Neuronal ceroïd-lipofuscinosis: Clinical, electroencephalographic, imaging, and genetic study of a maghrebian series.

Our study included 13 patients diagnosed with neuronal ceroidlipofuscinosis. It is a group of rare genetically-determined neurodegenerativediseases characterized by clinical and genetic heterogeneity. brain MRI andelectroencephalogram facilitate diagnosis.

Acute Movement Disorders in Childhood: A Cohort Study and Review of the Literature.

OBJECTIVES: Acute movement disorders (AMD) are frequent in neurological and pediatric emergencies. Few studies analyzed AMD in children, none in Tunisia or other African country. The purpose of this study was to describe the peculiarities of AMD in a Tunisian pediatric population with a literature review. METHODS: We conducted a retrospective descriptive study over 8 years including 80 children (sex ratio, 1.05; mean age of onset, 4.8 years) with AMD, followed in tertiary referral Child Neurology Department in North Tunisia. RESULTS: Acute movement disorders were mainly hyperkinetic (n = 67 with dystonia (n = 33; mostly due to inherited metabolic diseases (IMD) in 11; with status epilepticus in 10 children), chorea (n = 14; with Sydenham chorea in 5); myoclonus (n = 14; mostly with opsoclonus-myoclonus syndrome in 10) and tremor (n = 6; of posttraumatic origin in half). Hypokinetic movement disorder (MD) included acute parkinsonism in 5 children of infectious (n = 3), postinfectious (n = 1, malaria) and posttraumatic origin (n = 1). Mixed MD, found in 8 children, were mainly due to IMD in half of them, and to familial lupus in two. Paroxysmal MDs were seen in 2 children, one with multiple sclerosis and one of idiopathic origin. Psychogenic MDs were found in 7 patients mainly of dystonic type. Management of AMD comprised symptomatic treatment according to the phenomenology of the MD and causative treatment depending on its etiology. CONCLUSIONS: Our study illustrated the broad range of AMD in children and the wide spectrum of their etiologies. In our series, we described some exceptional findings and etiologies of AMD in children. These findings may denote a specific profile in of AMD in our country with predominant infectious, postinfectious, and IMD.

Muscle-Specific Kinase Autoimmune Myasthenia Gravis: Report of a Pediatric Case and Literature Review.

Myasthenia gravis (MG) with antibodies to the muscle-specific tyrosine kinase (MuSK-MG) receptor is a rare entity. It represents 5 to 8% of all MG patients. Few pediatric cases were reported. Clinical presentation is often atypical. It is characterized by predominant involvement of cranial, bulbar, and axial muscles and early respiratory crises. Myokymia and fasciculation are suggestive of MuSK-MG. The clinical course of patients with MuSK-MG is worse than other types of MG. Responses to standard therapies are variable. We report clinical, neurophysiological, serological, and outcome profile of a Tunisian child with MuSK-MG.

First report of an unusual novel double mutation affecting the transcription repression domain of MeCP2 and causing a severe phenotype of Rett syndrome: Molecular analyses and computational investigation.

Rett syndrome is an X-linked neurodevelopmental disorder that develops a profound intellectual and motor disability and affects 1 from 10 000 to 15 000 live female births. This disease is characterized by a period of apparently normal development until 6-18 months of age when motor and communication abilities regress which is caused by mutations occurred in the X-linked MECP2 gene, encoding the methyl-CpG binding protein 2. This research study reports a molecular analysis via an exhaustive gene sequencing which reveals an unusual novel double mutation (c.695 G > T; c.880C > T) located in a highly conserved region in MECP2 gene affecting the transcription repression domain (TRD) of MeCP2 protein and leading for the first time to a severe phenotype of Rett syndrome. Moreover, a computational investigation of MECP2 mutations demonstrates that the novel mutation c.695 G > T is highly deleterious which affects the MeCP2 protein showing also an adverse impact on MECP2 gene expression and resulting in an affected folding and decreased stability of MECP2 structures. Thus, the altered TRD domain engenders a disrupted process of MECP2 functions. Therefore, this is the first study which highlights a novel double mutation among the transcription repression domain (TRD) of MeCP2 protein in Rett patient with a severe clinical phenotype in North Africa region.

Early Life Epilepsy and Episodic Apnea Revealing an ATP1A3 Mutation: Report of a Pediatric Case and Literature Review.

