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Progression of cardiac involvement in patients with limb-girdle type 2 and Becker muscular dystrophies: A 9-year follow-up study
Abstract
To assess the degree and progression of cardiac involvement in patients with limb-girdle type 2 (LGMD2) and Becker muscular dystrophies (BMD).
A follow-up study of 100 LGMD2 (types A-L) and 30 BMD patients assessed by electrocardiogram (ECG) and echocardiography, supplemented by Holter-monitoring at follow-up.
After a median of 8.9years (range 0.4-13.7), twelve patients had died: LGMD2 (n=10, mean age 61±11years), BMD (n=2, age 43 and 45years). Of the remaining 118 patients, 89 completed follow-up: LGMD2 (n=64, age 48±13years) and BMD (n=25, age 40±13years). In BMD, LVEF decreased from 60% (10-62) to 50% (10-64), p=0.02 corresponding to a one percentage drop annually. Among patients with LGMD2, LVEF decreased significantly in patients with LGMD type 2I (n=28) from 59% (15-72) to 55% (20-61), p=0.03, i.e. a 0.4 percentage drop annually, and LVEF≤50% was associated with increased mortality in this subgroup. In LGMD2E, 3/5 patients (60%) at baseline and 4/5 (80%) at follow-up had LVEF≤50%. ECG abnormalities were non-progressive in BMD and in all subgroups of LGMD2. SVT and NSVT were present in both groups: BMD (3/14 (21%) and (2/14 (14%)), LGMD2 (16/51 (31%) and 8/51 (16%)), respectively, all asymptomatic.
LVEF decreased significantly in patients with BMD and LGMD2I, and the majority of patients with LGMD2E had left ventricular systolic dysfunction. This study emphasizes the need for tailored regular cardiac assessments according to molecular diagnosis with special focus on BMD and LGMD types 2I and 2E.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
... LGMD2 umfasst insgesamt 17 genetisch unterschiedliche Subtypen, LGMD2A-Q (Petri et al., 2015). Im Vergleich zur dominanten Variante (LGMD1) ist eine rezessive Erkrankung schwerer. ...
... Im Vergleich zur dominanten Variante (LGMD1) ist eine rezessive Erkrankung schwerer. Das Erkrankungsalter umfasst die Kindheit und reicht bis zur vierten Lebensdekade (Petri et al., 2015). ...
... Das Überleben und die Lebensqualität ist dabei vor allem von einer frühen Erkennung und Behandlung von Komplikationen abhängig (Poppe et al., 2004). Ein hohes Risiko besteht für Herz-und Atemversagen, wobei durch Fortschritte im Atemwegsmanagement Erkrankungen des Herzens eine zentrale Rolle eingenommen haben (Petri et al., 2015). ...
Gliedergürtelmuskeldystrophien (Limb Girdle Muscular Dystrophie, LGMD) sind durch eine Schwäche und Degeneration der Skelettmuskulatur gekennzeichnet und betreffen dabei vor allem die Schulter- und Beckengürtelmuskulatur. Patienten mit dem Subtyp LGMD2I weisen eine Mutation im FKRP-Protein auf, deren Erbgang autosomal-rezessiv ist. Die Entwicklung einer dilatativen Kardiomyopathie (DCM) und dadurch bedingte Tachyarrhythmien stellt bei diesem Subtyp eine wichtige Komplikation dar und beeinflusst das Überleben und die Lebensqualität. Dennoch ist bisher wenig über die Mechanismen der zugrundeliegenden Pathologie durch die Mutation bekannt. Aus einer Hautbiopsie wurden einem Patienten mit LGMD2I, DCM sowie rezidivierenden ventrikulären Tachyarrhythmien Zellen entnommen und zu Fibroblasten differenziert, welche eine homozygote Punktmutation im FKRP-Gen aufwiesen (826C>A; Leu276Ile). Diese wurden zusammen mit Zellen von drei gesunden Spendern zu humanen induzierten pluripotenten Stammzellen (hiPSCs) generiert und in Kardiomyozyten differenziert. Die Ionenkanalströme wurden per whole-cell Patch-Clamp-Verfahren aufgezeichnet und anschließend ausgewertet. Ebenfalls erfolgte die Analyse von strukturellen Veränderungen und der Expression verschiedener Gene mittels quantitativer PCR und Immunhistochemie. Es konnten erfolgreich hiPSC-Kardiomyozyten erzeugt werden, welche phänotypische Eigenschaften von DCM-Kardiomyozyten widerspiegelten. Dabei wiesen hiPSC-Kardiomyozyten des Patienten atypische Aktionspotentiale auf, die durch eine reduzierte Amplitude und Depolarisations-geschwindigkeit gekennzeichnet waren. Die Peak- und late-Na-Kanalströme (INa) sowie die Peak-L-Typ-Calciumkanalströme (ICa-L) waren signifikant reduziert. Die Expression von SCN5A und CACNA1C war in DCM-Kardiomyozyten reduziert, was mit der Reduktion von INa und ICa-L übereinstimmte. Die Kaliumkanäle wiesen einen reduzierten schnell verzögerten Gleichrichter-Kaliumstrom (IKr) auf, während der transiente (Ito) und der langsam verzögerte Gleichrichter-Kaliumstrom (IKs) keinen Unterschied zeigten. Weiterhin war die Calciumkonzentration durch einen reduzierten Ca2+-Transienten und reduzierte Spiegel in der Diastole und Systole gekennzeichnet. Die Ergebnisse der DCM hiPSC-Kardiomyozyten wiesen auf Ionenkanaldysfunktionen hin, welche für die wiederkehrenden ventrikulären Tachyarrhythmien verantwortlich sind. Die Verwendung von hiPSCs für die Analyse von Mechanismen kardialer elektrischer Dysfunktionen konnte phänotypische Veränderungen widerspiegeln und ermöglichte einen grundlegenden Erkenntnisgewinn von seltenen Erkrankungen.
... CI in BMD is frequent, but most likely less frequent than in DMD. 36) In a study of 48 BMD patients aged 26-56 years, 19% had dCMP. 37) Given that patients usually die between their 40s and 80s, the prognosis is more favourable than it is with DMD patients. ...
... 58) In LGMD2E, systolic dysfunction has been shown to progress during a follow-up of 9 years, whereas ECG parameters may remain unchanged. 36) LGMD2I appears to be the LGMD subtype in which CI is most commonly observed. In a study of 23 patients with LGMD2I, almost two thirds had systolic dysfunction, although none had arrhythmias. ...
... 62) In a study of 32 LGMD2I patients, systolic dysfunction was associated with increased mortality. 36) In LGMD2I, systolic function may deteriorate over time while ECG-parameters do not simultaneously worsen. Similar findings were observed in patients with unclassified autosomal recessive-LGMDs. ...
Little is known regarding cardiac involvement (CI) by neuromuscular disorders (NMDs). The purpose of this review is to summarise and discuss the major findings concerning the types, frequency, and severity of cardiac disorders in NMDs as well as their diagnosis, treatment, and overall outcome. CI in NMDs is characterized by pathologic involvement of the myocardium or cardiac conduction system. Less commonly, additional critical anatomic structures, such as the valves, coronary arteries, endocardium, pericardium, and even the aortic root may be involved. Involvement of the myocardium manifests most frequently as hypertrophic or dilated cardiomyopathy and less frequently as restrictive cardiomyopathy, non-compaction, arrhythmogenic right-ventricular dysplasia, or Takotsubo-syndrome. Cardiac conduction defects and supraventricular and ventricular arrhythmias are common cardiac manifestations of NMDs. Arrhythmias may evolve into life-threatening ventricular tachycardias, asystole, or even sudden cardiac death. CI is common and carries great prognostic significance on the outcome of dystrophinopathies, laminopathies, desminopathies, nemaline myopathy, myotonias, metabolic myopathies, Danon disease, and Barth-syndrome. The diagnosis and treatment of CI in NMDs follows established guidelines for the management of cardiac disease, but cardiotoxic medications should be avoided. CI in NMDs is relatively common and requires complete work-up following the establishment of a neurological diagnosis. Appropriate cardiac treatment significantly improves the overall long-term outcome of NMDs.
... Pathology presents similar to other LGMD subtypes, but is marked by highly elevated serum creatine kinase (CK) levels. Dilated cardiomyopathy and respiratory complications are also common and are the underlying cause of mortality [1,[7][8][9][10][11][12][13]. There is currently no cure for LGMD2i as research has been hampered by the relatively low disease prevalence and lack of appropriate animal models, at least until recently. ...
... LGMD2i patients. Moreover, initial studies of this model suggest that it recapitulates many disease markers exhibited by human patients including elevated serum CK, stereotypic histological markers of muscle degeneration and muscle weakness [7,8,11,14]. Phenotypic expression of pathology typically first presents at 2 or 3 weeks of age as the hind legs retract and in rare occurrences, more severe disorders of eye and brain developmental have been noted [7]. ...
Limb-girdle muscular dystrophy type 2i (LGMD2i) affects thousands of lives with shortened life expectancy mainly due to cardiac and respiratory problems and difficulty with ambulation significantly compromising quality of life. Limited studies have noted impaired gait in patients and animal models of different muscular dystrophies, but not in animal models of LGMD2i. Our goal, therefore, was to quantify gait metrics in the fukutin-related protein P448L mutant (P448L) mouse, a recently developed model for LGMD2i. The Noldus CatWalk XT motion capture system was used to identify multiple gait impairments. An average galloping body speed of 35 cm/s for both P448L and C57BL/6 wild-type mice was maintained to ensure differences in gait were due only to strain physiology. Compared to wild-type mice, P448L mice reach maximum contact 10% faster and have 40% more paw surface area during stance. Additionally, force intensity at the time of maximum paw contact is roughly 2-fold higher in P448L mice. Paw swing time is reduced in P448L mice without changes in stride length as a faster swing speed compensates. Gait instability in P448L mice is indicated by 50% higher instances of 3 and 4 paw stance support and conversely, 2-fold fewer instances of single paw stance support and no instance of zero paw support. This leads to lower variation of normal step patterns used and a higher use of uncommon step patterns. Similar anomalies have also been noted in muscular dystrophy patients due to weakness in the hip abductor muscles, producing a Trendelenburg gait characterized by "waddling" and more pronounced shifts to the stance leg. Thus, gait of P448L mice replicates anomalies commonly seen in LGMD2i patients, which is not only potentially valuable for assessing drug efficacy in restoring movement biomechanics, but also for better understanding them.
... The involvement of striated muscles impairment may result in reduced respiratory muscle function in patients with LGMD. Respiratory defects may be present early, particularly in LGMD 2I [23,24]. In our study all patients had a severe restrictive respiratory failure at the baseline visit, and 70% needed home mechanical ventilation at the end of the follow-up. ...
... Left ventricular cardiac dysfunction has already been associated with mortality in 2I LGMD (23,24). In our cohort, cardiac impairment was significantly associated with mortality. ...
Type 2C and 2D limb girdle muscular dystrophies (LGMD) are a group of autosomal recessive limb girdle muscular dystrophies manifested by proximal myopathy, impaired respiratory muscle function and cardiomyopathy. The correlation and the prognostic impact of respiratory and heart impairment are poorly described. We aimed to describe the long-term cardiac and respiratory follow-up of these patients and to determine predictive factors of cardio-respiratory events and mortality in LGMD 2C and 2D.Methods
We reviewed the charts of 34 LGMD patients, followed from 2005 to 2015, to obtain echocardiographic, respiratory function and sleep recording data. We considered respiratory events (acute respiratory failure, pulmonary sepsis, atelectasis or pneumothorax), cardiac events (acute heart failure, significant cardiac arrhythmia or conduction block, ischemic stroke) and mortality as outcomes of interest for the present analysis.ResultsA total of 21 patients had type 2C LGMD and 13 patients had type 2D. Median age was 30 years [IQR 24–38]. At baseline, median pulmonary vital capacity (VC) was 31% of predicted value [20–40]. Median maximal inspiratory pressure (MIP) was 31 cmH2O [IQR 20.25–39.75]. Median maximal expiratory pressure (MEP) was 30 cm H2O [20–36]. Median left ventricular ejection fraction (LVEF) was 55% [45–64] with 38% of patients with LVEF
... Cardiac involvement is frequent in LGMDR4; more than 60% of LGMDR4 patients suffer from dilated cardiomyopathy [16], with onset of cardiac involvement at around 25 years of age [6,7]. A recent study confirmed the higher prevalence of dilated cardiomyopathy in LGMDR4 presenting mono-or biallelic SGCB c.377_384dup [17], strengthening the existence of a phenotype-genotype correlation. In our patient, initial cardiac involvement was observed at the age of 16 years. ...
Limb-girdle muscular dystrophies (LGMD) are clinically and genetically heterogenous presentations displaying predominantly proximal muscle weakness due to the loss of skeletal muscle fibers. Beta-sarcoglycanopathy (LGMDR4) results from biallelic molecular defects in SGCB and features pediatric onset with limb-girdle involvement, often complicated by respiratory and heart dysfunction. Here we describe a patient who presented at the age of 12 years reporting high creatine kinase levels and onset of cramps after strenuous exercise. Instrumental investigations, including a muscle biopsy, pointed towards a diagnosis of beta-sarcoglycanopathy. NGS panel sequencing identified two variants in the SGCB gene, one of which (c.243+1548T>C) was found to promote the inclusion of a pseudoexon between exons 2 and 3 in the SGCB transcript. Interestingly, we detected the same genotype in a previously reported LGMDR4 patient, deceased more than twenty years ago, who had escaped molecular diagnosis so far. After the delivery of morpholino oligomers targeting the pseudoexon in patient-specific induced pluripotent stem cells, we observed the correction of the physiological splicing and partial restoration of protein levels. Our findings prompt the analysis of the c.243+1548T>C variant in suspected LGMDR4 patients, especially those harbouring monoallelic SGCB variants, and provide a further example of the efficacy of antisense technology for the correction of molecular defects resulting in splicing abnormalities.
