Vitamin D receptor gene BsmI (rs1544410) polymorphism: role in multiple sclerosis and genotype-phenotype correlations.

BACKGROUND: Multiple sclerosis (MS) has a complex pathophysiology which depends on many endogenous and exogenous factors. Vitamin D involvement has been largely studied in MS. The large distribution of the vitamin D receptor (VDR) in different immune cells is suggestive of an immunomodulatory role. The VDR gene polymorphisms have been proposed as potential risk factors for MS development or evolution with non-conclusive results. METHODS AND RESULTS: We conducted a cross-sectional study including patients ≥ 18 years, with a diagnosis of relapsing remitting MS according to the McDonald Criteria and having a minimum follow-up period of one year after starting a disease modifying therapy. Two study groups were compared based on the Multiple Sclerosis Severity Scale or MSSS: "a slow progressor" group for an MSSS ≤ 5, and a "fast progressor" group for an MSSS > 5. The rs1544410 VDR gene polymorphism was studied for all patients. Eighty patients were included. The fast progressor groups had a higher EDSS at onset, a higher total number of relapses, more frequent and shorter time to secondary progression. The progression profile was not statistically different between genotypes and alleles of the VDR gene polymorphism rs1544410. The CC genotype and wild-type allele exhibited a more aggressive disease phenotype with a higher number of relapses the first year, shorter time to secondary progression and cerebral atrophy on assessment. CONCLUSIONS: Our results suggest potential genotype-phenotype correlations for the rs1544410 VDR gene polymorphism in the disease course of MS. Future research on a larger scale is needed to confirm these findings.

COVID-19 Infection and Recurrent Stroke in Young Patients With Protein S Deficiency: A Case Report.

INTRODUCTION: Protein S deficiency and coronavirus disease 2019 (COVID-19) are rare etiologies of ischemic stroke. We describe a case of an ischemic stroke revealing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a patient with a history of protein S deficiency and cerebral imaging suggestive of vasculitis. CASE REPORT: A 52-year-old woman, with history of protein S deficiency, was admitted for right hemiparesis and aphasia that happened 6 hours before her consultation. Her National Institutes of Health Stroke Scale (NIHSS) was 11. She had hypoxia (SpO2 93%). COVID-19 polymerase chain reaction was positive. Cerebral computed tomography scan showed an ischemic stroke in the territory of the superficial left middle cerebral artery. The recommended time period for thrombolysis was exceeded and we did not dispose of sufficient resources to deliver thrombectomy. She was treated with aspirin, statins, antibiotic therapy, and oxygen. Considering the high risk of thromboembolic complications and the history of protein S deficiency, anticoagulation treatment with heparin followed by acenocoumarol was started. Evolution was marked by the appearance of 24 hours regressive, acute symptoms of confusion. Brain magnetic resonance imaging showed new ischemic strokes in both anterior cerebral arteries and on magnetic resonance angiography narrowing of the left internal carotid artery and both anterior cerebral arteries suggestive of vasculitis was seen. We maintained anticoagulation and prescribed methylprednisolone 500 mg daily for 3 days. Evolution was marked by improvement of clinical deficit and respiratory status. CONCLUSIONS: SARS-CoV-2 infection potentializes the prothrombotic effect and vascular inflammation by accentuating protein S deficit. The place of steroids seems justifiable in the presence of symptoms of vasculitis in brain imaging.

Knowledge and attitudes toward epilepsy among teachers in Tunisia.

BACKGROUND: The importance of school teachers' knowledge of and attitudes toward epilepsy and its contribution in improving the links between the Education and Health fields, is well recognized and appreciated. In order to clarify the amount of misconceptions about epilepsy among Tunisian teachers, we conducted a web-based survey. The main objectives of our study were, first, to determine the knowledge about and attitudes toward epilepsy, and second, to specify factors associated with a better understanding of this disease. METHODS: Data were collected using a web-based survey "Google Forms". RESULTS: The study showed a positive correlation between the level of teachers' knowledge of epilepsy and their attitudes toward a person with epilepsy. Despite the knowledge gaps revealed in Tunisian teachers, the overall attitude was at large positive. Familiarity with epilepsy, whether through family or work environment, made a tremendous contribution in redressing misconceptions about epilepsy in our study. CONCLUSION: More educational interventions and programs are needed to increase teachers' familiarity with epilepsy and, consequently, increase their awareness and knowledge.

Epileptic seizures and occupational exposure to solvents: a cases series.

INTRODUCTION: Organic solvents (OS) are substances with well-known nervous system tropism. Long-term exposure can cause several neurological and neuropsychic manifestations (mainly toxic encephalopathy). A potential causal relation between epileptic seizures and exposure to OS remains controversial. METHODS: We report seven cases of patients with no neurological history who had been professionally exposed to OS and who had at least one epileptic seizure after exposure. Selection of these cases was based on medical records of patients who were referred to the occupational health department of Charles Nicolle Hospital of Tunis during the period from January 1, 2010 to December 31, 2014. RESULTS: Cases studies concerned five men and two women aged between 29 and 46. Professional seniority ranged from 2 to 31 years. In all cases, epileptic seizures occurred after exposure to a mixture of solvents. It was concluded, according to workplace inspections, that there was an important daily and direct OS exposure. Working conditions were considered as defective. Six cases had generalized seizures, one patient presented with status epilepticus. Illness onset occurred between one and nine years after the beginning of exposure to OS. CONCLUSION: These cases suggest a possible relationship between OS exposure and onset of epilepsy.