ATP1A3 mutations have now been recognized in infants, children, and adults presenting with a diverse group of neurological phenotypes, including rapid-onset dystonia-parkinsonism, alternating hemiplegia of childhood, and most recently, cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss syndrome. The phenotypic spectrum of ATP1A3-related neurological disorders continues to expand. In this case study, we report on early life epilepsy with episodic apnea potentially secondary to ATP1A3 mutation in a Tunisian child.

Genetic investigation of the ubiquitin-protein ligase E3A gene as putative target in Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is caused by maternal chromosomal deletions, imprinting defects, paternal uniparental disomy involving chromosome 15 and the ubiquitin-protein ligase UBE3A gene mutations. However the genetic basis remains unclear for several patients. AIM: To investigate the involvement of UBE3A gene in AS and identifying new potential genes using exome sequencing. METHODS: We established a cohort study in 50 patients referred to Farhat Hached University Hospital between 2006 and 2021, with a strong suspicion of AS and absence of chromosomal aberrations. The UBE3A gene was screened for mutation detection. Two unrelated patients issued from consanguineous families were subjected to exome analysis. RESULTS: We describe seven UBE3A variants among them 3 none previously described including intronic variants c.2220+14T>C (intron14), c.2507+43T>A (Exon15) and insertion in Exon7: c.30-47_30-46. The exome sequencing revealed 22 potential genes that could be involved in AS-like syndromes that should be investigated further. CONCLUSION: Screening for UBE3A mutations in AS patients has been proven to be useful to confirm the diagnosis. Our exome findings could rise to new potential alternative target genes for genetic counseling.

3-Phosphoglycerate dehydrogenase deficiency: description of two new cases in Tunisia and review of the literature.

3-Phosphoglycerate dehydrogenase (3-PGDH) deficiency is a rare autosomal recessive disorder of serine biosynthesis. It is typically characterized by congenital microcephaly, intractable seizures of infantile onset, and severe psychomotor retardation. Diagnosis is suspected on decreased l-serine levels in plasma and cerebrospinal fluid (CSF) and confirmed by genetic study. Early diagnosis in index cases allows supplementation in serine and prevention of fixed lesions. Prenatal diagnosis and genetic counseling allows prevention of secondary cases. We report on the two first unrelated Tunisian families with 3-PGDH deficiency confirmed by biochemical and genetic study. We discuss clinical, biochemical, imaging, electroencephalographic, and therapeutic aspects and review the literature.

Pediatric Neurotuberculosis: A cases series and review of the literature.

Neurotuberculosis or central nervous system tuberculosis is a form of tuberculous infection that affects any part of the nervous system. Although it is more frequent in adults, pediatric cases have been reported in endemic countries and it is potentially a deadly affection. Therefore, any unusual neurological manifestation in a formerly healthy child, independently of their vaccination status, must bring suspicion of CNS tuberculosis among other diagnoses. We report four cases of pediatric neurotuberculosis with various clinical presentations and outcome and a brief review of the litterature. We conclude that clinical manifestations of pediatric neurotuberculosis are extremely variable and could be misleading. Extra-neurological sites are a key element for diagnosis especially in the pediatric population. A diagnosis and clinical outcome score, especially designed for children might help personalize the therapeutic approach and outcome measures.

Autoimmune Encephalitis in Tunisia: Report of a Pediatric Cohort.

BACKGROUND: Autoimmune encephalitis (AE) is a rapidly progressive encephalopathy caused by antibodies targeting neurons in the central nervous system generating specific immune responses. It is increasingly recognized in children. OBJECTIVE: To describe clinical, neuroimaging, and laboratory features, treatment, and outcome in a cohort of Tunisian children with AE. METHODS: We conducted a retrospective review of the medical records of all children attending the Department of Child and Adolescent Neurology (Tunis) with autoimmune encephalitis between 2004 and 2020. Clinical, neuroimaging, laboratory features, therapeutic data, and outcome were analyzed. RESULTS: Nineteen children were included in the study (12 girls and 7 boys). The median age at diagnosis was 7.68 years (range: 10 months-13 years). The most frequent manifestations were seizures and behavioral disorders. Eleven cases were diagnosed with anti-NMDA receptor encephalitis, 4 cases with anti-Ma2 encephalitis, 3 cases with anti-GAD encephalitis, and 1 case with anti-SOX1 encephalitis. Brain MRI showed increased T2 and fluid-attenuated inversion recovery (FLAIR) signal of the temporal lobe in 5 patients. Eighteen patients showed improvement following first-line immunotherapy (high-dose corticosteroids, intravenous immunoglobulin). One patient with anti-GAD encephalitis died despite escalating immunotherapy. CONCLUSION: Diagnosis of autoimmune encephalitis is challenging in children, because of misleading presentations. An early and accurate diagnosis is important to enable proper therapeutic interventions.

