Different Lower Limb Muscle MRI Patterns in Autosomal Dominant Titinopathies

P.15.8 Hereditary myopathy with early respiratory failure (HMERF) – Rapid increase of identified titinopathy families worldwide

Titin-related myopathies are heterogeneous clinical conditions associated with mutations in TTN. To define their histopathologic boundaries and try to overcome the difficulty in assessing the pathogenic role of TTN variants, we performed a thorough morphological skeletal muscle analysis including light and electron microscopy in 23 patients with different clinical phenotypes presenting pathogenic autosomal dominant or autosomal recessive (AR) mutations located in different TTN domains. We identified a consistent pattern characterized by diverse defects in oxidative staining with prominent nuclear internalization in congenital phenotypes (AR-CM) (n = 10), ± necrotic/regenerative fibers, associated with endomysial fibrosis and rimmed vacuoles (RVs) in AR early-onset Emery-Dreifuss-like (AR-ED) (n = 4) and AR adult-onset distal myopathies (n = 4), and cytoplasmic bodies (CBs) as predominant finding in hereditary myopathy with early respiratory failure (HMERF) patients (n = 5). Ultrastructurally, the most significant abnormalities, particularly in AR-CM, were multiple narrow core lesions and/or clear small areas of disorganizations affecting one or a few sarcomeres with M-band and sometimes A-band disruption and loss of thick filaments. CBs were noted in some AR-CM and associated with RVs in HMERF and some AR-ED cases. As a whole, we described recognizable histopathological patterns and structural alterations that could point toward considering the pathogenicity of TTN mutations.

I.02 Titin – The newly-emerged "titan" of the cardiac and skeletal muscle disease world

To map the phenotypic spectrum in 55 individuals with mutations in CACNA1S known to cause hypokalemic periodic paralysis (HypoPP) using medical history, muscle strength testing, and muscle MRI. Adults with a mutation in CACNA1S known to cause HypoPP were included. Medical history was obtained. Muscle strength and MRI assessments were performed. Fifty-five persons were included. Three patients presented with permanent muscle weakness and never attacks of paralysis. Seventeen patients presented with a mixed phenotype of periodic paralysis and permanent weakness. Thirty-one patients presented with the classical phenotype of periodic attacks of paralysis and no permanent weakness. Four participants were asymptomatic. Different phenotypes were present in 9 of 18 families. All patients with permanent weakness had abnormal replacement of muscle by fat on MRI. In addition, 20 of 35 participants with no permanent weakness had abnormal fat replacement of muscle on MRI. The most severely affected muscles were the paraspinal muscles, psoas, iliacus, the posterior muscles of the thigh and gastrocnemius, and soleus of the calf. Age was associated with permanent weakness and correlated with severity of weakness and fat replacement of muscle on MRI. Our results show that phenotype in individuals with HypoPP-causing mutations in CACNA1S varies from asymptomatic to periodic paralysis with or without permanent muscle weakness or permanent weakness as sole presenting picture. Variable phenotypes are found within families. Muscle MRI reveals fat replacement in patients with no permanent muscle weakness, suggesting a convergence of phenotype towards a fixed myopathy with aging.

Very few studies analyzing the pattern of muscle involvement in magnetic resonance imaging (MRI) of patients with McArdle disease have been reported to date. We aimed to examine the pattern of muscle fat replacement in patients with McArdle disease. We performed a retrospective study including all patients with genetically confirmed McArdle disease followed in our center from January 2010 to March 2021. Clinical data were collected from the medical record. Whole-body MRI was performed as part of the diagnostic evaluation. The distribution of muscle fat replacement and its severity were analyzed. Nine patients were included. Median age at onset was 7 y (range, 5-58) and median age at the time when MRI was performed was 57.3y (range, 37.2-72.8). At physical examination, four patients had permanent weakness: in three the weakness was limited to paraspinal muscles, whereas in one the weakness involved the paraspinal and proximal upper limb muscles. Muscle MRI showed abnormalities in six of the seven studied patients. In all of them, fat replacement of paravertebral muscles was found. Other muscles frequently affected were the tongue in three, subscapularis in three, and long head of biceps femoris and semimembranosus in two. Our findings suggest that paraspinal muscle involvement is common in McArdle disease and support the need to include this disease in the differential diagnosis of the causes of paraspinal muscle weakness. Involvement of the tongue and subscapularis are also frequent in McArdle disease.

