Muscular dystrophies are characterized by weakness and wasting of skeletal muscle tissues. Several drugs targeting the myostatin pathway have been used in clinical trials to increase muscle mass and ...function but most showed limited efficacy. Here we show that the expression of components of the myostatin signaling pathway is downregulated in muscle wasting or atrophying diseases, with a decrease of myostatin and activin receptor, and an increase of the myostatin antagonist, follistatin. We also provide in vivo evidence in the congenital myotubular myopathy mouse model (knock-out for the myotubularin coding gene Mtm1) that a down-regulated myostatin pathway can be reactivated by correcting the underlying gene defect. Our data may explain the poor clinical efficacy of anti-myostatin approaches in several of the clinical studies and the apparent contradictory results in mice regarding the efficacy of anti-myostatin approaches and may inform patient selection and stratification for future trials.
Cancer can occur in patients with inflammatory myopathies. This association is mainly observed in dermatomyositis, and myositis-specific antibodies have allowed us to delineate patients at an ...increased risk. Malignancy is also reported in patients with necrotizing autoimmune myopathies, but the risk remains elusive. Anti-signal recognition particle or anti-HMGCR antibodies have been specifically associated with necrotizing autoimmune myopathies. We aimed at screening the incidence of cancer in necrotizing autoimmune myopathies. A group of patients (n = 115) with necrotizing autoimmune myopathies with or without myositis-specific antibodies was analysed. Malignancy occurred more frequently in seronegative necrotizing autoimmune myopathies patients and in HMGCR-positive patients compared to anti-signal recognition particle positive patients. Synchronous malignancy was diagnosed in 21.4% and 11.5% of cases, respectively, and incidence of cancer was higher compared to the general population in both groups. No specific type of cancer was predominant. Patients suffering from a synchronous cancer had a decreased median survival time. Cancer screening is necessary in seronegative necrotizing autoimmune myopathies and in HMGCR-positive patients but not in anti-signal recognition particle-positive patients.
Outcome measures for clinical trials in neuromuscular diseases are typically based on physical assessments which are dependent on patient effort, combine the effort of different muscle groups, and ...may not be sensitive to progression over short trial periods in slow-progressing diseases. We hypothesised that quantitative fat imaging by MRI (Dixon technique) could provide more discriminating quantitative, patient-independent measurements of the progress of muscle fat replacement within individual muscle groups.
To determine whether quantitative fat imaging could measure disease progression in a cohort of limb-girdle muscular dystrophy 2I (LGMD2I) patients over a 12 month period.
32 adult patients (17 male;15 female) from 4 European tertiary referral centres with the homozygous c.826C>A mutation in the fukutin-related protein gene (FKRP) completed baseline and follow up measurements 12 months later. Quantitative fat imaging was performed and muscle fat fraction change was compared with (i) muscle strength and function assessed using standardized physical tests and (ii) standard T1-weighted MRI graded on a 6 point scale.
There was a significant increase in muscle fat fraction in 9 of the 14 muscles analyzed using the quantitative MRI technique from baseline to 12 months follow up. Changes were not seen in the conventional longitudinal physical assessments or in qualitative scoring of the T₁w images.
Quantitative muscle MRI, using the Dixon technique, could be used as an important longitudinal outcome measure to assess muscle pathology and monitor therapeutic efficacy in patients with LGMD2I.
Demyelinating Charcot-Marie-Tooth 4G (CMT4G) results from a recessive mutation in the 5'UTR region of the Hexokinase 1 (HK1) gene. HK participates in mitochondrial calcium homeostasis by binding to ...the Voltage-Dependent Anion Channel (VDAC), through its N-terminal porin-binding domain. Our hypothesis is that CMT4G mutation results in a broken interaction between mutant HK1 and VDAC, disturbing mitochondrial calcium homeostasis. We studied a cohort of 25 CMT4G patients recruited in the French gypsy population. The disease was characterized by a childhood onset, an intermediate demyelinating pattern, and a significant phenotype leading to becoming wheelchair-bound by the fifth decade of life. Co-IP and PLA studies indicated a strong decreased interaction between VDAC and HK1 in the patients' PBMCs and sural nerve. We observed that either wild-type HK1 expression or a peptide comprising the 15 aa of the N-terminal wild-type HK1 administration decreased mitochondrial calcium release in HEK293 cells. However, mutated CMT4G HK1 or the 15 aa of the mutated HK1 was unable to block mitochondrial calcium release. Taken together, these data show that the CMT4G-induced modification of the HK1 N-terminus disrupts HK1-VDAC interaction. This alters mitochondrial calcium buffering that has been shown to be critical for myelin sheath maintenance.
In patients with neuromuscular disorders, assessment of respiratory function relies on forced vital capacity (FVC) measurements. Providing complementary respiratory outcomes may be useful for ...clinical trials. Diaphragm sniff ultrasound (US) is a noninvasive technique that can assess diaphragm function that may be affected in patients with neuromuscular disorders.
We aimed to provide normal values of sniff diaphragm ultrasound, to assess the relationship between sniff diaphragm US, vital capacity (VC) and sniff nasal pressure. Additionally, we aimed to evaluate the diagnostic accuracy of sniff diaphragm US for predicting restrictive pulmonary insufficiency.
We included patients with neuromuscular disorders that had been tested with a sniff diaphragm US and functional respiratory tests. Healthy subjects were also included to obtain normal diaphragm sniff ultrasound. We performed diaphragm tissue Doppler imaging (TDI) and time movement (TM) diaphragm echography combined with sniff maneuver.