Rasmussen's Encephalitis: A Report of a Tunisian Pediatric Case and Literature Review.

Rasmussen's encephalitis (RE) is a rare progressive inflammatory disease of the central nervous system. It is characterized by unilateral hemispheric atrophy, pharmacoresistant focal seizures, and progressive neurological deficit. The exact etiopathogenesis still remains unknown. Brain imaging plays an important role in diagnosis and follow-up. Fluctuation of lesions in brain imaging was reported in few cases. Herein, we report an additional pediatric case of Rasmussen encephalitis with fluctuating changes in brain MRI.

Childhood opsoclonus-myoclonus syndrome: A case series from Tunisia.

INTRODUCTION: Opsoclonus myoclonus syndrome (OMS) is a rare immune-mediated disorder characterized by opsoclonus, myoclonus, ataxia and behavioral changes. The aim of our study was to investigate the epidemiology, clinical features, etiological aspects and outcome of OMS in Tunisian children. METHODS: We conducted a retrospective study over 11years (2005-2016) including all patients aged under 18years who were managed for newly diagnosed OMS in a tertiary care research centre for children with neurological symptoms. Epidemiological and clinical data were analyzed. RESULTS: Fifteen patients were included. The male-female ratio was 7:8. Median age of onset was 4.32years (range: 14months-16years). Time to diagnosis ranged between 2days and 10months. Median follow-up period was 3.8years (range: 2-6years). Acute ataxia was the preponderant inaugural feature. Mean severity score was 9 (range: 3-14). In "Tumor group" (n=7), the main underlying malignancy was neuroblastoma identified in 5 patient. In "No tumor group" (n=8), parainfectious and idiopathic OMS were identified in 5 and 3 patients, respectively. All patients received immunomodulatory treatment. Complete recovery of OMS symptoms was obtained in 12 children. Comparing the "Tumor group" and the "No tumor group", there were no differences in age of onset, sex ratio, main presenting symptom, median OMS severity score or responsiveness to treatment. However, sleep and behavioral disturbances were more frequent in the "No tumor group" (p=0.04). Neurological sequelae were equally found in both groups. CONCLUSION: Annual incidence of OMS in Tunisia could be estimated as 0.6 patients in children per million per year. Diagnosis may be challenging especially when the triad is incomplete. Although behavioral disturbances seem to be more frequent in the "No tumor group", our study suggests that there is no specific features differentiating paraneoplastic OMS from non paraneoplastic OMS. Acute symptoms are responsive to immunomodulatory treatment but long term follow up can reveal neurological (mainly cognitive) sequelae.

Pediatric Multiple Sclerosis in Tunisia: A Retrospective Study over 11 Years.

INTRODUCTION: Pediatric multiple sclerosis (pMS) is a rare demyelinating disorder with an onset before the age of 18 years. In this study, we aimed to investigate the characteristics of pMS in Tunisian children. PATIENTS AND METHODS: We conducted a retrospective study over 11 years (2005-2016) including all patients diagnosed with pMS according to the International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria of 2012 and followed up in a tertiary care research center. Epidemiological, clinical, neuroimaging, laboratory, and therapeutic data were collected and analyzed. RESULTS: There were 21 patients. The male-female ratio was 1 : 3. Mean age at onset was 11 years (range: 3-17 years). Three patients had type 1 diabetes. Polyfocal presentation was preponderant (81%) with motor dysfunction in 57% of patients. Paroxysmal dystonia was noticed in 24%. All patients were diagnosed with relapsing-remitting form. Interferon beta was prescribed in 80% with a reduction of annual relapse rate. CONCLUSION: The annual incidence of pMS in Tunisian children aged below 18 years could be estimated as 0.05 per 100,000. Singular features in our cohort were the frequent association with type 1 diabetes and the increased occurrence of dystonia. Greater awareness of pMS may be helpful to improve management strategies of children and their families.

Anti-Ma2-encephalitis in a 2 year-old child: A newly diagnosed case and literature review.