BackgroundThe diagnosis of patients with mutations in the VCP gene can be complicated due to their broad phenotypic spectrum including myopathy, motor neuron disease and peripheral neuropathy. Muscle MRI guides the diagnosis in neuromuscular diseases (NMDs); however, comprehensive muscle MRI features for VCP patients have not been reported so far.MethodsWe collected muscle MRIs of 80 of the 255 patients who participated in the “VCP International Study” and reviewed the T1-weighted (T1w) and short tau inversion recovery (STIR) sequences. We identified a series of potential diagnostic MRI based characteristics useful for the diagnosis of VCP disease and validated them in 1089 MRIs from patients with other genetically confirmed NMDs.ResultsFat replacement of at least one muscle was identified in all symptomatic patients. The most common finding was the existence of patchy areas of fat replacement. Although there was a wide variability of muscles affected, we observed a common pattern characterized by the involvement of periscapular, paraspinal, gluteal and quadriceps muscles. STIR signal was enhanced in 67% of the patients, either in the muscle itself or in the surrounding fascia. We identified 10 diagnostic characteristics based on the pattern identified that allowed us to distinguish VCP disease from other neuromuscular diseases with high accuracy.ConclusionsPatients with mutations in the VCP gene had common features on muscle MRI that are helpful for diagnosis purposes, including the presence of patchy fat replacement and a prominent involvement of the periscapular, paraspinal, abdominal and thigh muscles.

To clarify the classification of two previously reported groups of patients with anterior tibial distal dystrophy, to find additional patients with the disease, and to describe the clinical features of this disease. National survey of the records of patients with neuromuscular diseases in Finland. Findings of selected patients were compared with those of previously reported cases. Thirty-six previously described patients and 30 additional patients from the current survey, with 41 symptomatic patients and 25 subjectively asymptomatic affected relatives. There were 66 patients with late adult-onset tibial muscular dystrophy. Symptoms appear after the age of 35 years with reduced ankle dorsiflexion, and progress is slow without marked disability. Facial muscles, upper extremities, and proximal muscles are usually spared. Muscle biopsy results reveal nonspecific dystrophic changes in clinically affected muscles, and frequently severe adipose replacement in the anterior tibial muscles occurs. Asymptomatic muscles have mild myopathic changes only. Vacuolar degeneration is detected in a minority of patients. Electromyography shows profound myopathic changes in the anterior tibial muscle, but extensor brevis muscles are well preserved. Computed tomography or magnetic resonance imaging of muscles discloses marked involvement of tibial extensor muscles and focal patches of fatty degeneration in various asymptomatic muscles. Pedigree data suggest autosomal dominant inheritance. Tibial muscular dystrophy might represent a new form of distal myopathy and it is rather common, at least in Finland.

Subclinical semitendinosus and obturator externus involvement defines an autosomal dominant myopathy with early respiratory failure

Sir, In the recent letters by Hedberg et al. (2013) and Pfeffer et al. (2013), the important question of genetic variants determining the pathogenesis of human myopathy with early respiratory failure (HMERF) was discussed. We welcome the attention and scientific discussion about the molecular causes and downstream pathogenic alterations in patients affected by this debilitating disease. We recognize the increasing evidence that mutations in titin domain A150 are the major and often dominant cause of HMERF. However, the conclusions the authors draw are debatable for several reasons. Firstly, the availability of next-generation sequencing, which was not available 9 years ago, allows us now to confirm from our own analysis that all affected members of the originally reported families in (Lange et al. , 2005) with the R279W titin kinase (TK) variant (TK nomenclature of residues as in PDB 1TKI to allow comparison) carry a second titin variant in the A150/Fn3 119 domain, P30091L, as also shown in a subset of these patients by Hedberg et al. (2013). Moreover, by clarifying the segregation in the …

BackgroundDermatomyositis represents one of the major forms among the inflammatory myopathies (IIM). Although the muscle biopsy remains the definitive test, MRI has been used to detect unique patterns of muscle...

