A form of muscular dystrophy associated with pathogenic variants in JAG2.

JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7. In complementary studies, Jag2 downregulation in murine myoblasts led to downregulation of multiple components of the Notch pathway, including Megf10. Investigations in Drosophila suggested an interaction between Serrate and Drpr, the fly orthologs of JAG1/JAG2 and MEGF10, respectively. In silico analysis predicted that many Jagged2 missense variants are associated with structural changes and protein misfolding. In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction.

Quantitative muscle magnetic resonance imaging in limb-girdle muscular dystrophy type R1 (LGMDR1): A prospective longitudinal cohort study.

Limb-girdle muscular dystrophy (LGMD) type R1 (LGMDR1) is the most common subtype of LGMD in Europe. Prospective longitudinal data, including clinical assessments and new biomarkers such as quantitative magnetic resonance imaging (qMRI), are needed to evaluate the natural course of the disease and therapeutic options. We evaluated eight thigh and seven leg muscles of 13 LGMDR1 patients (seven females, mean age 36.7 years, body mass index 23.9 kg/m2) and 13 healthy age- and gender-matched controls in a prospective longitudinal design over 1 year. Clinical assessment included testing for muscle strength with quick motor function measure (QMFM), gait analysis and patient questionnaires (neuromuscular symptom score, activity limitation [ACTIVLIM]). MRI scans were performed on a 3-T MRI scanner, including a Dixon-based sequence, T2 mapping and diffusion tensor imaging. The qMRI values of fat fraction (FF), water T2 relaxation time (T2), fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity were analysed. Within the clinical outcome measures, significant deterioration between baseline and follow-up was found for ACTIVLIM (p = 0.029), QMFM (p = 0.012). Analysis of qMRI parameters of the patient group revealed differences between time points for both FF and T2 when analysing all muscles (FF: p < 0.001; T2: p = 0.016). The highest increase of fat replacement was found in muscles with an FF of between 10% and 50% at baseline. T2 in muscles with low-fat replacement increased significantly. No significant differences were found for the diffusion metrics. Significant correlations between qMRI metrics and clinical assessments were found at baseline and follow-up, while only T2 changes in thigh muscles correlated with changes in ACTIVLIM over time (ρ = -0.621, p < 0.05). Clinical assessments can show deterioration of the general condition of LGMDR1 patients. qMRI measures can give additional information about underlying pathophysiology. Further research is needed to establish qMRI outcome measures for clinical trials.

Pathological findings with vacuoles in anti-mitochondrial antibody-positive inflammatory myopathy.

BACKGROUND: A few patients with inflammatory myopathy showed anti-mitochondrial antibody (AMA) positivity. This study aimed to report the clinical and pathological findings with vacuoles in 3 cases of such patients. METHODS: Three cases with myositis from the Myositis Clinical Database of Peking University First Hospital were identified with AMA positivity. Their clinical records were retrospectively reviewed and the data was extracted. All the 3 cases underwent muscle biopsy. RESULTS: Three middle-aged patients presented with chronic-onset weakness of proximal limbs, marked elevation of creatine kinase, and AMA-positivity. Two of the 3 cases meet the criteria of primary biliary cholangitis. All the 3 cases presented with cardiac involvement and proteinuria. Two cases developed type 2 respiratory failure. MRI of the thigh muscle showed multiple patches of edema bilaterally in both cases, mostly in the adductor magnus. Pathological findings include degeneration of muscle fibers, diffused MHC-I positivity, and complement deposits on cell membranes. Vacuoles without rims of different sizes were discovered under the membrane of the muscle fibers. A few RBFs were discovered in case 1, while a diffused proliferation of endomysium and perimysium was shown in case 2. CONCLUSIONS: AMA-positive inflammatory myopathy is a disease that could affect multiple systems. Apart from inflammatory changes, the pathological findings of muscle can also present vacuoles.

[Expert recommendations for magnetic resonance imaging of muscle disorders]. / Expertenempfehlung zur Magnetresonanztomographie bei Muskelerkrankungen.

