Objectives
Magnetic resonance imaging (MRI) constitutes a powerful outcome measure in neuromuscular disorders, yet there is a broad diversity of approaches in data acquisition and analysis. Since ...each neuromuscular disease presents a specific pattern of muscle involvement, the recommended analysis is assumed to be the muscle-by-muscle approach. We, therefore, performed a comparative analysis of different segmentation approaches, including global muscle segmentation, to determine the best strategy for evaluating disease progression.
Methods
In 102 patients (21 immune-mediated necrotizing myopathy/IMNM, 21 inclusion body myositis/IBM, 10 GNE myopathy/GNEM, 19 Duchenne muscular dystrophy/DMD, 12 dysferlinopathy/DYSF, 7 limb-girdle muscular dystrophy/LGMD2I, 7 Pompe disease, 5 spinal muscular atrophy/SMA), two MRI scans were obtained at a 1-year interval in thighs and lower legs. Regions of interest (ROIs) were drawn in individual muscles, muscle groups, and the global muscle segment. Standardized response means (SRMs) were determined to assess sensitivity to change in fat fraction (ΔFat%) in individual muscles, muscle groups, weighted combinations of muscles and muscle groups, and in the global muscle segment.
Results
Global muscle segmentation gave high SRMs for ΔFat% in thigh and lower leg for IMNM, DYSF, LGMD2I, DMD, SMA, and Pompe disease, and only in lower leg for GNEM and thigh for IBM.
Conclusions
Global muscle segment Fat% showed to be sensitive to change in most investigated neuromuscular disorders. As compared to individual muscle drawing, it is a faster and an easier approach to assess disease progression. The use of individual muscle ROIs, however, is still of interest for exploring selective muscle involvement.
Key Points
• MRI-based evaluation of fatty replacement in muscles is used as an outcome measure in the assessment of 1-year disease progression in 8 different neuromuscular diseases.
• Different segmentation approaches, including global muscle segmentation, were evaluated for determining 1-year fat fraction changes in lower limb skeletal muscles.
• Global muscle segment fat fraction has shown to be sensitive to change in lower leg and thigh in most of the investigated neuromuscular diseases.
Phosphoglycerate kinase (PGK) deficiency is a rare X‐linked metabolic disorder caused by mutations in the PGK1 gene. Patients usually develop various combinations of nonspherocytic hemolytic anemia ...(NSHA), myopathy, and central nervous system disorders. In this national multicenter observational retrospective study, we recorded all known French patients with PGK deficiency, and 3 unrelated patients were identified. Case 1 was a 32‐year‐old patient with severe chronic axonal sensorimotor polyneuropathy resembling Charcot–Marie–Tooth (CMT) disease, mental retardation, microcephaly, ophthalmoplegia, pes cavus, and the new c.323G > A PGK1 hemizygous mutation. Case 2 was a 71‐year‐old patient with recurrent exertional rhabdomyolysis, and a c.943G > A PGK1 hemizygous mutation. Case 3 was a 48‐year‐old patient with NSHA, retinitis pigmentosa, mental retardation, seizures, stroke, parkinsonism, and a c.491A > T PGK1 hemizygous mutation. This study confirms that PGK deficiency is an extremely rare disorder with a wide phenotypic spectrum, and demonstrates for the first time that PGK deficiency may affect the peripheral nervous system and present as a CMT‐like disorder.
Acquired Myasthenia Gravis (MG) is a neuromuscular disease caused by autoantibodies against components of the neuromuscular junction. It is a prototype organ-specific autoimmune disease with ...well-defined antigenic targets mainly the nicotinic acetylcholine receptor (AChR). Patients suffer from fluctuating, fatigable muscle weakness that worsens with activity and improves with rest.Various therapeutic strategies have been used over the years to alleviate MG symptoms. These strategies aim at improving the transmission of the nerve impulse to muscle or at lowering the immune system with steroids or immunosuppressant drugs. Nevertheless, MG remains a chronic disease and symptoms tend to persist in many patients, some being or becoming refractory over time. In this review, based on recent experimental data on MG or based on results from clinical trials for other autoimmune diseases, we explore new potential therapeutic approaches for MG patients, going from non-specific approaches with the use of stem cells with their anti-inflammatory and immunosuppressive properties to targeted therapies using monoclonal antibodies specific for cell-surface antigens or circulating molecules.