Traditional posterior approaches to the hip, posterolateral and mini-posterior, violate the iliotibial band and the short external rotators, specifically the quadratus femoris and obturator externus muscles1-4. The direct anterior approach does not violate the iliotibial band or the quadratus femoris, resulting in earlier ambulation and lower dislocation rates1,5-9. The direct superior (DS) is a posterior approach that spares the iliotibial band, obturator externus tendon, and quadratus femoris muscle. The goal of minimally invasive surgery (MIS) is to disrupt the least amount of tissue necessary to adequately expose the hip and correctly place implants. Although MIS total hip arthroplasty (THA) has not lived up to all of its promises10-13, MIS-THA may enable early ambulation and decrease length of stay14-16. The patient is positioned in the lateral decubitus position. An 8 to 10-cm incision is made at a 60° oblique angle starting from the posterior-proximal corner of the greater trochanter. Only the gluteus maximus fascia is incised; the Iliotibial band is completely spared. The gluteus maximus muscle is split bluntly, exposing the gluteus medius muscle, piriformis tendon, and triceps coxae (the obturator internus and superior and inferior gemellus muscles). The piriformis and conjoined tendon are released from the greater trochanter and tagged. The gluteus minimus is elevated, exposing the posterior hip capsule. An arthrotomy is performed prior to dislocating the hip with flexion, adduction, internal rotation, and axial compression. The femoral neck is resected, the acetabulum is reamed, and components or trials are impacted into position. Hip stability is assessed. Final implants are placed. The posterior capsule, piriformis, and obturator internus tendons are repaired anatomically. The fascia and skin are closed. Posterolateral approach.Mini-posterior approach.Direct lateral approach.Anterolateral approach.Percutaneously assisted total hip (PATH).Supercapsular PATH (SuperPath). The DS approach to the hip differs from the traditional posterior and mini-posterior approaches because it preserves the iliotibial band, quadratus femoris muscle, and obturator externus tendon1, potentially suppressing dislocation. The DS approach to the hip causes less soft-tissue destruction, especially to the gluteus minimus and tensor fasciae latae muscles, compared with the direct anterior approach to the hip, suggesting DS-THA may enhance postoperative mobility1,3,14-16. DS-THA is extensile by extending the incision distally, incising the iliotibial band, and releasing the quadratus femoris muscle. This converts a DS approach to a standard posterolateral approach, providing additional visualization.

Genetic diagnosis of muscular dystrophies (MDs) has classically been guided by clinical presentation, muscle biopsy, and muscle MRI data. Muscle MRI suggests diagnosis based on the pattern of muscle fatty replacement. However, patterns overlap between different disorders and knowledge about disease-specific patterns is limited. Our aim was to develop a software-based tool that can recognize muscle MRI patterns and thus aid diagnosis of MDs. We collected 976 pelvic and lower limbs T1-weighted muscle MRIs from 10 different MDs. Fatty replacement was quantified using Mercuri score and files containing the numeric data were generated. Random forest supervised machine learning was applied to develop a model useful to identify the correct diagnosis. Two thousand different models were generated and the one with highest accuracy was selected. A new set of 20 MRIs was used to test the accuracy of the model, and the results were compared with diagnoses proposed by 4 specialists in the field. A total of 976 lower limbs MRIs from 10 different MDs were used. The best model obtained had 95.7% accuracy, with 92.1% sensitivity and 99.4% specificity. When compared with experts on the field, the diagnostic accuracy of the model generated was significantly higher in a new set of 20 MRIs. Machine learning can help doctors in the diagnosis of muscle dystrophies by analyzing patterns of muscle fatty replacement in muscle MRI. This tool can be helpful in daily clinics and in the interpretation of the results of next-generation sequencing tests. This study provides Class II evidence that a muscle MRI-based artificial intelligence tool accurately diagnoses muscular dystrophies.

