LAMA2-Related Muscular Dystrophy: The Importance of Accurate Phenotyping and Brain Imaging in the Diagnosis of LGMD.

We report three siblings from a non-consanguineous family presenting with contractural limb-girdle phenotype with intrafamilial variability. Muscle MRI showed posterior thigh and quadriceps involvement with a sandwich-like sign. Whole-exome sequencing identified two compound heterozygous missense TTN variants and one heterozygous LAMA2 variant. Brain MRI performed because of concentration difficulties in one of the siblings evidenced white-matter abnormalities, subsequently found in the others. The genetic analysis was re-oriented, revealing a novel pathogenic intronic LAMA2 variant which confirmed the LAMA2-RD diagnosis. This work highlights the importance of a thorough clinical phenotyping and the importance of brain imaging, in order to orientate and interpret the genetic analysis.

Effect of beam attenuation on muscle ultrasound echogenicity measurement in muscular dystrophies.

PURPOSE: In advanced muscular dystrophies (AMD), quantification of muscle echo-intensity (EI) may be influenced by ultrasound beam attenuation, due to fibrosis and fatty infiltration of muscle tissue. Objective of the study was to compare EI measurements using grayscale analysis between a superficial and whole-muscle region of interest (ROI) in subjects with advanced and mild-to-moderate muscular dystrophy (MMD). METHODS: Thirty-two adult subjects diagnosed with a muscular dystrophy and twenty-five matched healthy controls underwent ultrasound assessment of the biceps brachii (BB), rectus femoris (RF) and tibialis anterior (TA) muscles. Based on Heckmatt grading scale of muscles, two disease groups, an AMD (Heckmatt grades 3 or 4) and a MMD (Heckmatt grade 2), were analyzed. Superficial ROI was set as one-fourth of the whole-muscle area, located immediately below the superficial fascia and always inside muscle boundaries. RESULTS: Muscle EI was significantly higher in the superficial compared to whole-muscle ROI, in all evaluated muscle groups of AMD subjects (BB, p = 0.004/RF, p = 0.027/TA, p = 0.002). EI values in superficial ROIs, for individual muscle analysis using z-scores, were more representative in assessments of muscle abnormality in advanced stages of the disease course (Heckmatt grades 3 and 4). In MMD and healthy muscles, no statistical difference was found in EI measurements between the two ROI types. CONCLUSIONS: In AMD, selection of superficial ROI is better representative of changes in muscle texture, although caution should be exercised when comparing ROIs of different sizes.

The diagnostic value of T2 map, diffusion tensor imaging, and diffusion kurtosis imaging in differentiating dermatomyositis from muscular dystrophy.

BACKGROUND: Dermatomyositis (DM) and muscular dystrophy are clinically difficult to differentiate. PURPOSE: To confirm the feasibility and assess the accuracy of conventional magnetic resonance imaging (MRI), T2 map, diffusion tensor imaging (DTI), and diffusion kurtosis imaging (DKI) in the differentiation of DM from muscular dystrophy. MATERIAL AND METHODS: Forty-two patients with DM proven by diagnostic criteria were enrolled in the study along with 23 patients with muscular dystrophy. Conventional MR, T2 map, DTI, and DKI images were obtained in the thigh musculature for all patients. Intramuscular T2 value, apparent diffusion coefficient (ADC), fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK) values were compared between the patients with DM and muscular dystrophy. Student's t-tests and receiver operating characteristic (ROC) curve analyses were performed for all parameters. P values < 0.05 were considered statistically significant. RESULTS: The intramuscular T2, ADC, FA, MD, and MK values within muscles were statistically significantly different between the DM and muscular dystrophy groups (P<0.01). The MK value was statistically significantly different between the groups in comparison with T2 and FA value. As a supplement to conventional MRI, the parameters of MD and MK differentiated DM and muscular dystrophy may be valuable. The optimal cut-off value of ADC and MD values (with respective AUC, sensitivity, and specificity) between DM and muscular dystrophy were 1.698 ×10-3mm2/s (0.723, 54.1%, and 78.1%) and 1.80 ×10-3mm2/s (61.9% and 70.2%), respectively. CONCLUSION: Thigh muscle ADC and MD parameters may be useful in differentiating patients with DM from those with muscular dystrophy.

