Molecular combing reveals complex 4q35 rearrangements in Facioscapulohumeral dystrophy

Facioscapulohumeral dystrophy (FSHD), one of the most common hereditary neuromuscular disorders, is associated with a complex combination of genetic variations at the subtelomeric 4q35 locus. As molecular diagnosis relying on Southern blot (SB) might be challenging in some cases, molecular combing (MC) was recently developed as an additional technique for FSHD diagnosis and exploration of the genomic organization of the 4q35 and 10q26 regions. In complement to the usual SB, we applied MC in a large cohort of 586 individuals with clinical FSHD. In 332 subjects, the two 4q alleles were normal in size, allowing exclusion of FSHD1 while we confirmed FSHD1 in 230 patients. In 14 patients from 10 families, we identified a recurrent complex heterozygous rearrangement at 4q35 consisting of a duplication of the D4Z4 array and a 4qA haplotype, irresolvable by the SB technique. In five families, we further identified variations in the SMCHD1 gene. Impact of the different mutations was tested using a minigene assay and we analyzed DNA methylation after sodium bisulfite modification and NGS sequencing. We discuss the involvement of this rearrangement in FSHD since all mutations in SMCHD1 are not associated with D4Z4 hypomethylation and do not always segregate with the disease.     

Effects of ATP and GTP on voltage-gated K+ currents in glandular and muscular sympathetic neurons

This study assesses the effects of ATP and GTP on the kinetic properties of voltage-gated K+ currents in anatomically identified postganglionic sympathetic neurons innervating the submandibular gland and the masseter muscle in rats. Three types of K+ currents were isolated: the I(Af) steady-state inactivating at more hyperpolarized potentials, I(As) steady-state inactivating at less hyperpolarized potentials than I(Af) and the I(K) current independent of membrane potential. The kinetic properties of these currents were tested in neurons with ATP (4 mM) and GTP (0.5 mM) or without ATP and GTP in the intracellular solution.In glandular and muscular neurons in the absence of ATP and GTP in the intracellular solution, the current density of I(Af) was significantly larger (142 pA/pF and 166 pA/pF, respectively) comparing to cells with ATP and GTP (96 pA/pF and 100 pA/pF, respectively). The I(As) was larger only in glandular neurons (52 pA/pF vs. 37 pA/pF).Conversely, I(K) current density was smaller in glandular and muscular neurons without ATP and GTP (17 pA/pF and 31 pA/pF, respectively) comparing to cells with ATP and GTP (57 pA/pF and 58 pA/pF, respectively). In glandular (15.5 nA/ms vs. 6.9 nA/ms) and muscular (10.9 nA/ms vs. 7.5 nA/ms) neurons, the I(Af) activated faster in the absence of ATP and GTP. Half inactivation voltage of I(Af) in glandular (-110.0 mV vs. -119.7 mV) and muscular (-108.4 vs. -117.3 mV) neurons was shifted towards depolarization in the absence of ATP and GTP. We suggest that the kinetic properties of K+ currents in glandular and muscular sympathetic neurons change markedly in the absence of ATP and GTP in the cytoplasm. Effectiveness of steady-state inactivated currents (I(Af) and I(AS)) increased, while effectiveness of steady-state noninactivated currents decreased in the absence of ATP and GTP. The effects were more pronounced in glandular than in muscular neurons.     

Thalamic deep brain stimulation in the treatment of essential tremor

Background and purposeQuality of life can be severely impaired by essential tremor (ET) being the main cause of the patient's disability. The authors present a group of ET patients treated with deep brain stimulation of the ventral intermediate nucleus of the thalamus (Vim DBS). The aim of the study was to evaluate the efficacy and safety of Vim DBS in the treatment of ET.Material and methodsBetween 2006 and 2009, 8 female and 10 male ET patients were treated with Vim DBS. Mean age at implantation was 63 ± 15 years. ET lasted from 4 to 30 years (mean 12 years). Clinical condition of the group was evaluated before surgery and 3 months after implantation with spirography (spiral drawings), the modified Fahn (Tremor Rating Scale, TRS) scale, and the modified ADL (Activity of Daily Living) scale. The Vim was localized with CT and MRI. The procedures of implantation were performed under local and general anaesthesia. A bilateral procedure was performed in 11 cases and a unilateral procedure was performed in 7 cases.ResultsThe therapeutic effect of DBS was maintained at the follow-up in the third month following surgery. Mean contralateral limb tremor reduction was 79%. Head tremor reduction was reported by 75% of patients in the bilateral Vim DBS subgroup and 50% of patients in the unilateral Vim DBS subgroup. Mean ADL score improved by 61%.ConclusionsVim DBS is a safe and effective method of ET treatment. Vim DBS improves activities of daily living of ET patients.     

Submandibular giant sialoliths—2 case reports and review of the literature

Sialolithiasis is one of the most common diseases of the salivary gland. The submandibular gland and its duct appear to be the most susceptible. However, giant sialoliths have rarely been reported in the literature. Two case reports of giant sialoliths in the submandibular duct alone are presented. In both patients, a transoral removal of the stone was done under local anesthesia. The stones were 35 mm and 25 mm long, respectively. Follow-up showed asymptomatic and normal functioning glands. The etiology, pathogenesis and management of such giant sialoliths are discussed. It is interesting to note that both patients remained relatively asymptomatic in spite of such long-standing sialoliths. The glands also recovered normal function quickly following removal of stones, which is interesting as such longstanding stones usually produce irrereversible functional damage to the gland. A conservative approach to the gland will spare the patient the morbidity associated with gland removal.