... LGMD2C (gamma-sarcoglycanopathy), and LGMD2I, respectively. 17,21,22,23 Recommendations about the frequency of echocardiographic assessment in LGMD are based on expert consensus. 17 In our practice, we perform ECG and transthoracic echocardiography ...
... Around 60% of patients with LGMDR4 have cardiac manifestation including DCM, hypertrophic cardiomyopathy (HCM), conduction abnormalities, and increased risk of SCD [61]. Similar changes can be observed in LGMDR9 where the decline in LVEF correlates with mortality [62]. The levels of wall in long (arrows, 1b) and short axes (arrows 1d). ...
Purpose of Review
This review aims to outline the utility of cardiac magnetic resonance (CMR) in patients with different types of muscular dystrophies for the assessment of myocardial involvement, risk stratification and in guiding therapeutic decisions.
Recent Findings
In patients suffering from muscular dystrophies (MD), even mild initial dysfunction may lead to severe heart failure over a time course of years. CMR plays an increasing role in the diagnosis and clinical care of these patients, mostly due to its unique capability to precisely characterize subclinical and progressive changes in cardiac geometry, function in order to differentiate myocardial injury it allows the identification of inflammation, focal and diffuse fibrosis as well as fatty infiltration. CMR may provide additional information in addition to the physical examination, laboratory tests, ECG, and echocardiography.
Summary
Further trials are needed to investigate the potential impact of CMR on the therapeutic decision-making as well as the assessment of long-term prognosis in different forms of muscular dystrophies. In addition to the basic cardiovascular evaluation, CMR can provide a robust, non-invasive technique for the evaluation of subclinical myocardial tissue injury like fat infiltration and focal and diffuse fibrosis. Furthermore, CMR has a unique capability to detect the progression of myocardial tissue damage in patients with a preserved systolic function.
... (Groh et al., 2002;Nazarian et al., 2011) As we observed, cardiac conduction abnormalities were less prevalent than structural abnormalities in patients with BMD and LGMD. (Petri et al., 2015) Patients with dystrophinopathies did present with uniquely abnormal R-wave progression, and the various patterns assessed could serve to confirm a diagnosis of a dystrophinopathy given their high specificity. Furthermore, cardiomyopathy secondary to FSHD remains variably reported and any positive findings have included atrial arrhythmias and atrioventricular conduction delays, though electrophysiological assessment of FSHD patients in our study cohort was unremarkable. ...
Introduction
Heart disease remains a leading cause of mortality in patients with muscular dystrophy (MD), and cardiac assessment by standard imaging modalities is challenging due to the prominence of physical limitations.
Methods
In this prospective cohort study of 169 MD patients and 34 negative control patients, we demonstrate the clinical utility of a 12-lead electrocardiogram (ECG) as an effective modality for the assessment of cardiac status in patients with MD. We assessed the utility of conventional criteria for electrocardiogram-indicated left ventricular hypertrophy (ECG-LVH) as well as ECG morphologies.
Results
Cornell voltage, Cornell voltage-duration, Sokolow–Lyon voltage, and Romhilt-Estes point score criteria demonstrated low sensitivity and minimal positive predictive value for ECG-LVH when compared with cardiac imaging. Patients with LBBB had a high probability of a cardiomyopathy (relative risk [RR], 2.75; 95% confidence interval [CI], 2.14–3.53; p < .001), and patients with QRS fragmentation (fQRS) had a high probability of a cardiomyopathy (RR, 1.76; 95% CI, 1.20–2.59; p = .004), requiring cardiac medication and device intervention. We found that an R/S ratio >1 in V1 and V2 is highly specific (specificity, 0.89; negative predictive value [NPV], 0.89 and specificity, 0.82; NPV, 0.89, respectively) for patients with dystrophinopathies compared with other types of MD.
Conclusion
The identification of LBBB and fQRS was linked to cardiomyopathy in patients with MD, while ECG-LVH was of limited utility. Importantly, these findings can be applied to effectively screen a broad cohort of MD patients for structural heart disease and prompt further evaluation and therapeutic intervention.
... The presence of respiratory and heart dysfunction makes LGMDR4 close to Duchenne muscular dystrophy, although the pathophysiology of cardiac anomalies might be different (7). More than 60% of LGMDR4 patients suffer from dilated cardiomyopathy (8), a condition that is less frequently observed in LGMDR3 and LGMDR5 (9). Also, LGMDR4 is often associated with respiratory failure (10), a leading cause of death in affected individuals that is nowadays successfully prevented using non-invasive ventilation (NIV) (11). ...
Background: Limb-girdle muscular dystrophy 2E (LGMD 2E), recently renamed as autosomal recessive limb-girdle muscular dystrophy-4 (LGMDR4), is characterized by the lack of beta-sarcoglycan, normally expressed in skeletal muscles and cardiomyocytes. We hypothesized that progressive respiratory and left ventricular (LV) failure in LGMDR4 could be associated with the age and interrelated phenomena of the disease's natural history.
Methods: We conducted a retrospective review of the records of 26 patients with LGMDR4. Our primary objective was to compare the rates of decline among creatine phosphokinase (CPK) values, pulmonary function test (PFT) measures, and echocardiographic estimates and to relate them to patients' age.
Results: The rates of decline/year of CPK, PFTs, and LV function estimates are significatively bound to age, with the LV ejection fraction (EF) being the strongest independent variable describing disease progression. Moreover, the rate of decline of CPK, PFTs, and LV differed in patients grouped according to their genetic mutations, demonstrating a possible genotype–phenotype correlation. The parallel trend of decline in CPK, PFT, and EF values demonstrates the presence in LGMDR4 of a simultaneous and progressive deterioration in muscular, respiratory, and cardiac function.
Conclusions: This study expands the current knowledge regarding the trend of CPK values and cardiac and respiratory impairment in patients with LGMDR4, to optimize the monitoring of these patients, to improve their quality of life, and to provide clinical indices capable of quantifying the effects of any new gene or drug therapy.
... L'échographie cardiaque montre habituellement des défauts de contractilité ainsi qu'une diminution de la fraction d'éjection du ventricule gauche (FEVG). Récemment, une étude longitudinale évaluant la fonction cardiaque chez ces patients a montré une diminution de 0 à 4 % par an de la FEVG [17]. L'IRM cardiaque montre souvent une fibrose ainsi qu'une dégénérescence graisseuse du myocarde associées à la diminution de la fonction contractile et du volume du ventricule gauche [18]. ...
Mutations in the FKRP gene encoding the fukutin-related protein (FKRP) cause a wide spectrum of myopathies, ranging from severe forms of congenital muscular dystrophies associated with structural abnormalities of the central nervous system, to exertional myalgia or asymptomatic hyperCKemia, and to a form of limb girdle muscular dystrophy, LGMD-R9, (ex-LGMD-2I). LGMD-R9 is characterized by a proximal girdle deficit predominantly in the lower limbs to start with, with respiratory and cardiac damage that may affect the vital prognosis. Serum CK levels are markedly elevated and, on muscle biopsy, is detected a dystrophic formula associated with a reduction in the glycosylation of α-dystroglycan by immunostains and immunoblotting. Muscle MRI typically shows damage to proximal muscles (iliopsoas, adductors, gluteus maximus, quadriceps) with relative preservation of the muscles of the anterior compartment of the thighs (gracilis and sartorius). Genetic analysis, by specific sequencing of the FKRP gene or of a panel grouping together all the genes involved in the glycosylation of α-dystroglycan, or a larger panel of genes, generally confirms the diagnosis, the most frequent mutation being the missense p.(Leu276Ile). Currently, treatment of LGMD-R9 is symptomatic, requiring a multidisciplinary approach. A prospective study of the natural history of the disease is currently underway in Europe (GNT-015-FKRP). New therapeutic approaches are envisaged, such as gene therapy mediated by vectors derived from the adeno-associated virus (AAV). This is effective in animal models, allowing correction of defects in the glycosylation of alpha-dystroglycan and an increase in its binding capacity to the extracellular matrix. At the same time, preclinical studies have shown, in an animal model, the efficacy of ribitol, an alcohol pentose found in natural compounds, which has led to a phase I trial whose clinical development is underway.
... The presence of respiratory and heart disfunction in LGMDR4 patients makes this disease close to Duchenne Muscular Dystrophy, although the pathophysiology of cardiac anomalies might be different [7]. More than 60% of LGMDR4 patients suffer from dilated cardiomyopathy [8], a condition that is less frequently observed in LGMDR3 and LGMDR5 [9]. Also, LGMDR4 is frequently associated with respiratory failure [10], a leading cause of death in affected individuals that is nowadays successfully prevented using non-invasive ventilation (NIV) with a demonstrated gain in survival [11]. ...
Background: Limb Girdle Muscular Dystrophy 2E (LGMD 2E), recently renamed as autosomal recessive limb-girdle muscular dystrophy-4 (LGMDR4), is characterized by the lack of beta-sarcoglycan, normally expressed in skeletal muscles and cardiomyocytes. We hypothesized that progressive respiratory and left ventricular (LV) failure in LGMDR4 could be associated to the age and interrelated phenomena of disease’s natural history.
Methods: We conducted a retrospective review of the records of 26 patients with LGMDR4. Our primary objective was to compare the rates of decline among creatine phosphokinase (CPK) values, pulmonary function test (PFT) measures, and echocardiographic estimates and to relate them to patients’ age.
Results: The rates of decline/year of CPK, PFTs and LV function estimates are significatively bound to age, with the LV ejection fraction (EF) being the strongest independent variable describing disease progression. Moreover, the rate of decline of CPK, PFTs and LV differed in patients grouped according to their genetic mutations, demonstrating a possible genotype-phenotype correlation. The parallel trend of decline in CPK, PFTs and EF values demonstrates the presence in LGMDR4 of a simultaneous and progressive deterioration in muscular, respiratory, and cardiac function.
Conclusions: This study expands the current knowledge regarding the trend of CPK values and cardiac and respiratory impairment in patients with LGMDR4, to optimize the monitoring of these patients, to improve their quality of life and provide clinical indices capable of quantifying the effects of any new gene or drug therapy.
... Longer follow-up duration may be necessary to further identify potential cardiac and respiratory problems. Notably, all patients with LGMD2I, except for the youngest one (currently aged 17 years), have developed dilated cardiomyopathy and significant respiratory insufficiency even when some of them remain ambulant; the prevalence of cardiac involvement in our cohort was higher than that in European reports [26,27], although the deterioration rate of ejection fraction was similar [28]. One of our patients with LGMD2I had a cerebral infarction at the age of 20 years but the exact cause remained unclear. ...
Background:
Limb-girdle muscular dystrophy (LGMD) is a genetically heterogeneous, hereditary disease characterized by limb-girdle weakness and histologically dystrophic changes. The prevalence of each subtype of LGMD varies among different ethnic populations. This study for the first time analyzed the phenotypes and genotypes in Taiwanese patients with LGMD in a referral center for neuromuscular diseases (NMDs).
Results:
We enrolled 102 patients clinically suspected of having LGMD who underwent muscle biopsy with subsequent genetic analysis in the previous 10 years. On the basis of different pathological categories, we performed sequencing of target genes or panel for NMDs and then identified patients with type 1B, 1E, 2A, 2B, 2D, 2I, 2G, 2 N, and 2Q. The 1B patients with LMNA mutation presented with mild limb-girdle weakness but no conduction defect at the time. All 1E patients with DES mutation exhibited predominantly proximal weakness along with distal weakness. In our cohort, 2B and 2I were the most frequent forms of LGMD; several common or founder mutations were identified, including c.1097_1099delACA (p.Asn366del) in DES, homozygous c.101G > T (p.Arg34Leu) in SGCA, homozygous c.26_33dup (p.Glu12Argfs*20) in TCAP, c.545A > G (p.Tyr182Cys), and c.948delC (p.Cys317Alafs*111) in FKRP. Clinically, the prevalence of dilated cardiomyopathy in our patients with LGMD2I aged > 18 years was 100%, much higher than that in European cohorts. The only patient with LGMD2Q with PLEC mutation did not exhibit skin lesions or gastrointestinal abnormalities but had mild facial weakness. Muscle imaging of LGMD1E and 2G revealed a more uniform involvement than did other LGMD types.
Conclusion:
Our study revealed that detailed clinical manifestation together with muscle pathology and imaging remain critical in guiding further molecular analyses and are crucial for establishing genotype-phenotype correlations. We also determined the common mutations and prevalence for different subtypes of LGMD in our cohort, which could be useful when providing specific care and personalized therapy to patients with LGMD.
... Clinically, Pane et al. (2012) described cardiac involvement in 6% and pulmonary involvement in 12% of patients with congenital muscular dystrophies [20]. And significant cardiac disease can be seen in LGMD 2I, even leading to cardiac transplantation [21][22][23]. More recently, a study by Maricelli et al. also demonstrated cardiac dysfunction with and without exercise [24]. ...
Background:
Fukutin-related protein (FKRP) mutations are the most common cause of dystroglycanopathies known to cause both limb girdle and congenital muscular dystrophy. The P448Lneo- mouse model has a knock-in mutation in the FKRP gene and develops skeletal, respiratory, and cardiac muscle disease.
Methods:
We studied the natural history of the P448Lneo- mouse model over 9 months and the effects of twice weekly treadmill running. Forelimb and hindlimb grip strength (Columbus Instruments) and overall activity (Omnitech Electronics) assessed skeletal muscle function. Echocardiography was performed using VisualSonics Vevo 770 (FujiFilm VisualSonics). Plethysmography was performed using whole body system (ADInstruments). Histological evaluations included quantification of inflammation, fibrosis, central nucleation, and fiber size variation.
