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Objective: We investigated ultrasound patterns of muscle involvement in different types of spinal muscular atrophy (SMA) and their correlation with functional status to determine the pattern of muscle compromise in patients with SMA and the potential role of ultrasound to evaluate disease progression., Methods: We examined muscles (biceps brachii, rectus femoris, diaphragm, intercostals and thoracic multifidus) of 41 patients with SMA (types 1 to 4) and 46 healthy age- and sex-matched control individuals using B-mode ultrasound for gray-scale analysis (GSA), area (biceps brachii and rectus femoris) and diaphragm thickening ratio. Functional scales were applied to patients only. We analyzed ultrasound abnormalities in specific clinical subtypes and correlated findings with functional status., Results: Compared with controls, patients had reduced muscle area and increased mean GSA for all muscles (p < 0.001), with an established correlation between the increase in GSA and the severity of SMA for biceps brachii, rectus femoris and intercostals (p = 0.03, 0.01 and 0.004 respectively) when using the Hammersmith Functional Motor Scale Expanded. Diaphragm thickening ratio was normal in the majority of patients, and intercostal muscles had higher GSA than diaphragm in relation to the controls., Conclusion: Ultrasound is useful for quantifying muscular changes in SMA and correlates with functional status. Diaphragm thickening ratio can be normal even with severe compromise of respiratory muscles in quantitative analysis, and intercostal muscles were more affected than diaphragm., Competing Interests: Conflict of interest A.L.M. has received financial compensation from General Electric (GE Healthcare) for course teaching. R.H.M. and E.Z. have received financial compensation from Biogen for congress participation and for talks. R.H.M. and E.Z. participate as investigators in clinical trials sponsored by Roche. All other authors declare no competing interests., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to compare the accuracy of ultrasound (US) with that of magnetic resonance imaging (MRI) in identifying muscle abnormalities in patients with inclusion body myositis (IBM). Twelve patients with IBM underwent muscle US and MRI on the same day. Twelve muscle groups were analyzed per patient. On US, a visual grading system was used to detect whether the muscles were affected. On MRI, muscle atrophy, fat infiltration and edema patterns were analyzed. The inter- and intra-reader reproducibility was similar for US and MRI in the evaluation of muscle abnormalities. All patients with muscle abnormalities identified on US presented with fat infiltration on MRI, which was the most common abnormality identified on MRI. Most importantly, the accuracy of US compared with that of MRI for the detection of muscle abnormalities in patients with IBM was 86.8 (κ coefficient = 0.632), with a sensitivity of 84% and specificity of 100%. In conclusion all patients with muscle abnormalities identified on US presented with fat infiltration on MRI, and the marked increase in echo intensity observed in the muscles of IBM patients was related mostly to fatty replacement. Most importantly, US exhibited significant accuracy compared with MRI., Competing Interests: Conflict of interest disclosure The authors declare no conflicts of interest., (Copyright © 2021 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Exertional rhabdomyolysis may occur when an individual is subjected to strenuous physical exercise. It is occasionally associated with myoglobinuria (i.e. "cola-colored" urine) alongside muscle pain and weakness. The pathophysiology of exertional rhabdomyolysis involves striated muscle damage and the release of cellular components into extracellular fluid and bloodstream. This can cause acute renal failure, electrolyte abnormalities, arrhythmias and potentially death. Exertional rhabdomyolysis is observed in high-performance athletes who are subjected to intense, repetitive and/or prolonged exercise but is also observed in untrained individuals and highly trained or elite groups of military personnel. Several risk factors have been reported to increase the likelihood of the condition in athletes, including: viral infection, drug and alcohol abuse, exercise in intensely hot and humid environments, genetic polymorphisms (e.g. sickle cell trait and McArdle disease) and epigenetic modifications. This article reviews several of these risk factors and proposes screening protocols to identify individual susceptibility to exertional rhabdomyolysis as well as the relevance of proteomics for the evaluation of potential biomarkers of muscle damage., Competing Interests: Declarations of Competing Interest All authors declare no potential conflict of interest related to this manuscript., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Spinal muscular atrophy (SMA) is a motor neuron disease associated with progressive muscle weakness and motor disability. The motor unit number index (MUNIX) is a biomarker used to assess loss of motor units in later-onset SMA patients. Twenty SMA patients (SMA types 3 and 4), aged between 7 and 41 years, were clinically evaluated through the Hammersmith Motor Functional Scale Expanded and the Spinal Muscular Atrophy-Functional Rating Scale. The patients underwent compound motor action potential (CMAP) and MUNIX studies of the right abductor pollicis brevis, abductor digiti minimi and tibialis anterior (TA) muscles. Age-matched healthy controls (n = 20) were enrolled to obtain normative CMAP and MUNIX values from the same