Diagnostic interest of whole-body MRI in early- and late-onset LAMA2 muscular dystrophies: a large international cohort.

BACKGROUND: LAMA2-related muscular dystrophy (LAMA2-RD) encompasses a group of recessive muscular dystrophies caused by mutations in the LAMA2 gene, which codes for the alpha-2 chain of laminin-211 (merosin). Diagnosis is straightforward in the classic congenital presentation with no ambulation and complete merosin deficiency in muscle biopsy, but is far more difficult in milder ambulant individuals with partial merosin deficiency. OBJECTIVE: To investigate the diagnostic utility of muscle imaging in LAMA2-RD using whole-body magnetic resonance imaging (WBMRI). RESULTS: 27 patients (2-62 years, 21-80% with acquisition of walking ability and 6 never ambulant) were included in an international collaborative study. All carried two pathogenic mutations, mostly private missense changes. An intronic variant (c.909 + 7A > G) was identified in all the Chilean cases. Three patients (two ambulant) showed intellectual disability, epilepsy, and brain structural abnormalities. WBMRI T1w sequences or T2 fat-saturated images (Dixon) revealed abnormal muscle fat replacement predominantly in subscapularis, lumbar paraspinals, gluteus minimus and medius, posterior thigh (adductor magnus, biceps femoris, hamstrings) and soleus. This involvement pattern was consistent for both ambulant and non-ambulant patients. The degree of replacement was predominantly correlated to the disease duration, rather than to the onset or the clinical severity. A "COL6-like sandwich sign" was observed in several muscles in ambulant adults, but different involvement of subscapularis, gluteus minimus, and medius changes allowed distinguishing LAMA2-RD from collagenopathies. The thigh muscles seem to be the best ones to assess disease progression. CONCLUSION: WBMRI in LAMA2-RD shows a homogeneous pattern of brain and muscle imaging, representing a supportive diagnostic tool.

Whole-body muscle MRI characteristics of LAMA2-related congenital muscular dystrophy children: An emerging pattern.

Merosin-deficient or LAMA2-related congenital muscular dystrophy (CMD) belongs to a group of muscle diseases with an overlapping diagnostic spectrum. MRI plays an important role in the diagnosis and disease-tracking of muscle diseases. Whole-body MRI is ideal for describing patterns of muscle involvement. We intended to analyze the pattern of muscle involvement in merosin-deficient CMD children employing whole-body muscle MRI. Ten children with merosin-deficient CMD underwent whole-body muscle MRI. Eight of which were genetically-confirmed. We used a control group of other hereditary muscle diseases, which included 13 children (mean age was 13 SD +/- 5.5 years), (8 boys and 5 girls) for comparative analysis. Overall, 37 muscles were graded for fatty infiltration using Mercuri scale modified by Fischer et al. The results showed a fairly consistent pattern of muscle fatty infiltration in index group, which differs from that in control group. There was a statistically significant difference between the two groups in regard to the fatty infiltration of the neck, serratus anterior, intercostal, rotator cuff, deltoid, triceps, forearm, gluteus maximus, gluteus medius, gastrocnemius and soleus muscles. Additionally, the results showed relative sparing of the brachialis, biceps brachii, gracilis, sartorius, semitendinosus and extensor muscles of the ankle in index group, and specific texture abnormalities in other muscles. There is evidence to suggest that whole-body muscle MRI can become a useful contributor to the differential diagnosis of children with merosin deficient CMD. The presence of a fairly characteristic pattern of involvement was demonstrated. MRI findings should be interpreted in view of the clinical and molecular context to improve diagnostic accuracy.