BACKGROUND: Magnetic resonance (MRI) imaging of the skeletal muscles (muscle MRI for short) is increasingly being used in clinical routine for diagnosis and longitudinal assessment of muscle disorders. However, cross-centre standards for measurement protocol and radiological assessment are still lacking. OBJECTIVES: The aim of this expert recommendation is to present standards for the application and interpretation of muscle MRI in hereditary and inflammatory muscle disorders. METHODS: This work was developed in collaboration between neurologists, neuroradiologists, radiologists, neuropaediatricians, neuroscientists and MR physicists from different university hospitals in Germany. The recommendations are based on expert knowledge and a focused literature search. RESULTS: The indications for muscle MRI are explained, including the detection and monitoring of structural tissue changes and oedema in the muscle, as well as the identification of a suitable biopsy site. Recommendations for the examination procedure and selection of appropriate MRI sequences are given. Finally, steps for a structured radiological assessment are presented. CONCLUSIONS: The present work provides concrete recommendations for the indication, implementation and interpretation of muscle MRI in muscle disorders. Furthermore, it provides a possible basis for the standardisation of the measurement protocols at all clinical centres in Germany.

Assessing muscle-specific potassium concentrations in human lower leg using potassium magnetic resonance imaging.

Noninvasively assessing tissue potassium concentrations (TPCs) using potassium magnetic resonance imaging (39 K MRI) could give valuable information on physiological processes connected to various pathologies. However, because of inherently low 39 K MR image resolution and strong signal blurring, a reliable measurement of the TPC is challenging. The aim of this work was to investigate the feasibility of a muscle-specific TPC determination with a focus on the influence of a varying residual quadrupolar interaction in human lower leg muscles. The quantification accuracy of a muscle-specific TPC determination was first assessed using simulated 39 K MRI data. In vivo 39 K and corresponding sodium (23 Na) MRI data of healthy lower leg muscles (n = 14, seven females) were acquired on a 7-T MR system using a double-resonant 23 Na/39 K birdcage Tx/Rx RF coil. Additional 1 H MR images were acquired on a 3-T MR system and used for tissue segmentation. Quantification of TPC was performed after a region-based partial volume correction (PVC) using five external reference phantoms. Simulations not only underlined the importance of PVC for correctly assessing muscle-specific TPC values, but also revealed the strong impact of a varying residual quadrupolar interaction between different muscle regions on the measured TPC. Using 39 K T2 * decay curves, we found significantly higher residual quadrupolar interaction in tibialis anterior muscle (TA; ωq = 194 ± 28 Hz) compared with gastrocnemius muscle (medial/lateral head, GM/GL; ωq = 151 ± 25 Hz) and soleus muscle (SOL; ωq = 102 ± 32 Hz). If considered in the PVC, TPC in individual muscles was similar (TPC = 98 ± 11/96 ± 14/99 ± 8/100 ± 12 mM in GM/GL/SOL/TA). Comparison with tissue sodium concentrations suggested that residual quadrupolar interactions might also influence the 23 Na MRI signal of lower leg muscles. A TPC determination of individual lower leg muscles is feasible and can therefore be applied in future studies. Considering a varying residual quadrupolar interaction for PVC of 39 K MRI data is essential to reliably assess potassium concentrations in individual muscles.

Quantitative muscle magnetic resonance imaging depicts microstructural abnormalities but no signs of inflammation or dystrophy in post-COVID-19 condition.