Results:
P448Lneo- mice had significantly increased normalized tissue weights compared to controls at 9 months of age for the heart, gastrocnemius, soleus, tibialis anterior, quadriceps, and triceps. There were no significant differences seen in forelimb or hindlimb grip strength or activity monitoring in P448Lneo- mice with or without exercise compared to controls. Skeletal muscles demonstrated increased inflammation, fibrosis, central nucleation, and variation in fiber size compared to controls (p < 0.05) and worsened with exercise. Plethysmography showed significant differences in respiratory rates and decreased tidal and minute volumes in P448Lneo- mice (p < 0.01). There was increased fibrosis in the diaphragm compared to controls (p < 0.01). Echocardiography demonstrated decreased systolic function in 9-month-old mutant mice (p < 0.01). There was increased myocardial wall thickness and mass (p < 0.001) with increased fibrosis in 9-month-old P448Lneo- mice compared to controls (p < 0.05). mRNA expression for natriuretic peptide type A (Nppa) was significantly increased in P448Lneo- mice compared to controls at 6 months (p < 0.05) and for natriuretic peptide type B (Nppb) at 6 and 9 months of age (p < 0.05).
Conclusions:
FKRP-deficient P448Lneo- mice demonstrate significant deficits in cardiac and respiratory functions compared to control mice, and this is associated with increased inflammation and fibrosis. This study provides new functional outcome measures for preclinical trials of FKRP-related muscular dystrophies.
... Although LGMD2I is rare, DCM and respiratory complications are common in LGMD2I and are the main reason for mortality. [14][15][16] There is no specific therapy for LGMD2I because research has been hindered by the relatively low disease prevalence and lack of appropriate models of the diseases. The aims of this study were (1) to generate a cell line from a patient with LGMD2I that can model some phenotypic properties of DCM for mechanistic and therapeutic studies; (2) to uncover the mechanisms underlying the arrhythmogenesis in a patient with LGMD2I and DCM. ...
Background:
Limb-Girdle muscular dystrophies (LGMD) are a heritable group of genetically determined disorders with a primary involvement of the pelvic or shoulder girdle musculature with partially cardiac manifestation, such as dilated cardiomyopathy (DCM) and life-threatening tachyarrhythmia. We report here that human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes from a patient with LGMD2I and DCM associated with recurrent ventricular tachycardia displayed ion channel dysfunction and abnormality of calcium homeostasis.
Methods:
Dermal fibroblasts obtained from a patient with LGMD2I harboring a fukutin-related protein gene mutation (826C>A; Leu276Ile) and 3 healthy donors were reprogrammed to hiPSCs. The hiPSCs were differentiated into cardiomyocytes and used for biological and electrophysiological studies.
Results:
Compared with hiPSC cardiomyocytes from the healthy donors, the hiPSC cardiomyocytes from the patient exhibited abnormal action potentials characterized by reduced amplitude and upstroke velocity. The peak and late Na channel currents (INa) as well as the peak L-type calcium channel currents were significantly reduced. The expression of SCN5A and CACNA1C was reduced in DCM cardiomyocytes, consistent with reduction of INaand L-type calcium channel currents. In addition, the rapidly activating delayed rectifier potassium current (IKr) was reduced, whereas the transient outward current (Ito) and slowly activating delayed rectifier potassium current (IKs) were similar in DCM and control cardiomyocytes. Finally, a significant reduction of systolic and diastolic intracellular Ca2+concentrations was detected in DCM cardiomyocytes.
Conclusions:
This study demonstrates that patient-specific hiPSC cardiomyocytes can recapitulate some phenotypic properties of LGMD2I with DCM and provide a platform for studies on the cardiac events in LGMD.
... 87,88 In up to 50% of patients, echocardiographic abnormalities, including reduced systolic function, abnormal diastolic function, and chamber enlargement have also been described. 1,89,90 There may some variability in cardiac involvement in the sarcoglycanopathies that depends on the specific sarcoglycan and the particular mutation. 87,91 Importantly, the severity of cardiac involvement may not be correlated with the degree of skeletal muscle impairment. ...
Cardiovascular complications of neuromuscular diseases disproportionately affect the cardiac conduction system. Cardiomyopathy and cardiac arrhythmias produce significant morbidity and mortality. Patients with neuromuscular diseases should be carefully and frequently evaluated for the presence of bradycardia, heart block, and tachyarrhythmias. Preemptive treatment with permanent pacemakers or implanted defibrillators is appropriate in patients with conduction system disease or who are at risk for ventricular arrhythmias.
... Dilated cardiomyopathy has been reported in patients with mutations in the FKTN gene, 24 25 and a third of patients with LGMD2I develop cardiomyopathy. [26][27][28] Two patients with POMT1 mutations and a LGMD phenotype have also been reported with ventricular dilatation of the heart. 29 In the present study, two cases had reduced LVEF (cases 5 and 7), suggesting that patients with LGMD2N are at risk of developing pump failure. ...
Background
Mutations in the gene coding for protein O-mannosyl-transferase 2 (POMT2) are known to cause severe congenital muscular dystrophy, and recently, mutations in POMT2 have also been linked to a milder limb-girdle muscular dystrophy (LGMD) phenotype, named LGMD type 2N (LGMD2N). Only four cases have been reported so far. ClinicalTrials.gov ID: NCT02759302
Methods
We report 12 new cases of LGMD2N, aged 18–63 years. Muscle involvement was assessed by MRI, muscle strength testing and muscle biopsy analysis. Other clinical features were also recorded.
Results
Presenting symptoms were difficulties in walking, pain during exercise, delayed motor milestones and learning disabilities at school. All had some degree of cognitive impairment. Brain MRIs were abnormal in 3 of 10 patients, showing ventricular enlargement in one, periventricular hyperintensities in another and frontal atrophy of the left hemisphere in a third patient. Most affected muscle groups were hip and knee flexors and extensors on strength testing. On MRI, most affected muscles were hamstrings followed by paraspinal and gluteal muscles. The 12 patients in our cohort carried 11 alleles with known mutations, whereas 11 novel mutations accounted for the remaining 13 alleles.
Conclusion
We describe the first cohort of patients with LGMD2N and show that unlike other LGMD types, all patients had cognitive impairment. Primary muscle involvement was found in hamstring, paraspinal and gluteal muscles on MRI, which correlated well with reduced muscle strength in hip and knee flexors and extensors. The study expands the mutational spectrum for LGMD2N, with the description of 11 novel POMT2 mutations in the association with LGMD2N.
Clinical trial registration
NCT02759302.
... LGMD type 2E (LGMD2E), with a mutation in the betasarcoglycan (SGCB) gene, represents a severe form of LGMD [22,23], often associated with cardiomyopathy and abnormalities in the vasculature [23][24][25]. Currently, there is no cure for DMD or LGMD2E [26,27] and effective therapeutic approaches capable of counteracting muscle and vessel degeneration are needed. ...
Background
Dental pulp represents an easily accessible autologous source of adult stem cells. A subset of these cells, named dental pulp pluripotent-like stem cells (DPPSC), shows high plasticity and can undergo multiple population doublings, making DPPSC an appealing tool for tissue repair or maintenance.
Methods
DPPSC were harvested from the dental pulp of third molars extracted from young patients. Growth factors released by DPPSC were analysed using antibody arrays. Cells were cultured in specific differentiation media and their endothelial, smooth and skeletal muscle differentiation potential was evaluated. The therapeutic potential of DPPSC was tested in a wound healing mouse model and in two genetic mouse models of muscular dystrophy (Scid/mdx and Sgcb-null Rag2-null γc-null).
Results
DPPSC secreted several growth factors involved in angiogenesis and extracellular matrix deposition and improved vascularisation in all three murine models. Moreover, DPPSC stimulated re-epithelialisation and ameliorated collagen deposition and organisation in healing wounds. In dystrophic mice, DPPSC engrafted in the skeletal muscle of both dystrophic murine models and showed integration in muscular fibres and vessels. In addition, DPPSC treatment resulted in reduced fibrosis and collagen content, larger cross-sectional area of type II fast-glycolytic fibres and infiltration of higher numbers of proangiogenic CD206⁺ macrophages.
Conclusions
Overall, DPPSC represent a potential source of stem cells to enhance the wound healing process and slow down dystrophic muscle degeneration.
Electronic supplementary material
The online version of this article (doi:10.1186/s13287-017-0621-3) contains supplementary material, which is available to authorized users.
... Abdallah Fayssoil (France) indicated that cardiac involvement has been reported repeatedly in sarcoglycanopathies, mostly using electrocardiography and standard echocardiography [49][50][51], even reaching 60% in LGMD2E [52]. Cardiomyopathy is often preclinical (44% in an Italian study) [53] and sometimes dilated (17% in the Dutch study) [49]. ...
• Review on current states on clinical trial readiness for sarcoglycanopathies.
... A significant number of the LGMD gene mutations not only cause a muscular dystrophy, but also cardiac phenotypes, including a progressive reduction in ventricular ejection fraction, heart failure and cardiac arrhythmia [36]. Interestingly, in many cases, the pathology in the heart is early onset and more severe than in skeletal muscle [37]. ...
The Popeye domain containing (POPDC) genes encode a novel class of cAMP effector proteins, which are abundantly expressed in heart and skeletal muscle. Here we will review their role in striated muscle as deduced from work in cell and animal models and the recent analysis of patients carrying a missense mutation in POPDC1. Evidence suggests that POPDC proteins control membrane trafficking of interacting proteins. Furthermore, we will discuss the current catalogue of established protein-protein interactions. In recent years, the number of POPDC-interacting proteins is rising and currently includes ion channels (TREK-1), sarcolemma-associated proteins serving functions in mechanical stability (Dystrophin), compartmentalization (Caveolin 3), scaffolding (ZO-1), trafficking (NDRG4, VAMP2/3) and repair (Dysferlin), or acting as a guanine nucleotide exchange factor for Rho-family GTPases (GEFT). Recent evidence suggests that POPDC proteins might also control the cellular level of the nuclear proto-oncoprotein c-Myc. These data suggests that this family of cAMP-binding proteins probably serves multiple roles in striated muscle.
... [33] . According to the study by Petri et al [34] , ECG abnormalities were non-progressive in BMD and asymptomatic SVT and NSVT were present in 21% and 14%, respectively. Both ECG and Holter monitoring are necessary for DMD/BMD assessment. ...
Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked muscular diseases responsible for over 80% of all muscular dystrophies. Cardiac disease is a common manifestation, not necessarily related to the degree of skeletal myopathy; it may be the predominant manifestation with or without any other evidence of muscular disease. Death is usually due to ventricular dysfunction, heart block or malignant arrhythmias. Not only DMD/BMD patients, but also female carriers may present cardiac involvement. Clinically overt heart failure in dystrophinopathies may be delayed or absent, due to relative physical inactivity. The commonest electrocardiographic findings include conduction defects, arrhythmias (supraventricular or ventricular), hypertrophy and evidence of myocardial necrosis. Echocardiography can assess a marked variability of left ventricular dysfunction, independently of age of onset or mutation groups. Cardiovascular magnetic resonance (CMR) has documented a pattern of epicardial fibrosis in both dystrophinopathies' patients and carriers that can be observed even if overt muscular disease is absent. Recently, new CMR techniques, such as postcontrast myocardial T1 mapping, have been used in Duchenne muscular dystrophy to detect diffuse myocardial fibrosis. A combined approach using clinical assessment and CMR evaluation may motivate early cardioprotective treatment in both patients and asymptomatic carriers and delay the development of serious cardiac complications.
We aimed to investigate the epidemiology and natural history of FKRP-related limb-girdle muscular dystrophy R9 (LGMDR9) in Norway. We identified 153 genetically confirmed subjects making the overall prevalence 2.84/100,000, the highest reported figure worldwide. Of the 153 subjects, 134 (88 %) were homozygous for FKRP c.826C>A giving a carrier frequency for this variant of 1/101 in Norway. Clinical questionnaires and patient notes from 101 subjects, including 88 c.826C>A homozygotes, were reviewed, and 43/101 subjects examined clinically. Age of onset in c.826C>A homozygotes demonstrated a bimodal distribution. Female subjects showed an increased cumulative probability of wheelchair dependency and need for ventilatory support. Across the cohort, the need for ventilatory support preceded wheelchair dependency in one third of the cases, usually due to sleep apnea. In c.826C>A homozygotes, occurrence of cardiomyopathy correlated positively with male gender but not with age or disease stage. This study highlights novel gender differences in both loss of ambulation, need for ventilatory support and the development of cardiomyopathy. Our results confirm the need for vigilance in order to detect respiratory insufficiency and cardiac involvement, but indicate that these events affect males and females differently.
Purpose:
Cardiac involvement in limb-girdle muscular dystrophy (LGMD)2A and LGMD2B, the most common subgroups of LGMD, is controversial. Our study aims to determine whether myocardial dysfunction develops in LGMD2A and LGMD2B patients.
Methods:
The study included 16 LGMD2A, 12 LGMD2B patients, and 48 healthy individuals. Comparisons included demographic, clinical, and laboratory parameters of LGMD2A and LGMD2B subgroups and traditional echocardiography and two-dimensional speckle tracking echocardiography (2D-STE) parameters with the normal population.
Results:
The median age was 33 (22-39 interquartile range [IQR]) in the LGMD2A group, 33 (27-38 IQR) in the LGMD2B group, and 28 (25-35 IQR) in the control group. The left ventricular (LV) ejection fraction of both LGMD2A and LGMD2B groups was similar to the control group (p = 0.296 and p = 0.918). Apical 4-chamber longitudinal strain (LS), Apical 2-chamber LS, Apical 3-chamber LS, left ventricular global longitudinal strain (LVGLS)-mid-myocardial, LVGLS-endocardium, and LVGLS-epicardium were lower (less negative) in the LGMD2B group compared to the control group (p = 0.006, p = 0.001, p < 0.001, p < 0.001, p < 0.001, and p < 0.001, respectively).