Role of CMR Imaging in Diagnostics and Evaluation of Cardiac Involvement in Muscle Dystrophies.

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. 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.

Desminopathy presenting as late onset bilateral facial weakness, with diagnosis supported by lower limb MRI.

A 63 year old male presented with a 20 year history of facial weakness and several years of nasal regurgitation and dysphonia. Examination revealed bilateral facial weakness with nasal speech. Serum creatine kinase was 918 U/L. Neurophysiological studies suggested a myopathy and biopsy of the left vastus lateralis showed serpentine basophilic inclusions in the sarcoplasm and strong oxidative enzyme activity suggesting mitochondria accumulation. The muscle MRI showed selective fatty replacement within semitendinosus, gastrocnemius and soleus indicative of a desminopathy. A heterozygous missense variant c.17C>G (p.Ser6Trp) was identified within DES, predicted to be pathogenic in silico and previously described in a family with distal limb weakness. There are no previous case reports of desminopathy presenting with facial weakness, to our knowledge. Diagnosis was suggested following myoimaging of clinically unaffected muscles. Our study highlights the importance of muscle MRI in the diagnostic evaluation of muscle disease and further expands the known phenotypic heterogeneity of desminopathies.

A deep learning model for diagnosing dystrophinopathies on thigh muscle MRI images.

BACKGROUND: Dystrophinopathies are the most common type of inherited muscular diseases. Muscle biopsy and genetic tests are effective to diagnose the disease but cost much more than primary hospitals can reach. The more available muscle MRI is promising but its diagnostic results highly depends on doctors' experiences. This study intends to explore a way of deploying a deep learning model for muscle MRI images to diagnose dystrophinopathies. METHODS: This study collected 2536 T1WI images from 432 cases who had been diagnosed by genetic analysis and/or muscle biopsy, including 148 cases with dystrophinopathies and 284 cases with other diseases. The data was randomly divided into three sets: the data from 233 cases were used to train the CNN model, the data from 97 cases for the validation experiments, and the data from 102 cases for the test experiments. We also validated our models expertise at diagnosing by comparing the model's results on the 102 cases with those of three skilled radiologists. RESULTS: The proposed model achieved 91% (95% CI: 0.88, 0.93) accuracy on the test set, higher than the best accuracy of 84% in radiologists. It also performed better than the skilled radiologists in sensitivity : sensitivities of the models and the doctors were 0.89 (95% CI: 0.85 0.93) versus 0.79 (95% CI:0.73, 0.84; p = 0.190). CONCLUSIONS: The deep model achieved excellent accuracy and sensitivity in identifying cases with dystrophinopathies. The comparable performance of the model and skilled radiologists demonstrates the potential application of the model in diagnosing dystrophinopathies through MRI images.

Differential diagnosis of arrhythmogenic cardiomyopathy: phenocopies versus disease variants.

Arrhythmogenic cardiomyopathy (ACM) is a genetic heart muscle disease caused by mutations of desmosomal genes in about 50% of patients. Affected patients may have defective non-desmosomal genes. The ACM phenotype may occur in other genetic cardiomyopathies, cardio-cutaneous syndromes or neuromuscular disorders. A sizeable proportion of patients have non-genetic diseases with clinical features resembling ACM (phenocopies). The identification of biventricular and left-dominant phenotypic variants has made differential diagnosis more difficult because of the broader spectrum of phenocopies which requires a detailed clinical study with appropriate evaluation of most prominent and discriminatory disease features. Conditions that enter into differential diagnosis of ACM include heart muscle diseases affecting the right ventricle, the left ventricle, or both. To confirm a conclusive diagnosis of ACM, these differential possibilities need to be reasonably excluded by an accurate and targeted clinical evaluation. This article reviews the clinical and imaging features of major phenocopies of ACM and provides indications for differential diagnosis. The recent etiologic classification of Arrhythmogenic Cardiomyopathies, whose common denominator is the distinctive phenotype characterized by a hypokinetic and non-dilated ventricle with a large amount of myocardial fibrosis underlying its propensity to generate ventricular arrhythmias is also addressed.