BACKGROUND AND PURPOSE: Post-COVID-19 condition (PCC) has high impact on quality of life, with myalgia and fatigue affecting at least 25% of PCC patients. This case-control study aims to noninvasively assess muscular alterations via quantitative muscle magnetic resonance imaging (MRI) as possible mechanisms for ongoing musculoskeletal complaints and premature exhaustion in PCC. METHODS: Quantitative muscle MRI was performed on a 3 Tesla MRI scanner of the whole legs in PCC patients compared to age- and sex-matched healthy controls, including a Dixon sequence to determine muscle fat fraction (FF), a multi-echo spin-echo sequence for quantitative water mapping reflecting putative edema, and a diffusion-weighted spin-echo echo-planar imaging sequence to assess microstructural alterations. Clinical examination, nerve conduction studies, and serum creatine kinase were performed in all patients. Quantitative muscle MRI results were correlated to the results of the 6-min walk test and standardized questionnaires assessing quality of life, fatigue, and depression. RESULTS: Twenty PCC patients (female: n = 15, age = 48.8 ± 10.1 years, symptoms duration = 13.4 ± 4.2 months, body mass index [BMI] = 28.8 ± 4.7 kg/m2 ) were compared to 20 healthy controls (female: n = 15, age = 48.1 ± 11.1 years, BMI = 22.9 ± 2.2 kg/m2 ). Neither FF nor T2 revealed signs of muscle degeneration or inflammation in either study groups. Diffusion tensor imaging (DTI) revealed reduced mean, axial, and radial diffusivity in the PCC group. CONCLUSIONS: Quantitative muscle MRI did not depict any signs of ongoing inflammation or dystrophic process in the skeletal muscles in PCC patients. However, differences observed in muscle DTI depict microstructural abnormalities, which may reflect potentially reversible fiber hypotrophy due to deconditioning. Further longitudinal and interventional studies should prove this hypothesis.

Contribution of muscle MRI for diagnosis of myopathy.

Inherited myopathies are a group of disease, which, although distinct from a genetic and prognostic point of view, can lead to non-specific clinical pictures due to phenotypic overlap. Acquired immuno-mediated myopathies may also pose the problem of clinically accurate etiological orientation. The assessment of fatty infiltration and pathological increase in water volume of the muscle contingent on whole-body muscle MRI is becoming increasingly important in aiding the initial diagnosis of inherited and acquired myopathies. MRI helps orientating the clinical diagnostic hypotheses thanks to the patterns of muscle involved (more or less specific according to the entities), which led to the development of decision-making algorithms proposed in the literature. The aim of this article is to specify the proper MRI protocol for the evaluation of myopathies and the basis of the interpretation and to provide a summary of the most frequently inherited and acquired myopathies described in the literature.

Congenital myasthenic syndrome: Correlation between clinical features and molecular diagnosis.

OBJECTIVES: To present phenotype features of a large cohort of congenital myasthenic syndromes (CMS) and correlate them with their molecular diagnosis. METHODS: Suspected CMS patients were divided into three groups: group A (limb, bulbar or axial weakness, with or without ocular impairment, and all the following: clinical fatigability, electrophysiology compatible with neuromuscular junction involvement and anticholinesterase agents response), group B (limb, bulbar or axial weakness, with or without ocular impairment, and at least one of additional characteristics noted in group A) and group C (pure ocular syndrome). Individual clinical findings and the clinical groups were compared between the group with a confirmed molecular diagnosis of CMS and the group without molecular diagnosis or with a non-CMS molecular diagnosis. RESULTS: Seventy-nine patients (68 families) were included in the cohort: 48 in group A, 23 in group B and 8 in group C. Fifty-one were considered confirmed CMS (30 CHRNE, 5 RAPSN, 4 COL13A1, 3 DOK7, 3 COLQ, 2 GFPT1, 1 CHAT, 1 SCN4A, 1 GMPPB, 1 CHRNA1), 7 probable CMS, 5 non-CMS and 16 unsolved. The chance of a confirmed molecular diagnosis of CMS was significantly higher for group A and lower for group C. Some individual clinical features, alterations on biopsy and electrophysiology enhanced specificity for CMS. Muscle imaging showed at least mild alterations in the majority of confirmed cases, with preferential involvement of soleus, especially in CHRNE CMS. CONCLUSIONS: Stricter clinical criteria increase the chance of confirming a CMS diagnosis, but may lose sensitivity, especially for some specific genes.

Muscle magnetic resonance imaging in myotonic dystrophy type 1 (DM1): Refining muscle involvement and implications for clinical trials.

