Phenotypic and genetic spectrum of patients with limb-girdle muscular dystrophy type 2A from Serbia.

Limb-girdle muscular dystrophy (LGMD) type 2A (calpainopathy) is an autosomal recessive disease caused by mutation in the CAPN3 gene. The aim of this study was to examine genetic and phenotypic features of Serbian patients with calpainopathy. The study comprised 19 patients with genetically confirmed calpainopathy diagnosed at the Neurology Clinic, Clinical Center of Serbia and the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia during a ten-year period. Eighteen patients in this cohort had c.550delA mutation, with nine of them being homozygous. In majority of the patients, disease started in childhood or early adulthood. The disease affected shoulder girdle - upper arm and pelvic girdle - thigh muscles with similar frequency, with muscles of lower extremities being more severely impaired. Facial and bulbar muscles were spared. All patients in this cohort, except two, remained ambulant. None of the patients had cardiomyopathy, while 21% showed mild conduction defects. Respiratory function was mildly impaired in 21% of patients. Standard muscle histopathology showed myopathic and dystrophic pattern. In conclusion, the majority of Serbian LGMD2A patients have the same mutation and similar phenotype.

Magnetic resonance imaging of leg muscles in patients with myotonic dystrophies.

Magnetic resonance imaging (MRI) of muscles has recently become a significant diagnostic procedure in neuromuscular disorders. There is a lack of muscle MRI studies in patients with myotonic dystrophy type 1 (DM1), especially type 2 (DM2). To analyze fatty infiltration of leg muscles, using 3.0 T MRI in patients with genetically confirmed DM1 and DM2 with different disease durations. The study comprised 21 DM1 and 10 DM2 adult patients. Muscle MRI was performed in axial plane of the lower limbs using T1-weighted (T1w) sequence. Six-point scale by Mercuri et al. was used. Fatty infiltration registered in at least one muscle of lower extremities was found in 71% of DM1 and 40% of DM2 patients. In DM1 patients, early involvement of the medial head of gastrocnemius and tibialis anterior muscles was observed with later involvement of other lower leg muscles and of anterior and posterior thigh compartments with relative sparing of the rectus femoris. In DM2, majority of patients had normal MRI findings. Early involvement of lower legs and posterior thighs was found in some patients. Less severe involvement of the medial head of the gastrocnemius compared to other lower leg muscles was also observed, while involvement of proximal muscles was rather diffuse than selective. It seems that both in DM1 and DM2 some muscles may be affected before weakness is clinically noted and vice versa. We described characteristic pattern and way of progression of muscle involvement in DM1 and DM2.

Brugada syndrome: A general cardiologist's perspective.

Brugada syndrome (BrS) is one of the commonest inherited primary arrhythmia syndromes typically presenting with arrhythmic syncope or sudden cardiac death (SCD) due to polymorphic ventricular tachycardia and ventricular fibrillation precipitated by vagotonia or fever in apparently healthy adults, less frequently in children. The prevalence of the syndrome (0.01%-0.3%) varies among regions and ethnicities, being the highest in Southeast Asia. BrS is diagnosed by the "coved type" ST-segment elevation≥2mm followed by a negative T-wave in ≥1 of the right precordial leads V1-V2. The typical electrocardiogram in BrS is often concealed by fluctuations between normal, non-diagnostic and diagnostic ST-segment pattern in the same patient, thus hindering the diagnosis. Presently, the majority of BrS patients is incidentally diagnosed, and may remain asymptomatic for their lifetime. However, BrS is responsible for 4-12% of all SCDs and for ~20% of SCDs in patients with structurally normal hearts. Arrhythmic risk is the highest in SCD survivors and in patients with spontaneous BrS electrocardiogram and arrhythmic syncope, but risk stratification for SCD in asymptomatic subjects has not yet been fully defined. Recent achievements have expanded our understanding of the genetics and electrophysiological mechanisms underlying BrS, while radiofrequency catheter ablation may be an effective new approach to treat ventricular tachyarrhythmias in BrS patients with arrhythmic storms. The present review summarizes our contemporary understanding and recent advances in the inheritance, pathophysiology, clinical assessment and treatment of BrS patients.

A novel recessive TTN founder variant is a common cause of distal myopathy in the Serbian population.

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.

Multiple Major and Minor Anomalies Associated With Klippel-Feil Syndrome: A Case Report.

Klippel-Feil syndrome is defined as congenital fusion of two or more cervical vertebrae. In this article, we report a 55-year-old male patient with one-year history of neck pain, headaches, and one episode of syncope after a severe trauma. X-rays and magnetic resonance imaging of cervical spine revealed fused vertebral bodies of C2-C5. The major anomalies associated with Klippel-Feil syndrome (small stature, thoracic kyphoscoliosis, lumbar scoliosis, restricted opening mouth, and bilateral sensorineural hearing loss) as well as multiple minor anomalies (mild face asymmetry, high arched palate, rhinoscoliosis, high nasal bridge, inclined septi nasi, and thin upper lip) were detected. This is a rare case describing the anomalies of the nose in Klippel-Feil syndrome patients. Our patient had no central cord impairment following a severe trauma.

