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The finding of a short D4Z4-allele in a patient with shoulder-facial weakness is consistent with the diagnosis of FSHD1. However, when a normal or borderline length D4Z4 fragment is found, alternative diagnoses must be considered, and an extended diagnostic workout is then necessary. We analyzed 33 cases from 5 Italian neuromuscular Centers, tested for a clinical suspect of FSHD and displaying D4Z4 alleles > 38kb, classified according to the CCEF clinical categories (as per initial phenotype). Patients underwent extensive assessments, eventually including muscle biopsy and/or broad-spectrum genetic investigation, revealing pathogenic/likely pathogenic variants in different genes (ACMG classes 4 and 5), or significant comorbidities. Alternative diagnoses were distributed within the clinical categories as follows: category A: 6 SMCHD1, 1 COL6A , and 1 Inclusion-Body Myositis-like case; category B1: 3 SMCHD1 ; category D: 4 CAPN3 (2 recessive and 2 dominant), 3 COL6A, 1 DMPK, 2 DMD (Becker phenotype), 1 EMD , 1 FKRP , 1 GAA , 1 MYH7 , 1 RYR1 , 1 SEPN1 , 1 SGCG , and 1 PMP22 -linked CMT-like distal phenotype. Other FSHD-mimics included also a post-radiation cervical syndrome, a chronic inflammatory demyelinating polyneuropathy (CIDP), a multiple sclerosis (MS), and a Turner syndrome. D4Z4-allele genetic analysis is justified in all cases exhibiting facial and shoulder girdle weakness, but its interpretation requires a thorough characterization of phenotype. In fact, especially in cases with atypical features (Category D), various concomitant/alternative conditions may be diagnosed, besides the more common FSHD type 2 due to SMCHD1 mutations. Therefore, a cautious diagnostic conclusion is required, especially in cases with borderline length D4Z4 alleles. [ABSTRACT FROM AUTHOR]

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common dystrophy, in which different phenotypes can be observed, showing different disease progression and/or implying distinct genetic mechanisms. To date, the diagnostic criteria are based on the detection of the genetic signature (reduced D4Z4 allele, permissive haplotype, hypomethylation, mutations in modifiers genes as SMCHD1, LRF1 or DNMT3B). Still, the interpretation of the genetic test cannot ignore a careful correlation with the phenotype. We present data of a cohort of 43 patients from 24 families selected by phenotypic features, characterized by incomplete penetrance/atypical phenotypes according to the Comprehensive Clinical Evaluation Form (CCEF), in which a short D4Z4 allele segregated. The molecular characterization included the assessment of 4q subtype, DNA methylation levels, Whole Exome Sequencing (WES) and segregation analysis. In our cohort, methylation levels displayed high variability in relation to the disease phenotype. In more than half of the atypical phenotypes, despite the detection of the FSHD genetic signature, WES analysis identified VUS or likely pathogenic/pathogenic variants in other genes associated with neuromuscular disorders, compatible with the observed phenotype, or known FSHD-modifying genes. A definitive alternative diagnosis was obtained in 5 families. Our results further support the need to perform a detailed phenotypic characterization of patients with a suspect of FSHD, and, in cases of atypical phenotypes, to combine the D4Z4 sizing with other procedures such as WES. In this regard, methylation analysis represents a valuable tool to provide preliminary evidence for FSHD to be confirmed by further testing. [ABSTRACT FROM AUTHOR]

Magnetization transfer imaging (MTI) evaluates the exchange of magnetization between protons in free water molecules and protons bound to macromolecules, including lipids. Widely used in the study of central nervous system diseases, its application in the neuromuscular field has been previously explored only in a Spanish cohort of patients with late-onset Pompe disease (LOPD). To investigate the potential role of MTR as an early biomarker of muscle involvement, we here evaluate magnetization transfer ratio (MTR) and fat fraction (FF) in patients with LOPD in various stages of disease compared to healthy controls (HCs). Quantitative muscle MRI (qMRI) was performed on 31 LOPD patients (21 with mild and 10 with moderate/severe clinical involvement) and 31 matched HCs using 3T MRI. FF and MTR were measured in 11 thigh muscles. Correlations between FF and MTR were assessed. Additionally, FF and MTR were compared between groups of HCs vs. early vs. moderate/severe LOPD. We also explored whether MTR can detect muscle involvement in not yet fat-infiltrated muscles (FF ≤ 10%) in early LOPD. MTR of thigh muscles with FF ≤ 10% was significantly lower in LOPD compared to HCs. Changes in MTR could be detected even in mildly symptomatic patients, particularly in the medial and posterior compartments (Mann-Whitney U: p < 0.05). MTR and FF were inversely correlated in all subjects groups. We found significant differences in MTR and FF changes at the group level between mild and moderate/severe vs HCs. We conclude that MTI has potentially high sensitivity to detect mild muscle fiber damage, even before fat replacement has occurred, making it a useful biomarker to monitor early signs of disease, disease progression, and the efficacy of treatment approaches (Sanofi company provided support for this study, but had no role in study design, data collection and analysis, decision to publish, or preparation of the abstract). (The first and second authors contributed equally to this work) [ABSTRACT FROM AUTHOR]