A total of 89 patients with neuromuscular diseases and 27 healthy subjects were included in our study. In patients, the median age was 32 years 25; 50 and the median FVC was 34% of predicted 18; 55. Sniff diaphragm motion using TM ultrasound was significantly associated with sniff nasal pressure, both for the right hemidiaphragm (r = 0.6 p <0.0001) and the left hemidiaphragm (r = 0.63 p = 0.0008). Right sniff peak TDI velocity was also significantly associated with FVC (r = 0.72, p<0.0001) and with sniff nasal pressure (r = 0.66 p<0.0001). Sniff diaphragm ultrasound using either TM mode or TDI displayed significant accuracy for predicting FVC<60% with an area under curve (AUC) reaching 0.93 (p<0.0001) for the right sniff diaphragm ultrasound in TM mode and 0.86 (p<0.001) for right peak diaphragm TDI velocity.
Sniff diaphragm TM and TDI measures were significantly associated with sniff nasal pressure. Sniff diaphragm TM and TDI had a high level of accuracy to reveal respiratory involvement in patients with neuromuscular disorders. This technique is useful to assess and follow up diaphragm function in patients with neuromuscular disorders. It may be used as a respiratory outcome for clinical trials.
Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we ...present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.
Patiente, âgée de 58 ans, adressée en 2020 pour un déficit moteur et une amyotrophie des mains intéressant les muscles thénars, hypothénars et les extenseurs des doigts associés à une hypoesthésie ...des doigts et du dos des mains. Les réflexes ostéotendineux sont abolis aux membres supérieurs et présents aux membres inférieurs. La patiente rapporte depuis l’âge de 14 ans des épisodes de faiblesse motrice distale et proximale, parfois douloureux, des membres supérieurs avec récupération motrice incomplète. Le diagnostic de neuropathie avec hypersensibilité à la pression a été posé à 20 ans, sans preuve génétique.
En 2021, la patiente se plaint 10 jours après une vaccination contre la COVID-19, d’une douleur intense localisée à l’omoplate gauche irradiant vers le bras et l’avant-bras gauche rapidement suivi d’une déficit moteur complet des extenseurs des doigts, du poignet et du long supinateur gauche. L’ENMG met en évidence une atteinte sensitivomotrice hétérogène et asymétrique évoquent une atteinte plexique bilatérale, prédominant au membre supérieur gauche. Un examen paraclinique va permettre d’établir le diagnostic de ce déficit moteur et sensitif des membres supérieurs évoluant depuis l’adolescence.
JAG2 has recently been involved in autosomal recessive forms of muscular dystrophy as illustrated in this clinical vignette. In many ways, this disease can mimick a COL6-related retractile myopathy ...including at the imaging level.
Emery-Dreifuss muscular dystrophy (EDMD) is a rare disorder characterized by early joint contractures, muscular dystrophy, and cardiac involvement with conduction defects and arrhythmias. So far, ...only 35% of EDMD cases are genetically elucidated and associated with
EMD or
LMNA gene mutations, suggesting the existence of additional major genes. By whole-genome scan, we identified linkage to the Xq26.3 locus containing the
FHL1 gene in three informative families belonging to our
EMD- and
LMNA-negative cohort. Analysis of the
FHL1 gene identified seven mutations, in the distal exons of
FHL1 in these families, three additional families, and one isolated case, which differently affect the three FHL1 protein isoforms: two missense mutations affecting highly conserved cysteines, one abolishing the termination codon, and four out-of-frame insertions or deletions. The predominant phenotype was characterized by myopathy with scapulo-peroneal and/or axial distribution, as well as joint contractures, and associated with a peculiar cardiac disease characterized by conduction defects, arrhythmias, and hypertrophic cardiomyopathy in all index cases of the seven families. Heterozygous female carriers were either asymptomatic or had cardiac disease and/or mild myopathy. Interestingly, four of the
FHL1-mutated male relatives had isolated cardiac disease, and an overt hypertrophic cardiomyopathy was present in two. Expression and functional studies demonstrated that the FHL1 proteins were severely reduced in all tested patients and that this was associated with a severe delay in myotube formation in the two patients for whom myoblasts were available. In conclusion,
FHL1 should be considered as a gene associated with the X-linked EDMD phenotype, as well as with hypertrophic cardiomyopathy.
To determine the clinical spectrum of limb-girdle muscular dystrophy 2E (LGMD2E) and to investigate whether genetic or biochemical features can predict the phenotype of the disease.
All LGMD2E ...patients followed in participating centers were included. A specific clinical protocol was created, including quantitative evaluation of motor, respiratory, and cardiac function. Phenotype was defined as severe or mild if the age at loss of ambulation occurred before or after 18 years. Molecular analysis of SGCB gene and biochemical features of muscle biopsies were reviewed.
Thirty-two patients were included (16 male, 16 female; age 7-67 years; 15 severe, 12 mild, and 5 unknown). Neurologic examination showed proximal muscle weakness in all patients, but distal involvement was also observed in patients with severe disease early in the disease course. Cardiac involvement was observed in 20 patients (63%) even before overt muscle involvement. Six patients had restrictive respiratory insufficiency requiring assisted ventilation (19%). Seventeen different mutations were identified, and 3 were recurrent. The c.377_384dup (13 alleles) was associated with the severe form, the c.-22_10dup (10) with the milder form, and the c.341C>T (9) with both. The entire sarcoglycan complex was undetectable by muscle immunohistochemistry or Western blot in 9/10 severe cases and reduced in 7/7 mild cases. The residual amount of sarcoglycan in muscle resulted a predictor of age at loss of ambulation.
This study expands the spectrum of phenotype in β-sarcoglycanopathy and provides strong evidence that severity of clinical involvement may be predicted by SGCB gene mutation and sarcoglycan protein expression.
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