Search

Background: Limb girdle muscular dystrophy type R1/2A (LGMDR1/LGMD2A) is a progressive myopathy caused by deficiency of calpain 3, a calcium-dependent cysteine protease of skeletal muscle, and it represents the most frequent type of LGMD worldwide. In the last few years, muscle magnetic resonance imaging (MRI) has been proposed as a tool for identifying patterns of muscular involvement in genetic disorders and as a biomarker of disease progression in muscle diseases. In this study, 57 molecularly confirmed LGMDR1 patients from a European cohort (age range 7–78 years) underwent muscle MRI and a global evaluation of functional status (Gardner-Medwin and Walton score and ability to raise the arms). Results: We confirmed a specific pattern of fatty substitution involving predominantly the hip adductors and hamstrings in lower limbs. Spine extensors were more severely affected than spine rotators, in agreement with higher incidence of lordosis than scoliosis in LGMDR1. Hierarchical clustering of lower limb MRI scores showed that involvement of anterior thigh muscles discriminates between classes of disease progression. Severity of muscle fatty substitution was significantly correlated with CAPN3 mutations: in particular, patients with no or one "null" alleles showed a milder involvement, compared to patients with two null alleles (i.e., predicting absence of calpain-3 protein). Expectedly, fat infiltration scores strongly correlated with functional measures. The "pseudocollagen" sign (central areas of sparing in some muscle) was associated with longer and more severe disease course. Conclusions: We conclude that skeletal muscle MRI represents a useful tool in the diagnostic workup and clinical management of LGMDR1. [ABSTRACT FROM AUTHOR]

Background: To evaluate the prevalence of cardiac involvement in patients with congenital myopathies and the association to specific genotypes. Methods: We evaluated patients with physical examination, electrocardiogram, echocardiography, and 48-h Holter monitoring. Follow-up was performed for major events. Results: We included 130 patients, 55 men (42%), with a mean age of 34 ± 17 years. A genetic diagnosis was established in 97 patients (75%). Right bundle branch block was observed in three patients: 2/34 patients with a ryanodine receptor 1 (RYR1) and 1/6 with a tropomyosin two gene (TPM2) gene mutation. Echocardiography showed left-ventricular hypertrophy in five patients: 2/17 and 3/34 patients with a Dynamin 2 (DNM2) and a RYR1 mutation, respectively. One patient with a myosin heavy-chain (MYH7) mutation had dilated cardiomyopathy and heart failure. On Holter monitoring, frequent ventricular premature contractions were observed in one patient with a DNM2 mutation. Two patients with a TPM2 and a RYR1 mutation, respectively, had a single short run of non-sustained ventricular tachycardia. Atrioventricular nodal re-entry tachycardia was observed in a 20-year-old man with an actin 1 gene mutation. During follow-up (median 8.4 years), four patients died, all of non-cardiac causes. Conclusion: Congenital myopathies are generally associated with a mild cardiac phenotype. Our findings substantiate the literature and indicate that, except for patients with specific genotypes, such as MYH7 and TTN mutations, repeated cardiac assessments can be minimized, given a normal initial cardiac screening at time of diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: Inherited myopathies are major causes of muscle atrophy and are often characterized by rigid spine syndrome, a clinical feature designating patients with early spinal contractures. We aim to present a decision algorithm based on muscular whole body magnetic resonance imaging (mWB-MRI) as a unique tool to orientate the diagnosis of each inherited myopathy long before the genetically confirmed diagnosis.Methods: This multicentre retrospective study enrolled 79 patients from referral centres in France, Brazil and Chile. The patients underwent 1.5-T or 3-T mWB-MRI. The protocol comprised STIR and T1 sequences in axial and coronal planes, from head to toe. All images were analyzed manually by multiple raters. Fatty muscle replacement was evaluated on mWB-MRI using both the Mercuri scale and statistical comparison based on the percentage of affected muscle.Results: Between February 2005 and December 2015, 76 patients with genetically confirmed inherited myopathy were included. They were affected by Pompe disease or harbored mutations in RYR1, Collagen VI, LMNA, SEPN1, LAMA2 and MYH7 genes. Each myopathy had a specific pattern of affected muscles recognizable on mWB-MRI. This allowed us to create a novel decision algorithm for patients with rigid spine syndrome by segregating these signs. This algorithm was validated by five external evaluators on a cohort of seven patients with a diagnostic accuracy of 94.3% compared with the genetic diagnosis.Conclusion: We provide a novel decision algorithm based on muscle fat replacement graded on mWB-MRI that allows diagnosis and differentiation of inherited myopathies presenting with spinal rigidity.Key Points: • Inherited myopathies are rare, diagnosis is challenging and genetic tests require specialized centres and often take years. • Inherited myopathies are often characterized by spinal rigidity. • Whole body magnetic resonance imaging is a unique tool to orientate the diagnosis of each inherited myopathy presenting with spinal rigidity. • Each inherited myopathy in this study has a specific pattern of affected muscles that orientate diagnosis. • A novel MRI-based algorithm, usable by every radiologist, can help the early diagnosis of these myopathies. [ABSTRACT FROM AUTHOR]

