Familial childhood onset, slowly progressive myopathy plus cardiomyopathy expands the phenotype related to variants in the TTN gene.

This report describes a novel TTN -related phenotype in two brothers, both affected by a childhood onset, very slowly progressive myopathy with cores, associated with dilated cardiomyopathy only in their late disease stages. Clinical exome sequencing documented in both siblings the heterozygous c.2089A>T and c.19426+2T>A variants in TTN. The c.2089A>T, classified in ClinVar as possibly pathogenic, introduces a premature stop codon in exon 14, whereas the c.19426+2T>A affects TTN alternative splicing. The unfeasibility of segregation studies prevented us from establishing the inheritance mode of the muscle disease in this family, although the lack of any reported muscle or heart symptoms in both parents might support an autosomal recessive transmission. In this view, the occurrence of cardiomyopathy in both probands might be related to the c.2089A>T truncating variant in exon 14, and the childhood onset, slowly progressive myopathy to the c.19426+2T>A splicing variant, possibly allowing translation of an almost full length TTN protein.

Hospital admissions from the emergency department of adult patients affected by myopathies.

BACKGROUND AND PURPOSE: Myopathies are associated with classic signs and symptoms, but also with possible life-threatening complications that may require assistance in an emergency setting. This phenomenon is understudied in the literature. We aimed to assess the presentation, management, and outcomes of clinical manifestations potentially related to a muscle disorder requiring referral to the adult emergency department (ED) and hospitalization. METHODS: Anonymized patient data retrieved using the International Classification of Diseases, Ninth Revision codes related to muscle disorders over 4 years were retrospectively analyzed. Medical reports were evaluated to extract demographic and clinical variables, along with outcomes. Two groups were defined based on the presence (known diagnosis [KD] group) or absence (unknown diagnosis [UD] group) of a diagnosed muscle disorder at arrival. RESULTS: A total of 244 patients were included, 51% of whom were affected by a known myopathy, predominantly limb-girdle muscular dystrophies and myotonic dystrophies. The main reasons for ED visits in the KD group were respiratory issues, worsening of muscle weakness, and gastrointestinal problems. Heart complications were less prevalent. In the UD group, 27 patients received a new diagnosis of a specific primary muscle disorder after the ED access, mostly an inflammatory myopathy. Death during hospitalization was recorded in 26 patients, with a higher rate in the KD group and in patients affected by mitochondrial and inflammatory myopathies. Sepsis and dyspnea were associated with increased death risk. CONCLUSIONS: Respiratory complications are the most common reason for myopathic patients accessing the ED, followed by gastrointestinal issues. Infections are severe threats and, once hospitalized, these patients have relatively high mortality.

Whole exome sequencing highlights rare variants in CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1 as associated with FSHD.

Introduction: Despite the progress made in the study of Facioscapulohumeral Dystrophy (FSHD), the wide heterogeneity of disease complicates its diagnosis and the genotype-phenotype correlation among patients and within families. In this context, the present work employed Whole Exome Sequencing (WES) to investigate known and unknown genetic contributors that may be involved in FSHD and may represent potential disease modifiers, even in presence of a D4Z4 Reduced Allele (DRA). Methods: A cohort of 126 patients with clinical signs of FSHD were included in the study, which were characterized by D4Z4 sizing, methylation analysis and WES. Specific protocols were employed for D4Z4 sizing and methylation analysis, whereas the Illumina® Next-Seq 550 system was utilized for WES. The study included both patients with a DRA compatible with FSHD diagnosis and patients with longer D4Z4 alleles. In case of patients harboring relevant variants from WES, the molecular analysis was extended to the family members. Results: The WES data analysis highlighted 20 relevant variants, among which 14 were located in known genetic modifiers (SMCHD1, DNMT3B and LRIF1) and 6 in candidate genes (CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1). Most of them were found together with a permissive short (4-7 RU) or borderline/long DRA (8-20 RU), supporting the possibility that different genes can contribute to disease heterogeneity in presence of a FSHD permissive background. The segregation and methylation analysis among family members, together with clinical findings, provided a more comprehensive picture of patients. Discussion: Our results support FSHD pathomechanism being complex with a multigenic contribution by several known (SMCHD1, DNMT3B, LRIF1) and possibly other candidate genes (CTCF, DNMT1, DNMT3A, EZH2, SUV39H1) to disease penetrance and expressivity. Our results further emphasize the importance of extending the analysis of molecular findings within the proband's family, with the purpose of providing a broader framework for understanding single cases and allowing finer genotype-phenotype correlations in FSHD-affected families.

ANCA-negative microscopic polyangiitis with neuromuscular involvement: When pathology could make the difference.

Microscopic polyangiitis (MPA) is a necrotizing small vessel vasculitis with little or absent immune deposits (pauci-immune vasculitis), usually associated with the presence of antineutrophil cytoplasmic autoantibodies (ANCA) and a wide spectrum of organ manifestations. In our report we describe the case of a 74-year-old Asian man, who rapidly developed lower limb weakness and impaired renal and pulmonary functions. ANCA detection remained borderline throughout the disease course. Electrophysiological and instrumental studies revealed a picture of neuromuscular involvement; renal and muscle biopsies disclosed a small vessel vasculitis. He was started on a targeted immunosuppressive combination therapy and his clinical status progressively improved. In the framework of a multi-organ disease, microscopic polyangiitis should be considered as a differential diagnosis in case of acute/subacute onset of muscle weakness, even in the absence of ANCA detection.

Diagnostic magnetic resonance imaging biomarkers for facioscapulohumeral muscular dystrophy identified by machine learning.

BACKGROUND: The diagnosis of facioscapulohumeral muscular dystrophy (FSHD) can be challenging in patients not displaying the classical phenotype or with atypical clinical features. Despite the identification by magnetic resonance imaging (MRI) of selective patterns of muscle involvement, their specificity and added diagnostic value are unknown. METHODS: We aimed to identify the radiological features more useful to distinguish FSHD from other myopathies and test the diagnostic accuracy of MRI. A retrospective cohort of 295 patients (187 FSHD, 108 non-FSHD) studied by upper and lower-limb muscle MRI was analyzed. Scans were evaluated for the presence of 15 radiological features. A random forest machine learning algorithm was used to identify the most relevant for FSHD diagnosis. Different patterns were created by their combination and diagnostic accuracy of each of them was tested. RESULTS: The combination of trapezius involvement and bilateral subscapularis muscle sparing achieved the best diagnostic accuracy (0.89, 95% Confidence Interval [0.85-0.92]) with 0.90 [0.85-0.94] sensitivity and 0.88 [0.80-0.93] specificity. This pattern correctly identified 91% atypical FSHD patients of our cohort. The combination of trapezius involvement, bilateral subscapularis and iliopsoas sparing and asymmetric involvement of upper and lower-limb muscles was pathognomonic for FSHD, yielding a specificity of 0.99 [0.95-1.00]. CONCLUSIONS: We identified MRI patterns that showed a high diagnostic power in promptly discriminating FSHD from other muscle disorders, with comparable performance irrespective of typical or atypical clinical features. Upper girdle in addition to lower-limb muscle imaging should be extensively implemented in the diagnostic workup to support or exclude a diagnosis of FSHD.