Genetic heterogeneity within a consanguineous family involving TTPA and SETX genes.

Autosomal recessive cerebellar ataxias (ARCA) constitute a highly heterogeneous group of progressive neurodegenerative disorders that typically occur prior to adulthood. Despite some clinical resemblance between these disorders, different genes are involved. We report in this study four Tunisian patients belonging to the same large consanguineous family, sharing autosomal recessive cerebellar ataxia phenotypes but with clinical, biological, electrophysiological, and radiological differences leading to the diagnosis of two distinct ARCA caused by two distinct gene defects. Two of our patients presented ataxia with the vitamin E deficiency (AVED) phenotype, and the other two presented ataxia with oculo-motor apraxia 2 (AOA2). Genetic testing confirmed the clinical diagnosis by the detection of a frameshift c.744delA pathogenic variant in the TTPA gene, which is the most frequent in Tunisia, and a new variant c.1075dupT in the SETX gene. In Tunisia, data suggest that genetic disorders are common. The combined effects of the founder effect and inbreeding, added to genetic drift, may increase the frequency of detrimental rare disorders. The genetic heterogeneity observed in this family highlights the difficulty of genetic counseling in an inbred population. The examination and genetic testing of all affected patients, not just the index patient, is essential to not miss a treatable ataxia such as AVED, as in the case of this family.

A Tunisian patient with CLCN2-related leukoencephalopathy.

CLCN2-related leukoencephalopathy (CC2L OMIM#: 615651) is a recently identified rare disorder. It is caused by autosomal recessive mutations in the CLCN2 gene and leads to the dysfunction of its encoded CLC-2 chloride channel protein with characteristic brain MRI features of leukoencephalopathy. We report the first Tunisian patient with clinical features of ClCN-2-related leukoencephalopathy. A 54-year-old female with a family history of leukemia, male infertility, motor disability, and headaches who initially presented with a tension-type headache and normal physical examination. At the follow-up, she developed mild gait ataxia and psycho-cognitive disturbances. A previously reported homozygous NM_004366.6(CLCN2):c.1709G > A (p.Trp570Ter) stop gained mutation was identified. This report expands the knowledge related to CC2L and highlights the clinical features in affected individuals of African descent.

B Cells Specific CpG Induces High IL-10 and IL-6 Expression In Vitro in Neuro-Behçet's Disease.

Remitting-RelapsingMultiple Sclerosis (RRMS) and Neuro-Behçet Disease (NBD) are two chronic neuroinflammatory disorders leading to neurological damage. Herein, we investigated in these patients the IL-10-producing cells during the early stages of these disorders. Cellular and molecular investigations were carried out on treatment naive patients suffering from RRMS and NBD recruited at the first episode of clinical relapse. Our findings demonstrate that CSF-B cells from NBD patients, but not RRMS, are the major source of intrathecal IL-10 as compared to T-CD4 cells. Moreover, we showed a lower expression of TGF-ß and IL35, in the CSF cells of NBD patients as compared to the control group. Specific in vitro CpG stimulation of peripheral blood B cells from NBD patients resulted in a concomitant early mRNA expression of IL6 and IL10 but was limited to IL10 for RRMS patients. Furthermore, mRNA expression of IL-6 and IL-10 receptors was assessed and intriguingly IL6ST receptor subunit was significantly lower in NBD CSF, but not RRMS while IL10RB was increased in both. Deciphering the role of increased IL-10-producing B cells and IL10RB despite relapsing disease as well as the discordant expression of IL6 and IL6ST may pave the way for a better understanding of the pathophysiology of these neuro-inflammatory disorders.

Neuromyelitis optica and concomitant pulmonary tuberculosis: a case report.

BACKGROUND: Concomitant diagnosis of neuromyelitis optica spectrum disease and pulmonary tuberculosis has rarely been reported. CASE REPORT: We report a case involving a young Tunisian male patient who developed dry cough followed, 2 months later, by weakness in the lower limbs. The findings of central nervous system imaging and anti-aquaporin-4 antibody positivity were compatible with the diagnosis of neuromyelitis optica spectrum disease. Constellation of the clinical and the typical radiological pulmonary findings in our patient, coming from an endemic region, allowed the diagnosis of pulmonary tuberculosis, although sputum smear examination for acid-fast bacilli and cultures was negative. The patient received anti-tuberculous polytherapy associated with immunomodulation, consisting of methylprednisolone and intravenous immunoglobulins. Pulmonary infection symptoms initially improved but with no motor recovery. The patient suddenly died at home 4 months after the onset of the first symptoms. Current data regarding the clinical presentation of this underreported concomitant or associated condition, the possible pathophysiological mechanisms, and the therapeutic options were reviewed. CONCLUSIONS: This case underscores the necessity to understand the exact mechanism of these coincident entities and to clarify the best immunomodulatory choice since immunosuppression targeting neuromyelitis optica spectrum disease can lead to dissemination of pulmonary tuberculosis.

Myasthenia gravis and COVID-19: A case series and comparison with literature.

