Case report: Compound heterozygous variants detected by next-generation sequencing in a Tunisian child with ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is an autosomal recessive primary immunodeficiency disorder (PID) caused by biallelic mutations occurring in the serine/threonine protein kinase (ATM) gene. The major role of nuclear ATM is the coordination of cell signaling pathways in response to DNA double-strand breaks, oxidative stress, and cell cycle checkpoints. Defects in ATM functions lead to A-T syndrome with phenotypic heterogeneity. Our study reports the case of a Tunisian girl with A-T syndrome carrying a compound heterozygous mutation c.[3894dupT]; p.(Ala1299Cysfs3;rs587781823), with a splice acceptor variant: c.[5763-2A>C;rs876659489] in the ATM gene that was identified by next-generation sequencing (NGS). Further genetic analysis of the family showed that the mother carried the c.[5763-2A>C] splice acceptor variant, while the father harbored the c.[3894dupT] variant in the heterozygous state. Molecular analysis provides the opportunity for accurate diagnosis and timely management in A-T patients with chronic progressive disease, especially infections and the risk of malignancies. This study characterizes for the first time the identification of compound heterozygous ATM pathogenic variants by NGS in a Tunisian A-T patient. Our study outlines the importance of molecular genetic testing for A-T patients, which is required for earlier detection and reducing the burden of disease in the future, using the patients' families.

Complex genotypes in family with metachromatic leukodystrophy: Effect of trans and cis mutations distribution on the phenotype variability.

Metachromatic leukodystrophy (MLD) is a severe metabolic disorder caused by the deficient activity of arylsulfatase A due to ARSA gene mutations. According to the age of onset, MLD is classified into three forms: infantile, juvenile, and adult. In our study, we aimed to perform a genetic analysis for two siblings with juvenile MLD for a better characterization of the molecular mechanisms behind the disease. A consanguineous family including two MLD patients (PII.1 and PII.2) was enrolled in our study. The diagnosis was made based on the clinical and neuroimaging investigations. The sequencing of ARSA gene was performed followed by in silico analysis. Besides, the cis/trans distribution of the variants was verified through a PCR-RFLP. The ARSA gene sequencing revealed three known variants, two exonic c.1055A > G and c.1178C > G and an intronic one (c.1524 + 95A > G) in the 3'UTR region. All variants were present at heterozygous state in the two siblings and their mother. The assessment of the cis/trans distribution showed the presence of these variants in cis within the mother, while PII.2 and PII.2 present the c.1055A > G/c.1524 + 95A > G and the c.1178C > G in trans. Additionally, PII.1 harbored a de novo novel missense variant c.1119G > T, whose pathogenicity was supported by our predictive results. Our genetic findings, supported by a clinical examination, confirmed the affection of the mother by the adult MLD. Our results proved the implication of the variable distribution of the found variants in the age of MLD onset. Besides, we described a variable severity between the two siblings due to the de novo pathogenic variant. In conclusion, we identified a complex genotype of ARSA variants within two MLD siblings with a variable severity due to a de novo variant present in one of them. Our results allowed the establishment of an adult MLD diagnosis and highlighted the importance of an assessment of the trans/cis distribution in the cases of complex genotypes.

Juvenile Dermatomyositis Without Skin Lesions in an Antinuclear Matrix Protein 2 Antibody Seropositive Pediatric Case.

ABSTRACT: We report a 5-year-old boy who presented with progressive weakness in 4 limbs and gait disorders over 7 months. No skin rash was observed on admission. A symmetrical proximodistal weakness was found. The creatine kinase level was normal with a slightly elevated lactate dehydrogenase level. Biopsy specimens showed infiltration of mononuclear cells, few necrotic fibers, and perifascicular atrophy. Screening for myositis-specific antibodies was positive for the antinuclear matrix protein 2 antibody, which is mainly associated with dermatomyositis. Symptoms improved on receiving corticosteroids. Our findings suggest that in cases where inflammatory muscle disease is suspected, antinuclear matrix protein 2 antibody analyses should be considered for precise diagnosis, even with the absence of dermatological symptoms. The case suggests consideration of juvenile dermatomyositis in children with no associated skin manifestations or elevated creatine kinase levels and highlights the importance of screening for myositis-specific antibodies in helping with the diagnosis, given the possible heterogeneity of its clinical presentations.