Analysis of the Variability of Epstein-Barr Virus Genes in Infectious Mononucleosis: Investigation of the Potential Correlation with Biochemical Parameters of Hepatic Involvement.

BACKGROUND: Primary Epstein-Barr virus (EBV) infection is usually asymptomatic, although at times it results in the benign lymphoproliferative disease, infectious mononucleosis (IM), during which almost half of patients develop hepatitis. The aims of the present study are to evaluate polymorphisms of EBV genes circulating in IM isolates from this geographic region and to investigate the correlation of viral sequence patterns with the available IM biochemical parameters. METHODS: The study included plasma samples from 128 IM patients. The genes EBNA2, LMP1, and EBNA1 were amplified using nested-PCR. EBNA2 genotyping was performed by visualization of PCR products using gel electrophoresis. Investigation of LMP1 and EBNA1 included sequence, phylogenetic, and statistical analyses. RESULTS: The presence of EBV DNA in plasma samples showed correlation with patients' necessity for hospitalization (p=0.034). The majority of EBV isolates was genotype 1. LMP1 variability showed 4 known variants, and two new deletions (27-bp and 147-bp). Of the 3 analyzed attributes of LMP1 isolates, the number of 33-bp repeats less than the reference 4.5 was the only one that absolutely correlated with the elevated levels of transaminases. EBNA1 variability was presented by prototype subtypes. A particular combination of EBNA2, LMP1, and EBNA1 polymorphisms, deleted LMP1/P-thr and non-deleted LMP1/P-ala, as well as genotype 1/ 4.5 33-bp LMP1 repeats or genotype 2/ 4.5 33-bp LMP1 repeats showed correlation with elevated AST (aspartate aminotransferase) and ALT (alanine transaminase). CONCLUSIONS: This is the first study which identified the association between EBV variability and biochemical parameters in IM patients. These results showed a possibility for the identification of hepatic related diagnostic EBV markers.

Endometrioid adenocarcinoma of the ovary: MRI findings with emphasis on diffusion-weighted imaging for the differentiation of ovarian tumors.

BACKGROUND: Preoperative differentiation of ovarian malignant tumors still remains a challenge. Diffusion-weighted imaging (DWI) provides information about cellularity of the lesion and might facilitate discrimination between different malignant ovarian lesions. PURPOSE: To evaluate magnetic resonance imaging (MRI) findings of endometrioid adenocarcinoma of the ovary and to determine the value of DWI in the differential diagnosis of malignant and benign adnexal tumors. MATERIAL AND METHODS: The following MRI findings were reviewed in 162 patients (21 endometrioid adenocarcinoma, 103 other malignant tumors, 38 benign tumors): lesion size, morphological appearance, T2-weighted (T2W) signal intensity, T1-weighted (T1W) signal intensity, contrast-enhancement pattern, DWI signals with apparent diffusion coefficient (ADC) calculated for b = 800 s/mm(2) in solid tumor components. RESULTS: The most common morphological appearance was predominantly cystic lesion, found in 90.3% of patients with endometriod adenocarcinoma. The solid parts were slightly hyperintense on T2W images in 19 patients with marked enhancement after contrast administration. No significant difference (P = 0.13) in conventional MRI features was found between endometrioid adenocarcinoma and other malignant ovarian tumors. Hyperintensity on DWI was more frequently observed in malignant tumors than in benign lesions (P < 0.001). ADC values were significantly lower in endometrioid adenocarcinoma than other malignant tumors (0.79 ± 0.21 vs. 0.90 ± 0.19; P = 0.04) and in all malignant lesions compared with benign tumors (0.88 ± 0.31 vs. 1.33 ± 0.17; P < 0.001). CONCLUSION: DWI with ADC measurement could indicate the presence of endometrioid adenocarcinomas due to a slightly but significantly lower ADC values compared to other malignant ovarian lesions. Thus, DWI is beneficial and should be part of a standard protocol for the evaluation of indeterminate adnexal lesions.

Oncological and functional outcome after surgical treatment of early glottic carcinoma without anterior commissure involvement.

