Reticulon 2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity.

Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to scarcity of supporting evidence. In our study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping. All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70 years. Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite Reticulon-2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress. Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with Reticulon-2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN, and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN.

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.

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.

Hypomyelination and Congenital Cataract: Clinical, Imaging, and Genetic Findings in Three Tunisian Families and Literature Review.

Hypomyelination and congenital cataract (HCC) is characterized by congenital cataract, progressive neurologic impairment, and diffuse myelin deficiency. This autosomal recessive disorder is caused by homozygous variant in the FAM126A gene. Five consanguineous Tunisian patients, belonging to three unrelated families, underwent routine blood tests, electroneuromyography, and magnetic resonance imaging of the brain. The direct sequencing of FAM126A exons was performed for the patients and their relatives. We summarized the 30 previously published HCC cases. All of our patients were carriers of a previously reported c.414 + 1G > T (IVS5 + 1G > T) variant, but the clinical spectrum was variable. Despite the absence of a phenotype-genotype correlation in HCC disease, screening of this splice site variant should be performed in family members at risk.

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.

Novel POLR1C mutation in RNA polymerase III-related leukodystrophy with severe myoclonus and dystonia.

INTRODUCTION: RNA polymerase III (Pol III)-related leukodystrophies are a group of autosomal recessive neurodegenerative disorders caused by mutations in POLR3A and POLR3B. Recently a recessive mutation in POLR1C causative of Pol III-related leukodystrophies was identified. METHODS: We report the case of a Tunisian girl of 14 years of age who was referred to our department for evaluation of progressive ataxia that began at the age of 5. Genetic diagnosis was performed by NGS and Sanger analysis. In silico predictions were performed using SIFT, PolyPhen-2, and Mutation Taster. RESULTS: Neurological examination showed cerebellar and tetrapyramidal syndrome, mixed movement disorders with generalized dystonia and severe myoclonus leading to death at 25 years. Brain MRI scans showed diffuse hypomyelination associated with cerebellar atrophy. It also showed bilateral T2 hypointensity of the ventrolateral thalamus, part of the posterior limb of the internal capsule, the substantia nigra and the subthalamic nucleus. Next generation sequencing leukodystrophy panel including POLR3A and POLR3B was negative. Sanger sequencing of the coding regions of POLR1C revealed a novel homozygous mutation. CONCLUSION: The clinical and imaging findings of patients with POLR1C hypomyelinating leukodystrophy are reviewed. Interestingly, severe myoclonic dystonia and T2 hypointensity of the substantia nigra and the subthalamic nucleus are not reported yet and could be helpful for the diagnosis of POLR1C hypomyelinating leukodystrophy.

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.

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.

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.

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.

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.

Mixed movements disorders as an initial feature of pediatric lupus.

UNLABELLED: Systemic lupus erythematosus (SLE) is an immunologic disease of the early adulthood. In children, SLE is rare and neurological onset is uncommon. We report on an observation of pediatric lupus in heterozygous twins revealed by mixed movement disorders. CASE REPORT: An 8-year-old boy, born to non consanguineous parents, with a family history of depression and a personal history of macular eruption, inflammatory polyarthralgias and a recurrent angina presented with acute movement and mood disorders. Neurological exam showed mild generalized choreic movements with motor and vocal tics. Antinuclear antibodies were positive. Brain MRI was normal. One year after, his twin brother presented with the same features. DISCUSSION: Movement disorders are described in pediatric lupus but are unusual as inaugural features of the disease. In SLE, movement disorders such as chorea are usually reported. However, Tics seem to be exceptional. Pathophysiology remains unclear. Early onset and familial form support genetic implication in the pathogenesis of lupus. CONCLUSION: Immune-mediated movement disorders such as in SLE are an established cause of acute movement disorders in child.

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.

Mirror movements and myelomeningocele: report of a single case and review of literature.

OBJECTIVE: Mirror movements (MM) have been described in several pathological conditions. Their association with neural tube defects is rare, and only 5 cases have been reported in literature to date. We report on a case of MM associated with cervical myelomeningocele, and we discuss the diffusion tensor imaging findings and the underlying mechanism.

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.