanco-Arias P, et al. A novel MYH7 mutation links congenital fiber type disproportion and myosin storage myopathy. Neuromuscul Disord 2011; 21:254–262. Cullup T, Lamont PJ, Cirak S, et al. Mutations in MYH7 cause Multiminicore Disease (MmD) with variable cardiac involvement. Neuromuscul Disord 2012; 22:1096–1104. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation 2008; 117:e350–e408. Limongelli G, Elliott P. The genetics of heart failure. Oxford Textbook of Heart Failure. Oxford: Oxford University Press; 2011. Vol. 5. pp. 39–54. Berardo A, DiMauro S, Hirano M. A diagnostic algorithm for metabolic myopathies. Curr Neurol Neurosci Rep 2010; 10:118–126. Bushby K, Finkel R, Birnkrant DJ, et al., DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial managemen. Lancet Neurol 2010; 9:77–93. Binder JS, Weidemann F, Schoser B, et al. Spongious hypertrophic cardiomyopathy in patients with mutations in the four-and-a-half LIM domain 1 gene. Circ Cardiovasc Genet 2012; 5:490–502.



122 123

124

125

126 127

128

129

130

131

132

133

Selcen D. Myofibrillar myopathies. Curr Opin Neurol 2010; 23:477–481. Villard E, Perret C, Gary F, et al. A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy. Eur Heart J 2011; 32:1065–1076. Cooper LT, Baughman KL, Feldman AM, et al., American Heart Association; American College of Cardiology; European Society of Cardiology. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Circulation 2007; 116:2216–2233. Verhaert D, Richards K, Rafael-Fortney JA, Raman SV. Cardiac involvement in patients with muscular dystrophies: magnetic resonance imaging phenotype and genotypic considerations. Circ Cardiovasc Imaging 2011; 4:67–76. Wattjes MP, Kley RA, Fischer D. Neuromuscular imaging in inherited muscle diseases. Eur Radiol 2010; 20:2447–2460. Meune C, Van Berlo JH, Anselme F, et al. Primary prevention of sudden death in patients with lamin A/C gene mutations. N Engl J Med 2006; 354:209–210. Pasotti M, Klersy C, Pilotto A, et al. Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol 2008; 52:1250–1260. Van Rijsingen IA, Nannenberg EA, Arbustini E, et al. Gender-specific differences in major cardiac events and mortality in lamin A/C mutation carriers. Eur J Heart Fail 2013; 15:376–384. van Rijsingen IA, Arbustini E, Elliott PM, et al. Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study. J Am Coll Cardiol 2012; 59:493–500. Buyse G, Mertens L, Di Salvo G, et al. Idebenone treatment in Friedreich’s ataxia: neurological, cardiac, and biochemical monitoring. Neurology 2003; 60:1679–1681. Payne RM, Pride PM, Babbey CM. Cardiomyopathy of Friedreich’s ataxia: use of mouse models to understand human disease and guide therapeutic development. Pediatr Cardiol 2011; 32:366–378; doi: 10.1007/ s00246-011-9943-6. Payne RM. The heart in Friedreich’s ataxia: basic findings and clinical implications. Prog Pediatr Cardiol 2011; 31:103–109.

134

135

136

137

138

139

140

141

142

143

144 145

Hanley A, Corrigan R, Mohammad S, MacMahon B. Friedreich’s ataxia cardiomyopathy: case based discussion and management issues. Ir Med J 2010; 103:117–118. Lynch DR, Regner SR, Schadt KA, et al. Management and therapy for cardiomyopathy in Friedreich’s ataxia. Expert Rev Cardiovasc Ther 2012; 10:767–777; doi: 10.1586/erc.12.57. Lagedrost SJ, Sutton MS, Cohen MS, et al. Idebenone in Friedreich ataxia cardiomyopathy-results from a 6-month phase III study (IONIA). Am Heart J 2011; 161:639–645; e1. Herman D, Jenssen K, Burnett R, et al. Histone deacetylase inhibitors reverse gene silencing in Friedreich’s ataxia. Nat Chem Biol 2006; 2:551–558. Chinnery PF. Mitochondrial disorders overview. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. Source GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2000 updated 16 September 2010]. Bushby KMD, Muntoni F, Bourke JP. Cardiac involvement in muscular dystrophy and myotonic dystrophy: Report on 107th ENMC International Workshop. Neuromusc Disord 2003; 13:166–172. Cohn RD, van Erp C, Habashi JP, et al. Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat Med 2007; 13:204–210. Cirak S, Arechavala-Gomeza V, Guglieri M, et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an openlabel, phase 2, dose-escalation study. Lancet 2011; 378:595–605. Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev 2008; 1:CD003725. Biggar WD, Harris VA, Eliasoph L, Alman B. Long-term benefi ts of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade. Neuromuscul Disord 2006; 16:249–255. Skuk D, Vilquin JT, Tremblay JP. Experimental and therapeutic approaches to muscular dystrophies. Curr Opin Neurol 2002; 15:563–569. Vilquin JT, Catelain C, Vauchez K. Cell therapy for muscular dystrophies: advances and challenges. Curr Opin Organ Transplant 2011; 16:640– 649.


Mitochondrial involvement in skeletal muscle insulin resistance.

Mitochondrial involvement and impact in aging skeletal muscle.

Skeletal muscle imaging in facioscapulohumeral muscular dystrophy, pattern and asymmetry of individual muscle involvement.

Two-dimensional electrophoresis of heart muscle proteins in human cardiomyopathies.

α-Actinin involvement in Z-disk assembly during skeletal muscle C2C12 cells in vitro differentiation.

Involvement of sarcoplasmic reticulum 'Ca2+ release channels' in excitation-contraction coupling in vertebrate skeletal muscle.

Expression of SERPINA3s in cattle: focus on bovSERPINA3-7 reveals specific involvement in skeletal muscle.

Skeletal Muscle Satellite Cells, Mitochondria, and MicroRNAs: Their Involvement in the Pathogenesis of ALS.

Anaplastic large cell lymphoma with primary involvement of the skeletal muscle: A case report.

Myotonia dystrophica with heart involvement: an electron microscopic study of skeletal, cardiac, and smooth muscle.

Magnetic resonance imaging of primary skeletal muscle diseases: patterns of distribution and severity of involvement.

Adiponectin action in skeletal muscle.

Glycolysis in skeletal muscle regeneration.

Contractile activation in skeletal muscle.

Charge movements in skeletal muscle.

Skeletal muscle in heart failure.

Sex differences in cardiomyopathies.

Arrhythmias in cardiomyopathies. Preface.

Arrhythmias in cardiomyopathies. Foreword.

Infiltrative Cardiomyopathies.

Overexpression of SMPX in adult skeletal muscle does not change skeletal muscle fiber type or size.

Reversible Cardiomyopathies.

Inherited cardiomyopathies.

Cardiomyopathies in Negroes.