Frederico Jorge

Distinction between MOG antibody–positive and AQP4 antibody–positive NMO spectrum disorders

Objective: To evaluate clinical features among patients with neuromyelitis optica spectrum disorders (NMOSD) who have myelin oligodendrocyte glycoprotein (MOG) antibodies, aquaporin-4 (AQP4) antibodies, or seronegativity for both antibodies. Methods: Sera from patients diagnosed with NMOSD in 1 of 3 centers (2 sites in Brazil and 1 site in Japan) were tested for MOG and AQP4 antibodies using cell-based assays with live transfected cells. Results: Among the 215 patients with NMOSD, 7.4% (16/215) were positive for MOG antibodies and 64.7% (139/215) were positive for AQP4 antibodies. No patients were positive for both antibodies. Patients with MOG antibodies represented 21.1% (16/76) of the patients negative for AQP4 antibodies. Compared with patients with AQP4 antibodies or patients who were seronegative, patients with MOG antibodies were more frequently male, had a more restricted phenotype (optic nerve more than spinal cord), more frequently had bilateral simultaneous optic neuritis, more often had a single attack, had spinal cord lesions distributed in the lower portion of the spinal cord, and usually demonstrated better functional recovery after an attack. Conclusions: Patients with NMOSD with MOG antibodies have distinct clinical features, fewer attacks, and better recovery than patients with AQP4 antibodies or patients seronegative for both antibodies.

Cerebrospinal fluid aquaporin‐4 antibody levels in neuromyelitis optica attacks

To elucidate immunopathogenetic roles of aquaporin‐4 antibodies in the cerebrospinal fluid (CSF) of neuromyelitis optica spectrum disorders (NMOSD), we analyzed aquaporin‐4 antibody titers, cellular and inflammatory markers in the CSF collected from 11 aquaporin‐4 antibody seropositive patients. The CSF aquaporin‐4 antibody levels during attacks (but not in sera) closely correlated with pleocytosis, inflammatory cytokines including interleukin‐6 that can regulate antibody‐producing plasmablasts, and glial fibrillary acidic protein levels in the CSF. The amount of aquaporin‐4 antibodies present in the central nervous system may have therapeutic implications, as it is associated with astrocyte injury and inflammatory responses during NMOSD attacks. Ann Neurol 2014;76:305–309

Gene expression profiling for human iPS-derived motor neurons from sporadic ALS patients reveals a strong association between mitochondrial functions and neurodegeneration

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that leads to widespread motor neuron death, general palsy and respiratory failure. The most prevalent sporadic ALS form is not genetically inherited. Attempts to translate therapeutic strategies have failed because the described mechanisms of disease are based on animal models carrying specific gene mutations and thus do not address sporadic ALS. In order to achieve a better approach to study the human disease, human induced pluripotent stem cell (hiPSC)-differentiated motor neurons were obtained from motor nerve fibroblasts of sporadic ALS and non-ALS subjects using the STEMCCA Cre-Excisable Constitutive Polycistronic Lentivirus system and submitted to microarray analyses using a whole human genome platform. DAVID analyses of differentially expressed genes identified molecular function and biological process-related genes through Gene Ontology. REVIGO highlighted the related functions mRNA and DNA binding, GTP binding, transcription (co)-repressor activity, lipoprotein receptor binding, synapse organization, intracellular transport, mitotic cell cycle and cell death. KEGG showed pathways associated with Parkinsons disease and oxidative phosphorylation, highlighting iron homeostasis, neurotrophic functions, endosomal trafficking and ERK signaling. The analysis of most dysregulated genes and those representative of the majority of categorized genes indicates a strong association between mitochondrial function and cellular processes possibly related to motor neuron degeneration. In conclusion, iPSC-derived motor neurons from motor nerve fibroblasts of sporadic ALS patients may recapitulate key mechanisms of neurodegeneration and may offer an opportunity for translational investigation of sporadic ALS. Large gene profiling of differentiated motor neurons from sporadic ALS patients highlights mitochondrial participation in the establishment of autonomous mechanisms associated with sporadic ALS.

Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center

Abstract Objective: To investigate gene mutations in familial form (FALS) and sporadic form (SALS) of amyotrophic lateral sclerosis (ALS) in a highly miscegenated population. Methods: Frequencies of mutations in the C9orfF72, TARDBP, SOD1, FUS and VAPB genes were investigated in a cohort of FALS (n = 39) and SALS (n = 189) subjects from the Research Centre of the University of São Paulo School of Medicine. All patients were subjected to C9orf72 and TARDBP analyses. SOD1, FUS and VAPB were also evaluated in FALS subjects. Results: Mutations were identified in FALS (61.3%) and SALS (5.3%) patients. Mutations in C9orf72 (12.8%, >45 GGGGCC hexanucleotide repeats), VAPB (43.6%, P56S) and SOD1 (7.7%, L145S) were identified in FALS subjects. Pathogenic C9orf72 expansions (2.64%) were identified in some SALS patients. Similar changes of TARDBP were found in SALS (2.64%) but not in FALS subjects. No FUS mutations were seen in any FALS subjects. Conclusions: TARDBP and C9orf72 mutations in this cohort were similar to those found in other centres worldwide. VAPB mutation (P56S) was highly prevalent in Brazilian FALS patients.

A severe phenotype of Kennedy's disease associated with a very large CAG repeat expansion

pupillary function is incomplete. The classification of isolated internal ophthalmoplegia in association with bulbar palsy warrants discussion. Recently, we examined the disease characteristics of 15 historical case reports of patients diagnosed as having polyneuritis cranialis and produced diagnostic criteria. We concluded that a diagnosis of polyneuritis cranialis should only be made in patients who displayed ocular (cranial nerves III, IV, and/or VI) and bulbar (cranial nerves IX, X, and/or XII) weakness. Although rare, we suggested that polyneuritis cranialis should be classified as a subtype of GBS and MFS, rather than overlap between acute ophthalmoparesis and acute pharyngeal weakness, which are also very rare. Based on this classification, the patient we described could therefore be diagnosed with polyneuritis cranialis. This was also supported by the presence of IgG anti-GQ1b antibodies, which has been found to be the most commonly identified antibody in patients with polyneuritis cranialis.

A disturbed processing of graviceptive pathways may be involved in the pathophysiology of balance disorders in patients with multiple sclerosis

The purpose of this study was to determine the relationship between perception of verticality and balance disorders in multiple sclerosis patients. We evaluated patients and healthy controls. Patients were divided into two groups according to their risk of fall, with or without risk of fall, measured by a Dynamic Gait Index scale. Graviceptive perception was assessed using the subjective visual vertical test. Patients with risk of fall showed worse perception than those without risk of fall, p < 0.001. Misperception of verticality was correlated with the dynamic gait index scores (p < 0.001), suggesting that the larger the error for verticality judgment, the greater risk for falling. Considering that the perception of verticality is essential for postural control, our results suggested that the disturbed processing of graviceptive pathways may be involved in the pathophysiology of balance disorders in these patients.