BACKGROUND: Only a few studies have reported muscle imaging data on small cohorts of patients with myotonic dystrophy type 1 (DM1). We aimed to investigate the muscle involvement in a large cohort of patients in order to refine the pattern of muscle involvement, to better understand the pathophysiological mechanisms of muscle weakness, and to identify potential imaging biomarkers for disease activity and severity. METHODS: One hundred and thirty-four DM1 patients underwent a cross-sectional muscle magnetic resonance imaging (MRI) study. Short tau inversion recovery (STIR) and T1 sequences in the lower and upper body were analyzed. Fat replacement, muscle atrophy and STIR positivity were evaluated using three different scales. Correlations between MRI scores, clinical features and genetic background were investigated. RESULTS: The most frequent pattern of muscle involvement in T1 consisted of fat replacement of the tongue, sternocleidomastoideus, paraspinalis, gluteus minimus, distal quadriceps and gastrocnemius medialis. Degree of fat replacement at MRI correlated with clinical severity and disease duration, but not with CTG expansion. Fat replacement was also detected in milder/asymptomatic patients. More than 80% of patients had STIR-positive signals in muscles. Most DM1 patients also showed a variable degree of muscle atrophy regardless of MRI signs of fat replacement. A subset of patients (20%) showed a 'marbled' muscle appearance. CONCLUSIONS: Muscle MRI is a sensitive biomarker of disease severity alsofor the milder spectrum of disease. STIR hyperintensity seems to precede fat replacement in T1. Beyond fat replacement, STIR positivity, muscle atrophy and a 'marbled' appearance suggest further mechanisms of muscle wasting and weakness in DM1, representing additional outcome measures and therapeutic targets for forthcoming clinical trials.

Muscle-MRI and Functional Levels for the Evaluation of Upper Limbs in Duchenne Muscular Dystrophy: A Critical Review of the Literature.

Many qualitative and quantitative Magnetic Resonance Imaging (MRI) techniques have been applied to evaluate muscle fat degeneration in Duchenne muscular dystrophy (DMD) subjects, but only few studies have focused on the upper limbs. We reviewed the literature in order to evaluate the association between muscle MRI findings and motor function levels in the upper limbs of DMD patients. Ten studies with upper limb muscle MRI data were available. Four explored all upper limb segments, while six explored only the forearm. Functional assessments were performed in nine of the ten studies. All of the studies showed a significant correlation between muscle MRI changes and motor function levels in both ambulant and non-ambulant DMD patients.

A founder mutation in the GMPPB gene [c.1000G > A (p.Asp334Asn)] causes a mild form of limb-girdle muscular dystrophy/congenital myasthenic syndrome (LGMD/CMS) in South Indian patients.

Twelve patients from seven unrelated South Indian families with a limb-girdle muscular dystrophy-congenital myasthenic syndrome (LGMD/CMS) phenotype and recessive inheritance underwent deep clinical phenotyping, electrophysiological evaluation, muscle histopathology, and next-generation sequencing/Sanger sequencing-based identification of the genetic defect. Homozygosity mapping was performed using high-throughput genome-wide genotyping for mapping the mutation and to evaluate the founder effect. The age of disease onset among patients ranged from childhood to 40 years of age. The key clinical manifestations observed were progressive fatigable limb-girdle weakness, muscle hypertrophy/atrophy, and preferential weakness in a dystrophic pattern. The ages at last follow-up ranged from 30 to 64 years; nine were independently ambulant, two required assistance, and one was wheelchair-bound. Lower limb muscle MRI showed varying degrees of fat replacement in the glutei, hamstrings, anterior leg muscles, and medial gastrocnemius. All patients showed significant decrement on repetitive nerve stimulation (RNS). Muscle biopsy in 7 patients revealed varying degrees of dystrophic and neurogenic changes. Treatment with pyridostigmine and/or salbutamol resulted in variable improvement in 10 patients. Genetic analysis showed an identical homozygous GMPPB mutation c.1000G > A (p.Asp334Asn) in all affected patients. A region of homozygosity (6Mbp) was observed flanking the c.1000G > A change in carrier chromosomes. This study identifies c.1000G > A in GMPPB as a common founder mutation in an ethnic community of South Indian descent with milder yet variable degree of clinical presentation of GMPPB-associated LGMD-CMS.

The feasibility of quantitative MRI of extra-ocular muscles in myasthenia gravis and Graves' orbitopathy.