OBJECTIVE: To describe presenting symptoms, clinical outcomes, and therapeutic management of concurrent Coronavirus disease 2019 (COVID-19) infections in patients with a pre-existing myasthenia gravis (MG). METHODS: We conducted a retrospective study in patients with preexisting MG presenting with concurrent COVID-19 between September 21st and November 4th, 2020 when attending the emergency department or routine neurology consultation at the National Institute Mongi Ben Hamida of Neurology of Tunis, Tunisia. RESULTS: Five patients were identified. The Myasthenia Gravis Foundation of America scores (MGFA) prior to COVID-19 infection were class I in one patient, class II (IIa, IIb) in two patients, and class IIIb in one patient. Four patients had mild to moderate courses of COVID-19 infection. One patient presented a critical infection with acute respiratory disease syndrome (ARDS) requiring mechanical ventilation. Two of them also demonstrated signs of MG exacerbation requiring the use of intravenous immunoglobulin in one case. We maintained immunosuppressant therapy to MG in all our patients. All our patients received Azithromycin (AZM) as a part of specific drug treatment of COVID-19 infection. Outcome was favorable in 4 patients and rapidly fatal evolution was observed in the patient with ADRS. DISCUSSIONS AND CONCLUSION: The results from our study suggest that prior MG activity could partially influence the subsequent clinical outcomes. It emerged also that ongoing long-term immunosuppressive immunotherapy to MG should be maintained during the COVID-19 pandemic and that AZM can be used safely in MG patients and concurrent COVID-19 infection.

Differential Gene Expression Patterns in Blood and Cerebrospinal Fluid of Multiple Sclerosis and Neuro-Behçet Disease.

Inflammatory demyelinating disorders of the central nervous system are debilitating conditions of the young adult, here we focus on multiple sclerosis (MS) and neuro-Behçet disease (NBD). MS is an autoimmune disorder of the central nervous system. NBD, a neurological manifestation of an idiopathic chronic relapsing multisystem inflammatory disease, the behçet disease. The diagnosis of MS and NBD relies on clinical symptoms, magnetic resonance imaging and laboratory tests. At first onset, clinical and imaging similarities between the two disorders may occur, making differential diagnosis challenging and delaying appropriate management. Aiming to identify additional discriminating biomarker patterns, we measured and compared gene expression of a broad panel of selected genes in blood and cerebrospinal fluid (CSF) cells of patients suffering from NBD, MS and non inflammatory neurological disorders (NIND). To reach this aim, bivariate and multivariate analysis were applied. The Principal Analysis Component (PCA) highlighted distinct profiles between NBD, MS, and controls. Transcription factors foxp3 in the blood along with IL-4, IL-10, and IL-17 expressions were the parameters that are the main contributor to the segregation between MS and NBD clustering. Moreover, parameters related to cellular activation and inflammatory cytokines within the CSF clearly differentiate between the two inflammatory diseases and the controls. We proceeded to ROC analysis in order to identify the most distinctive parameters between both inflammatory neurological disorders. The latter analysis suggested that IL-17, CD73 in the blood as well as IL-1ß and IL-10 in the CSF were the most discriminating parameters between MS and NBD. We conclude that combined multi-dimensional analysis in blood and CSF suggests distinct mechanisms governing the pathophysiology of these two neuro-inflammatory disorders.

Discriminative expression of CD39 and CD73 in Cerebrospinal fluid of patients with Multiple Sclerosis and Neuro-Behçet's disease.

Treg-mediated immune suppression involves many molecular mechanisms including the cleavage of inflammatory extracellular ATP to adenosine by CD39 ectoenzyme. In the peripheral blood of Multiple Sclerosis (MS) patients, it has been suggested that CD39+ Treg cells have the potential to suppress pro-inflammatory IL-17 secreting cells. Herein, we studied cellular phenotype and mRNA expression of CD39 and CD73 ectoenzymes in the Cerebrospinal fluid (CSF) of MS patients and another neuro-inflammatory disease: the Neuro-behçet's disease (NBD). Using qRT-PCR, we assessed mRNA expression of CD39 and CD73 as well as anti-inflammatory (IL-10) and pro-inflammatory (IL-6, TNF-α, IL-1ß) cytokines in patients Peripheral blood mononuclear cells (PBMCs) and CSF of 28 relapsing-remitting multiple sclerosis (RRMS), 20 NBD and 22 controls with non inflammatory neurological disorders (NIND). The most substantial result in the CSF was the higher expression of CD39 in both RRMS and NBD patients compared to NIND. While, the expression of CD73 in CSF samples of NBD was low. In RRMS samples, we detected a significant positive correlation of both CD39 and CD73 with IL-10 expression. Moreover, results by flow cytometry revealed a high percentage of CD39 Treg cells in RRMS CSF. CD39 was preferentially expressed on B cells of NBD. Regarding inflammatory response, we showed a significant increase of IL-6 mRNA expression in NBD patients CSF while in RRMS this increase concerned TNF-α. These results bring evidence that CD39 correlates positively with an anti-inflammatory IL-10 response in RRMS. In contrast, no such association was observed in CSF of NBD patients and CD39 was preferentially expressed on B cells.