I. Kraoua

Mutations in B9D1 and MKS1 cause mild Joubert syndrome: expanding the genetic overlap with the lethal ciliopathy Meckel syndrome

Joubert syndrome is a clinically and genetically heterogeneous ciliopathy characterized by a typical cerebellar and brainstem malformation (the “molar tooth sign”), and variable multiorgan involvement. To date, 24 genes have been found mutated in Joubert syndrome, of which 13 also cause Meckel syndrome, a lethal ciliopathy with kidney, liver and skeletal involvement. Here we describe four patients with mild Joubert phenotypes who carry pathogenic mutations in either MKS1 or B9D1, two genes previously implicated only in Meckel syndrome.

Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes

Background Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene. Methods Exome sequencing was performed in 145 patients with Joubert syndrome (JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes. Results We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy (JATD). The CEP120-associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype. Conclusion Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype–phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies.

Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort.

Mutations in the PLA2G6 gene are causative of PLA2G6‐associated neurodegeneration (PLAN), a spectrum of neurodegenerative conditions including infantile, childhood and adult onset forms.

Severe dysautonomia as a main feature of anti-GAD encephalitis: Report of a paediatric case and literature review

INTRODUCTIONnAnti-glutamic acid decarboxylase (anti-GAD65) antibodies are a rare cause of autoimmune encephalitis. This entity is mainly recognized in adults and very few cases were reported in children. We report on a paediatric case of anti-GAD encephalitis with severe presentation and uncontrollable dysautonomia.nnnCASE STUDYnA 9-year-old girl was referred to our department for refractory seizures and behavioral disturbances. Brain magnetic resonance imaging (MRI) was normal. Repeat screening for antineuronal antibodies showed negative results for anti-NMDA receptor antibodies but positive results for anti-GAD65 with a low positivity of anti-Ma2 antibodies. Although a transient improvement was noticed after immunomodulatory treatment, the patient developed severe intractable autonomic imbalance including dysrythmia, alternating bradycardia/tachycardia, hypotension/hypertension, hypothermia/hyperthermia and hyperhidrosis. She deceased six months after onset.nnnCONCLUSIONnOur report intends to raise awareness of autoimmune encephalitis with anti-GAD65 antibodies which may involve extralimbic brain regions and manifest with fatal dysautonomia. We highlight the need for prompt diagnosis and aggressive management for this underdiagnosed entity in children.

Pyridoxine-dependent epilepsy: A novel mutation in a Tunisian child

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive metabolic disease characterized by seizures in neonates or infants, which is unresponsive to antiepileptic drugs but controlled by pyridoxine. Without prompt treatment, continued seizures and severe encephalopathy result. Mutations in the ALDH7A1 gene encoding α-amino-adipic semialdehyde (α-AASA) dehydrogenase (antiquitin) have been identified as the cause of PDE. We report on a novel ALDH7A1 mutation in a Tunisian child with PDE.

Elevated aspartate aminotransferase and lactate dehydrogenase levels are a constant finding in PLA2G6-associated neurodegeneration.

I. Kraoua, M. Romani, D. Tonduti, H. BenRhouma, G. Zorzi, F. Zibordi, A. Ardissone, N. Gouider-Khouja, I. Ben Youssef-Turki, N. Nardocci and E. M. Valente Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, Tunis, Tunisia, IRCCS Casa Sollievo della Sofferenza, Mendel Laboratory, San Giovanni Rotondo, Italy, Child Neurology Department, Neurological Institute C. Besta Foundation IRCCS, Milan, Italy and Section of Neurosciences, Department of Medicine and Surgery, University of Salerno, Salerno, Italy

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

Abstract 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.

Acquired demyelinating syndromes of the central nervous system in children: study of a cohort of 47 cases

Multiple sclerosis (MS) is a chronic neurological disorder defined by recurrent episodes of central nervous system (CNS) demyelination, ultimately culminating in physical and cognitive disability. While it is rare in the paediatric population, MS in children is likely to have a profound impact on their lifetime academic, social, and vocational achievements. The advent of disease-modifying therapies for MS and the recent evidence of improved long-term outcome, associated with early initiation of therapy, emphasize the need for prompt diagnosis and coordinated care for children affected with MS.