Conclusion:
LV 2D-STE parameters of LGMD2A patients were similar to the control group, while they decreased significantly (less negative) in LGMD2B patients, indicating that LV subclinical myocardial dysfunction may develop in LGMD2B patients.
This international multidisciplinary document is intended to guide electrophysiologists, cardiologists, other clinicians, and health care professionals in caring for patients with arrhythmic complications of neuromuscular disorders (NMDs). The document presents an overview of arrhythmias in NMDs followed by detailed sections on specific disorders: Duchenne muscular dystrophy, Becker muscular dystrophy, and limb-girdle muscular dystrophy type 2; myotonic dystrophy type 1 and type 2; Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B; facioscapulohumeral muscular dystrophy; and mitochondrial myopathies, including Friedreich ataxia and Kearns-Sayre syndrome, with an emphasis on managing arrhythmic cardiac manifestations. End-of-life management of arrhythmias in patients with NMDs is also covered. The document sections were drafted by the writing committee members according to their area of expertise. The recommendations represent the consensus opinion of the expert writing group, graded by class of recommendation and level of evidence utilizing defined criteria. The recommendations were made available for public comment; the document underwent review by Heart Rhythm Society Scientific and Clinical Documents Committee and external review and endorsement by the partner and collaborating societies. Changes were incorporated based on these reviews. By using a breadth of accumulated available evidence, the document is designed to provide practical and actionable clinical information and recommendations for the diagnosis and management of arrhythmias and thus improve the care of patients with NMDs.
Background
Truncating variants in titin (TTNtv) are the most common cause of dilated cardiomyopathy (DCM). We evaluated the genotype-phenotype correlation in TTNtv-DCM, with a special focus on long-term outcomes, arrhythmias, response to treatment and sex-related presentation.
Methods
Data on patient characteristics and outcomes were collected retrospectively from electronic health records of patients genotyped at two Danish heart transplantation centres.
Results
We included 115 patients (66% men). At diagnosis of DCM, mean age was 46±13 years and left ventricular ejection fraction (LVEF) was 28%±13%. During a median follow-up of 7.9 years, 26% reached a composite outcome of left ventricular assist device implantation, heart transplantation or death. In 20% an arrhythmia preceded the DCM diagnosis. In total, 43% had atrial fibrillation (AF) and 23% had ventricular arrhythmias. Long-term left ventricular reverse remodelling (LVRR; LVEF increase ≥10% points or normalisation) was achieved in 58% and occurred more frequently in women (72% vs 51%, p=0.042).
In multivariable proportional hazards analyses, occurrence of LVRR was a strong independent negative predictor of the composite outcome (HR: 0.05 (95% CI 0.02 to 0.14); p<0.001). Female sex independently predicted lower rates of ventricular arrhythmias (HR: 0.33 (95% CI 0.11 to 0.99); p=0.05), while the location of the TTNtv was not associated with cardiovascular outcomes.
Conclusion
DCM caused by TTNtv presented in midlife and was associated with a high burden of AF and ventricular arrhythmias, which often preceded DCM diagnosis. Furthermore, LVRR occurred in a high proportion of patients and was a strong negative predictor of the composite outcome. Female sex was positively associated with occurrence of LVRR and longer event-free survival.
N. Arora et al. (eds.), Neuromuscular Urgencies and Emergencies
Most of the pediatric neuromuscular diseases often manifest by slowly progressive or fluctuating motor weakness. However, there are some neuromuscular conditions that present with acute weakness which could terrify parents as well as children and are often a diagnostic and therapeutic challenge for clinicians. A timely and methodical approach to diagnosis and subsequent treatment is paramount. This chapter discusses the common neuromuscular diseases that could present in the emergency department with a focus on characteristic symptoms, evaluation, treatment, and prognosis.
Prompt attention to the common neuromuscular emergencies (NME) that could present during pregnancy is essential for maternal-fetal wellbeing. Pregnancy in itself has its own challenges in management, and dealing with an NME during that critical time period is of utmost importance. This chapter describes common neuromuscular emergencies that could present during pregnancy.
Neurologists are often expected to deal with a neuromuscular emergency in a pregnant female. It is often difficult to evaluate and treat these patients without proper understanding of the disease process. The physiologic changes during pregnancy, labor, and puerperium increase the maternal risk of neuromuscular complications. The purpose of the chapter is not to detail about every single neurologic disorder which could happen in pregnant females but to focus on commonly encountered neuromuscular emergencies confronted by the treating physician and how to practically deal with it. Most common disorders are listed below according to the location of injury:
1. Spinal cord: Trauma
2. Nerve and nerve roots: Guillain-Barre syndrome, compression-related nerve injuries
3. NM junction: Myasthenia gravis
4. Muscle: Inflammatory muscle disease
This book functions as a practical reference for recognizing various patient presentations, signs, and symptoms that must be considered when treating neuromuscular disorders (NMD). It emphasizes the importance of recognizing these preexisting conditions as this can be crucial to treating patients properly with appropriate medications and procedures.
Concise yet comprehensive, this 10-chapter guide analyses various neuromuscular weaknesses including respiratory and progressive muscle weakness. Chapters address the involvement of multiple organ systems in NMD, with specific attention to cardiomyopathy, cardiac arrhythmias, and dystrophinopathies. Discussions also address the challenges practitioners face when treating vulnerable demographics such as pregnant women and those with hyper metabolic conditions.
Written by experts in the field, Neuromuscular Urgencies and Emergencies is an invaluable resource for neurologists, emergency medicine physicians, physician assistants, and the interventional neurologist.
Neuromuscular diseases (NMD) are a group of diseases that affect multiple organ systems. Cardiac involvement is a common manifestation in these individuals and the presentation can vary depending on the involvement of the heart musculature or the conduction apparatus. The diagnosis and treatment become critical due to an increased morbidity and mortality associated with cardiac complications that develop in NMD patients. The drawback of limited literature available on specific cardiovascular pathologies, the natural course of the disease, and targeted treatment options in patients with NMD makes it a challenging task for the managing physician. This chapter outlines cardiac manifestations encountered in different NMDs, the diagnostic tools, available treatment modalities, and screening techniques that can be utilized for a tailored approach in these patients.
Neuromuscular disorders comprise a large group of diseases caused by dysfunction of motor neurons, peripheral nerves and skeletal muscles. A fair proportion of neuromuscular disorders have a genetic cause. The incidence and prevalence of cardiomyopathies associated with inherited neuromuscular diseases, particularly with muscular dystrophies, have long been underestimated, even though cardiac involvement, presenting as cardiac conduction abnormalities, cardiomyopathy with heart failure and sudden cardiac death, is either the direct or indirect cause of death in many of these diseases.
Introduction:
Reported frequencies of cardiomyopathy in limb girdle muscular dystrophy R9 (LGMDR9) vary. We describe the frequency and age at onset of cardiomyopathy in an LDMDR9 cohort.
Methods:
Echocardiograms from 56 subjects (157 echocardiograms) with LGMDR9 were retrospectively reviewed. The cumulative probability of having an abnormal echocardiogram as a function of age was assessed by survival analysis for interval-censored data by genotype. Correlations between cardiac and clinical function were evaluated.
Results:
Twenty-five (45%) participants had cardiomyopathy. The median age at first abnormal echocardiogram for subjects homozygous for the c.826C>A variant was 54.2 y compared to 18.1 y for all other fukutin-related protein (FKRP) genotypes (P < .0001). There was a weak correlation between ejection fraction and 10-Meter Walk Test speed (r = 0.25), but no correlation with forced vital capacity (r = 0.08).
Discussion:
Cardiomyopathy is prevalent among those with LGMDR9 and occurs later in subjects homozygous for the c.826C>A mutation. These data will help to guide surveillance and management.
Limb-girdle muscular dystrophy 2i (LGMD2i) is a dystroglycanopathy that compromises myofiber integrity and primarily reduces power output in limb muscles, but can influence cardiac muscle as well. Previous studies have made use of a transgenic mouse model for LGMD2i in which a proline to leucine (P448L) mutation in fukutin-related protein (FKRP) severely reduces glycosylation of α-dystroglycan. Muscle function is compromised in P448L mice in a manner similar to human LGMD2i patients. In situ studies reported lower maximal twitch force and depressed force-velocity curves in medial gastrocnemius (MG) muscles of male P448L mice. Here, we measured Ca2+-activated force generation and cross-bridge kinetics in both demembranated MG fibers and papillary muscle strips from P448L mice. Maximal activated tension of P448L MG fibers was 37% lower than controls, and the tension of papillary strips was 18% lower. We also found that the rates of cross-bridge recruitment and detachment were slightly faster in P448L MG fibers compared to controls. These increases in skeletal cross-bridge cycling could reduce the unitary force output from individual cross-bridges by lowering the ratio of time spent in a force bearing state. This suggests that the decreased force production observed in LGMD2i may be due (at least in part) to altered cross-bridge kinetics. This finding is notable as the majority of studies germane to muscular dystrophies have focused on sarcolemmal or whole muscle properties whereas our findings suggest that the disease pathology is also influenced by potential down-stream effects on cross-bridge behavior.
Patients with muscular dystrophy face a lifetime of physical challenges due to their neuromuscular disease. Physical challenges are faced on a daily basis, and as such this is the initial focus from a clinical perspective. Over the past decades, improvements in physical and respiratory therapy, coupled with advances in technology, have substantially improved quality of life for this patient group. Improvements in computer technology such as voice recognition have increased access to education and allowed greater independence for muscular dystrophy patients. Use of assisted cough techniques and ventilatory support, particularly non-invasive support, has significantly prolonged the lifespan of patients with neuromuscular disease, particularly Duchenne muscular dystrophy. As a result, cardiac disease is now thought to be the leading cause of death among those with Duchenne muscular dystrophy, and represents a new medical challenge for the current generation of patients.
Background: Limb-girdle muscular dystrophy type 2I (LGMD2I) is an autosomal recessive hereditary disorder caused by mutations in the fukutin-related protein (FKRP) gene. Although the features of the disorder in European patients have been summarized, Asian patients with LGMD2I have rarely been reported. Thus, the clinical differences in LGMD2I between Asian and European patients and the associated genetic changes remain unclear.
Methods: We reported detailed clinical data as well as results from muscle biopsy, muscle MRI and genetic analysis of the FKRP gene in two unrelated Chinese families with LGMD2I. Additionally, a review of the literature focusing on the clinical and mutational features of LGMD2I in Asian patients was performed.
Results: The muscle biopsy results showed dystrophic features. Immunohistochemical staining revealed decreased glycosylations on α-dystroglycan. The muscle MRI results showed that the gluteus maximus, adductor, biceps femoris, vastus intermedius and vastus lateralis were severely affected. The patients in the two families harbored the same compound heterozygous mutations (c.545A>G and c.948delC). One patient showed significant clinical improvement after corticosteroid treatment.
Conclusion: Our study expanded the reported spectrum of Asian LGMD2I patients. Our literature review revealed that pathogenic mutations in the FKRP gene in Asian LGMD2I patients are compound heterozygous rather than homozygous. Compound heterozygous Asian patients have a mild phenotype but frequently show respiratory and cardiac impairments. Corticosteroids may be beneficial for the treatment of LGMD2I and should be further investigated.
The fukutin-related protein P448L mutant mouse replicates pathologies common to limb-girdle muscular dystrophy 2i (LGMD2i) and is a strong candidate for relevant drug screening studies. Because striated muscle function remains relatively uncharacterized in this mouse, we sought to identify metabolic, functional and histological metrics of exercise and cardiac performance by quantifying voluntary exercise on running wheels, forced exercise on respiratory treadmills and cardiac output with echocardiography and isoproterenol stress tests. Voluntary exercise revealed few differences between wild-type and P448L mice. By contrast, peak oxygen consumption (VO2peak) was lower in P448L mice or reduced with repeated low intensity treadmill exercise while it increased in wild-type mice. P448L mice fatigued quicker and ran shorter distances while expending 2-fold more calories/meter. They also received 6-fold more motivational shocks with repeated exercise. Differences in VO2peak and resting metabolic rate were consistent with left ventricle dysfunction, which often develops in human LGMD2i patients and was more evident in female P448L mice, as indicated by lower fractional shortening and ejection fraction values and higher left ventricle systolic volumes. Several traditional markers of dystrophinopathies were expressed in P448L mice and were exacerbated by exercise, some in a muscle-dependent manner. These include elevated serum creatine kinase and muscle central nucleation, smaller muscle fiber cross-sectional area and more striated muscle fibrosis. These studies together identified several markers of disease pathology that are shared between P448L mice and human subjects with LGMD2i. They also identified novel metrics of exercise and cardiac performance that could prove invaluable in preclinical drug trials.
Neuromuscular disorders comprise a large group of diseases caused by dysfunction of motor neurons, peripheral nerves, and skeletal muscles. A fair proportion of neuromuscular disorders have a genetic cause. The incidence and prevalence of cardiomyopathies associated with inherited neuromuscular diseases, particularly with muscular dystrophies, have until recently been underestimated, even though cardiac involvement is either the direct or indirect cause of death in many of these diseases. © Springer International Publishing Switzerland 2016. All rights are reserved.
Introduction: Dystrophinopathies, due to mutations in the dystrophin gene, include four different phenotypes: Duchenne muscular Dystrophy (DMD), Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy (XL-DCM) and cardiomyopathy of Duchenne/Becker carriers.
Areas covered: Dystrophinopathic cardiomyopathy is a stepwise process starting with a pre-symptomatic stage and evolving toward stages of overt heart involvement such as dilated cardiomyopathy, intractable heart failure and death. It is an almost constant feature of dystrophinopathies and often the first presentation of the disease. Strategic use of established medications might delay the evolution of heart involvement.
