Data_Sheet_1_Case report: A novel patient presenting TRIM32-related limb-girdle muscular dystrophy.pdf

Limb-girdle muscular dystrophy autosomal recessive 8 (LGMDR8) is a rare clinical manifestation caused by the presence of biallelic variants in the TRIM32 gene. We present the clinical, molecular, histopathological, and muscle magnetic resonance findings of a novel 63-years-old LGMDR8 patient of Italian origins, who went undiagnosed for 24 years. Clinical exome sequencing identified two TRIM32 missense variants, c.1181G > A p.(Arg394His) and c.1781G > A p.(Ser594Asp), located in the NHL1 and NHL4 structural domains, respectively, of the TRIM32 protein. We conducted a literature review of the clinical and instrumental data associated to the so far known 26 TRIM32 variants, carried biallelically by 53 LGMDR8 patients reported to date in 20 papers. Our proband's variants were previously identified only in three independent LGMDR8 patients in homozygosis, therefore our case is the first in literature to be described as compound heterozygous for such variants. Our report also provides additional data in support of their pathogenicity, since p.(Arg394His) is currently classified as a variant of uncertain significance, while p.(Ser594Asp) as likely pathogenic. Taken together, these findings might be useful to improve both the genetic counseling and the diagnostic accuracy of this rare neuromuscular condition.</p

Image_1_Case report: A novel ACTA1 variant in a patient with nemaline rods and increased glycogen deposition.pdf

BackgroundCongenital myopathies are a group of heterogeneous inherited disorders, mainly characterized by early-onset hypotonia and muscle weakness. The spectrum of clinical phenotype can be highly variable, going from very mild to severe presentations. The course also varies broadly resulting in a fatal outcome in the most severe cases but can either be benign or lead to an amelioration even in severe presentations. Muscle biopsy analysis is crucial for the identification of pathognomonic morphological features, such as core areas, nemaline bodies or rods, nuclear centralizations and congenital type 1 fibers disproportion. However, multiple abnormalities in the same muscle can be observed, making more complex the myopathological scenario.Case presentationHere, we describe an Italian newborn presenting with severe hypotonia, respiratory insufficiency, inability to suck and swallow, requiring mechanical ventilation and gastrostomy feeding. Muscle biopsy analyzed by light microscopy showed the presence of vacuoles filled with glycogen, suggesting a metabolic myopathy, but also fuchsinophilic inclusions. Ultrastructural studies confirmed the presence of normally structured glycogen, and the presence of minirods, directing the diagnostic hypothesis toward a nemaline myopathy. An expanded Next Generation Sequencing analysis targeting congenital myopathies genes revealed the presence of a novel heterozygous c.965 T > A p. (Leu322Gln) variant in the ACTA1 gene, which encodes the skeletal muscle alpha-actin.ConclusionOur case expands the repertoire of molecular and pathological features observed in actinopathies. We highlight the value of ultrastructural examination to investigate the abnormalities detected at the histological level. We also emphasized the use of expanded gene panels in the molecular analysis of neuromuscular patients, especially for those ones presenting multiple bioptic alterations.</p

Additional file 1 of Megaconial congenital muscular dystrophy due to novel CHKB variants: a case report and literature review

Additional file1: Supplementary Table 1. Clinical, instrumental, histological and molecular features of CHKB-mutated MCMD patients reported so far (y: years; m: months; d: days; NA: not assessed; DCM: dilated cardiomyopathy; LVFS: left ventricular systolic function; PDA: Patent ductus arteriosus)

Data_Sheet_1_Givinostat for Becker muscular dystrophy: A randomized, placebo-controlled, double-blind study.PDF

