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Hypomyelinating leukodystrophy-5 (HLD5) is a rare autosomal recessive hypomyelination disorder characterized by congenital cataract, progressive neurologic impairment, and myelin deficiency in the central and peripheral nervous system, caused by mutations in the HYCC1 gene. Here we report a 23-year-old girl with HLD5 from unrelated families. Molecular analysis was performed using sequence screening of the HYCC1 gene. In addition, in silico prediction tools and molecular investigation were used to predict the structural effect of the mutations. Results showed a novel compound heterozygous mutation in the HYCC1 gene. Moreover, in silico tools and 3D structural modeling revealed that c.521C > A (p.Ala174Glu) and c.652C > G (p.Gln218Glu) mutations could affect the structure, stability, and conformational analyses in the N-ter domain of the Hyccin protein. We also, we compared the phenotype of our patient with those of previously reported cases with HLD5 syndrome and our findings indicate the absence of reliable genotype-phenotype correlations. To the best of our knowledge, this is the first report describing a Tunisian HLD5 patient with compound heterozygous mutations (c.521C > A (p.Ala174Glu) and c.652C > G (p.Gln218Glu)) in HYCC1 gene., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: The study was conducted in accordance with the principles stated in the Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects, Helsinki, Finland, 1964, and as amended in Fortaleza, Brazil, 2013. The study design was approved by the committee on research ethics of the University of Sfax, Tunisia. Consent to participate: Informed consent for publication of this study was obtained from all patients and/or families involved. Consent for publication: We certify that all contributors have read and approved the submission to this journal and that there is no financial or commercial involvement, or other conflict of interest by any author., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

The clinical diagnosis of patients with multisystem involvement including a pronounced neurologic damage is challenging. High-throughput sequencing methods remains crucial to provide an accurate diagnosis. In this study, we reported a Tunisian patient manifesting hypotonia and global developmental delay with visual and skin abnormalities. Exome sequencing was conducted followed by segregation analysis and, subsequently additional investigations. In silico analysis of non-synonymous variants (nsSNPs) described in COG5 in conserved positions was made. Results revealed a homozygous missense variant c.298 C > T (p.Leu100Phe) in the COG5 inherited from both parents. This variant altered both protein solubility and stability, in addition to a putative disruption of the COG5-COG7 interaction. This disruption has been confirmed using patient-derived cells in vitro in a COG5 co-immuno-precipitation, where interaction with binding partner COG7 was abrogated. Hence, we established the COG5-CDG diagnosis. Clinically, the patient shared common features with the already described cases with the report of the ichtyosis as a new manifestation. Conversely, the CADD scoring revealed 19 putatively pathogenic nsSNPs (Minor Allele Frequency MAF < 0.001, CADD > 30), 11 of which had a significant impact on the solubility and/or stability of COG5. These properties seem to be disrupted by six of the seven missense COG5-CDG variants. In conclusion, our study expands the genetic and phenotypic spectrum of COG5-CDG disease and highlight the utility of the next generation sequencing as a powerful tool in accurate diagnosis. Our results shed light on a likely molecular mechanism underlying the pathogenic effect of missense COG5 variants, which is the alteration of COG5 stability and solubility., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Intellectual disabilities (ID) and autism spectrum disorders (ASD) have a variety of etiologies, including environmental and genetic factors. Our study reports a psychiatric clinical investigation and a molecular analysis using whole exome sequencing (WES) of two siblings with ID and ASD from a consanguineous family. Bioinformatic prediction and molecular docking analysis were also carried out. The two patients were diagnosed with profound intellectual disability, brain malformations such as cortical atrophy, acquired microcephaly, and autism level III. The neurological and neuropsychiatric examination revealed that P2 was more severely affected than P1, as he was unable to walk, presented with dysmorphic feature and exhibited self and hetero aggressive behaviors. The molecular investigations revealed a novel TRAPPC9 biallelic nonsense mutation (c.2920 C > T, p.R974X) in the two siblings. The more severely affected patient (P2) presented, along with the TRAPPC9 variant, a new missense mutation c.166 C > T (p.R56C) in the MID2 gene at hemizygous state, while his sister P1 was merely a carrier. The 3D modelling and molecular docking analysis revealed that c.166 C > T variant could affect the ability of MID2 binding to Astrin, leading to dysregulation of microtubule dynamics and causing morphological abnormalities in the brain. As our knowledge, the MID2 mutation (p.R56C) is the first one to be detected in Tunisia and causing phenotypic variability between the siblings. We extend the genetic and clinical spectrum of TRAPPC9 and MID2 mutations and highlights the possible concomitant presence of X-linked as well as autosomal recessive inheritance to causing ID, microcephaly, and autism., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

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., (© 2023 International Society for Developmental Neuroscience.)