The aim of this study is to assess the long-term cardiac prognosis of adults with mitochondrial diseases.
Between January 2000 and May 2014, we retrospectively included in this study 260 consecutive ...patients (60% women) ≥18 years (interquartile range 31-54), with genetically proven mitochondrial diseases, including 109 with mitochondrial DNA (mtDNA) single large-scale deletions, 64 with the m.3243A>G mutation in MT-TL1, 51 with other mtDNA point mutations, and 36 patients with nuclear gene mutations. Cardiac involvement was present at baseline in 81 patients (30%). Single and multiple variable analyses were performed in search of predictors of major adverse cardiac events (MACEs), and hazard ratios (HRs) and 95% confidence intervals (CI) were calculated. Over a median follow-up of 7 years (3.6-11.7), 27 patients (10%) suffered a MACE, defined as sudden death, death due to heart failure (HF), resuscitated cardiac arrest, third-degree atrioventricular block, sinus node dysfunction, cardiac transplantation, or hospitalization for management of HF. Patients with single large-scale mtDNA deletions or m.3243A>G mutations had the highest incidence of MACE. By multiple variable analysis, intraventricular conduction block (HR = 16.9; 95% CI: 7.2-39.4), diabetes (HR = 7.0; 95% CI: 2.9-16.7), premature ventricular complexes (HR = 3.6; 95% CI: 1.4-9.2), and left ventricular (LV) hypertrophy (HR = 2.5; 95% CI: 1.1-5.8) were independent predictors of MACEs. In patients with zero, one, and two or more risk factors, the incidences of MACE were 1.7, 15 and 42%, respectively.
Patients with mitochondrial diseases are at high risk of MACE, independently predicted by intraventricular conduction block, diabetes, ventricular prematurity, and LV hypertrophy.
Beyond the observed alterations in cellular structure and mitochondria, the mechanisms linking rare genetic mutations to the development of heart failure in patients affected by desmin mutations ...remain unclear due in part, to the lack of relevant human cardiomyocyte models.
To shed light on the role of mitochondria in these mechanisms, we investigated cardiomyocytes derived from human induced pluripotent stem cells carrying the heterozygous DES
mutation that were either isolated from a patient or generated by gene editing. To increase physiological relevance, cardiomyocytes were either cultured on an anisotropic micropatterned surface to obtain elongated and aligned cardiomyocytes, or as a cardiac spheroid to create a micro-tissue. Moreover, when applicable, results from cardiomyocytes were confirmed with heart biopsies of suddenly died patient of the same family harboring DES
mutation, and post-mortem heart samples from five control healthy donors.
The heterozygous DES
mutation leads to dramatic changes in the overall cytoarchitecture of cardiomyocytes, including cell size and morphology. Most importantly, mutant cardiomyocytes display altered mitochondrial architecture, mitochondrial respiratory capacity and metabolic activity reminiscent of defects observed in patient's heart tissue. Finally, to challenge the pathological mechanism, we transferred normal mitochondria inside the mutant cardiomyocytes and demonstrated that this treatment was able to restore mitochondrial and contractile functions of cardiomyocytes.
This work highlights the deleterious effects of DES
mutation, demonstrates the crucial role of mitochondrial abnormalities in the pathophysiology of desmin-related cardiomyopathy, and opens up new potential therapeutic perspectives for this disease.
FSHD1 and FSHD2 form a disease continuum Sacconi, Sabrina; Briand-Suleau, Audrey; Gros, Marilyn ...
Neurology,
2019-May-07, Letnik:
92, Številka:
19
Journal Article
Recenzirano
Odprti dostop
To compare the clinical features of patients showing a classical phenotype of facioscapulohumeral muscular dystrophy (FSHD) with genetic and epigenetic characteristics of the FSHD1 and FSHD2 loci ...D4Z4 and
.
This is a national multicenter cohort study. We measured motor strength, motor function, and disease severity by manual muscle testing sumscore, Brooke and Vignos scores, clinical severity score (CSS), and age-corrected CSS, respectively. We correlated these scores with genetic (D4Z4 repeat size and haplotype;
variant status) and epigenetic (D4Z4 methylation) parameters.