X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term. [ABSTRACT FROM AUTHOR]

Abstract: To describe muscle involvement on whole-body MRI scans in adult patients at different stages of late-onset Pompe disease. Twenty patients aged 37 to 75 were examined. Five were bedridden and required ventilatory support. Axial and coronal T1 turbo-spin-echo sequences were performed on 1.5T or 3T systems. MRI was scored for 47 muscles using Mercuri’s classification. Whole-body scans were obtained with a mean in-room time of 29min. Muscle changes consisted of internal bright signals of fatty replacement without severe retraction of the muscles’ corpus. Findings were consistent with previous descriptions of spine extensors and pelvic girdle, but also provided new information on recurrent muscle changes particularly in the tongue and subscapularis muscle. Moreover thigh involvement was more heterogeneous than previously described, in terms of distribution across muscles as well as with respect to the overall clinical presentation. Whole-body MRI provides a very evocative description of muscle involvement in Pompe disease in adults. [Copyright &y& Elsevier]

Abstract: McArdle’s disease is the most common muscle glycogenosis. It is caused by the deficiency of myophosphorylase, encoded by the PYGM gene. We studied 123 patients previously diagnosed with McArdle’s disease and we identified 20 novel mutations (10 missense and 3 nonsense mutations, 3 small deletions, 2 gross deletions and 2 small insertions). Most patients of this cohort belong to Spanish and French populations. This allowed us to determine the differences between the allelic frequencies of the common mutations R50X and G205S of these populations. The R50X has an allelic frequency in this cohort of about 61.7%, being 68.5% in French and 53.7% in Spanish patients. The G205S had a higher allelic frequency in the Spanish (10.2%) than in the French population (3.2%). Moreover, a clinical study of 91 patients was performed to establish both genotype–phenotype correlation and gender influence in the severity of the disease. We conclude that no genotype–phenotype correlation is evident and that no gender effect is related to the phenotype. [Copyright &y& Elsevier]

Abstract: Limb girdle muscular dystrophy type 2L (LGMD2L) is an adult-onset slowly progressive muscular dystrophy associated with recessive mutations in the ANO5 gene. We analysed the muscle MRI pattern in a cohort of 25 LGMD2L patients in order to understand the extent and progression of muscle pathology in LGM2L and assess if muscle MRI might help in the diagnostic work-up of these patients. Our results showed a homogeneous pattern of muscle pathology on muscle MRI, with a predominant involvement of the posterior compartment muscles in both the thighs and calves. The muscles of the anterior compartments in the leg together with the sartorius and gracilis muscles were best preserved, which partially overlaps with patterns observed for other recessive LGMDs. Muscle MRI therefore does not appear to be as useful in the diagnostic work up of LGMD2L as for other neuromuscular diseases, such as Bethlem myopathy or myofibrillar myopathy. [Copyright &y& Elsevier]