Browsing by Author "Stojanović, Vidosava Rakočević (6603893359)"

Variants in the TTN gene have been associated with distal myopathies and other distinctive phenotypes involving skeletal and cardiac muscle. Through whole-exome sequencing we identified a novel stop-gain variant (c.107635C>T, p.(Gln35879Ter)) in the TTN gene, coding a part of the M-line of titin, in 14 patients with autosomal recessive distal myopathy and Serbian ancestry. All patients share a common 1 Mb core haplotype associated with c.107635C>T, suggesting a founder variant. In compound heterozygotes, nine other TTN variants were identified: four stop-gain, three frameshift, one missense and one splice donor variant. Patients homozygous for the common variant did not show significant clinical differences to the compound heterozygous patients. The clinical presentation of all patients was an adult onset distal myopathy with predominant lower limb involvement. In addition, most patients had normal to mildly elevated serum creatine kinase levels, myopathic electromyograms, normal cardiologic and respiratory tests and muscle pathology consistent with a dystrophic process. In this study, we describe a distinct phenotype for patients with distal myopathy associated with novel recessive TTN variants including a Serbian founder variant. Our results expand the phenotypic and genetic spectrum of titinopathies and will facilitate the diagnosis of this condition in patients of Serbian origin.

Variants in the TTN gene have been associated with distal myopathies and other distinctive phenotypes involving skeletal and cardiac muscle. Through whole-exome sequencing we identified a novel stop-gain variant (c.107635C>T, p.(Gln35879Ter)) in the TTN gene, coding a part of the M-line of titin, in 14 patients with autosomal recessive distal myopathy and Serbian ancestry. All patients share a common 1 Mb core haplotype associated with c.107635C>T, suggesting a founder variant. In compound heterozygotes, nine other TTN variants were identified: four stop-gain, three frameshift, one missense and one splice donor variant. Patients homozygous for the common variant did not show significant clinical differences to the compound heterozygous patients. The clinical presentation of all patients was an adult onset distal myopathy with predominant lower limb involvement. In addition, most patients had normal to mildly elevated serum creatine kinase levels, myopathic electromyograms, normal cardiologic and respiratory tests and muscle pathology consistent with a dystrophic process. In this study, we describe a distinct phenotype for patients with distal myopathy associated with novel recessive TTN variants including a Serbian founder variant. Our results expand the phenotypic and genetic spectrum of titinopathies and will facilitate the diagnosis of this condition in patients of Serbian origin.

Background/Aim. Duchenne muscular dystrophy (DMD) and its allelic form Becker muscular dystrophy (BMD) are X-linked diseases that affect males, characterized by progressive muscle and cardiopulmonary weakness, especially in DMD as a severe form of the disease. They result from mutations in the dystrophin gene, and the most common changes are large intragenic deletions and duplications (80%). One third of patients have de novo mutation and 2/3 of the mothers are estimated as carriers. The aim of the study was to analyze the frequency of duplications versus deletions in the dystrophin gene in patients with dystrophinopathies, as well as to analyze the phenotypic effect of large mutations obtained and to determine the carrier status of female relatives in probands with duplications. Methods. We examined 22 DMD and 35 BMD unrelated patients and 6 female relatives of the probands where duplications were found. We used polymerase chain reaction (PCR) and multiplex ligation-dependent probe amplification (MLPA) methods, according to the protocol, to detect or confirm mutations in probands and female carriers. Results. In probands, there were 34 (59.6%) large deletions (mostly affected exons 44–60) and 6 (10.5%) large duplications in 4 DMD and 2 BMD patients. Also, duplications were found in 3 out of 4 (75%) tested mothers. The distribution of duplications was heterogeneous, affecting N-terminal and central rod domain, and included more exons, except for one DMD patient who had duplication of exon 2. An exception from the Monaco rule was present in 9.5% of DMD and 15.8% of BMD probands, i.e. in 12.5% of DMD/BMD cases. Conclusion. In 57 DMD/BMD probands, we found 59.6% of large deletions and 10.5% of large duplications. The most affected region of the DMD gene was the central rod domain. An exception to Monaco's rule was present in 12.5% of DMD/BMD cases. Three out of 4 examined proband's mothers were confirmed as carriers. © 2020 Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved.

To analyze the presence of autonomic dysfunction in different subgroups of myasthenia gravis (MG) patients. Standard cardiovascular reflex tests according to Ewing, spectral and time domain analysis of heart rate variability (HRV) at rest were assessed in 27 patients with thymoma-associated acetylcholine receptor (AChR)-positive MG, 25 AChR-positive MG patients without thymoma and 23 patients with muscle-specific tyrosine kinase (MuSK) MG. All patients were compared to the healthy controls, matched for sex and age. In the group of AChR-positive MG patients with thymoma, hand grip (p < 0.05), orthostasis (p < 0.05), breathing test (p < 0.05) and Valsalva maneuver (p < 0.01) were more often pathological than in the controls. Analysis of the spectral domain of HRV showed increased low-frequency (p < 0.05) and decreased high-frequency component (p < 0.05). Time domain parameters of HRV and baroreflex sensitivity (BRS) at rest were significantly reduced (p < 0.01). In the patients with AChR MG without thymoma, Valsalva maneuver test was more often pathological (p < 0.05) and higher rate of supraventricular extrasystoles (p < 0.01) was registered than in the healthy controls. In the patients with MuSK-positive MG, hand grip and Valsalva maneuver tests were more often pathological than in the controls (p < 0.05). Low-frequency component of the spectral domain of HRV (p < 0.05) and the frequency of cardiac arrhythmia were increased. BRS at rest was significantly lower in patients compared to the controls (p < 0.01). We determined the presence of autonomic failure in all subgroups of MG patients. Since autonomic dysfunction can lead to cardiac arrhythmias and even sudden death, it is of major importance to be aware of this association and to properly diagnose and treat these patients. © 2014, Springer-Verlag Berlin Heidelberg.

To analyze the presence of autonomic dysfunction in different subgroups of myasthenia gravis (MG) patients. Standard cardiovascular reflex tests according to Ewing, spectral and time domain analysis of heart rate variability (HRV) at rest were assessed in 27 patients with thymoma-associated acetylcholine receptor (AChR)-positive MG, 25 AChR-positive MG patients without thymoma and 23 patients with muscle-specific tyrosine kinase (MuSK) MG. All patients were compared to the healthy controls, matched for sex and age. In the group of AChR-positive MG patients with thymoma, hand grip (p < 0.05), orthostasis (p < 0.05), breathing test (p < 0.05) and Valsalva maneuver (p < 0.01) were more often pathological than in the controls. Analysis of the spectral domain of HRV showed increased low-frequency (p < 0.05) and decreased high-frequency component (p < 0.05). Time domain parameters of HRV and baroreflex sensitivity (BRS) at rest were significantly reduced (p < 0.01). In the patients with AChR MG without thymoma, Valsalva maneuver test was more often pathological (p < 0.05) and higher rate of supraventricular extrasystoles (p < 0.01) was registered than in the healthy controls. In the patients with MuSK-positive MG, hand grip and Valsalva maneuver tests were more often pathological than in the controls (p < 0.05). Low-frequency component of the spectral domain of HRV (p < 0.05) and the frequency of cardiac arrhythmia were increased. BRS at rest was significantly lower in patients compared to the controls (p < 0.01). We determined the presence of autonomic failure in all subgroups of MG patients. Since autonomic dysfunction can lead to cardiac arrhythmias and even sudden death, it is of major importance to be aware of this association and to properly diagnose and treat these patients. © 2014, Springer-Verlag Berlin Heidelberg.