Compensatory swallowing methods in a patient with dysphagia due to lateral medullary syndrome-vacuum and prolonged swallowing: A case report.

INTRODUCTION: The nature of pharyngeal swallowing function during the course of recovery of dysphagia due to lateral medullary syndrome (LMS) is unclear. Vacuum swallowing is a compensatory swallowing method that improves the pharyngeal passage of a bolus by creating negative pressure during swallowing in the esophagus in patients with dysphagia due to LMS. We present a case involving a patient with dysphagia due to LMS who involuntarily acquired a swallowing method with prolonged and increased pharyngeal contraction and vacuum swallowing. PATIENT CONCERNS: We report a unique case involving a 52-year-old patient with dysphagia due to LMS. His dysphagia was severe but improved gradually with swallowing rehabilitation. The patient involuntarily acquired a swallowing method with prolonged and increased pharyngeal contraction and vacuum swallowing. DIAGNOSIS: The patient presented with dysphagia due to left LMS. A videofluoroscopic examination of swallowing revealed pharyngeal residue. INTERVENTIONS: Forty-five days after the onset of the dysphagia, the swallowing pressure along the pharynx and esophagus was measured using high-resolution manometry. OUTCOMES: Vacuum swallowing was observed in six out of 19 swallows (32.5%). The velopharyngeal contractile integral (CI) and mesohypopharyngeal CI values increased during swallowing, reflecting prolonged and increased pharyngeal contraction. We named this swallowing method "prolonged swallowing." CONCLUSION: The findings in this case indicate that vacuum and prolonged swallowing may be compensatory swallowing methods observed in individuals recovering from dysphagia due to LMS. Further research is needed to clarify the relationship between these swallowing methods and the pathophysiology, prognosis, and treatment of dysphagia in patients with LMS.

Altered oligomeric states in pathogenic ALS2 variants associated with juvenile motor neuron diseases cause loss of ALS2-mediated endosomal function.

Familial amyotrophic lateral sclerosis type 2 (ALS2) is a juvenile autosomal recessive motor neuron disease caused by the mutations in the ALS2 gene. The ALS2 gene product, ALS2/alsin, forms a homophilic oligomer and acts as a guanine nucleotide-exchange factor (GEF) for the small GTPase Rab5. This oligomerization is crucial for both Rab5 activation and ALS2-mediated endosome fusion and maturation in cells. Recently, we have shown that pathogenic missense ALS2 mutants retaining the Rab5 GEF activity fail to properly localize to endosomes via Rac1-stimulated macropinocytosis. However, the molecular mechanisms underlying dysregulated distribution of ALS2 variants remain poorly understood. Therefore, we sought to clarify the relationship between intracellular localization and oligomeric states of pathogenic ALS2 variants. Upon Rac family small GTPase 1 (Rac1) activation, all mutants tested moved from the cytosol to membrane ruffles but not to macropinosomes and/or endosomes. Furthermore, most WT ALS2 complexes were tetramers. Importantly, the sizes of an ALS2 complex carrying missense mutations in the N terminus of the regulator of chromosome condensation 1-like domain (RLD) or in-frame deletion in the pleckstrin homology domain were shifted toward higher molecular weight, whereas the C-terminal vacuolar protein sorting 9 (VPS9) domain missense mutant existed as a smaller dimeric or trimeric smaller form. Furthermore, in silico mutagenesis analyses using the RLD protein structure in conjunction with a cycloheximide chase assay in vitro disclosed that these missense mutations led to a decrease in protein stability. Collectively, disorganized higher structures of ALS2 variants might explain their impaired endosomal localization and the stability, leading to loss of the ALS2 function.

Nuclear translocation of the heterotrimeric CCAAT binding factor of Aspergillus oryzae is dependent on two redundant localising signals in a single subunit.

The CCAAT-binding complex in the Aspergillus species, also known as the Hap complex, consists of at least three subunits, namely HapB, HapC and HapE. Each Hap subunit contains an evolutionary conserved core domain. Recently, we have found that the HapC and HapE subunits do not carry a nuclear localisation signal. Furthermore, when in complex with HapB, they are transported into the nucleus via a 'piggy back mechanism' in A. nidulans. To extend our findings to other filamentous fungi, we examined the nuclear localisation of the A. oryzae Hap subunits by analysing several GFP fusion proteins with these Hap subunits in the hap deletion strains of A. nidulans. The nuclear translocation of the A. oryzae complex was found to be dependent on two redundant localising signals in HapB.