We included 103 patients: 54 men and 49 women. Among them, we identified 64 patients with FSHD1 and 20 patients with FSHD2. Seven patients had genetic and epigenetic characteristics of FSHD1 and FSHD2, all carrying repeats of 9-10 D4Z4 repeat units (RU) and a pathogenic
variant. In the remaining patients, FSHD was genetically excluded or remained unconfirmed. All clinically affected
mutation carriers had a D4Z4 repeat of 9-16 RU on a disease permissive 4qA haplotype. These patients are significantly more severely affected by all clinical scales when compared to patients with FSHD1 with upper-sized FSHD1 alleles (8-10 RU).
The overlap between FSHD1 and FSHD2 patients in the 9-10 D4Z4 RU range suggests that FSHD1 and FSHD2 form a disease continuum. The previously established repeat size threshold for FSHD1 (1-10 RU) and FSHD2 (11-20 RU) needs to be reconsidered.
NCT01970735.
•MUNIX values are decreased in type III and IV spinal muscular atrophy (SMA) patients compared to healthy controls.•The MUNIX profile of SMA patients correlates with muscle strength and ...disability.•The MUSIX values of SMA patients are increased and Suggesting active re-innervation.
Objective of this study is the comprehensive characterisation of motor unit (MU) loss in type III and IV Spinal Muscular Atrophy (SMA) using motor unit number index (MUNIX), and evaluation of compensatory mechanisms based on MU size indices (MUSIX).
Nineteen type III and IV SMA patients and 16 gender- and age-matched healthy controls were recruited. Neuromuscular performance was evaluated by muscle strength testing and functional scales. Compound motor action potential (CMAP), MUNIX and MUSIX were studied in the abductor pollicis brevis (APB), abductor digiti minimi (ADM), deltoid, tibialis anterior and trapezius muscles. A composite MUNIX score was also calculated.
SMA patients exhibited significantly reduced MUNIX values (p < 0.05) in all muscles, while MUSIX was increased, suggesting active re-innervation. Significant correlations were identified between MUNIX/MUSIX and muscle strength. Similarly, composite MUNIX scores correlated with disability scores. Interestingly, in SMA patients MUNIX was much lower in the ADM than in the ABP, a pattern which is distinctly different from that observed in Amyotrophic Lateral Sclerosis.
MUNIX is a sensitive measure of MU loss in adult forms of SMA and correlates with disability.
MUNIX evaluation is a promising candidate biomarker for longitudinal studies and pharmacological trials in adult SMA patients.
Background
To evaluate the prevalence of cardiac involvement in patients with congenital myopathies and the association to specific genotypes.
Methods
We evaluated patients with physical examination, ...electrocardiogram, echocardiography, and 48-h Holter monitoring. Follow-up was performed for major events.
Results
We included 130 patients, 55 men (42%), with a mean age of 34 ± 17 years. A genetic diagnosis was established in 97 patients (75%). Right bundle branch block was observed in three patients: 2/34 patients with a ryanodine receptor 1 (
RYR1
) and 1/6 with a tropomyosin two gene (
TPM2
) gene mutation. Echocardiography showed left-ventricular hypertrophy in five patients: 2/17 and 3/34 patients with a Dynamin 2 (
DNM2
) and a
RYR1
mutation, respectively. One patient with a myosin heavy-chain (
MYH7)
mutation had dilated cardiomyopathy and heart failure. On Holter monitoring, frequent ventricular premature contractions were observed in one patient with a
DNM2
mutation. Two patients with a
TPM2
and a
RYR1
mutation, respectively, had a single short run of non-sustained ventricular tachycardia. Atrioventricular nodal re-entry tachycardia was observed in a 20-year-old man with an
actin 1 gene
mutation. During follow-up (median 8.4 years), four patients died, all of non-cardiac causes.
Conclusion
Congenital myopathies are generally associated with a mild cardiac phenotype. Our findings substantiate the literature and indicate that, except for patients with specific genotypes, such as
MYH7
and
TTN
mutations, repeated cardiac assessments can be minimized, given a normal initial cardiac screening at time of diagnosis.
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