Expert opinion: Treatment of cardiomyopathy is a major challenge for cardiologists routinely involved in the care of patients with dystrophinopathies. At least yearly cardiac appropriate work up with careful clinical examination and instrumental investigations including routine electrocardiogram (ECG), stress testing, long-term ECG, and echocardiography are recommended also in asymptomatic or minimal symptomatic patients to prevent the onset of serious events. More frequent controls may be necessary according to the stage of cardiomyopathy and patient’s needs. Adeno-associated virus-mediated gene therapy has recently been reported to significantly improve the outcomes in rodent models of DMD. Guidelines regarding the proper treatment of dystrophinopathic cardiomyopathy are necessary to enable patients to be eligible for future therapies.
• Review on current states on clinical trial readiness for FKRP-related muscular dystrophies.
Purpose of review:
The aim of the study was to describe the clinical spectrum of limb girdle muscular dystrophies (LGMDs), the pitfalls of the current classification system for LGMDs, and emerging therapies for these conditions.
Recent findings:
Close to half of all LGMD subtypes have been discovered within the last 6 years of the 21-year-period in which the current classification system for LGMD has existed. The number of letters for annotation of new recessive LGMD conditions is exhausted, and multiple already classified LGMDs do not strictly fulfill diagnostic criteria for LGMD or are registered in other classification systems for muscle disease. On the contrary, diseases that fulfill classical criteria for LGMD have found no place in the LGMD classification system. These shortcomings call for revision/creation of a new classification system for LGMD. The rapidly expanding gene sequencing capabilities have helped to speed up new LGMD discoveries, and unveiled pheno-/genotype relations. Parallel to this progress in identifying new LGMD subtypes, emerging therapies for LGMDs are under way, but no disease-specific treatment is yet available for nonexperimental use.
Summary:
The field of LGMD is rapidly developing from a diagnostic and therapeutic viewpoint, but a uniform and universally agreed classification system for LGMDs is needed.
Cardiac involvement with progressive myocardial fibrosis leading to dilated cardiomyopathy is a major cause of death in muscular dystrophy patients. Extracellular volume fraction (ECV) measurement based on T1-mapping pre- and post-contrast promises the detection of early 'diffuse' myocardial fibrosis that cannot be depicted by conventional contrast-imaging based on late gadolinium enhancement (LGE). With this study, we evaluated the presence of diffuse myocardial fibrosis in regions of 'normal' (LGE-negative) and 'diseased' (LGE-positive) appearing myocardium as well as its relation to the extent of left ventricular (LV) dysfunction and the occurrence of arrhythmias in Becker muscular dystrophy (BMD) patients.
Twenty-seven BMD patients (35 ± 12 years) and 17 matched male healthy controls (33 ± 8 years) underwent cardiovascular magnetic resonance (CMR) studies including ECV measurement and LGE-imaging. Ambulatory monitoring of arrhythmic events was performed by means of an external event loop recorder. Twenty BMD patients (74%) demonstrated cardiac involvement as detected by typical inferolateral presence of LGE. Twelve patients (44%) had an impaired LV ejection fraction-all being LGE-positive. Global myocardial ECV was significantly higher in the BMD group (29 ± 6%) compared with the control group (24 ± 2%, P = 0.001). Patients with cardiac involvement demonstrated higher global ECV (31 ± 6%) as well as significantly increased regional ECV not only in LGE-positive segments (34 ± 6%), but also in LGE-negative segments (28 ± 6%) compared with BMD patients without cardiac involvement and to controls, respectively (24 ± 3 and 24 ± 2%, P = 0.005). Global ECV in patients with cardiac involvement substantially correlated to LV ejection fraction (r = -0.629, P = 0.003) and to the number of LGE-positive segments (r = 0.783, P < 0.001). On univariable analysis, global ECV-but not the categorical presence of LGE per se--was significantly associated with arrhythmic events (OR: 1.97, CI: 32.22-1.21, P = 0.032).
ECV measurement by CMR is a useful tool in assessing the total extent of myocardial fibrosis as well as in depicting subtle diffuse fibrosis in areas of normal appearing myocardium on LGE-images. Thus, myocardial ECV is a potential additional quantitative tool for accurate detection of cardiac involvement and risk stratification in muscular dystrophy patients.
Duchenne muscular dystrophy (DMD), an X-linked disorder affects approximately 1 in 5000 males, is universally associated with heart disease. We previously identified myocardial disease by late gadolinium enhancement (LGE) in DMD subjects at various stages of disease, but the true prevalence is unclear. Cardiovascular magnetic resonance (CMR) is well established for both assessment of ventricular function and myocardial fibrosis by LGE. We sought to establish i) prevalence and distribution of LGE in a large DMD population and ii) relationship among LGE, age, LVEF by CMR and current living status.
Current living status, demographic and CMR data including ventricular volumes, LVEF and LGE from 314 DMD patients undergoing evaluation at a single large tertiary referral center were analyzed.
113 of 314 (36%) of DMD subjects showed LGE positivity with prevalence increasing from 17% of patients <10 years to 34% of those aged 10-15 years and 59% of those > 15 years-old. Patients with LVEF >=55% were LGE positive in 30% of cases; this increased to 84%for LVEF <55%. LGE was more prevalent in the free wall (531/1243, 42.7%) vs. septal segments (30/565, 5.3%). Patients with septal involvement were significantly older and had lower LVEF than those with isolated free wall LGE. Ten percent (11/113) patients who had LGE died 10.8 months after CMR. Only one patient from the LGE negative group died. Patients who died had higher heart rate, larger left ventricular volume and mass, greater number of positive LGE segment and increase incident of septal LGE compared to those who remained alive.
In DMD patients, LGE occurs early, is progressive and increases with both age and decreasing LVEF. Segmentally, the incidence of the number of positive LGE segments increase with age and lower LVEF. Older patients and those who died during the study period had more septal LGE involvement. The current studies suggest that the time course and distribution of LGE-positivity may be an important clinical biomarker to aid in the management of DMD-associated cardiac disease.
We evaluated the course of cardiac involvement in 27 previously reported patients with Becker muscular dystrophy (BMD) originating
from nine kindreds. Since almost all affected individuals of each kindred were included, intrafamilial variability could be
studied. We also attempted to identify associations between cardiac involvement, functional ability and mutations at DNA level.
The mean follow-up period was 12.5 years. The number of patients with electrocardiographic abnormalities progressed from 44%
to 71%. Dilated cardiomyopathy (DCM) with or without congestive heart failure was now present in 33% as compared with 15%
in the previous study. In addition, 22% developed borderline echocardiographic abnormalities. Six patients (22%) became symptomatic
and four patients died of congestive heart failure. In all families cardiac abnormalities were found. There was no association
between DCM and mutation type. Despite equal functional motor ability, there was a considerable intrafamilial variation in
cardiac involvement, even in brother pairs. We conclude that cardiac abnormalities are the rule and not the exception in BMD
and are progressive over time. Left ventricular dilatation may begin at any moment in the course of BMD and the rate of progression
is unpredictable. A substantial proportion of patients will develop an incapacitating and life-threatening DCM.
Limb girdle muscular dystrophies (LGMD) are inclusive of 7 autosomal dominant and 14 autosomal recessive disorders featuring progressive muscle weakness and atrophy. Studies of cardiac function have not yet been well-defined in deficiencies of dysferlin (LGMD2B) and fukutin related protein (LGMD2I). In this study of patients with these two forms of limb girdle muscular dystrophy, cardiovascular magnetic resonance (CMR) was used to more specifically define markers of cardiomyopathy including systolic dysfunction, myocardial fibrosis, and diastolic dysfunction.
Consecutive patients with genetically-proven LGMD types 2I (n = 7) and 2B (n = 9) and 8 control subjects were enrolled. All subjects underwent cardiac magnetic resonance (CMR) on a standard 1.5 Tesla clinical scanner with cine imaging for left ventricular (LV) volume and ejection fraction (EF) measurement, vector velocity analysis of cine data to calculate myocardial strain, and late post-gadolinium enhancement imaging (LGE) to assess for myocardial fibrosis.
Sixteen LGMD patients (7 LGMD2I, 9 LGMD2B), and 8 control subjects completed CMR. All but one patient had normal LV size and systolic function; one (type 2I) had severe dilated cardiomyopathy. Of 15 LGMD patients with normal systolic function, LGE imaging revealed focal myocardial fibrosis in 7 (47%). Peak systolic circumferential strain rates were similar in patients vs. controls: εendo was -23.8 ± 8.5vs. -23.9 ± 4.2%, εepi was -11.5 ± 1.7% vs. -10.1 ± 4.2% (p = NS for all). Five of 7 LGE-positive patients had grade I diastolic dysfunction [2I (n = 2), 2B (n = 3)]. that was not present in any LGE-negative patients or controls.
LGMD2I and LGMD2B generally result in mild structural and functional cardiac abnormalities, though severe dilated cardiomyopathy may occur. Long-term studies are warranted to evaluate the prognostic significance of subclinical fibrosis detected by CMR in these patients.
Cardiac involvement has been reported in carriers of dystrophin mutations giving rise to Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). The progress of these abnormalities during long-term follow-up is unknown. We describe the long-term follow-up of dilated cardiomyopathy (DCM) in DMD/BMD carriers.
A long-term follow-up study was performed among Dutch DMD/BMD carriers first analyzed in 1995. A cardiac history was taken, and all carriers were assigned a functional score to assess skeletal muscle involvement. Electrocardiography and M-mode and 2-D echocardiography were performed. DCM was defined as an enlarged left ventricle with a global left ventricle dysfunction or fractional shortening less than 28%. Slow vital capacity of the lung was measured by a hand-held spirometer.
Ninety-nine carriers were monitored with a median follow-up of 9 years (range 7.0-10.6 years). Eleven carriers with DCM (10 DMD, 1 BMD) were identified. Nine of them developed DCM in the follow-up period. One of the patients with DCM reported in the 1995 study died of cardiac failure at age 57 years. DCM was more frequently found in carriers who were functionally symptomatic.
Cardiac abnormalities in DMD/BMD carriers are progressive, as in patients with DMD/BMD.
A cross-sectional study was performed in the Netherlands to define the clinical characteristics of the various subtypes within the broad and heterogeneous entity of limb girdle muscular dystrophy (LGMD). An attempt was made to include all known cases of LGMD in the Netherlands. Out of the reported 200 patients, 105 who fulfilled strictly defined criteria were included. Forty-nine patients, mostly suffering from dystrophinopathies and facioscapulohumeral muscular dystrophy, appeared to be misdiagnosed. Thirty-four cases were sporadic, 42 patients came from autosomal recessive and 29 from autosomal dominant families. The estimated prevalence of LGMD in the Netherlands was at least 8.1×10−6. The clinical features of the autosomal recessive and sporadic cases were indistinguishable from those of the autosomal dominant patients, although calf hypertrophy was seen more frequently, and the course of the disease was more severe in autosomal recessive and sporadic cases. The pectoralis, iliopsoas and gluteal muscles, hip adductors and hamstrings were the most affected muscles. Distal muscle involvement occurred late in the course of the disease. Facial weakness was a rare phenomenon. The severity of the clinical picture was correlated with a deteriorating lung function. All autosomal dominantly inherited cases showed a mild course, although in two families life-expectancy was reduced because of concomitant cardiac involvement.
We evaluated the course of cardiac involvement in 27 previously reported patients with Becker muscular dystrophy (BMD) originating from nine kindreds. Since almost all affected individuals of each kindred were included, intrafamilial variability could be studied. We also attempted to identify associations between cardiac involvement, functional ability and mutations at DNA level. The mean follow-up period was 12.5 years. The number of patients with electrocardiographic abnormalities progressed from 44% to 71%. Dilated cardiomyopathy (DCM) with or without congestive heart failure was now present in 33% as compared with 15% in the previous study. In addition, 22% developed borderline echocardiographic abnormalities. Six patients (22%) became symptomatic and four patients died of congestive heart failure. In all families cardiac abnormalities were found. There was no association between DCM and mutation type. Despite equal functional motor ability, there was a considerable intrafamilial variation in cardiac involvement, even in brother pairs. We conclude that cardiac abnormalities are the rule and not the exception in BMD and are progressive over time. Left ventricular dilatation may begin at any moment in the course of BMD and the rate of progression is unpredictable. A substantial proportion of patients will develop an incapacitating and life-threatening DCM.
Limb-girdle muscular dystrophy type 2D (LGMD 2D) is an autosomal recessive disorder caused by mutations in the alpha-sarcoglycan gene. To determine how alpha-sarcoglycan deficiency leads to muscle fiber degeneration, we generated and analyzed alpha-sarcoglycan- deficient mice. Sgca-null mice developed progressive muscular dystrophy and, in contrast to other animal models for muscular dystrophy, showed ongoing muscle necrosis with age, a hallmark of the human disease. Sgca-null mice also revealed loss of sarcolemmal integrity, elevated serum levels of muscle enzymes, increased muscle masses, and changes in the generation of absolute force. Molecular analysis of Sgca-null mice demonstrated that the absence of alpha-sarcoglycan resulted in the complete loss of the sarcoglycan complex, sarcospan, and a disruption of alpha-dystroglycan association with membranes. In contrast, no change in the expression of epsilon-sarcoglycan (alpha-sarcoglycan homologue) was observed. Recombinant alpha-sarcoglycan adenovirus injection into Sgca-deficient muscles restored the sarcoglycan complex and sarcospan to the membrane. We propose that the sarcoglycan-sarcospan complex is requisite for stable association of alpha-dystroglycan with the sarcolemma. The Sgca-deficient mice will be a valuable model for elucidating the pathogenesis of sarcoglycan deficient limb-girdle muscular dystrophies and for the development of therapeutic strategies for this disease.