Practical approach to the genetic diagnosis of unsolved dystrophinopathies: a stepwise strategy in the genomic era.

OBJECTIVE: To investigate the diagnostic value of implementing a stepwise genetic testing strategy (SGTS) in genetically unsolved cases with dystrophinopathies. METHODS: After routine genetic testing in 872 male patients with highly suspected dystrophinopathies, we identified 715 patients with a pathogenic DMD variant. Of the 157 patients who had no pathogenic DMD variants and underwent a muscle biopsy, 142 patients were confirmed to have other myopathies, and 15 suspected dystrophinopathies remained genetically undiagnosed. These 15 patients underwent a more comprehensive evaluation as part of the SGTS pipeline, which included the stepwise analysis of dystrophin mRNA, short-read whole-gene DMD sequencing, long-read whole-gene DMD sequencing and in silico bioinformatic analyses. RESULTS: SGTS successfully yielded a molecular diagnosis of dystrophinopathy in 11 of the 15 genetically unsolved cases. We identified 8 intronic and 2 complex structural variants (SVs) leading to aberrant splicing in 10 of 11 patients, of which 9 variants were novel. In one case, a molecular defect was detected on mRNA and protein level only. Aberrant splicing mechanisms included 6 pseudoexon inclusions and 4 alterations of splice sites and splicing regulatory elements. We showed for the first time the exonisation of a MER48 element as a novel pathogenic mechanism in dystrophinopathies. CONCLUSION: Our study highlights the high diagnostic utility of implementing a SGTS pipeline in dystrophinopathies with intronic variants and complex SVs.

CGG expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy with neurological manifestations.

Oculopharyngodistal myopathy (OPDM) is a rare hereditary muscle disease characterized by progressive distal limb weakness, ptosis, ophthalmoplegia, bulbar muscle weakness and rimmed vacuoles on muscle biopsy. Recently, CGG repeat expansions in the noncoding regions of two genes, LRP12 and GIPC1, have been reported to be causative for OPDM. Furthermore, neuronal intranuclear inclusion disease (NIID) has been recently reported to be caused by CGG repeat expansions in NOTCH2NLC. We aimed to identify and to clinicopathologically characterize patients with OPDM who have CGG repeat expansions in NOTCH2NLC (OPDM_NOTCH2NLC). Note that 211 patients from 201 families, who were clinically or clinicopathologically diagnosed with OPDM or oculopharyngeal muscular dystrophy, were screened for CGG expansions in NOTCH2NLC by repeat primed-PCR. Clinical information and muscle pathology slides of identified patients with OPDM_NOTCH2NLC were re-reviewed. Intra-myonuclear inclusions were evaluated using immunohistochemistry and electron microscopy (EM). Seven Japanese OPDM patients had CGG repeat expansions in NOTCH2NLC. All seven patients clinically demonstrated ptosis, ophthalmoplegia, dysarthria and muscle weakness; they myopathologically had intra-myonuclear inclusions stained with anti-poly-ubiquitinated proteins, anti-SUMO1 and anti-p62 antibodies, which were diagnostic of NIID (typically on skin biopsy), in addition to rimmed vacuoles. The sample for EM was available only from one patient, which demonstrated intranuclear inclusions of 12.6 ± 1.6 nm in diameter. We identified seven patients with OPDM_NOTCH2NLC. Our patients had various additional central and/or peripheral nervous system involvement, although all were clinicopathologically compatible; thus, they were diagnosed as having OPDM and expanding a phenotype of the neuromyodegenerative disease caused by CGG repeat expansions in NOTCH2NLC.

Diagnostic Value of Muscle Ultrasound for Myopathies and Myositis.