Although quantitative MRI can be instrumental in the diagnosis and assessment of disease progression in orbital diseases involving the extra-ocular muscles (EOM), acquisition can be challenging as EOM are small and prone to eye-motion artefacts. We explored the feasibility of assessing fat fractions (FF), muscle volumes and water T2 (T2water ) of EOM in healthy controls (HC), myasthenia gravis (MG) and Graves' orbitopathy (GO) patients. FF, EOM volumes and T2water values were determined in 12 HC (aged 22-65 years), 11 MG (aged 28-71 years) and six GO (aged 28-64 years) patients at 7 T using Dixon and multi-echo spin-echo sequences. The EOM were semi-automatically 3D-segmented by two independent observers. MANOVA and t-tests were used to assess differences in FF, T2water and volume of EOM between groups (P < .05). Bland-Altman limits of agreement (LoA) were used to assess the reproducibility of segmentations and Dixon scans. The scans were well tolerated by all subjects. The bias in FF between the repeated Dixon scans was -0.7% (LoA: ±2.1%) for the different observers; the bias in FF was -0.3% (LoA: ±2.8%) and 0.03 cm3 (LoA: ± 0.36 cm3 ) for volume. Mean FF of EOM in MG (14.1% ± 1.6%) was higher than in HC (10.4% ± 2.5%). Mean muscle volume was higher in both GO (1.2 ± 0.4 cm3 ) and MG (0.8 ± 0.2 cm3 ) compared with HC (0.6 ± 0.2 cm3 ). The average T2water for all EOM was 24.6 ± 4.0 ms for HC, 24.0 ± 4.7 ms for MG patients and 27.4 ± 4.2 ms for the GO patient. Quantitative MRI at 7 T is feasible for measuring FF and muscle volumes of EOM in HC, MG and GO patients. The measured T2water was on average comparable with skeletal muscle, although with higher variation between subjects. The increased FF in the EOM in MG patients suggests that EOM involvement in MG is accompanied by fat replacement. The unexpected EOM volume increase in MG may provide novel insights into underlying pathophysiological processes.

Skeletal muscle magnetic resonance imaging in Pompe disease.

Pompe disease is characterized by a deficiency of acid alpha-glucosidase that results in muscle weakness and a variable degree of disability. There is an approved therapy based on enzymatic replacement that has modified disease progression. Several reports describing muscle magnetic resonance imaging (MRI) features of Pompe patients have been published. Most of the studies have focused on late-onset Pompe disease (LOPD) and identified a characteristic pattern of muscle involvement useful for the diagnosis. In addition, quantitative MRI studies have shown a progressive increase in fat in skeletal muscles of LOPD over time and they are increasingly considered a good tool to monitor progression of the disease. The studies performed in infantile-onset Pompe disease patients have shown less consistent changes. Other more sophisticated muscle MRI sequences, such as diffusion tensor imaging or glycogen spectroscopy, have also been used in Pompe patients and have shown promising results.

Muscle involvement assessed by quantitative magnetic resonance imaging in patients with anoctamin 5 deficiency.

OBJECTIVE: Using magnetic resonance imaging (MRI) and stationary dynamometry, the aim was to investigate the muscle affection in paraspinal muscles and lower extremities and compare the muscle affection in men and women with anoctamin 5 (ANO5) deficiency. METHODS: Seventeen patients (seven women) with pathogenic ANO5-mutations were included. Quantitative muscle fat fraction of back and leg muscles were assessed by Dixon MRI. Muscle strength was assessed by stationary dynamometer. Results were compared with 11 matched, healthy controls. RESULTS: Muscle involvement pattern in men with ANO5-deficiency is characterized by a severe fat replacement of hamstrings, adductor and gastrocnemius muscles, while paraspinal muscles are only mildly affected, while preserved gracilis and sartorius muscles were hypertrophied. Women with ANO5-myopathy, of the same age as male patients, were very mildly affected, showing muscle affection and strength resembling that found in healthy persons, with the exception of the gluteus minimus and medius and gastrocnemii muscles that were significantly replaced by fat. Although individual muscles showed clear asymmetric involvement in a few muscle groups, the overall muscle involvement was symmetric. CONCLUSIONS: Patients with ANO5-deficiency have relatively preserved paraspinal muscles on imaging and only mild reduction of trunk extension strength in men only. Our study quantifies the large difference in muscle affection in lower extremity between women and men with ANO5-deficiency. The clinical notion is that affection may be very asymmetric in ANO5-deficiency, but the present study shows that while this may be true for a few muscles, the general impression is that muscle affection is very symmetric.