Comment on ‘Acute flaccid myelitis in childhood: a retrospective cohort study’

Dear Editor, We have read with great interest the paper by Andersen et al., ‘Acute flaccid myelitis in childhood: a retrospective cohort study’, in the European Journal of Neurology (June 2017) [1]. This retrospective cohort study reports eight children with acute flaccid paralysis with extensive longitudinal myelitis and preferential involvement of grey matter. The newly recognized entity termed ‘acute flaccid myelitis’ (AFM) is uncommon and has been related mainly to nonpolio enteroviruses. We would like to share our viewpoint based on our experience. In January 2016, a 4-year-old girl with no family or medical history was admitted for progressive weakness and pain of the lower limbs over 2 days. She complained of gastric pain 1 week earlier. Neurological examination showed a flaccid paraplegia with absent deep tendon reflexes and plantor flexor. No sensitive or cranial nerve involvement was noticed. Guillain Barr e syndrome (GBS) was initially suspected. Electroneuromyographic study showed prolonged F-wave latencies. Five days after onset, the child had brisk tendon reflexes, Babinski sign and urinary retention. Brain and spinal magnetic resonance imaging (MRI) was performed revealing pontine increased signal and spinal abnormalities confined to the central grey matter on T2-weighted images extending from C5 to the terminal cone without gadolinium enhancement (Fig. 1). Routine biological tests were normal. Cerebrospinal fluid (CSF) analysis showed a pleocytosis (25 cells/ll) with normal protein level (0.18 g/l). Viral and bacterial serological analysis of herpes simplex virus, Epstein–Barr virus, varicella zoster virus, cytomegalovirus, rubella virus, hepatitis B and C, mycoplasma, West Nile virus, human immunodeficiency virus, lyme disease and syphilis and CSF polymerase chain reaction for enterovirus were negative. Immunological tests (anti nuclear, anti neuromyelitis optica, anti rheumatoid factor and anti Sm antibodies) were negative. AFM was diagnosed and the patient received intravenous immunoglobulins (IVIG) (0.4 g/kg/day for 5 days) with a full recovery. Two months later, cerebral and spinal MRI showed persistent pontine and spinal abnormalities. This observation highlights the rarity of AFM as a differential diagnosis of GBS and transverse myelitis with a unique feature involving electively the spinal grey matter and residual neurological deficits in 90% of patients [1–3]. Awareness of this disorder especially in countries where polio has been eradicated may lead to more rapid diagnosis and avoid delay of treatment, mainly with IVIG, which

Lésion mésencéphalique avec rehaussement annulaire : tuberculome ou toxoplasmose ?

Cette fillette de 18 mois, sans antécédents familiaux ni personnels notables, avait présenté brutalement au réveil une impotence fonctionnelle de l’hémicorps gauche avec asymétrie faciale. Il n’y avait pas de contexte traumatique ou infectieux. L’examen clinique pratiqué quelques heures après l’installation des troubles a objectivé une hémiparésie gauche flasque, un signe de Babinski à gauche et une parésie faciale périphérique droite. L’état général était conservé et les constantes hémodynamiques étaient stables. Le reste de l’examen clinique était sans particularités. Devant ce syndrome alterne de type Millard-Gübler de survenue brutale, un accident vasculaire cérébral (AVC) protubérantiel a été suspecté. Les examens biologiques (numération-formule sanguine, glycémie, vitesse de sédimentation, taux de protéine C réactive (CRP), ionogramme sanguin, transaminases, gamma-glutamyl transpeptidase, bilirubine totale et conjuguée, azotémie, créatininémie) se sont avérés normaux. Une imagerie par résonance magnétique (IRM) encéphalique a été réalisée 36 heures après l’installation des troubles (fig. 1). Cet examen comportait des coupes en pondération T2, FLAIR, diffusion, perfusion et T1 sans et avec injection intraveineuse de gadolinium.