PURPOSE OF REVIEW: The purpose of this review is to critically discuss the use of ultrasound in the evaluation of muscle disorders with a particular focus on the emerging use in inflammatory myopathies. RECENT FINDINGS: In myopathies, pathologic muscle shows an increase in echogenicity. Muscle echogenicity can be assessed visually, semi-quantitatively, or quantitatively using grayscale analysis. The involvement of specific muscle groups and the pattern of increase in echogenicity can further point to specific diseases. In pediatric neuromuscular disorders, the value of muscle ultrasound for screening and diagnosis is well-established. It has also been found to be a responsive measure of disease change in muscular dystrophies. In chronic forms of myositis like inclusion body myositis, ultrasound is very suitable for detecting markedly increased echogenicity and atrophy in affected muscles. Acute cases of muscle edema show only a mild increase in echogenicity, which can also reverse with successful treatment. Muscle ultrasound is an important imaging modality that is highly adaptable to study various muscle conditions. Although its diagnostic value for neuromuscular disorders is high, the evidence in myositis has only begun to accrue in earnest. Further systematic studies are needed, especially in its role for detecting muscle edema.

Miopatía de Bethlem: cuando el fenotipo confunde / Bethlem myopathy: when the phenotype is misleading

No disponible

Cervical Hyperextension Treated by Posterior Spinal Correction and Fusion in A Patient with Ullrich Congenital Muscular Dystrophy: A Case Report.

CASE: An 18-year-old man with Ullrich congenital muscular dystrophy (UCMD) noted difficulty of looking forward and discomfort swallowing and breathing because of his hyperextended neck. We treated his cervical deformity with posterior spinal correction and fusion alone. He underwent a tracheotomy because of lung function deterioration 2 years after cervical surgery. The tracheotomy was performed safely because the anterior cervical spine anatomy was normalized and soft tissues around trachea were preserved by the posterior cervical correction. CONCLUSION: Cervical hyperextension can be a problem in patients with UCMD. Posterior spinal correction and fusion may be a preferable solution.

Differential Diagnoses of Inclusion Body Myositis.

Inclusion body myositis is a slowly progressive myopathy, characteristically affecting quadriceps and long finger flexors. Atypical presentations do occur, however, and there is overlap with other myopathies, including inflammatory and hereditary etiologies. This article discusses atypical cases and differential diagnoses and considers the role of imaging and histopathology in differentiating inclusion body myositis.

Lower Extremity Muscle Involvement in the Intermediate and Bethlem Myopathy Forms of COL6-Related Dystrophy and Duchenne Muscular Dystrophy: A Cross-Sectional Study.

Collagen VI-related dystrophies (COL6-RDs) and Duchenne muscular dystrophy (DMD) cause progressive muscle weakness and disability. COL6-RDs are caused by mutations in the COL6 genes (COL6A1, COL6A2 and COL6A3) encoding the extracellular matrix protein collagen VI, and DMD is caused by mutations in the DMD gene encoding the cytoplasmic protein dystrophin. Both COL6-RDs and DMD are characterized by infiltration of the muscles by fatty and fibrotic tissue. This study examined the effect of disease pathology on skeletal muscles in lower extremity muscles of COL6-RDs using timed functional tests, strength measures and qualitative/ quantitative magnetic resonance imaging/spectroscopy measures (MRI/MRS) in comparison to unaffected (control) individuals. Patients with COL6-RD were also compared to age and gender matched patients with DMD.Patients with COL6-RD presented with a typical pattern of fatty infiltration of the muscle giving rise to an apparent halo effect around the muscle, while patients with DMD had evidence of fatty infiltration throughout the muscle areas imaged. Quantitatively, fat fraction, and transverse relaxation time (T2) were elevated in both COL6-RD and DMD patients compared to unaffected (control) individuals. Patients with COL6-RD had widespread muscle atrophy, likely contributing to weakness. In contrast, patients with DMD revealed force deficits even in muscle groups with increased contractile areas.