A new case with the recurrent PURA p.(Phe233del) pathogenic variant: Expansion of the phenotype and review of the literature.

In the process of neuronal development, the protein Purα (encoded by the PURA gene) is essential for neuronal proliferation, dendritic maturation, and the transportation of mRNA to translation sites. Mutations in the PURA gene may alter normal brain development and impair neuronal function, contributing to developmental delays and seizures. Recently, PURA syndrome is described as developmental encephalopathy with or without epilepsy, neonatal hypotonia, feeding difficulties, global developmental delay, and severe intellectual disability. In our study, we aimed to perform a genetic analysis by whole exome sequencing (WES) in a Tunisian patient presented with developmental and epileptic encephalopathy to provide a molecular explanation for the developed phenotype. We collected, also, clinical data of all PURA p.(Phe233del) patients reported yet and compared the clinical features with those of our patient. Results revealed the presence of the known PURA c.697_699del, p.(Phe233del) variant. Our studied case shares some clinical features including hypotonia, feeding difficulties, severe developmental delay, epilepsy, and language delay (nonverbal) but presents a radiological finding undescribed before. Our finding defines and expands the phenotypic and genotypic spectrum of the PURA syndrome supporting the absence of reliable genotype-phenotype correlations and the existence of a highly variable, wide-ranging clinical spectrum.

Acute Demyelinating Syndromes: A report of child neurology department of Sfax University Hospital.

INTRODUCTION: The yearly incidence of Acute Demyelinating Syndromes (ADS) in a multiethnic cohort of children published by Langer-Gould and al in 2011 was estimated at about 1.66 per 100,000. Nevertheless, the real incidence for these disorders is still underestimated as the iterative revision for diagnosis criteria have failed to classify a significant number of children with ADS. PURPOSE: This work was aimed to describe clinical and paraclinical characteristics of ADS in a pediatric population. MATERIAL AND METHODS: Demographic, clinical and paraclinical data of 42 children (24 females; 18 male; SR = 1.33), were collected from the medical records of patients admitted to the child neurology department of Sfax University Hospital between 2008 and 2021 for clinical events with presumed inflammatory origin. Next, patients were categorized as per M. N. Nouri and al. up dated classification for ADS. Finally, characteristics of different ADS categories were compared. RESULTS: The mean age onset was 6 years (± 3.5 years). For a mean follow-up period of 28 months, 69% of patients had a monophasic course. ADS in our pediatric population were Acute disseminated encephalomyelitis (ADEM) (36%), Clinically isolated syndrome (CIS) (24%), Multiple sclerosis (MS) (19%), Neuromyelitis optica spectrum disorder (NMOSD) (7%), Myelin oligodendrocyte glycoprotein antibodies-associated diseases (MOGAD) (2%) and Recurrent demyelinating disease not otherwise specified (RD-NOS) (10%). At presentation, patients showed different clinical picture according to ADS-subtype with more patients with epileptic seizure in ADEM-group (53.3%), optic neuritis in CIS-group (70%), motor deficit in MS-group (62.5%), area postrema syndrome in NMOSD-group (33.3%) and vesico-sphincter dysfunction in RD-NOS-group (75%). Among patients presenting with visual impairment (21.4%), Visual evoked potential (VEP) guided the diagnosis of NMOSD in 22.2% by objectifying axonal optic nerve damage. Different ADS subtypes were identified according to MRI results in 100% of ADEM-patients and 75% of MS-patients and on antibody testing in three patients. The ADS-subtype was recognized based on antibody testing in three patients. Two patients from CIS-group: the first with isolated optic neuritis (ON) was positive for antiaquaporin 4 antibodies (anti-AQP4) and the other with clinically polyfocal ADS was positive for antinuclear antibodies (ANA) type anti-RNP. The remaining patients who presented with ADEM-phenotype was positive for anti-myelin oligodendrocyte glycoprotein (anti-MOG). SIGNIFICANCE: Recognizing distinctive features of each ADS category may improve diagnosis accuracy as well as the indication of suitable treatment.

Knowledge and attitudes toward epilepsy among people in Sfax region, Tunisia.

