Experiences in the molecular genetic and histopathological evaluation of calpainopathies.

Calpainopathy is mainly characterized by symmetric and progressive weakness of proximal muscles. Several reports showed that the most common LGMD subtype is LGMDR1 or calpainopathy, which had previously been defined as LGMD2A. Until now, more than 500 likely pathogenic/pathogenic variants in the CAPN3 gene have been reported. However, a clear genotype-phenotype association had not yet been established and this causes major difficulties in predicting the prognosis in asymptomatic patients and in providing genetic counseling for prenatal diagnosis. In this report, we aimed to add new data to the literature by evaluating 37 patients with likely pathogenic/pathogenic variants for the detected variants' nature, patients' phenotypes, and histopathological features. As a result, the general clinical presentation of the 23 different variants was presented, the high frequency of NM_000070.3:c.550delA mutation in Exon 4 was discussed, and some novel genotype-phenotype associations were suggested. We have underlined that calpainopathy can be misdiagnosed with inflammatory myopathies histopathologically. We have also emphasized that, in young or adult patients with mild to moderate proximal muscle weakness and elevated CK levels, calpainopathy should be the first suspected diagnosis.

Impact of next-generation sequencing panels in the evaluation of limb-girdle muscular dystrophies.

INTRODUCTION: Limb-girdle muscular dystrophy (LGMD) is the fourth most common muscular dystrophy, with progressive proximal muscle weakness. However, a large number of neuromuscular conditions are similarly presented. Because of this, the use of high-throughput methods such as next-generation sequencing (NGS) is important in the evaluation of LGMD. METHODS: In this report, we applied a custom target capture-based NGS panel covering 31 LGMD-associated genes (MYOT, LMNA, CAV3, DES, DNAJB6, FLNC, CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TCAP, TRIM32, FRKP, TTN, POMT1, ANO5, FKTN, POMT2, POMGnT1, DAG1, PLEC, GAA, GMPPB, HNRNPDL, TNPO3, LIMS2, POMK, TRAPPC11, ISPD) in 74 patients suspected of LGMD. RESULTS: In 25 (33.8%) out of 74 patients analyzed, one or more pathogenic/likely pathogenic variants in 13 different genes were detected. Six of the patients had the variants that were not found in databases and literature; thus, they were interpreted as novel pathogenic variants. DISCUSSION: The diagnosis rate achieved (33.8%) is consistent with previous literature reports and underlines the efficiency and importance of NGS technology in the molecular genetic evaluation of LGMD.

Optic disc and retinal nerve fiber layer parameters as indicators of neurodegenerative brain changes in patients with obstructive sleep apnea syndrome.

PURPOSE: Retina is a unique part of the central nervous system (CNS) for visualizing the processes of axonal and neuronal degeneration. Optical coherence tomography (OCT) allows direct visualization and measurement of retinal nerve fiber layer (RNFL) thickness, macular volume, and optic disc (OD) parameters. One of the disorders associated with atrophy in different brain regions is obstructive sleep apnea syndrome (OSAS). In the present study, we aimed to determine OD and RNFL changes measured by OCT for investigating the progress of neurodegeneration development in OSAS, excluding all the other conditions that can directly affect RNFL thickness and optic nerve parameters. METHODS: Both eyes of 101 patients with OSAS and 20 controls were investigated by OCT. Full-night polysomnography (PSG) and ophthalmologic examination including automated visual field (VF) examination and OCT were performed in all of the patients. RESULTS: According to the OSAS grading, patients were grouped as mild (n=15), moderate (n=27), and severe (n=59). We found significant decrease in RNFL thickness only in the patients with severe OSAS compared with the other groups and decreased macular ganglion cell thickness in the severe OSAS group compared with the control group. VF parameters were significantly worsened in all the OSAS subgroups compared to the control group. We found different data such as normal or increased optic nerve parameters as result of subtle OD edema, which may mask possible peripapillar axonal loss. CONCLUSIONS: We think that evaluation of neurodegeneration in OSAS is not always possible by examining OD and RNFL because there are difficulties due to the confounding issues of cerebral atrophy and OD edema.

Pupil cycle time: as indicator of visual pathway dysfunction in multiple sclerosis.

To evaluate the value of pupil cycle time (PCT) as an indicator of optic nerve dysfunction in patients with multiple sclerosis (MS), 42 patients with MS and 35 control subjects were included to the study. Patients with MS with a history of ON were accepted as group 1, without a history of ON as group 2 and healthy control subjects as group 3. Groups were compared with Chi-square and one-way ANOVA tests. Correlations of PCT results with age, best corrected visual acuity, duration of MS, visual field (VF) test, visual evoked potential (VEP) latans, retinal nerve fiber layer (RNFL), and ganglion cell layer-inner plexiform layer (GCL-IPL) thicknesses were analyzed. Mean PCT was 1286.4 ± 357.8 ms in group 1, 1021.3 ± 102.3 ms in group 2, and 872.5 ± 69.4 ms in group 3 (p < 0.001). Moderate-to-significant correlations were found between PCT measurements and duration of MS, VF test, VEP latans, RNFL, and GCL-IPL thicknesses. PCT might be an alternative method to evaluate the optic nerve function in patients with MS.