Sarcoglycan gene mutations cause various limb-girdle muscular dystrophies. The sarcoglycans are expressed both in skeletal and cardiac muscle but, surprisingly, so far only a few sarcoglycanopathy patients have had documented cardiomyopathy. We studied six patients with beta-sarcoglycanopathy. Immunohistochemical and immunoblot analysis performed on skeletal muscle biopsies from five patients, showed the loss of all sarcoglycans in three cases and marked reduction in two patients. Non-invasive cardiac examinations revealed that three patients had cardiac involvement: one had a severe Duchenne-like dystrophy, lethal dilated cardiomyopathy, and shared the same mutation reported in another cardiomyopathic patient; the other two patients had limb-girdle dystrophy and moderate cardiac involvement (one of them has a novel gene mutation). Given the age profile of the patients studied, the 50% cardiac involvement found in our LGMD2E patients is likely to be a conservative estimate. Careful cardiac monitoring should be carried out in beta-sarcoglycanopathy patients who are at high risk of developing cardiomyopathy.
Becker muscular dystrophy (BMD) is an X linked mutation of the dystrophin gene characterised by skeletal muscle dystrophy and progressive heart failure which frequently leads to a fatal outcome.1 Cardiac involvement is not accurately predicted by gene mutation and may occur in patients without muscle weakness. Consequently, systematic cardiac examinations are required. Tissue Doppler echocardiography (TDE) allows accurate quantification of regional myocardial function and may be a reliable method for early detection of myocardial dysfunction in BMD.2
Twenty four consecutive men with genetically documented BMD were prospectively investigated after informed consent and compared to 17 age matched controls. All patients underwent clinical examination, ECG, radionuclide ventriculography, and conventional echocardiography with TDE imaging.
Radionuclide ventriculography (gamma camera General Electric, Starport 400AT, interfaced with ADAC computer, DPS 3000) was performed after in vitro red cell labelling with 15 mCi of technetium-99m.
Ultrasound examinations (HDI5000, ATL ultrasound, Bothell, Washington DC) were recorded and analysed offline (HDILab Software) by two cardiologists unaware of any information. Radial left ventricular (LV) thickening was interrogated using colour M mode TDE acquisitions in the posterior wall. Myocardial wall motion velocities were extracted in endocardium (EndoV) and epicardium (EpiV) …
Patients with myotonic dystrophy type 1 (DM1) have a three-fold higher risk of sudden cardiac death (SCD) than age-matched healthy controls. Despite numerous attempts to define the cardiac phenotype and natural history, existing literature suffers from low power, selection-bias and lack of controls. Thus, the optimal strategy for assessing cardiac involvement in DM1 is unclear.
In this large single-centre study, we evaluated 129 unselected DM1 patients (49.6% men), mean (SD) age 44 (14.7) years with family history, physical examination, electrocardiogram (ECG), echocardiography, Holter-monitoring and muscle strength testing.
Cardiac involvement was found in 71 patients (55%) and included: 1) Conduction abnormalities: atrio-ventricular block grade I (AVB grade I) (23.6%), AVB grade II (5.6%), right/left bundle branch block (5.5/3.2%) and prolonged QTc (7.2%); 2) arrhythmias: atrial fibrillation/flutter (4.1%), other supraventricular tachyarrhythmia (7.3%) and non-sustained ventricular tachycardia (4.1%); and 3) structural abnormalities: left ventricular systolic dysfunction (20.6%) and reduced global longitudinal strain (21.7%). A normal ECG was not significantly associated with normal findings on Holter-monitoring or echocardiography. Patients with abnormal cardiac findings had weaker muscle strength than those with normal cardiac findings: ankle dorsal flexion (median (range) 4.5 (0-5) vs. 5.0 (2.5-5), p=0.004) and handgrip (median 4.0 (0-5) vs. 4.50 (2-5), p=0.02).
The cardiac phenotype of DM1 includes a high prevalence of conduction disorders, arrhythmias and risk factors of SCD. Systematic cardiac screening with ECG, Holter-monitoring and echocardiography is needed in order to make a proper characterization of cardiac involvement in DM1.
Introduction:
The aim of this study is to describe the frequency, nature, severity, and progression of cardiac abnormalities in a cohort of Dutch sarcoglycanopathy patients.
Methods:
In this cross-sectional cohort study, patients were interviewed using a standardized questionnaire and assigned a functional score. Electrocardiography (ECG), echocardiography, and 24-h ECG were performed.
Results:
Twenty-four patients with sarcoglycanopathy had a median age of 25 years (range, 8-59 years). Beta blockers were used by 13%, and 17% used angiotensin-converting enzyme inhibitors. ECG abnormalities were present in 5 (21%), and 4 (17%) fulfilled the criteria for dilated cardiomyopathy (DCM). There were no significant differences in median age or severity of disease between patients with or without DCM. Eleven patients were examined earlier. Median follow-up time was 10 years. Two of the 11 patients (18%) developed DCM during follow-up.
Conclusions:
Seventeen percent of the patients with sarcoglycanopathy were found to have dilated cardiomyopathy. We recommend biannual cardiac monitoring, including ECG and echocardiography.
With transition to the genetic era, the number of muscular dystrophies has grown significantly, but so too has our understanding of their pathogenic underpinnings. Clinical features associated with each muscular dystrophy still guide us to the diagnosis. However, improved diagnostic abilities refine and expand phenotypic and genotypic correlates. This article discusses the epidemiology, clinical features, and diagnosis of these disorders.
Some important recent advancements include (1) a much greater understanding of the pathogenetic pathways underlying facioscapulohumeral muscular dystrophy and myotonic dystrophy type 1; (2) the publication of diagnostic and treatment guidelines for Duchenne muscular dystrophy; and (3) further clarification of the many genetic muscle disorders presenting a limb-girdle pattern of weakness.
Muscular dystrophies are genetic, progressive, degenerative disorders with the primary symptom of muscle weakness. Duchenne, Becker, facioscapulohumeral, and myotonic muscular dystrophies are most prevalent and tend to have distinctive features helpful in diagnosis. The limb-girdle, Emery-Dreifuss, and oculopharyngeal muscular dystrophies are less common but often may also be diagnosed on the basis of phenotype. Researchers hope to help patients with future discoveries effective in slowing or halting disease progression, reversing or preventing underlying mechanisms, and repairing previously damaged muscle.
The medical profession should play a central role in evaluating the evidence related to drugs, devices, and procedures for the detection, management, and prevention of disease. When properly applied, expert analysis of available data on the benefits and risks of these therapies and procedures can
Background:
The reported prevalence of left ventricular noncompaction (LVNC) varies widely and its prognostic impact remains controversial. We sought to clarify the prevalence and prognostic impact of LVNC in patients with Duchenne/Becker muscular dystrophy (DMD/BMD).
Methods:
We evaluated the presence of LNVC in patients with DMD/BMD aged 4-64 years old at the study entry (from July 2007 to December 2008) and prospectively followed-up their subsequent courses (n=186). The study endpoint was all-cause death and the presence of LVNC was blinded until the end of the study (median follow-up: 46 months; interquartile range: 41-48 months).
Results:
There were no significant differences in baseline characteristics between patients with LVNC (n=35) and control patients without LVNC (n=151), with the exception of LV function. Patients with LVNC showed, in comparison with patients without LVNC, a significant negative correlation between age and LVEF (R=-0.7 vs. R=-0.4) at baseline; and showed a significantly greater decrease in absolute LVEF (-8.6 ± 4.6 vs. -4.3 ± 4.5, p<0.001) during the follow-up. A worse prognosis was observed in patients with LVNC (13/35 died) than in patients without LVNC (22/151 died, Log-rank p<0.001). Multivariate Cox analysis revealed that LVNC is an independent prognostic factor (relative hazard 2.67 [95% CI: 1.19-5.96]).
Conclusion:
LVNC was prevalent in patients with DMD/BMD. The presence of LVNC is significantly associated with a rapid deterioration in LV function and higher mortality. Neurologists and cardiologists should pay more careful attention to the presence of LVNC.
Limb girdle muscular dystrophy (LGMD) is a heterogeneous group of genetic disorders characterized by progressive muscle weakness with dystrophic muscle pathology caused by autosomal dominant or recessive gene mutations. Recently, several novel causative gene mutations have been associated with LGMD, due in part to recent scientific advances such as next generation sequencing. Interestingly, some of these novel forms of LGMD are allelic with other muscle diseases such as the dystroglycanopathy subtype of congenital muscular dystrophy. For the clinical diagnosis of LGMD, a comprehensive approach is typically needed, which may include a thorough evaluation by an experienced clinician, serum creatine kinase measurements, genetic testing, and muscle biopsy. On a research basis, the continued discovery of novel LGMD genes will be expedited with the increasing use of next generation sequencing technologies in combination with traditional approaches such as linkage analysis.
The originally published version of this paper was incorrect. In the table on page 1816, the Class of recommendation and Level of evidence for ‘The patient is pacemaker dependent as a result of AV nodal ablation’ should have read ‘IIa’ and ‘B’ respectively.
Appendix: six tables ([3][1
To estimate the degree of cardiac involvement regarding left ventricular ejection fraction, conduction abnormalities, arrhythmia, risk of sudden cardiac death (SCD) and the associations between cardiac involvement and cytosine-thymine-guanine (CTG)-repeat, neuromuscular involvement, age and gender in patients with myotonic dystrophy type 1 (MD1).
A Pub-Med search for the period 1980 to 2010 was performed according to specified criteria. Cardiac parameters including left ventricular ejection fraction (LVEF), conduction abnormalities and arrhythmia were compiled and only studies without ascertainment bias were included. Eighteen studies, 1828 MD1-patients, were included. The prevalence of atrioventricular block grade 1 (AVB1) was 28.2%, QTc>440ms 22%, QRS>120ms 19.9%, frequent ventricular premature contractions (VPC) 14.6%, atrial fibrillation/flutter (AF/AFL) 5%, right/left bundle branch block (RBBB/LBBB) 4.4/5.7% and non-sustained ventricular tachycardia (NSVT) 4.1%. Left ventricular systolic dysfunction (LVSD) was reported in 7.2% of the patients. There was an overall positive association between CTG-repeat size and cardiac involvement and between the degree of neuromuscular and cardiac involvement. Male gender and age were positively associated with arrhythmia and conduction abnormalities. The prevalence of pacemaker- (PM) and implantable cardioverter defibrillator-(ICD) implantations were 4.1% and 1.1%, respectively. The risk of SCD in this MD1-population was 0.56% per year.
MD1-patients have a high level of cardiac morbidity and mortality, strongly emphasizing the need of pre-symptomatic screening for arrhythmia and heart failure, as effective and well-documented preventive means are available.
Cardiac dysfunction is a frequent manifestation of Duchenne muscular dystrophy (DMD) and a common cause of death for individuals with this condition. Early diastolic dysfunction and focal fibrosis proceed to dilated cardiomyopathy (DCM), complicated by heart failure and arrhythmia in most patients. Improvements in the management of respiratory insufficiency in DMD have improved lifespan and overall prognosis, but heart failure and sudden death continue to impact survival and quality of life for people with DMD. Since the specific mechanisms resulting in heart failure for people with DMD are poorly understood, current treatments are not targeted, but rely on approaches that are considered standard for DCM. These approaches include angiotensin-converting enzyme (ACE) inhibitors and β-adrenoceptor antagonists. Data from one trial in DMD support the use of ACE inhibitors before the onset of left ventricular dysfunction. Angiotensin receptor blockers have shown similar efficacy to ACE inhibitors in numerous studies of dilated cardiomyopathy, and are a good choice for patients who cannot tolerate ACE inhibition. The pathogenesis of DMD-associated cardiomyopathy may be similar to other genetic disorders of the cytoskeletal complex of ventricular myocytes, though unique features offer targeted opportunities to impact treatment. Novel areas of investigation are focused on the regulatory role of dystrophin in relation to neuronal nitric oxide synthase (nNOS) and transient receptor potential canonical channels (TRPC). Inhibition of phosphodiesterase-5 (PDE5) addresses several aspects of regulatory dysfunction induced by dystrophin deficiency, and studies with PDE5-inhibitors have shown benefits in murine models of DMD. PDE5-inhibitors are currently under investigation in at least one study in humans. This article focuses on mechanisms of cardiac dysfunction, as well as potential targets for pharmacologic manipulation to prevent or improve cardiomyopathy in DMD.
Mutations in the FKRP gene may be associated with cardiac involvement. The aim of our study was to assess myocardial involvement in patients with LGMD2I, using physical examination, echocardiography, resting and 24-h ambulatory electrocardiogram and cardiac magnetic resonance imaging, with particular attention to the detection of myocardial morphologic abnormalities. Patients were compared to matched controls. Twenty-three patients were enrolled (men 10--women 13; 32.3+/-9.5 years). Twenty-two had the C826A gene mutation (homozygous 12, heterozygous 10). Nine patients had severe muscle alterations, 10 had milder muscle involvement and 4 had isolated exertional myoglobinuria. When compared to controls, LGMD2I patients had reduced left ventricular ejection fraction (50.8+/-13.9 versus 66.6+/-3.8%, p<0.0001). Sixty percent of patients had reduced left ventricular ejection fraction, including 8% with severe reduced left ventricular ejection fraction <30%. None had significant arrhythmia. Gene mutation and the severity of the muscle disease were not predictive of cardiac involvement. Cardiac magnetic resonance imaging displayed a high prevalence of myocardial functional abnormalities, fatty replacement and fibrosis, among the 13 patients investigated. Reduced contractility and cardiac magnetic resonance imaging morphological abnormalities are highly prevalent in LGMD2I patients suggesting that all patients should be referred for cardiac evaluation.
The developmental expression pattern of four human genes, three of which are involved in progressive muscular dystrophies, was investigated. The rationale for these experiments is that these patterns might provide useful information on the pathophysiology underlying these myopathies. Despite the presence of overlapping clinical signs, the spatiotemporal expression profiles of the corresponding genes differed widely. Transcripts of alpha-sarcoglycan (SGCA) were visible as soon as myotomes were formed, and constitute, together with titin transcripts, precocious muscular system landmarks. beta-sarcoglycan (SGCB) was initially transcribed in a ubiquitous manner, and, toward the second part of the embryonic period, became specific to striated muscle, heart, and the central nervous system. Whereas titin (TTN) transcription and translation seem to be coupled, for the sarcoglycans, translation seemed restricted to skeletal muscle. Calpain3 (CAPN3) RNA was found in only skeletal muscles during the fetal period. It was, however, present earlier in the whole heart, where it selectively disappeared. Finally, evidence for differentially spliced calpain3 variants in smooth muscles was also seen. The expression profiles of these genes is suggestive of their having a role during myogenesis, knowledge of which could be pertinent to the understanding of the pathophysiology of the associated diseases.