A study of the phenotypic variability and disease progression in Laing myopathy through the evaluation of muscle imaging.

BACKGROUND: Laing myopathy is characterized by broad clinical and pathological variability. They are limited in number and protocol of study. We aimed to delineate muscle imaging profiles and validate imaging analysis as an outcome measure. METHODS: This was a cross-sectional and longitudinal cohort study. Data from clinical, functional and semi-quantitative muscle imaging (60 magnetic resonance imaging [MRI] and six computed tomography scans) were studied. Hierarchical analysis, graphic heatmap representation and correlation between imaging and clinical data using Bayesian statistics were carried out. RESULTS: The study cohort comprised 42 patients from 13 families harbouring five MYH7 mutations. The cohort had a wide range of ages, age at onset, disease duration, and myopathy extension and Gardner-Medwin and Walton (GMW) functional scores. Intramuscular fat was evident in all but two asymptomatic/pauci-symptomatic patients. Anterior leg compartment muscles were the only affected muscles in 12% of the patients. Widespread extension to the thigh, hip, paravertebral and calf muscles and, less frequently, the scapulohumeral muscles was commonly observed, depicting distinct patterns and rates of progression. Foot muscles were involved in 40% of patients, evolving in parallel to other regions with absence of a disto-proximal gradient. Whole cumulative imaging score, ranging from 0 to 2.9 out of 4, was associated with disease duration and with myopathy extension and GMW scales. Follow-up MRI studies in 24 patients showed significant score progression at a variable rate. CONCLUSIONS: We confirmed that the anterior leg compartment is systematically affected in Laing myopathy and may represent the only manifestation of this disorder. However, widespread muscle involvement in preferential but variable and not distance-dependent patterns was frequently observed. Imaging score analysis is useful to categorize patients and to follow disease progression over time.

Longitudinal Motor Functional Outcomes and Magnetic Resonance Imaging Patterns of Muscle Involvement in Upper Limbs in Duchenne Muscular Dystrophy.

Background and Objectives: The aim of this study was to evaluate longitudinal changes using both upper limb muscle Magnetic Resonance Imaging (MRI) at shoulder, arm and forearm levels and Performance of upper limb (PUL) in ambulant and non-ambulant Duchenne Muscular Dystrophy (DMD) patients. We also wished to define whether baseline muscle MRI could help to predict functional changes after one year. Materials and Methods: Twenty-seven patients had both baseline and 12month muscle MRI and PUL assessments one year later. Results: Ten were ambulant (age range 5-16 years), and 17 non ambulant (age range 10-30 years). Increased abnormalities equal or more than 1.5 point on muscle MRI at follow up were found on all domains: at shoulder level 12/27 patients (44%), at arm level 4/27 (15%) and at forearm level 6/27 (22%). Lower follow up PUL score were found in 8/27 patients (30%) at shoulder level, in 9/27 patients (33%) at mid-level whereas no functional changes were found at distal level. There was no constant association between baseline MRI scores and follow up PUL scores at arm and forearm levels but at shoulder level patients with moderate impairment on the baseline MRI scores between 16 and 34 had the highest risk of decreased function on PUL over a year. Conclusions: Our results confirmed that the integrated use of functional scales and imaging can help to monitor functional and MRI changes over time.

Thigh muscle MRI findings in myopathy associated with anti-mitochondrial antibody.