LMNA gene mutations have been associated with several diseases. Some of them are muscle disorders, including the autosomal dominant and recessive forms of Emery-Dreifuss muscular dystrophy (EDMD2 and EDMD3), limb-girdle muscular dystrophy 1B (LGMD1B) and congenital muscular dystrophy (MDCL). With few exceptions, most of the studies are focused on one of these phenotypes and data on large cohorts of myopathic patients are lacking. The aim of our study was to evaluate clinical, neurophysiologic, histological and molecular features of 77 myopathic patients mutated in LMNA gene and followed in different Italian neuromuscular centres. Patients with predominant or exclusively progeroid/lipodystrophic or cardiac phenotype were excluded. The cohort included 36 (46.8%) patients with LGMD1B phenotype, 30 (39%) with EDMD2 and 11 with MDCL (14.3%). Mean age at onset was 10.3±12.3years in patients with EDMD2, 29.5±17.6 in LGMD1B and 0.4±0.5 in MDCL. Independent walking was reached in all patients, with the exception of 4 (5.2%) MDCL, who never acquired the ability to stand up. Another 4 (5.2%) patients (3 LGMD1B and 1 EDMD2) lost ambulation, and 3 EDMD2 (3.9%), required monolateral support to walk. Cardiac involvement was found in 57 (74%) patients. Pacemaker or ICD were implanted in 42 (54.5%) patients (21 EDMD2, 18 LGMD1B and 3 MDCL), while heart transplant was performed in 5 (6.5%) patients (3 EDMD2 and 2 with LGMD1B). Six (7.8%) patients died due to cardiac problems (3 EDMD2 and 3 MDCL). Only 5 (6.5%) patients required non-invasive ventilation (4 EDMD2 and 1 CMD), confirming that respiratory problems are not a major issue in LMNA-associated myopathies. Ten novel mutations were detected. Despite EDMD2, LGMD1B and MDCL phenotypes are part of a continuum spectrum, their identification is clinically and prognostically relevant. [ABSTRACT FROM AUTHOR]

We have conducted a study to evaluate tolerability and efficacy of salbutamol in 45 type III adult SMA patients. Patients enrolled in the study were randomly divided into two groups treated, under double-blind conditions, with salbutamol or identical placebo tablets at the same dosing schedule. Patients were evaluated at baseline, and after 3, 6, and 12months of treatment by Manual Muscle Testing, North Star Ambulatory Assessment scale, 6-Minute Walk Test and forced vital capacity. Molecular analyses included SMN2 gene copy number, SMN2 transcript, and SMN protein levels. Thirty-six patients completed the study (19 in the treated-group and 17 in the placebo-group): 8 patients were lost at the follow-up, 1 salbutamol-treated patient was withdrawn from the trial after 6months because of diffuse erythematic eruption, improbably related to the drug. SMN2-fl transcript levels progressively increased in all salbutamol-treated patients (p <0.00001), while remained highly stable in the placebo-group (p >0.61). SMN protein levels in longitudinal samples were highly variable in both groups. In the treated-group, 8/11 walking patients showed a statistically significant increase in NSAA score (p =0.03) and in the 6MWT (p =0.02). In both ambulant and non-ambulant subjects, MRC total score significantly increased in 11/19 patients from the treated-group (p =0.003) but not in the placebo group (p =0.80). We did not observe any correlation between SMN2-fl level increase and variation of clinical outcome measures. Of the 36 patients who had completed the double-blind study, 21 continued the follow-up and were re-evaluated after 1year, with the same protocol. Our study shows that salbutamol is well tolerated, significantly increases SMN2-fl transcripts, and induces a clinically meaningful improvement of motor performance in the majority of patients. [Copyright &y& Elsevier]