Single-center reports on percutaneous transluminal septal myocardial ablation (PTSMA) in patients with hypertrophic obstructive cardiomyopathy have shown considerable differences in outcome.
We report the long-term outcome of 313 PTSMA procedures performed in 279 patients with hypertrophic obstructive cardiomyopathy aged 59±14 years from 1999 to 2010 in 4 Scandinavian centers. Sixty-nine percent of patients had ≥1 comorbidity at baseline. The median (interquartile range) of left ventricular outflow tract gradient at rest was reduced from 58 mm Hg (34 to 89 mm Hg) at baseline to 12 mm Hg (8 to 24 mm Hg) at 1-year (P<0.001) and during Valsalva maneuver from 93 mm Hg (70 to 140 mm Hg) to 21 mm Hg (11 to 42 mm Hg) (P<0.001). The proportion of patients with syncope was reduced from 18% to 2% (P<0.001), and the proportion in New York Heart Association class III/IV was reduced from 94% to 21% (P<0.001). All treatment effects remained stable during the follow-up. New York Heart Association class III/IV at the most recent follow-up (2.9±2.6 years) was associated with diabetes mellitus (P=0.03), chronic obstructive pulmonary disease (P=0.02), and valve disease unrelated to hypertrophic cardiomyopathy (P<0.01). In-hospital mortality was 0.3%. The 1-, 5- and 10-year survival rates were 97%, 87%, and 67%, respectively (P=0.06 versus an age- and sex-matched background population) in all patients and 99%, 94%, and 88%, respectively (P=0.12) in patients aged <60 years (48±9 years, n=141). Age (hazard ratio, 1.07; 95% CI, 1.03 to 1.1) was the only predictor of survival.
In this multicenter study, the in-hospital mortality after PTSMA was low despite considerable comorbidities. The hemodynamic and symptomatic effects were sustained long term. The long-term symptomatic outcome was associated with baseline comorbidities. The 10-year survival rate was comparable to that in an age- and sex-matched background population, and age was the only predictor of survival.
In this study we evaluated two families with Becker muscular dystrophy and although the patients were completely asymptomatic and with normal ECG and echocardiogram, their left ventricular function was abnormal and the presence of subepicardial scar tissue was identified in the majority of them. The latter was also documented in one of the mothers, who had normal systolic function and was free of symptoms. Cardiac evaluation with cardiovascular magnetic resonance is sensitive enough to detect abnormal findings in BMD patients, missed by conventional echocardiography. Due to its ability to perform tissue characterization non-invasively, cardiovascular magnetic resonance can detect silent myocardial lesions in patients with Becker muscular dystrophy.
Cardiac disease is a common clinical manifestation of neuromuscular disorders, particularly of muscular dystrophies. Heart muscle cells as well as specialized conducting myocardial fibres may be affected by the dystrophic process. The incidence and nature of cardiac involvement vary with different types of muscular dystrophies. Some mainly lead to myocardial disease, resulting in cardiomyopathy and heart failure, while others particularly affect the conduction system, leading to arrhythmias and sudden death. As prognosis of muscular dystrophy patients may be directly related to cardiac status, surveillance and timely management of cardiac complications are important. However, recognition of cardiac involvement requires active investigation and remains challenging since typical signs and symptoms of cardiac dysfunction may not be present and progression is unpredictable. In this review, we present a comprehensive overview of hereditary muscular dystrophies associated with cardiac disease to provide an efficient strategy for the expertise and management of these diseases.
Limb-girdle muscular dystrophy type 2I (LGMD-2I) is caused by mutations in the fukutin-related protein gene (FKRP) that lead to abnormal glycosylation of alpha-dystroglycan in skeletal muscle. Heart involvement in LGMD-2I is common, but little is known about a underlying cardiac pathology. Herein we describe two patients with LGMD-2I (homozygous FKRP mutation c.826C>A, p.Leu276Ile) who developed severe congestive heart failure that required cardiac transplantation. The dystrophic pathology and impairment of alpha-dystroglycan glycosylation were severe in the heart but mild in skeletal muscle, underscoring the lack of correlation between cardiac and skeletal muscle involvement in some LGMD-2I patients.
Patients with Duchenne muscular dystrophy (DMD) often have severe heart failure with a high mortality rate. Most DMD patients with cardiomyopathy became symptomatic in their early to middle teens and usually die of congestive heart failure within 2-3 years from the onset of symptoms. It has been reported that the combination of an angiotensin-converting enzyme (ACE) inhibitor and a beta-blocker has additive benefits in patients with heart failure. The aim of this study was to assess whether the combination of an ACE inhibitor and a beta-blocker is associated with long-term survival of DMD patients with left ventricular (LV) dysfunction.
We retrospectively analyzed the outcomes of 52 DMD patients who had begun treatment for heart failure with an ACE inhibitor and a beta-blocker at National Yakumo Hospital during the period from 1992 to 2005. All patients used wheelchairs in their daily lives. Patients were classified as symptomatic or asymptomatic at the initiation of treatment with these two drugs. Twelve patients who had already had apparent symptoms due to heart failure were enrolled in a treatment group. Forty patients who had no symptoms with reduced LV ejection fraction (≤ 45% in echocardiography) were enrolled in a prevention group.
Five-year and 7-year survival rates of all patients were 93 and 84%, respectively. In the treatment group, 5-year and 7-year survival rate were 81 and 71%, respectively. Survival rate became zero at 10.9 years. In the prevention group, 5-year and 7-year survival rates were 97 and 84%, respectively, and 10-year survival rate was 72%. Nine patients in the prevention group remained event-free over 10 years.
In this study, the combination of an ACE inhibitor and a beta-blocker had a beneficial effect on long-term survival of DMD patients with heart failure. The treatment was particularly effective for asymptomatic patients with LV dysfunction.
Sarcoglycanopathies (SGs) are autosomal recessive limb-girdle muscular dystrophies (LGMD). These dystrophies are caused by mutations in any of the four sarcoglycan genes: alpha (LGMD 2D), beta (LGMD 2E), gamma (LGMD 2C) and delta (LGMD 2F). We discuss heart involvement in these diseases.
To investigate the extent of cardiac involvement in patients with 1 of the 12 groups of recessively inherited limb-girdle muscular dystrophy type 2 (LGMD2A-L) and Becker muscular dystrophy (BMD).
Prospective screening.
Neuromuscular Clinic and Department of Cardiology at Rigshospitalet. Patients One hundred one patients with LGMD2A-I and BMD and 29 patients with LGMD2 and no molecular diagnosis.
Clinical investigation, echocardiography, and electrocardiographic findings.
Cardiac involvement was present in 24 of 100 patients (24%) with LGMD2A-I and in 14 of 30 patients (47%) with BMD. Only a few patients with LGMD2A and unclassified LGMD2 had mild cardiac involvement, whereas 29% and 67% of patients with LGMD2I and LGMD2E, respectively, had cardiac involvement. Cardiac involvement was not correlated with age, muscle strength, or the level of dystrophic changes on muscle biopsy.
This study demonstrates a high prevalence of cardiac involvement in patients with LGMD2I, LGMD2E, and BMD. Patients with LGMD2A, LGMD2D, and unclassified LGMD2 have a much lower and milder prevalence of cardiac involvement.
To evaluate the features and the course of cardiomyopathy in Becker muscular dystrophy, 68 patients--identified by clinical assessment and by reduced dystrophin labeling and/or DNA analysis--were followed in the years 1976-1993, for periods ranging from 3 to 18 years (mean 8). Patients periodically underwent clinical, electrocardiographic, echocardiographic, nuclear, and radiological assessments. Preclinical cardiac involvement was found in 67.4% of patients under 16 years of age, decreasing to 30% in patients older than 40. Clinically evident cardiomyopathy was found in 15% of patients under 16 years of age, increasing to 73% in patients older than 40. A real, dilated cardiomyopathy is the most frequent type of myocardial involvement after the age of 20. Results show that the severity of cardiac involvement can be unrelated to the severity of skeletal muscle damage and confirm that cardiac dysfunction is a primary feature of Becker muscular dystrophy.
We have investigated 67 patients with proven Becker muscular dystrophy (BMD) using a standard protocol including a detailed history and a functional and clinical examination. Our aim was to define the natural history of the disease in a large cohort of patients in the light of the diagnostic methods now available. In all patients with or without an X-linked family history, the diagnosis was confirmed by the identification of a deletion or other abnormality in the dystrophin gene, and abnormal dystrophin on immunoblotting and immunocytochemistry of muscle biopsy samples. In graphs of functional and muscle score against age, two groups of patients emerged. In the larger group the disease was milder and patients remained ambulant into their forties or beyond. A smaller group had more severe disease with a slightly earlier onset, much earlier loss of ambulation, more frequent abnormal electrocardiographic findings and much lower reproductive fitness. The relationship of these clinical findings to the genetic and protein abnormalities found in the patients is explored in the accompanying paper.
A cross-sectional study in a cohort of DNA proven carriers of Duchenne (DMD) and Becker (BMD) muscular dystrophy was undertaken with the following objectives: (1) to estimate the frequency of electrocardiographic (ECG) and echocardiographic abnormalities; (2) to establish the proportion of carriers with dilated cardiomyopathy and (3) to assess possible associations between dilated cardiomyopathy and genotype. One hundred and twenty nine DMD and BMD carriers, aged 18-60 years, were traced through the files of the central register kept at the department of Human Genetics in Leiden. Investigations included full medical history, physical examination, ECG and two-dimensional and M-mode echocardiographic examination. Forty-seven percent had ECG changes. Thirty-six percent (DMD 41%, BMD 27%) had at least one abnormality as is usually found in the male patients. Echocardiographic examination was abnormal in 36% (DMD 38%, BMD 34%). Dilated cardiomyopathy was found in seven DMD carriers (8%), and in none of BMD carriers. In addition, 18% had left ventricle dilatation (DMD 19%, BMD 16%). Only 38% had a completely normal investigation of the heart. We found no association between genotype and cardiac manifestations. Our study underlines that cardiac involvement is part of the dystrophinopathies. Carriers should be told about the increased risk of this complication when asking genetic advice. It also implicates that a complete cardiological evaluation should be performed at least once in all carriers. If left ventricle dilatation or dilated cardiomyopathy is present a yearly follow up is needed, in order to start timely therapy.
Transcripts of calpain3, the gene involved in limb girdle muscular dystrophy type 2A, appear in organs other than the skeletal muscle during human development, the first of which being the early embryonic heart. We examined more precisely the spatio-temporal transcription pattern of calpain3 during human cardiogenesis and the appearance of its protein in fetal tissues, and correlated it to titin expression. Different events of the heart's maturation can be recognized: (i) the presence of titin RNA or protein constitute very precocious developmental cardiac markers appearing before the fusion of the two lateral endocardial tubes; (ii) the disappearance of calpain3 RNA from the ventricular compartment later in the embryonic heart. Finally, although calpain3 transcripts are present in the heart, the corresponding protein is not detected elsewhere than in skeletal muscle.
The limb-girdle muscular dystrophies are a group of inherited neuromuscular disorders which are clinically and genetically heterogeneous. We have been able to carry out a follow-up study on 10 patients from a large Palestinian family with a confirmed mutation in the dysferlin gene. These patients have been followed for more than 23 years since the onset of the disease. They all had normal developmental milestones. The onset of the disease was usually in the second decade, more rarely in the third and fourth decades. The first symptoms were difficulty with running and climbing stairs. Patients showed a distinct type of gait due to the unique pattern of muscle involvement which was characterised by early involvement of the posterior muscle compartment of the thighs and legs (hamstrings, adductors, gastrocnemius and soleus). The shoulder and upper limb musculature became involved later, especially supra and infraspinatus and biceps. In the early stages of disease these patients may clinically show only proximal lower limb-girdle muscle weakness; however, the use of muscle imaging techniques were very important, always detecting in these patients also distal lower limb muscle involvement, so that the pattern of muscle involvement found in dysferlin deficiency may not strictly conform to the definition of limb-girdle muscular dystrophy. The pattern of muscular dystrophy is essentially uniform and has clearly distinct features (involving mainly the initial pattern of muscle involvement and the mode of gait) which differ significantly from the well reported clinical features associated with sarcoglycanopathy, calpainopathy and Miyoshi myopathy.
Cardiac abnormalities, cardiomyopathy and skeletal muscle weakness have been described in female carriers of the Xp21 (Duchenne and Becker) muscular dystrophies (J Neurol 1975;209(4):279-285; Br Med J 1969;2:418-420; J AmMed Assoc 1996;275(17):1335-1338; Neurology 1980;30(5):497-501; Neuromusc Disord 1999;9:347-351; Arch Neurol 1989;46:673-675). We have screened volunteers from our Xp21 genetics register and found the prevalence of previously unrecognized, clinically relevant, abnormalities in this group to be less than previously reported. We studied 91 women (56 carriers and 35 controls), aged between 18 and 69 years, from our local population known to the Oxford Regional Genetics Register. Our study included controls, with the investigators being blind to the subject's genetic status. The prevalence of previously unrecognised cardiac abnormalities on echocardiogram and ECG was 18% (10/56). Seven percent (4/56) of carriers had cardiomyopathy, defined by significant LV dilatation and decreased shortening fraction. In most cases, subjects with abnormal cardiac findings were asymptomatic. Echocardiography was more frequently abnormal than electrocardiography, but in many subjects the measurements of left ventricular dimensions were only just outside the normal ranges. The prevalence of skeletal muscle weakness was 12% (7/56). It was usually recognized by the individual, although not previously volunteered, but was mild and did not substantially affect activities of daily living.