Myasthenia gravis demonstrates a distinct predilection for involvement of the extraocular muscles (EOM), and we have hypothesized that this may be due to a unique immunological environment. To assess this hypothesis, we took an unbiased approach to analyze RNA expression profiles in EOM, diaphragm, and extensor digitorum longus (EDL) in rats with experimentally acquired myasthenia gravis (EAMG). Experimentally acquired myasthenia gravis was induced in rats by intraperitoneal injection of antibody directed against the acetylcholine receptor (AChR), whereas control rats received antibody known to bind the AChR but not induce disease. After 48 hours, animals were killed and muscles analyzed by RNA expression profiling. Profiling results were validated using qPCR and immunohistochemical analysis. Sixty-two genes common among all muscle groups were increased in expression. These fell into four major categories: 12.8% stress response, 10.5% immune response, 10.5% metabolism, and 9.0% transcription factors. EOM expressed 212 genes at higher levels, not shared by the other two muscles, and a preponderance of EOM gene changes fell into the immune response category. EOM had the most uniquely reduced genes (126) compared with diaphragm (26) and EDL (50). Only 18 downregulated genes were shared by the three muscles. Histological evaluation and disease load index (sum of fold changes for all genes) demonstrated that EOM had the greatest degree of pathology. Our studies demonstrated that consistent with human myasthenia gravis, EOM demonstrates a distinct RNA expression signature from EDL and diaphragm, which is based on differences in the degree of muscle injury and inflammatory response.

Neutral lipid storage disease (NLSD) is a rare inherited disorder of lipid metabolism resulting in lipid droplets accumulation in different tissues. Skeletal muscle could be affected in both two different form of disease: NLSD with myopathy (NLSD-M) and NLSD with ichthyosis (NLSD-I). We present the muscle imaging data of 12 patients from the Italian Network for NLSD: ten patients presenting NLSD-M and two patients with NLSD-I. In NLSD-M gluteus minimus, semimembranosus, soleus and gastrocnemius medialis in the lower limbs and infraspinatus in the upper limbs were the most affected muscles. Gracilis, sartorius, subscapularis, pectoralis, triceps brachii and sternocleidomastoid were spared. Muscle involvement was not homogenous and characteristic “patchy” replacement was observed in at least one muscle in all the patients. Half of the patients showed one or more STIR positive muscles. In both NLSD-I cases muscle involvement was not observed by T1-TSE sequences, but one of them showed positive STIR images in more than one muscle in the leg. Our data provides evidence that muscle imaging can identify characteristic alterations in NLSD-M, characterized by a specific pattern of muscle involvement with “patchy” areas of fatty replacement. Larger cohorts are needed to assess if a distinct pattern of muscle involvement exists also for NLSD-I.

Background and Objectives: We performed anterolateral total hip arthroplasty (ALS THA) with the purpose of complete muscle-tendon preservation without muscle-tendon dissection. This study aimed to evaluate muscle damage in the periprosthetic hip joint muscles of patients undergoing ALS THA at 1-year post-operative hip magnetic resonance imaging (MRI). Materials and Methods: We evaluated changes in the muscle cross-sectional area (M-CSA) and fatty atrophy of the periprosthetic muscles. We also assessed the Harris hip score on pre-operative and 12-month post-operative MRI in 66 patients who underwent ALS THA. The grade of M-CSA atrophy was classified into no atrophy, slight atrophy, moderate atrophy, and severe atrophy. Fatty atrophy was classified as improved, no change, and worsened using the Goutallier classification. Results: More than 90% of patients’ M-CSA had no atrophy in the obturator internus (Oi), obturator externus (Oe), gluteus medius (Gmed), and gluteus minimus (Gmin), and some improvement was observed in terms of fatty atrophy. In contrast, M-CSA of the tensor fascia latae (TFL) muscle was clearly decreased, and there was no improvement in the TFL fatty atrophy. However, the presence or absence of TFL atrophy did not affect clinical outcome. Conclusions: We performed the complete muscle preserving procedure, ALS THA, with attention to preserving the Oi and Oe by direct visual confirmation and gentle treatment of the Gmed and Gmin with effective retraction. Post-operative M-CSA atrophy evaluation on MRI showed that the Oi, Oe, Gmed, and Gmin were satisfactorily preserved; however, the TFL was clearly atrophic. In the ALS approach, where entry is made between Gmed and TFL, atrophy of the TFL due to superior gluteal nerve injury must be tolerated to some extent.