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Dilated Cardiomyopathy
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Marco Merlo, Alessia Paldino, Giulia De Angelis, Gianfranco Sinagra
Although DCM is not typically characterized by specific ECG findings, a careful analysis can provide several clues about the etiology as well as the duration of the disease. For example, dystrophin-related DCM is generally characterized by a “posterolateral pseudonecrosis” aspect, atrioventricular blocks can suggest a mutation in LMNA, and myotonic dystrophy and Emery Dreifuss disease can be associated with sinus bradycardia and atrial standstill.17 Left atrial enlargement is frequent in DCM and is usually an expression of a long-standing disease.48 Left bundle-branch block is usually a marker of long-standing disease with prognostic and therapeutic implications.49,50 In general, the ECG is important prognostically. Antero-lateral T-wave inversion, low QRS voltages, and fragmented QRS have been reported as independent predictors of death, heart transplantation, SCD, and malignant ventricular arrhythmias in a cohort of 414 patient with DCM.51,52
Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
DCM may also occur in mitochondrial cytopathies and inherited metabolic disorders (e.g. haemochromatosis). Neuromuscular disease may accompany DCM, and in some forms of neuromuscular disease, the presenting feature may be cardiac. LMNA mutations can present with or without muscle disease, and the muscle disease ranges from limb-girdle muscular dystrophy to Emery-Dreifuss muscular dystrophy. In LMNA- and SCN5A-mediated cardiomyopathies, arrhythmias including atrial fibrillation or ventricular arrhythmias may be the presenting finding. Both X-linked and autosomal neuromuscular diseases can present with cardiomyopathy, and this includes Duchenne muscular dystrophy, as well as the autosomal recessive forms of sarcoglycanopathies. In these disorders, skeletal muscle disease usually appears in childhood with a typical DCM arising in the teenage years or early twenties. Both forms of myotonic muscular dystrophy, type 1 and type 2, can be associated with DCM. Atrial and ventricular arrhythmias are common in these tri- and tetra-nucleotide repeat expansion disorders. For several subtypes of genetic cardiomyopathy, arrhythmias may be the earliest manifestation. Myotonic dystrophy type 2 usually presents in older individuals, and the diagnosis can be easily missed especially if neuromuscular symptoms are not so pronounced.22
Muscle Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Kourosh Rezania, Peter Pytel, Betty Soliven
The skeletal muscle may show nonspecific myopathic changes including an increase in myofiber size, an increased number of myofibers with internalized nuclei, and mild features of myofiber degeneration/regeneration. EMD1 cases usually indicate a loss of emerin expression on immunocytochemical analysis. LMNA gene mutations, however, typically show preserved expression of lamin A/C. Some studies have described irregularities of the nuclear membrane and the peripheral arrangement of heterochromatin by electron microscopy.
Progeria: a perspective on potential drug targets and treatment strategies
Published in Expert Opinion on Therapeutic Targets, 2022
Ignacio Benedicto, Xue Chen, Martin O Bergo, Vicente Andrés
HGPS is an ultra-rare genetic disease (prevalence 1 in 18 million people) characterized by accelerated aging and premature death at an average age of 14.6 years (www.progeriaresearch.org). Most HGPS patients are heterozygous carriers of a de novo synonymous mutation (c.1824C>T) in the LMNA gene [1,2], which encodes the nuclear lamina proteins lamin A and C, generated by alternative splicing. In normal cells, lamin A maturation includes the farnesylation, methylation, and subsequent cleavage of its C-terminus by the zinc metalloprotease ZMPSTE24. The HGPS mutation activates the use of a cryptic splice donor site in exon 11, generating an aberrant lamin A variant called progerin that lacks 50 amino acids spanning the ZMPSTE24 cleavage site and therefore remains permanently farnesylated and methylated [3] (Figure 1).
The Diagnostic Yield of Electromyography at Detecting Abnormalities on Muscle Biopsy: A Single Center Experience
Published in The Neurodiagnostic Journal, 2021
Patrick B. Moloney, Stela Lefter, Aisling M. Ryan, Michael Jansen, Niamh Bermingham, Brian McNamara
Our study highlights clinical scenarios where EMG and muscle biopsy may show conflicting findings. Four patients had EMG abnormalities consistent with a neurogenic disorder and muscle biopsy findings diagnostic for IBM. IBM can mimic amyotrophic lateral sclerosis (ALS) and in a study of patients with biopsy-proven IBM, 13% had an initial diagnosis of ALS, based on clinical and electrodiagnostic findings (Dabby et al. 2001). In cases with EMG abnormalities concerning for ALS, disproportionate finger flexion weakness should prompt a search for IBM by muscle biopsy. Three patients with chronic neuromuscular disorders had discordant investigations. “Pseudomyopathic” findings on muscle biopsy in spinal muscular atrophy and poliomyelitis have long been recognized (Dastur and Razzak 1973) and may have contributed to apparent discordance in 2 cases. The patient diagnosed with an unclassified LGMD by consensus opinion at our MDM had a myopathic EMG with predominantly neurogenic findings on muscle biopsy. Certain LGMDs cause combined dystrophy and neuropathy, including those associated with MYOT or LMNA pathogenic variants (Benedetti et al. 2005; Selcen 2011). Moreover, chronic myopathies may develop a neurogenic appearance on EMG, characterized by long duration motor unit potentials (Lacomis 2012). Lastly, dual pathology may lead to conflicting EMG and muscle biopsy findings, as was seen in 3 cases in our study.
Nucleic acid therapeutics: a focus on the development of aptamers
Published in Expert Opinion on Drug Discovery, 2021
Swati Jain, Jaskirat Kaur, Shivcharan Prasad, Ipsita Roy
Small nucleic acids may also act via trans-splicing at the post-transcriptional level. Trans-splicing is catalyzed by the cellular spliceosome machinery which substitutes intrinsic unwanted sequences in the pre-mRNA with the correct sequence containing built-in donor and acceptor splice sites and a hybridization domain for targeted action. This results in a mutation-free, chimeric functional mRNA transcript [15–17]. Spliceosome-mediated RNA trans-splicing (SMaRT) was used to correct LMNA (lamin A)-related congenital muscular dystrophy in mice [16]. Pre-trans-spliced molecules (PTMs) containing the wild-type lamin A coding sequence, flanked by splicing sites and a hybridization domain were used to target mutant intron 5 of lamin A pre-mRNA by an adenoviral vector. Although the trans-splicing efficiency was quite low, it was sufficient to improve phenotype in homozygous LmnaΔK32 mice [16], showing the promise of the approach.