muscles. Compared to healthy controls, SMA patients showed significant reductions in MUNIX values among all muscles studied, whereas CMAP showed reductions only in the weaker muscles (abductor digiti minimi and TA). MUNIX variability was significantly higher in the SMA group than in the control group. MUNIX variability in TA correlated with CMAP variability. Motor functional scores correlated with TA MUNIX. The MUNIX study is feasible in later-onset SMA patients, and TA MUNIX values correlate with disease severity in patients with mild motor impairment., Competing Interests: Declaration of Competing Interest RHM and EZ have received financial compensation from Biogen for congress participation and for talks. RHM and EZ participate as investigators in clinical trials sponsored by Roche., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study was designed to analyze the sensitivity, specificity, and accuracy of jitter parameters combined with repetitive nerve stimulation (RNS) in congenital myasthenic syndrome (CMS), chronic progressive external ophthalmoplegia (CPEO), and congenital myopathies (CM). Jitter was obtained with a concentric needle electrode during voluntary activation of the Orbicularis Oculi muscle in CMS (n = 21), CPEO (n = 20), and CM (n = 18) patients and in controls (n = 14). RNS (3 Hz) was performed in six different muscles for all patients (Abductor Digiti Minimi, Tibialis Anterior, upper Trapezius, Deltoideus, Orbicularis Oculi, and Nasalis). RNS was abnormal in 90.5% of CMS patients and in only one CM patient. Jitter was abnormal in 95.2% of CMS, 20% of CPEO, and 11.1% of CM patients. No patient with CPEO or CM presented a mean jitter higher than 53.6 µs or more than 30% abnormal individual jitter (> 45 µs). No patient with CPEO or CM and mild abnormal jitter values presented an abnormal decrement. Jitter and RNS assessment are valuable tools for diagnosing neuromuscular transmission abnormalities in CMS patients. A mean jitter value above 53.6 µs or the presence of more than 30% abnormal individual jitter (> 45 µs) strongly suggests CMS compared with CPEO and CM., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Mutations in RAPSN are an important cause of congenital myasthenic syndrome (CMS), leading to endplate acetylcholine receptor deficiency. We present three RAPSN early-onset CMS patients (from a Brazilian cohort of 61 CMS patients). Patient 1 and patient 2 harbor the mutation p.N88K in homozygosity, while patient 3 harbors p.N88K in compound heterozygosity with another pathogenic variant (p.V165M; c.493G ≥ A). At onset, patient 3 presented with more severe symptoms compared to the other two, showing generalized weakness and repeated episodes of respiratory failure in the first years of life. During adolescence, she became gradually less symptomatic and does not require medication anymore, presenting better long-term outcomes than patients 1 and 2. This case series illustrates the variability of RAPSN early-onset CMS, with patient 3, despite severe onset, revealing an almost complete reversal of myasthenic symptoms, not limited to apneic episodes. Moreover, it suggests that RAPSN CMS may be underdiagnosed in non-European countries., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Mutations in RYR1 give rise to diverse skeletal muscle phenotypes, ranging from classical central core disease to susceptibility to malignant hyperthermia. Next-generation sequencing has recently shown that RYR1 is implicated in a wide variety of additional myopathies, including centronuclear myopathy. In this work, we established an international cohort of 21 patients from 18 families with autosomal recessive RYR1-related centronuclear myopathy, to better define the clinical, imaging, and histological spectrum of this disorder. Early onset of symptoms with hypotonia, motor developmental delay, proximal muscle weakness, and a stable course were common clinical features in the cohort. Ptosis and/or ophthalmoparesis, facial weakness, thoracic deformities, and spinal involvement were also frequent but variable. A common imaging pattern consisted of selective involvement of the vastus lateralis, adductor magnus, and biceps brachii in comparison to adjacent muscles. In addition to a variable prominence of central nuclei, muscle biopsy from 20 patients showed type 1 fiber predominance and a wide range of intermyofibrillary architecture abnormalities. All families harbored compound heterozygous mutations, most commonly a truncating mutation combined with a missense mutation. This work expands the phenotypic characterization of patients with recessive RYR1-related centronuclear myopathy by highlighting common and variable clinical, histological, and imaging findings in these patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Skeletal muscle involvement as a neurologic manifestation in individuals with HIV is rare, especially as rod myopathy. We describe a 41-year-old male with HIV infection who presented progressive proximal muscle weakness and limb-girdle atrophy. A muscle magnetic resonance image showed bilateral fatty infiltration and post-contrast enhancement in the arm and thigh muscles. The muscle biopsy revealed intracytoplasmic aggregates with appearance of nemaline rod bodies with Gomori trichrome staining and electron microscopy in most fibers. The patient underwent six cycles of intravenous methylprednisolone pulses, presenting clinical improvement. Post-treatment muscle biopsy showed fewer nemaline bodies and muscle magnetic resonance image depicted a pronounced reduction of muscular edema. These findings corroborate that deposition of nemaline