INTRODUCTION: Epilepsy is one of the most stigmatizing disorders. Stigma and negative attitudes associated with epilepsy are due to poor public awareness and knowledge. This study evaluated knowledge, awareness, and attitude toward epilepsy among Tunisian general population. METHODS: This was a cross-sectional study conducted between 2017 and 2019. On national epilepsy day on February and during awareness campaigns at Sfax Tunisia, we asked people who visited the epilepsy stand to anonymously answer a 31-item questionnaire on epilepsy. RESULTS: Five hundred and four participants have been included. About 43.6% of participants had personal or familial history of epilepsy. More than seventy percent of subjects thought that epilepsy is a neurological disease and 34.1% believed it is psychiatric. Majority (92.1%) of our population believed that epilepsy is non-contagious but 37.7% thought it is hereditary and 55.8% thought it causes intellectual deficiency. EEG was the most reported diagnostic method (61.7%). The two most popular therapeutic modalities reported in our population were drug treatment alone (85.3%) and associated with Quran (35.3%). Most (91.1%) of people thought that a person with epilepsy can get married. A person with epilepsy is able to study according to 92.7% of respondents, but 66.3% assumed that he/she suffers from difficulty concentrating. Subjects younger than 45 years were more aware of the ability of people with epilepsy to study and get married. We did not find any significant differences in knowledge and attitudes between subjects familiar with epilepsy and the rest of the population. CONCLUSION: The public knowledge and attitudes toward epilepsy were acceptable with regard to this study. However, negative attitudes and misunderstanding still exist.

Disruptions of neurological services, its causes and mitigation strategies during COVID-19: a global review.

BACKGROUND: The COVID-19 pandemic leads to disruptions of health services worldwide. To evaluate the particular impact on neurological services a rapid review was conducted. METHODS: Studies reporting the provision of neurological services during the pandemic and/or adopted mitigation strategies were included in this review. PubMed and World Health Organization's (WHO) COVID-19 database were searched. Data extraction followed categories used by WHO COVID-19 pulse surveys and operational guidelines on maintaining essential health services during COVID-19. FINDINGS: The search yielded 1101 articles, of which 369 fulfilled eligibility criteria, describing data from 210,419 participants, being adults (81%), children (11.4%) or both (7.3%). Included articles reported data from 105 countries and territories covering all WHO regions and World Bank income levels (low income: 1.9%, lower middle: 24.7%, upper middle: 29.5% and high income; 44.8%). Cross-sectoral services for neurological disorders were most frequently disrupted (62.9%), followed by emergency/acute care (47.1%). The degree of disruption was at least moderate for 75% of studies. Travel restrictions due to lockdowns (81.7%) and regulatory closure of services (65.4%) were the most commonly reported causes of disruption. Authors most frequently described telemedicine (82.1%) and novel dispensing approaches for medicines (51.8%) as mitigation strategies. Evidence for the effectiveness of these measures is largely missing. INTERPRETATION: The COVID-19 pandemic affects all aspects of neurological care. Given the worldwide prevalence of neurological disorders and the potential long-term neurological consequences of COVID-19, service disruptions are devastating. Different strategies such as telemedicine might mitigate the negative effects of the pandemic, but their efficacy and acceptability remain to be seen.

Clinical and genetic aspect of 30 tunisian families with febrile seizures.

BACKGROUND: FS are the most benign occasional seizures in childhood. Little is known about the long term follow up.  Aim: To describe a long term follow-up of FS in Tunisian families. METHODS: Field study was conducted for 30 patients with FS. We analyzed clinical phenotype of FS and associated afebrile seizures with genetic study. RESULTS: We collected 107 individuals with febrile and / or afebrile seizures. Afebrile seizures were found in 28.3% of patients. The "FS" phenotype was found in 18 families (60%), "GEFS +" in 7 (23.33%), and idiopathic generalized epilepsy in 5 (16.66%). Sequencing analyses of SCN1A, SCN1B and GABRG2 genes revealed a novel SCN1B gene mutation in one family with FS and a known SCN1A mutation in GEFS+ family. CONCLUSION: If FS are apparently isolated and infrequent, they occur most often in a family setting. The genetic studies remain difficult mainly because of the lack of phenotype-genotype correlation.