INTRODUCTION: Myopathy associated with anti-mitochondrial antibody (AMA) has recently been characterized as a distinct type of idiopathic inflammatory myopathy. The purpose of this study is to evaluate the pattern of involvement in thigh muscles in AMA myopathy using MRI. METHODS: Six patients with AMA myopathy were identified and their muscle MRI findings evaluated. RESULTS: On thigh muscle MRI, all six patients showed high signal intensity with short-tau inversion recovery that reflected disease activity mostly in the adductor magnus, called a "cuneiform sign." Fatty degeneration was also prominent in the adductor magnus, as well as the semimembranosus muscles. DISCUSSION: These characteristic changes on MRI contrast with those of other inflammatory myopathies. From these observations, we concluded that the localization pattern of the inflammatory changes in muscle MRI can contribute to the diagnosis of AMA myopathy.

Longitudinal reliability of outcome measures in patients with Duchenne muscular dystrophy.

INTRODUCTION: The definition of reliable outcome measures is of increasing interest in patients with Duchenne muscular dystrophy (DMD). METHODS: In this retrospective study, we analyzed the longitudinal reliability of clinical and radiological endpoints in 29 ambulant patients with DMD. Clinical outcome measures included motor function measure (MFM) and timed function tests, while quantitative MRI data were mean fat fraction (MFF) and T2 relaxation time of thigh muscles. Statistical analysis was based on 3-, 6-, and 12-month follow-up data. RESULTS: Quantitative MRI using the MFF was the most sensitive and powerful marker of disease progression with a sample size of four at 1-year follow-up, followed by the D1 domain of MFM (standing and transfer function) with a sample size of 12. DISCUSSION: Our data support the longitudinal design of clinical trials over at least 12 months and the combinational use of clinical and radiological surrogate outcome measures.

Phenotypic correlations in a large single-center cohort of patients with BSCL2 nerve disorders: a clinical, neurophysiological and muscle magnetic resonance imaging study.

BACKGROUND AND PURPOSE: BSCL2 heterozygote mutations are a common cause of distal hereditary motor neuropathies (dHMNs). A series of BSCL2 patients is presented and clinical, neurophysiological and muscle magnetic resonance imaging (MRI) findings are correlated. METHODS: Twenty-six patients from five families carrying the p.N88S mutation were identified. Age of onset, clinical phenotype (dHMN, Charcot-Marie-Tooth, spastic paraplegia), physical examination, disability measured as a modified Rankin Scale score and neurophysiological findings were collected. A whole body muscle MRI had been performed in 18 patients. The pattern of muscle involvement on T1-weighted and short time inversion recovery sequences was analysed. Hierarchical analysis using heatmaps and an MRI Composite Score were generated. Statistical analysis was carried out with STATA SE v.15 (TX, USA). RESULTS: The mean age was 51.54 ± 19.94 years and 14 patients were men. dHMN was the most common phenotype (50%) and five patients (19.23%) showed no findings on examination. Disease onset was commonly in childhood and disability was low (modified Rankin Scale score 1.34 ± 1.13) although median time since onset of disease was 32 years (range 10-47). Charcot-Marie-Tooth-like patients were more disabled and disability correlated with age. On muscle MRI, thenar eminence, soleus and tibialis anterior were most frequently involved, irrespective of clinical phenotype. MRI Composite Score was strongly correlated with disability. CONCLUSION: Patients with the p.N88S BSCL2 gene mutation are phenotypically variable, although dHMN is most frequent and generally slowly progressive. Muscle MRI pattern is consistent regardless of phenotype and correlates with disease severity, probably serving as a reliable outcome measure for future clinical trials.

A case of GNE myopathy mimicking hereditary motor neuropathy.

A 36-year-old woman who presented with upper limb distal weakness since the age of 15 years, with gradual progression to the lower limbs, is reported. Hereditary motor neuropathy was initially suspected based on distal weakness and hyporeflexia; however, whole exome sequencing accidentally revealed a compound heterozygous variant in the GNE gene, and ultrasound revealed increased homogeneous echogenicity in the involved muscles, which is characteristic of myopathic changes. Muscle magnetic resonance imaging revealed fatty infiltration in all limb muscles, sparing the triceps brachii, vastus lateralis and vastus medialis. Muscle biopsy revealed intracytoplasmic rimmed vacuole, supporting the diagnosis of GNE myopathy.