Background: Moyamoya angiopathy is a rare cerebral vasculopathy and an underdiagnosed cause of arterial ischemic stroke in children. We aim to report the clinical and radiological presentations in a Tunisian pediatric cohort., Methods: We identified moyamoya angiopathy in pediatric patients managed at the Child Neurology Department of Hedi Chaker Sfax University Hospital between 2008 and 2020 and reviewed their clinical and radiological data as well as their evolutionary profile., Results: We collected 14 patients with median age 40.6 months and a female predominance (sex ratio of 0.75). An arterial ischemic stroke (AIS) revealed the disease in all patients, with the major symptom being a motor deficit. Symptoms related to a transient ischemic attack before the diagnostic consultation were reported in four patients. Carotid territory was, clinically and radiologically, the most frequently involved. Brain magnetic resonance imaging with angiography was performed in 12 patients confirming the diagnosis by revealing the development of collateral vessels. All the investigations concluded to moyamoya disease in 57.2% and moyamoya syndrome in 42.8%. The latter was related to Down syndrome in five patients and neurofibromatosis type 1 in one patient. With a mean follow-up of 2.35 years, two patients had at least two more AISs during the first two years following diagnosis and 42.8% of patients were diagnosed with vascular or poststroke epilepsy. Full recovery was noted in 14.3% of cases., Conclusions: Moyamoya angiopathy in children is a serious condition that needs to be recognized due to the high risk of recurrent ischemic strokes., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Ataxia with isolated vitamin E deficiency (AVED) is a rare autosomal recessive cerebellar ataxia disorder that is caused by a mutation in the alpha-tocopherol transfer protein gene TTPA, leading to a lower level of serum vitamin E. Although it is almost clinically similar to Friedreich's ataxia, its devastating neurological features can be prevented with appropriate treatment. In this study, we present a patient who was initially diagnosed with Friedreich's ataxia, but was later found to have AVED. Frataxin gene screening revealed the absence of GAA expansion in homozygous or heterozygous state. However, TTPAgene sequencing showed the presence of the c.744delA mutation, leading to a premature stop codon (p.E249fx). In addition, the result of mutational analysis of MT-DNA genes revealed the presence of several variants, including the m.10044A>G mutation in MT-TG gene. Here, we report for the first time the coexistence of both mitochondrial and nuclear genes mutations in AVED., (© 2020. Belgian Neurological Society.)

Intellectual disability (ID) often co-occurs with other neurologic phenotypes making molecular diagnosis more challenging particularly in consanguineous populations with the co-segregation of more than one ID-related gene in some cases. In this study, we investigated the phenotype of three patients from a large Tunisian family with significant ID phenotypic variability and microcephaly and performed a clinical exome sequencing in two cases. We identified, within the first branch, a homozygous variant in the TRAPPC9 gene (p.Arg472Ter) in two cases presenting severe ID, absent speech, congenital/secondary microcephaly in addition to autistic features, supporting the implication of TRAPPC9 in the "secondary" autism spectrum disorders and congenital microcephaly. In the second branch, we identified a homozygous variant (p.Lys189ArgfsTer15) in the CDK5RAP2 gene associated with an heterozygous TRAPPC9 variant (p.Arg472Ter) in one case harbouring primary hereditary microcephaly (MCPH) associated with an inter-hypothalamic adhesion, mixed hearing loss, selective thinning in the retinal nerve fiber layer and parafoveal ganglion cell complex, and short stature. Our findings expand the spectrum of the recently reported neurosensorial abnormalities and revealed the variable phenotype expressivity of CDK5RAP2 defect. Our study highlights the complexity of the genetic background of microcephaly/ID and the efficiency of the exome sequencing to provide an accurate diagnosis and to improve the management and follow-up of such patients., (Copyright © 2021. Published by Elsevier Masson SAS.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)