Neuromuscular Involvement in Glycogen Storage Disease Type III in Fifty Tunisian Patients: Phenotype and Natural History in Young Patients.

BACKGROUND: Our aim was to describe the natural history of neuromuscular involvement (NMI) in glycogen storage disease type III (GSDIII). METHODS: We conducted a longitudinal study of 50 Tunisian patients, 9.87 years old in average. RESULTS: NMI was diagnosed at an average age of 2.66 years and was clinically overt in 85% of patients. Patients with clinical features were older (p = 0.001). Complaints were dominated by exercise intolerance (80%), noticed at 5.33 years in average. Physical signs, observed at 6.75 years in average, were dominated by muscle weakness (62%). Functional impairment was observed in 64% of patients, without any link with age (p = 0.255). Among 33 patients, 7 improved. Creatine kinase (CK) and aspartate aminotransferase (AST) levels were higher with age.Electrophysiological abnormalities, diagnosed in average at 6.5 years, were more frequent after the first decade (p = 0.0005). Myogenic pattern was predominant (42%). Nerve conduction velocities were slow in two patients. Lower caloric intake was associated with more frequent clinical and electrophysiological features. Higher protein intake was related to fewer complaints and physical anomalies. CONCLUSION: Neuromuscular investigation is warranted even in asymptomatic patients, as early as the diagnosis of GSDIII is suspected. Muscle involvement can be disabling even in children. Favorable evolution is possible in case of optimal diet.

A lower energetic, protein and uncooked cornstarch intake is associated with a more severe outcome in glycogen storage disease type III: an observational study of 50 patients.

Background Glycogen storage disease type III (GSDIII), due to a deficiency of glycogen debrancher enzyme (GDE), is particularly frequent in Tunisia. Phenotypic particularities of Tunisian patients remain unknown. Our aim was to study complications of GSDIII in a Tunisian population and to explore factors interfering with its course. Methods A retrospective longitudinal study was conducted over 30 years (1986-2016) in the referral metabolic center in Tunisia. Results Fifty GSDIII patients (26 boys), followed for an average 6.75 years, were enrolled. At the last evaluation, the median age was 9.87 years and 24% of patients reached adulthood. Short stature persisted in eight patients and obesity in 19 patients. Lower frequency of hypertriglyceridemia (HTG) was associated with older patients (p<0.0001), higher protein diet (p=0.068) and lower caloric intake (p=0.025). Hepatic complications were rare. Cardiac involvement (CI) was frequent (91%) and occurred early at a median age of 2.6 years. Severe cardiomyopathy (50%) was related to lower doses of uncooked cornstarch (p=0.02). Neuromuscular involvement (NMI) was constant, leading to a functional discomfort in 64% of cases and was disabling in 34% of cases. Severe forms were related to lower caloric (p=0.005) and protein intake (p<0.015). Conclusions A low caloric, protein and uncooked cornstarch intake is associated with a more severe outcome in GSDIII Tunisian patients. Neuromuscular and CIs were particularly precocious and severe, even in childhood. Genetic and epigenetic factors deserve to be explored.

TOP3B: A Novel Candidate Gene in Juvenile Myoclonic Epilepsy?

Juvenile myoclonic epilepsy (JME) is characterized by seizures, severe cognitive abnormalities, and behavior impairments. These features could evolve over time and get worse, especially when the encephalopathy is pharmacoresistant. Thus, genetic studies should provide a better understanding of infantile epilepsy syndromes. Herein, we investigate the genetics of JME in a consanguineous family analyzing the copy number variations detected using over 700 K SNP arrays. We identified a 254-kb deletion in the 22q11.2 region, including only the TOP3B gene, detected in the patient and her father. TOP3B encodes a topoisomerase DNA (III) ß protein and has been implicated in several neurological diseases such as schizophrenia and autism. In this study, we discuss the implication of the 22q11.2 region in neurodevelopmental disorders and the association of TOP3B with epilepsy.

Gastrointestinal Dysfunction and Neuropathologic Correlations in Parkinson Disease.

