Dynamics of AQP4 upon exposure to seropositive patient serum before and after Rituximab therapy in Neuromyelitis Optica: A cell-based study.

Neuromyelitis Optica (NMO) is an autoimmune inflammatory disease that affects the optic nerves and spinal cord. The autoantibody is generated against the abundant water channel protein of the brain, Aquaporin 4 (AQP4). Of the two isoforms of AQP4, the shorter one (M23) often exists as a supramolecular assembly known as an orthogonal array of particles (OAPs). There have been debates about the fate of these AQP4 clusters upon binding to the antibody, the exact mechanism of its turnover, and the proteins associated with the process. Recently several clinical cases of NMO were reported delineating the effect of Rituximab (RTX) therapy. Extending these reports at the cell signaling level, we developed a glioma based cellular model that mimicked antibody binding and helped us track the subsequent events including a variation of AQP4 levels, alterations in cellular morphology, and the changes in downstream signaling cascades. Our results revealed the extent of perturbations in the signaling pathways related to stress involving ERK, JNK, and AKT1 together with markers for cell death. We could also decipher the possible routes of degradation of AQP4, post-exposure to antibody. We further investigated the effect of autoantibody on AQP4 transcriptional level and involvement of FOXO3a and miRNA-145 in the regulation of transcription. This study highlights the differential outcome at the cellular level when treated with the serum of the same patient pre and post RTX therapy and for the first time mechanistically describes the effect of RTX.

Mutation Location and Cognitive Impairment in Duchenne Muscular Dystrophy.

BACKGROUND: Cognitive impairment is commonly seen in patients with Duchenne muscular dystrophy (DMD). Few studies have shown a correlation between loss of different isoforms of the DMD gene and cognitive impairment. OBJECTIVE: The objective of the study was to determine whether correlation exists in the location of mutation in DMD gene or loss of different isoforms and cognitive impairment in children with DMD in the Indian population. MATERIALS AND METHODS: Ten children were evaluated. Gene mutation analysis was done by multiplex ligation-dependent probe amplification method. The isoforms affected were inferred from mutation location in each of these patients. Binet Kamat Intelligence Test (BKT) and Bender Gestalt test (BGT) were administered. RESULTS: All male patients were aged between 4 and 9 years. Genetic analysis showed deletion in all patients, with seven having deletion in "hotspot" regions (exon 43-52). Psychometric analysis by BGT and BKT showed mean score of 8.6 and mean IQ score of 85.5, respectively. Comparison between patients with hotspot mutations and mutations in other regions, for mean IQ score and BGT score, was statistically significant (P = 0.132 and P = 0.005, respectively). The difference in the IQ score between patients with isolated Dp427 loss (n = 3) and cumulative Dp427/Dp260/Dp140utr loss (n = 6) was statistically significant (P = 0.011). Visuomotor functioning was more impaired in patients with isolated Dp427 loss. CONCLUSION: The role of cumulative loss of isoforms along with importance of loss of Dp140pc isoform was seen in our study. One patient with loss of Dp140utr isoform had intellectual impairment which is not commonly seen. Visuomotor functioning is more affected in more upstream mutations as shown in our study.

White matter changes in Wilson's disease: A radiological enigma.

Wilson's disease is a metabolic disorder which presents with hepatitis or hepatic decompensation commonly. Neurologic manifestations are late and include movement disorders, personality changes, and seizures. Magnetic resonance imaging (MRI) brain shows high signal changes in putamen, lentiform nucleus, thalamus, and brainstem. White matter lesions are rare. We report a child of Wilson's disease who presented to us with dystonia, rigidity, myoclonus and had symmetrical white matter changes in the fronto-parietooccipital region. Diffusion restriction in bilateral frontoparietal areas was also seen which is rare in chronic cases like ours. Atypical MRI characteristics should be considered in patients with clinical signs of neurological involvement in Wilson's disease as it is a devastating but treatable disease.