BACKGROUND: Anti-Ma2-associated encephalitis is a rare paraneoplastic neurological syndrome characterized by isolated or combined limbic, diencephalic, or brainstem dysfunction. It is rarely reported in children. CASE STUDY: We describe the clinical data of a 2-year-old girl referred to our department for refractory focal seizures associated with fever, followed by behavioural changes, speech disturbances and confusional episodes. Brain magnetic resonance imaging (MRI) showed left temporoparietal brain involvement. Haematological, biochemical and infectious evaluations were unremarkable. Autoimmune encephalitis was suspected. Paraneoplastic antibodies tests showed positive results for anti-Ma2 antibodies. Screening for underlying tumour was negative. Immunomodulatory treatment was administrated. The patient showed improvement of vigilance and behaviour. However, she kept refractory epilepsy. CONCLUSION: Although poor response to immunotherapy, early diagnosis and appropriate treatment of this disorder may prevent irreversible sequelae.

Postencephalitic parkinsonism and selective involvement of substantia nigra in childhood.

Parkinsonism is a rare complication of encephalitis in childhood. Association to an isolated involvement of substantia nigra is exceptional. Mechanisms of nigral cells neurotropism remain hypothetic. We report on three children presenting with postencephalitic parkinsonism and selective involvement of substantia nigra, with literature review and we discuss pathogenic mechanisms.

Lesch Nyhan syndrome: a novel complex mutation in a Tunisian child.

Lesch Nyhan syndrome (LNS) is an X-linked recessive disorder due to complete deficiency of the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. Defect of the enzymatic activity is related to mutations of the HPRT1 gene. The disorder severity is due to neurological features and renal complications. Up to now, more than 300 mutations have been reported. We report on a Tunisian child with a severe phenotype due to a novel identified complex mutation.

Novel double deletions in the MECP2 gene in Tunisian Rett patient.

Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively girls. Rett patients present an apparently normal psychomotor development during the first 6-18 months of life. Thereafter, they show a short period of developmental stagnation followed by a rapid regression in language and motor development. RTT is currently considered as monogenic X-linked dominant disorder due to mutations in the MECP2 gene, encoding the methyl-CpG binding protein 2. The aim of this study was to perform a mutational analysis of the MECP2 gene in a classical Rett patient.The results showed the presence of a novel point mutation c.C1142T (p.P381L) and two deletions at the heterozygous state: a novel deletion c.1075delTTC (p.S359) and a known one c.1157del44 (p.L386Q fs X2) in the C-terminal region of MeCP2.

Novel mutations in the C-terminal region of the MECP2 gene in Tunisian Rett syndrome patients.

Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder in females, is caused mainly by de novo mutations in the methyl-CpG-binding protein 2 gene (MECP2). Rett patients present an apparently normal psychomotor development during the first 6 to 18 months of life. Thereafter, they show a short period of developmental stagnation followed by a rapid regression in language and motor development. In the present study, we performed a mutational analysis of the MECP2 gene in 2 typical Rett syndrome patients and in 1 atypical Rett syndrome girl. The results showed the presence of 3 de novo point mutations in the C-terminal region: 2 novel mutations: c.1065C>A (p.S355R) and c.1030C>G (p.R344G) in the 2 typical Rett syndrome girls, but also the c.996C>T (p.S332S) mutation first described in the atypical Rett syndrome patient.

Movement disorders in neuro-metabolic diseases.

Inborn errors of metabolism (IEM) are a group of genetic disorders characterized by dysfunction of an enzyme or other protein involved in cellular metabolism.(1) Most IEMs involve the nervous system (neuro-metabolic diseases or NMD). NMD often present with a complex clinical picture: psychomotor retardation and/or regression, pyramidal signs, ataxia, hypotonia and epilepsy and movement disorders.(1) Movement disorders are more frequently part of this complex picture than a predominant symptom, however in some instances the clinical picture may be summarized in an invalidating movement disorder.(2) On a phenomenology basis, one can distinguish eight main types of movement disorders: dystonia and athetosis, chorea, tremor with or without parkinsonism, ballismus, myoclonus, tics and stereotypies. Most of these abnormal involuntary movements generate from a dysfunction or a lesion in the basal ganglia, excepting myoclonus, the origin of which can vary (cortical, brainstem, basal ganglia, spinal and even peripheral nervous system).(3) Classically the most frequently observed movement disorders in NMD are: dystonia, myoclonus, chorea, tremor and parkinsonism (Fig. 1). The primary goal of this article is, departing from the literature and a large personal series, to describe the types of movement disorders most frequently observed in NMD and to discuss their clinical value in the setting of specific types of NMD.