INTRODUCTION: Recently, an increasing interest to nonmotor symptoms of Parkinson disease (PD) has shown. Gastrointestinal dysfunction is a prominent nonmotor manifestation of PD and precedes motor symptoms for several years. Neuropathologic studies show early accumulation of α-synuclein (α-SYN) in Lewy neurites and Lewy body in the enteric nervous system (ENS) and dorsal motor nucleus of the vagus in PD. Our study aims to investigate relationship between α-SYN deposition in ENS and gastrointestinal dysfunction in PD. MATERIALS AND METHODS: We conducted a study in Neurology Department of Charles Nicolle Hospital of Tunis during 2 years (2013 to 2014) including PD patients. Clinical data were analyzed. Digestive endoscopy with biopsies of upper digestive tract (UDT) and immunohistochemistry study were performed. RESULTS: Thirty patients (16♂/14♀) and 13 (7♂/6♀) controls were included. Average age was 65 years for patients and 63.5 years for controls. Gastrointestinal symptoms were the most frequent nonmotor symptoms occurring in 73%. Endoscopy showed motor dysfunction of upper digestive tract in 5 patients. Lesion load in α-SYN was significantly correlated with frequency and severity of gastrointestinal dysfunction and PD motor disability. CONCLUSIONS: Gastrointestinal disturbances are frequent in PD. ENS's synucleinopathy could entirely explain pathophysiology of digestive dysfunction and is correlated with severity of gastrointestinal symptoms in PD. Biopsies may show α-SYN aggregates in immunoreactive Lewy neurites in the submucosal and myenteric plexus. Thus, endoscopic and immunohistochemical exploration of ENS may be a biomarker for Parkinson enteropathy and for PD overall.

Novel presenilin 1 mutation (p.I83T) in Tunisian family with early-onset Alzheimer's disease.

A minority of Alzheimer disease (AD) patients begin presenting symptoms before the age of 65 years. A familial aggregation is often found in this group of early-onset AD, and, in a subset of families, the pattern of inheritance is consistent with autosomal dominant inheritance. Fully penetrant variants in amyloid precursor protein, presenilin 1 (PSEN1), and presenilin 2 are the only causative mutations reported for autosomal dominant AD. This study is to explore the PSEN1 gene mutation in a Tunisian familial Alzheimer's disease. The patient in this family showed a novel missense mutation in exon 4 of the PSEN1 gene (complementary DNA 248T>C), altering isoleucine to threonine at 83 position. Because the change occurred in conserved domains of this gene, and cosegregated with affected family member, we suggested that this change may have a mutagenic and probably pathogenic effect.

Parkinsonism and Sjögren's Syndrome: A Fortuitous Association or a Shared Immunopathogenesis?

Background. The Sjögren Syndrome (SS) can include various manifestations of central nervous system impairment. Extrapyramidal signs are known to be very rare and unusually discovered on early onset in this pathology. Observation. A 46-year-old woman with a history of progressive Parkinsonism for 6 years and a normal brain magnetic resonance imaging was partially improved with levodopa therapy. The later discovery of a sicca syndrome led to performing of further investigations, which revealed the presence of anti-SSA antibodies and a sialoadenitis of grade 4 according to Chisholm's classification on labial salivary gland biopsy. The diagnosis of primary SS was established and the adjunction of corticotherapy has remarkably improved Parkinson's signs without use of other immunosuppressive agents. Conclusion. Based on these findings, we discuss the hypothesis of either a causal link between SS and Parkinsonism or a fortuitous association of two distinct pathologies with or without a shared immunopathogenesis.

High APOE epsilon 4 allele frequencies associated with Alzheimer disease in a Tunisian population.

The goal of the study was to examine the Apolipoprotein E (APOE) genotypes in a Tunisian sample of patients with Alzheimer disease (AD) and normal controls, and to compare the results with the findings from the literature. A hospital-based case-control study of two groups (58 patients with AD, 71 controls) was conducted. Patients received a detailed clinical history, neurological examination, neuropsychological testing and brain imaging. A neurological examination and the Arabic version of the Mini-Mental State Examination were made for controls. Genotyping was performed using the PCR restriction fragment length polymorphism (PCR-RFLP) method. There were no statistical differences in age (p = 0.05) and gender (p = 0.046) between the two groups. The APOE ε4/4 genotype was over represented in the AD group in comparison with the controls (13.3 vs. 2.8%). A significant increased risk of AD among APOE ε4 allele carriers was observed. The odds ratio for the association of AD patients with homozygous and heterozygous ε4 allele was, respectively, 5.40 (1.35-21.48) and 2.90 (1.27-6.62). Our results in addition to previously published genetic studies suggest that AD disease is multifactor in origin. Ethnicity, genetic and environmental factors contribute to AD risk in different ethnic groups.

Obsessive-compulsive disorder: a new risk factor for Alzheimer disease?

We describe a case of a 75-year-old woman referred to the Memory Clinic of the neurological Department of Charles Nicolle Hospital, Tunis, for cognitive decline and behavioral disturbances. Her past medical history was marked by severe obsessive-compulsive disorder (OCD) with contamination obsessions and washing compulsions. She has a family history for OCD and/or of dementia in 15 members. Clinical features, along with neuropsychological findings and Brain imaging were in favor of Alzheimer disease (AD). The present report is the first family study reporting the possible association of OCD and AD. The glutamatergic dysfunction may be a common pathophysiology of OCD and AD explaining this association.