INTRODUCTION: Glottic carcinoma can be successfully diagnosed in its early stages and treated with high percentage of success. Organ preservation and optimal functional outcomes could be achieved with wide array of surgical techniques for early glottic cancer, including endoscopic approaches or open laryngeal preserving procedures, making surgery the preferred method of treatment of early glottic carcinoma in the last few years. MATERIAL AND METHODS: Prospective study was done on 59 patients treated for Tis and T1a glottic carcinoma over a one-year time period in a tertiary medical center. Patients were treated with endoscopic laser cordectomy (types II-IV cordectomies according to European Laryngological Society classification of endoscopic cordectomies) and open cordectomy through laryngofissure. Follow-up period was 60 months. Clinical and oncological results were followed postoperatively. Voice quality after the treatment was assessed using multidimensional voice analysis 12 months after the treatment. RESULTS: There were no significant differences between oncological and functional results among two groups of patients, though complications were more frequent in patients treated with open cordectomy. CONCLUSION: Endoscopic laser surgery should be the first treatment of choice in treatment of early glottic carcinomas, though open approach through laryngofissure should be available for selected cases where anatomical factors present limiting adequate tumor removal.

MRI in evaluation of neoplastic invasion into preepiglottic and paraglottic space.

OBJECTIVE: The purpose of this study was to evaluate whether magnetic resonance (MR) imaging can accurately predict invasion of the preepiglottic and paraglottic space in patients with laryngeal carcinoma. Identification of these fat filling spaces is important for surgical treatment and prognosis. MATERIALS AND METHODS: The study was based on the prospective analysis of MRI images in a series of 40 patients (90% males), overall average age 60.1 ± 7.3 years, (49-70 years), with histopathologically diagnosed laryngeal squamous cell carcinoma. Unenhanced T2w, T2w FS, T1w, and contrast-enhanced T1w FS scans were analyzed for the presence of preepiglottic and paraglottic neoplastic invasion and were compared to postoperative histopathologic analysis. RESULTS: In 28 patients (70%) the tumor was glottic and in 12 patients (30%) supraglottic. No statistical difference was found in the number of patients with positive MRI findings in comparison to postsurgical patohistology for infiltration of the preepiglottic space (23% vs 20%, respectively). Sensitivity for infiltration of preepiglottic space was 89% and specificity was 97%. However, infiltration of the paraglottic spaces was observed more frequently on MRI than on postsurgical patohistology analysis (60% vs 40%, respectively; p<0.05), with a sensitivity of 67% and a specificity 50%. According to MRI findings, 26 (65%) patients were classified as T3, 14 (35%) patients as T2 while according to histopathologic analysis of specimens after surgery, 19 patients were classified as T3 (48%) and 21 as T2 (52%). CONCLUSION: MRI has been shown to be a reliable method for assessment of preepiglottic space while the diagnostic accuracy in patients with infiltration of the paraglottic space is limited.

Clinical outcome of early glottic carcinoma in Serbia.

OBJECTIVE: Proposed methods for treating early glottic carcinoma are cordectomy through laryngofissure, laser cordectomy, and radiotherapy. The aim of the study was to conduct comprehensive study to evaluate oncological and functional results of different treatment modalities for Tis and T1 glottic carcinoma, identify prognostic factors for the outcome of treatment and decide where we stand in applying worldwide standards of early glottic carcinoma treatment. METHODS: Prospective study was conducted on 221 patients treated with Tis and T1 glottic carcinoma from 1998 to 2003 (72 patients were treated endoscopically with CO2 laser, 75 patients with cordectomy through laryngofissure and 74 with radiotherapy), with follow-up period from 38 to 107 months. Important demographic and clinical variables were analyzed. Voice quality after the treatment was assessed using multidimensional voice analysis. RESULTS: Comparing oncological results of three modalities of treatment, there were no significant differences. Functional results of treatment were better after laser cordectomy and primary radiotherapy than following the open cordectomy. Five-year survival rate was almost identical in all three groups of patients, and important prognostic factors for survival were age and histological grade of the tumor. CONCLUSION: Considering that the choice of treatment in our country is also greatly influenced by other paramedical factors, such as distance from treatment facility, reliability of follow-up, significant time delay of radiotherapy because of small number of radiology centers and strong patients' surgeon and treatment preference, we consider endoscopic laser surgery highly efficient and preferred choice of treatment for early glottic carcinoma.

Magnetic resonance imaging features of multiple duodenal lipomas: a rare cause of intestinal obstruction.

A 65-year-old man was evaluated because of vomiting and epigastric pain. The patient underwent upper gastrointestinal endoscopy and endoscopic ultrasound examination and was found to have multiple polypoid lesions in the D1 and D2 portions of the duodenum, causing almost complete obstruction of the duodenal lumen. The lesions were hyperintense on T1-weighted and intermediately intense on T2-weighted images, with a drop in signal on T1- and T2-weighted fat-suppressed images, consistent with a diagnosis of duodenal lipomas. Pathohistological examination confirmed the diagnosis of duodenal lipomas.

Integrative role of MRI in the evaluation of primary biliary cirrhosis.