Sarcoglycanopathies constitute a subgroup of limb-girdle recessive muscular dystrophies due to defects in sarcoglycan complex that comprises five distinct transmembrane proteins called alpha-, beta-, gamma-, delta-and epsilon-sarcoglycans. As it is well known that sarcoglycans are expressed both in heart and in skeletal muscles and a complete deficiency in delta-sarcoglycan is the cause of the Syrian hamster BIO.14 cardiomyopathy, we studied cardiac and respiratory involvement in 20 patients with sarcoglycanopathies by clinical, electrocardiographic, echocardiographic, scintigraphic and spirometric assessments. A normal heart function was found in 31.3% of all patients; a preclinical cardiomyopathy in 43.7%; an arrhythmogenic cardiomyopathy in 6.3% and initial signs of dilated cardiomyopathy in 18.7%. In one patient the data were examined retrospectively. No correlation was found between cardiac and skeletal muscle involvement. With reference to the type of sarcoglycanopathy, signs of hypoxic myocardial damage occurred in beta-, gamma- and delta-sarcoglycanopathies, while initial signs of a dilated cardiomyopathy in gamma- and delta-sarcoglycanopathies were found. A normal respiratory function was observed in 23.5% of all patients, a mild impairment in 35.4%, a moderate impairment in 29.4%, and a severe impairment in 11.7%.
In this article, we review the molecular pathology of muscular dystrophies caused by defects of proteins located within or near cell membranes. These disorders include Bethlem myopathy, merosinopathy, dystrophinopathy, sarcoglycanopathies, integrinopathy, dysferlinopathy and caveolinopathy. We refer to these diseases collectively as sarcolemmopathy. Here, we describe the biological functions of these proteins in the context of muscular contractions and their roles in the infrastructure of muscle; defects of muscle infrastructures cause those diseases.
As an example, in dystrophinopathy, cell membranes have mechanical defects due to the absence of dystrophin. Cracks of the cell membrane induced by muscle contraction may allow the influx and efflux of substances that trigger muscle cell degeneration. However, such cracks may be resealed on relaxation. In addition, dystrophinopathy causes secondary defects of various dystrophin‐associated proteins suggesting that defects in cell signaling participate in the pathologic process. With regard to other sarcolemmopathies, we discuss pathological mechanisms based on available data.
Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin, a 427 kd protein normally found at the cytoplasmic face of the sarcolemma. In normal muscle, dystrophin is associated with a multimolecular glycoprotein complex. Primary mutations in the genes encoding members of this glycoprotein complex are also associated with muscular dystrophy. The dystrophin-glycoprotein complex provides a physical linkage between the internal cytoskeleton of myofibers and the extracellular matrix, but the precise functions of the dystrophin-glycoprotein complex remain uncertain. In this review, five potential pathogenetic mechanisms implicated in the initiation of myofiber injury in dystrophin-glycoprotein complex deficiencies are discussed: (1) mechanical weakening of the sarcolemma, (2) inappropriate calcium influx, (3) aberrant cell signaling, (4) increased oxidative stress, and (5) recurrent muscle ischemia. Particular emphasis is placed on the multifunctional nature of the dystrophin-glycoprotein complex and the fact that the above mechanisms are in no way mutually exclusive and may interact with one another to a significant degree.
Mutations in the fukutin-related protein gene FKRP cause limb-girdle muscular dystrophy (LGMD2I) as well as a form of congenital muscular dystrophy (MDC1C).
To define the phenotype in LGMD2I.
The authors assessed 16 patients from 14 families with FKRP gene mutations and LGMD and collected the results of mutation analysis, protein studies, and respiratory and cardiac investigations.
Thirteen patients, most with adult presentation, were homozygous for the common C826A mutation in FKRP. The three other cases were compound heterozygotes for C826A and two of them presented in childhood, with more progressive disease. The pattern of muscle involvement, frequently including calf hypertrophy, was similar to dystrophinopathy. Complications in patients with LGMD2I were common and sometimes out of proportion to the skeletal muscle involvement. Six patients had cardiac involvement, and 10 had respiratory impairment: five required nocturnal respiratory support. All patients had serum creatine kinase at least 5 to 70 times normal. The most consistent protein abnormality found on muscle biopsy was a reduction of laminin alpha2 immunolabeling, either on muscle sections or immunoblotting alone.
LGMD2I due to FKRP mutations appears to be a relatively common cause of LGMD, with respiratory and cardiac failure as prominent complications.
A large and complex gene on the X chromosome encodes dystrophin. Many mutations have been described in this gene, most of which affect the expression of the muscle isoform, the best-known protein product of this locus. These mutations result in the Duchenne and Becker muscular dystrophies (DMD and BMD). However, there are several other tissue specific isoforms of dystrophin, some exclusively or predominantly expressed in the brain or the retina. Mutations affecting the correct expression of these tissue-specific isoforms have been associated with the CNS involvement common in DMD. Rare mutations also account for the allelic disorder X-linked dilated cardiomyopathy, in which dystrophin expression or function is affected mostly or exclusively in the heart. Genotype definition of the dystrophin gene in patients with dystrophinopathies has taught us much about functionally important domains of the protein itself and has provided insights into several regulatory mechanisms governing the gene expression profile. Here, we focus on current understanding of the genotype-phenotype relation for mutations in the dystrophin gene and their implications for gene functions.
The dystrophin glycoprotein complex (DGC) is a specialization of cardiac and skeletal muscle membrane. This large multicomponent complex has both mechanical stabilizing and signaling roles in mediating interactions between the cytoskeleton, membrane, and extracellular matrix. Dystrophin, the protein product of the Duchenne and X-linked dilated cardiomyopathy locus, links cytoskeletal and membrane elements. Mutations in additional DGC genes, the sarcoglycans, also lead to cardiomyopathy and muscular dystrophy. Animal models of DGC mutants have shown that destabilization of the DGC leads to membrane fragility and loss of membrane integrity, resulting in degeneration of skeletal muscle and cardiomyocytes. Vascular reactivity is altered in response to primary degeneration in striated myocytes and arises from a vascular smooth muscle cell-extrinsic mechanism.
In this review, we draw attention to the multiple mechanisms responsible for the pathogenesis of cardiomyopathies in patients with muscular dystrophies. More than one single mechanism is likely to be involved in the development of skeletal and cardiac muscle pathology even when there is a single protein defect. The best example is dystrophin deficiency, in which increased sarcolemmal permeability following eccentric exercise, reduced force generation, and abnormal signaling are all likely to contribute to the progressive muscle damage observed. In other conditions, such as the sarcoglycanopathies, a protein deficiency both in the striated cardiomyocte and the vascular smooth muscle appears to play a significant role. An entirely different mechanism of disease is likely in defects of nuclear envelope proteins, although the precise pathogenesis of this group of conditions is still not clear. Differences between the organization of skeletal and cardiac muscle protein complex are also only starting to emerge and will very likely be the focus of future research.
Dystrophin gene mutations cause 2 common muscular dystrophies, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Both are frequently associated with dilated cardiomyopathy (DCM) and premature death. We hypothesized that early diagnosis and treatment of DCM in DMD/BMD patients would lead to ventricular remodeling and that specific dystrophin gene mutations would predict cardiac involvement.
Sixty-nine boys with DMD (n=62) and BMD (n=7) (mean age, 12.9 and 13.7 years, respectively) were referred to our Cardiovascular Genetics Clinic for evaluation, including echocardiography and DNA analysis. Follow-up evaluations were scheduled yearly until the first abnormal echocardiogram indicative of DCM and quarterly thereafter. After the first abnormal echocardiogram, angiotensin-converting enzyme inhibitor or beta-blocker therapy was started. beta-Blockers were added if echocardiography showed no ventricular remodeling in angiotensin-converting enzyme inhibitor-treated patients after 3 months. DCM was diagnosed in 31 subjects (DMD, 27/62, 44%; BMD, 4/7, 57%) (mean age at onset, 15.4+/-2.8 years; range, 10.4 to 21.2 years). All 31 subjects were begun on pharmacological therapy after diagnosis. On follow-up (n=29), 2 subjects (both DMD) showed stable DCM, 8 subjects (all DMD) showed improvement, and 19 subjects (16 DMD; 3 BMD) showed normalization of left ventricular size and function (total improvement, 27/29 [93%]). DNA analysis in 47 cases (68%) revealed a significant association between DCM and exon 12 and 14 to 17 mutations, possible protection against DCM by exon 51 to 52 mutations, and a trend toward significant association between onset of DCM and exon 31 to 42 mutations. Statistical significance was based on nominal probability values.
Early diagnosis and treatment of DCM may lead to ventricular remodeling in DMD/BMD patients. Specific dystrophin gene mutations appear to be predictive of cardiac involvement, while other mutations may protect against or inhibit development of DCM. Further studies evaluating the impact of early intervention strategies on left ventricular geometry and function in muscular dystrophy patients seem warranted.
Duchenne’s muscular dystrophy (DMD) is one of the most common neuromuscular disorders. Boys with DMD lose independent ambulation by the age of 12 and die of respiratory failure or cardiomyopathy in their late teens or early 20s.1
Histological changes in the heart include fibrosis, degeneration and fatty infiltration starting from the left ventricular posterior wall, which is a specific finding for DMD.2 The posterior wall can be more sensitive in identifying impaired myocardial function.
Recent consensus guidelines on the early cardiac follow up and for the treatment of asymptomatic dysfunction have been proposed.3 An unresolved issue is, however, the timing of introducing treatment. Some authors have proposed that, in view of the almost invariable development of dilated cardiomyopathy (DCM), treatment should be started even in the absence of echocardiographic signs of dysfunction. It is therefore important to be able to identify early changes that precede DCM.3
We hypothesised that strain rate (SR) can identify early myocardial dysfunction in young asymptomatic boys with DMD without conventional echocardiographic signs of DCM. We related SR to the development of cardiomyopathy over a three-year follow up.
Fifty six consecutive asymptomatic boys with DMD (mean age 8.8 (2.85) years) were enrolled. Diagnosis was confirmed by DNA analysis, unequivocal findings in muscle biopsy, or positive family history. The patients were not taking any cardiac drugs and had normal ECGs and routine echocardiograms (fractional shortening > 29%). Twenty two healthy volunteers (mean age 9 (SD 2.96) years) were recruited from the children’s outpatient department.
We used the HDI 5000 (Phillips Medical Systems) machine equipped with a P4-2 transducer for conventional and tissue Doppler imaging echocardiographic studies. The conventional study included two dimensional and Doppler blood flow velocity measurements …
Quantification of cardiac chamber size, ventricular mass and function ranks among the most clinically important and most frequently requested tasks of echocardiography. Over the last decades, echocardiographic methods and techniques have improved and expanded dramatically, due to the introduction of higher frequency transducers, harmonic imaging, fully digital machines, left-sided contrast agents, and other technological advancements. Furthermore, echocardiography due to its portability and versatility is now used in emergency rooms, operating rooms, and intensive care units. Standardization of measurements in echocardiography has been inconsistent and less successful, compared to other imaging techniques and consequently, echocardiographic measurements are sometimes perceived as less reliable. Therefore, the American Society of Echocardiography, working together with the European Association of Echocardiography, a branch of the European Society of Cardiology, has critically reviewed the literature and updated the recommendations for quantifying cardiac chambers using echocardiography. This document reviews the technical aspects on how to perform quantitative chamber measurements of morphology and function, which is a component of every complete echocardiographic examination.
The C826A mutation in the fukutin-related protein (FKRP) gene is typically associated with autosomal recessive limb-girdle muscular dystrophy 2I (LGMD2I) but oligosymptomatic phenotypes and patients with predominant cardiac involvement are also described.
To assess cardiac involvement in patients with LGMD2I.
Nine patients from 5 families (2 female, 7 male) homozygous for the 826C > A FKRP mutation were included.
Additional to conventional cardiac investigations (electrocardiography and echocardiography) the patients underwent cardiovascular magnetic resonance imaging (CMR).
Cardiac involvement was detected by CMR in eight of nine patients (reduced left ventricular ejection fraction in 6, enlargement of left ventricular end-diastolic volume in 2 and left ventricular mass in 2) and in four patients by conventional cardiac diagnostic investigations. Two of the nine patients showed no muscle weakness or atrophy but suffered myalgias; both had cardiac manifestation of the disease. CMR is a sensitive method for detecting cardiac abnormalities in patients with LGMD2I and can be used for early detection of mild or subclinical cardiac involvement.
The role of angiotensin-converting enzyme inhibitors in the management of cardiomyopathy related to Duchenne muscular dystrophy has not been completely defined. The purposes of this study were to describe the response to enalapril and its relation to dystrophin mutation type, ventricular size, or age at the onset of left ventricular (LV) systolic dysfunction. Serial clinical and echocardiographic data from 50 patients with Duchenne muscular dystrophy (aged 10 to 20 years) were retrospectively reviewed. Twenty-seven patients (46%) developed LV systolic dysfunction (mean age 13.2 +/- 2.4 years). Ten (43%) responded to enalapril with the normalization of function. Responders and nonresponders developed LV systolic dysfunction at similar ages (p = 0.91). At the onset of LV systolic dysfunction, only 2 patients (1 responder, 1 nonresponder) had dilated left ventricles. The positive response to enalapril was sustained in 7 patients (median follow-up 23 months, range 5 to 58). No specific mutation was associated with the response to enalapril (p = 0.66) or predictive of the development of LV systolic dysfunction (p = 0.8). In conclusion, 10 of 26 patients (43%) with Duchenne muscular dystrophy responded to the use of enalapril with normalization of the shortening fraction. Age at the onset of LV systolic dysfunction and the type of mutation were not predictors of response to enalapril.