bodies in these patients might be related to an immune response triggered by the virus., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This study aimed to investigate the performance on pair-matching tasks in children with Spinal Muscular Atrophy type I (SMA-I) and the relationship between this performance and motor function, functional independence and quality of life. SMA-I (n = 12; 6.0 ± 2.3 yrs; 9 boys, 3 girls) and control sex-, age-matched children (n = 12; 6.2 ± 2.6 yrs) performed four pair-matching figure, number and letter tasks. The eye tracker detected eye movements. SMA-I children were assessed with CHOP INTEND, Pediatric Evaluation of Disability Inventory, and Pediatric Quality of Life Inventory. Analysis of variance showed that SMA-I children had a lower percentage of correct answers and longer timed performance compared to controls (p < 0.05). Pediatric Evaluation of Disability Inventory score (social function domain) was correlated to the percentage of correct answers on the pair-matching tasks on task 1 (r = 0.81; p = 0.001) and task 2 (r = 0.66; p = 0.020). Pair-matching performance of SMA-I children was poorer than the performance of control children. There was a relationship between pair-matching performance and social function. The restricted interaction with the environment, due to severe paralysis and poor verbal communication, is associated with cognitive difficulties in SMA-I children. The eye tracker was helpful in cognitive assessment of SMA-I children, who responded to the cognitive tests with eye movements., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We report a 3-year-old female with type I spinal muscular atrophy (SMA) born to a young and non-consanguineous couple. The child presented at two months of life with intense muscle weakness affecting predominantly proximal portions of the limbs, especially the legs, muscle hypotonia, fasciculation of the tongue, and severe respiratory muscle involvement. She remained in an intensive care unit with an assisted ventilation system from the fourth month of life. She died at 3 years of age from pulmonary infection. Molecular analysis confirmed the diagnosis of SMA but revealed that only the father was an asymptomatic carrier. Because SMN1 is mapped in a complex region containing repetitive elements due to an inverted duplication of approximately 500 kb, we carry out an SNP array and detected a 1.3 Mb deletion including the SMN1 and SMN2 genes that explain the disease., (Copyright © 2013 Elsevier B.V. All rights reserved.)

X-linked myotubular myopathy due to mutations in the MTM1 gene is classically characterized by a severe neonatal phenotype and a typical muscle biopsy presenting globular and centrally located nuclei in muscle myofibers. Recently, four patients with mild late-onset form have been described, a male with a hemizygous mutation and three females with heterozygous mutations in the MTM1 gene. The muscle biopsies were performed at 13-35 years of age and a new histological marker, the necklace fibers, was described. Here, we report two siblings with the pathogenic c.664 C>T mutation in the MTM1 gene, presenting a severe muscle weakness and respiratory impairment requiring ventilatory support since the first months of life until death, at the age of 36 months and 5 months. In the older brother the muscle biopsy, performed at the age of 30 months, showed almost 100% of necklace fibers, which were not present in the younger one submitted to muscle biopsy at 5 months of age. Our findings confirm the necklace fibers can be a histopathological finding of MTM1 myopathies, even in the severe neonatal form, and suggest that the necklace fibers appear or increase in number over time., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Nemaline myopathy is a structural congenital myopathy which may show both autosomal dominant and autosomal recessive inheritance patterns. Mutations in three different genes have been identified as the cause of nemaline myopathy: the gene for slow alpha-tropomyosin 3 (TPM3) at 1q22-23, the nebulin gene (NEB) at 2q21.1-q22, and the actin gene (ACTA1) at 1q42. The typical autosomal recessive form appears to be the most common one and is caused by mutations in the nebulin gene. We have studied the pattern of nebulin labeling, in patients with the typical congenital form (ten patients), the severe congenital form (two patients) or the mild, childhood-onset form (one patient), using antibodies against three different domains of nebulin. A qualitative and quantitative nebulin analysis in muscle tissue showed the presence of nebulin in myofibers from all patients. Some differences relating to the rod structure were observed. The majority of the largest subsarcolemmal rods were not labeled with the N2 nebulin antibody (I-band epitope) and showed an indistinct pattern with the two antibodies directed to the Z-band portion of nebulin (epitopes M176-181 and serine-rich domain). Diffuse rods were not revealed using the three antibodies. A discordant pattern of nebulin N2 epitope labeling was found in two affected sisters with a mutation in the nebulin gene, suggesting that modifications in nebulin distribution inside the rods might occur with the progression of the disease. Western blot analysis showed no direct correlation with immunofluorescence data. In nine patients, the band had a molecular weight comparable to the normal control, while in one patient, it was detected with a higher molecular weight. Our results suggest that presence/absence of specific nebulin Z-band epitopes in rod structures is variable and could depend on the degree of rod organization.