OBJECTIVES: To evaluate magnetic resonance imaging (MRI) findings in patients with primary biliary cirrhosis (PBC) and to determine the value of diffusion-weighted imaging (DWI) in the assessment of liver fibrosis. MATERIALS AND METHODS: The following MRI findings were reviewed in 44 patients: periportal T2-weighted hyperintensity, periportal halo sign (T1- and T2-weighted periportal hypointensity), lymphadenopathy, signs of portal hypertension and morphological liver changes. Apparent diffusion coefficient (ADC) was calculated for six locations in the liver for b = 800 s/mm(2). RESULTS: Periportal hyperintensity and periportal halo sign were observed in 72.7% and 66.7% of patients, respectively. Lymphadenopathy was noted in 28 patients (63.6%) and diffuse hepatomegaly in 18 (40.9%). Significant positive correlation was observed between histological stage and periportal halo sign (p = 0.613), hepatomegaly (p = 0.443), and portosystemic collaterals (p = 0.391). The mean ADCs (×10(-3) mm(2)/s) were significantly different at stage I versus III and IV, and stage II versus IV. No significant difference was found between stages II and III. For prediction of stage ≥ II and stage ≥ III areas under receiver operating characteristic curves were 0.879 and 0.906, respectively. CONCLUSION: MRI with DWI could be used as a part of diagnostic protocol in the further evaluation of PBC patients providing noninvasive assessment of liver fibrosis progression. KEY POINTS: • MRI provides insight into the morphological liver changes in primary biliary cirrhosis (PBC) • The periportal "halo" sign is a highly specific finding in PBC • Diffusion-weighted MR imaging allows noninvasive assessment of liver fibrosis grade.

Diagnosis of mesh infection after abdominal wall hernia surgery - role of radionuclide methods.

BACKGROUND/AIMS: The aim of this investigation was to evaluate the role of detection of late mesh infection following incisional hernia repair with radiolabeled antigranulocyte antibodies. METHODOLOGY: Mesh infection diagnoses were set up with clinical examination and laboratory analysis and confirmed by ultrasonography (US), computerized tomography (CT), scintigraphy with 99mTc-antigranulocyte antibodies and microbiological examination. RESULTS: Of the 17 patients investigated, 6 had a late mesh infection, and 11 had both mesh infection and recurrent incisional hernia. Clear clinical signs of late mesh infection were present in 13 patients. Four remaining patients had non-specific discomfort and recurrent incisional hernia without clinical manifestation of mesh infection ('silent infection'). US was positive in 12/17 patients, CT in 13/17 patients, while scintigraphy with antigranulocyte antibodies in 17/17 patients. Therefore, sensitivity of US was 71%, of CT 76% and of scintigraphy 100%. In four patients late mesh infection was confirmed exclusively by 99mTc-antigranulocyte antibody scintigraphy, while US and CT did not indicate the infection. CONCLUSIONS: According to the present results, scintigraphy with 99mTc antigranulocyte antibodies is a useful method for the detection of 'silent' abdominal wall infections after surgery, which is very important for prompt and appropriate therapy.

Diagnostic significance of magnetic resonance imaging in preoperative evaluation of patients with laryngeal tumors.

To evaluate the diagnostic accuracy of pretreatment surgical magnetic resonance images (MRI) in the assessment of patients with laryngeal tumors. The prospective study included 34 patients (mean age 62.2 ± 5.1 years) with suspected tumors of the larynx who underwent laryngeal endoscopy, followed by MRI. The MRI images were evaluated for the invasion of anterior commissure, subglottis, paraglottic and preepiglotic space, cartilage invasion, extension to extralaryngeal tissue and lymph nodes, and were compared to pathological examination of surgical specimen. In 15 patients (44%) the tumor was glottic, in 10 patients (29%) supraglottic, in 9 (27%) patients tumor was transglottic. No statistical difference was seen in the number of patients with positive MRI findings in comparison to postsurgical pathohistology for extension to subglottic subside (29 vs. 38%), growth to the anterior commissure (48 vs. 48%), preepiglottic space (33 vs. 29%), and cartilage infiltration (19 vs. 14%), respectively. However, infiltration of the paraglottic spaces was observed more frequently on MRI (71 vs. 47%), p < 0.05. According to MR findings, 4 (12%) patients were classified as T2, 26 (76%) patients as T3 and 4 (12%) patients as T4, while on pathohystological specimens after surgery, 12 patients were classified as T2 (35%), 18 as T3 (53%), and 4 as T4 (12%). Based on MRI, 76% of the patients were correctly classified, which was shown to be statistically significant (ρ = 0.56, <0.05). Fifteen patients had metastases in regional lymph nodes and only two were detected on MRI. MRI has been shown to be a method that contributes to presurgical assessment of patients with tumor of the larynx.