ObjectiveNo treatments are approved for Becker muscular dystrophy (BMD). This study investigated the efficacy and safety of givinostat, a histone deacetylase pan-inhibitor, in adults with BMD.MethodsMales aged 18–65 years with a diagnosis of BMD confirmed by genetic testing were randomized 2:1 to 12 months treatment with givinostat or placebo. The primary objective was to demonstrate statistical superiority of givinostat over placebo for mean change from baseline in total fibrosis after 12 months. Secondary efficacy endpoints included other histological parameters, magnetic resonance imaging and spectroscopy (MRI and MRS) measures, and functional evaluations.ResultsOf 51 patients enrolled, 44 completed treatment. At baseline, there was greater disease involvement in the placebo group than givinostat, based on total fibrosis (mean 30.8 vs. 22.8%) and functional endpoints. Mean total fibrosis did not change from baseline in either group, and the two groups did not differ at Month 12 (least squares mean [LSM] difference 1.04%; p = 0.8282). Secondary histology parameters, MRS, and functional evaluations were consistent with the primary. MRI fat fraction in whole thigh and quadriceps did not change from baseline in the givinostat group, but values increased with placebo, with LSM givinostat–placebo differences at Month 12 of −1.35% (p = 0.0149) and −1.96% (p = 0.0022), respectively. Adverse events, most mild or moderate, were reported by 88.2% and 52.9% patients receiving givinostat and placebo.ConclusionThe study failed to achieve the primary endpoint. However, there was a potential signal from the MRI assessments suggesting givinostat could prevent (or slow down) BMD disease progression.</p

Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy

<div><p>Objective</p><p>Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the <i>SPP1</i> promoter, rs10880 and the VTTT/IAAM haplotype in <i>LTBP4</i>) also modify DCM onset.</p><p>Methods</p><p>A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m² as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up.</p><p>Results</p><p>Patients were followed up to an average age of 15.9 ± 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at <i>SPP1</i> rs28357094 and recessive T allele at <i>LTBP4</i> rs10880, which was statistically significant in steroid-treated patients for <i>LTBP4</i> rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027).</p><p>Conclusions</p><p>We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts.</p></div

Median age at DCM onset by <i>SPP1</i> and <i>LTBP4</i> genotype.

<p>*Significant difference between genotypes (log-rank p<0.05).</p><p>§DCM onset was observed in less than 50% of patients, so no median value can be calculated.</p><p>Total n for <i>LTBP4</i> differs due to limited DNA availability in a few patients. For <i>SPP1</i>, patients included in the previous report about loss of ambulation (Pegoraro et al, 2011) were also excluded. <i>SPP1</i>: Secreted PhosphoProtein 1. <i>LTBP4</i>: latent transforming growth factor beta binding protein 4. DCM: dilated cardiomyopathy.</p><p>Median age at DCM onset by <i>SPP1</i> and <i>LTBP4</i> genotype.</p

Scatter plot of age at LoA and DCM onset in 57 patients shows no strong correlation (r = 0.31).

<p>Scatter plot of age at LoA and DCM onset in 57 patients shows no strong correlation (r = 0.31).</p

Kaplan-Meier plots of LoA by genotypes and steroid treatment.

<p>Triangles indicate censoring. (A) <i>SPP1</i> rs28357094 genotype: T/T red, T/G-G/G blue; (B) <i>LTBP4</i> rs10880: T/T red, C/C-C/T blue; (C) LTBP4 haplotype: IAAM/IAAM red, VTTT/VTTT grey, other blue; (D) rs28357094 genotype and steroid treatment: T/T red, T/G-G/G blue, solid treated (>1 year before LoA), dashed untreated; (E) rs10880 and steroid treatment: T/T red, C/C-C/T blue, solid treated, dashed untreated; (F) LTBP4 haplotype and steroid treatment: IAAM/IAAM red, other (including VTTT) grey, solid treated, dashed untreated.</p

Risk of losing ambulation within 2 years in relation to different cut-off points of 6MWD and NSAA scores at baseline.

<p>Risk of losing ambulation within 2 years in relation to different cut-off points of 6MWD and NSAA scores at baseline.</p

Mean changes in 6MWT and in NSAA scores in patients below the age of 7 years at baseline (grey line) and above (black line).

<p>Mean changes in 6MWT and in NSAA scores in patients below the age of 7 years at baseline (grey line) and above (black line).</p