Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females

Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the PCDH19 gene, was found in one male patient. To confirm that PCDH19 is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional SCN1A-negative patients. Nine different point mutations (four missense and five truncating mutations) were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the PCDH19 deletion. Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences) in those with PCDH19 mutations. These results suggest that PCDH19 plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism

Influenza A(H1N1)–Associated Ischemic Stroke in a 9-Month-Old Child

International audienc

Influenza A(H1N1)–Associated Ischemic Stroke in a 9-Month-Old Child

International audienc

Prognostic factors for the sequelae and severity of Guillain‐Barré syndrome in children

International audienceIntroduction: Guillain-Barré syndrome (GBS) is an inflammatory polyradiculoneuritis.Our aim in this study was to describe the clinical characteristics and the long-termsequelae of GBS in a French pediatric population.Methods: In this multicenter, retrospective study we evaluated clinical signs, radio-logical examinations, laboratory tests, treatments, and outcomes.Results: One hundred ten children were included in this investigation. These childrenpresented with walking difficulties, muscle weakness, and cranial nerve impairment.Electrodiagnostic testing revealed 70% with acute inflammatory demyelinating poly-radiculoneuropathy (AIDP) and 16% with acute motor axonal neuropathy (AMAN).One hundred children received immunoglobulins. At follow-up, 77% were cured,whereas 9% had sequelae, associated with an axonal form (P < .01) and a short inter-val between symptom onset and hospitalization (P < .01). The need for intubationwas correlated with peripheral facial paralysis (P < .01) and dysautonomia (P < .01).Discussion: Although AIDP and AMAN present in a similar way, the axonal form isassociated with a worse outcome

Prognostic factors for the sequelae and severity of Guillain‐Barré syndrome in children

International audienceIntroduction: Guillain-Barré syndrome (GBS) is an inflammatory polyradiculoneuritis.Our aim in this study was to describe the clinical characteristics and the long-termsequelae of GBS in a French pediatric population.Methods: In this multicenter, retrospective study we evaluated clinical signs, radio-logical examinations, laboratory tests, treatments, and outcomes.Results: One hundred ten children were included in this investigation. These childrenpresented with walking difficulties, muscle weakness, and cranial nerve impairment.Electrodiagnostic testing revealed 70% with acute inflammatory demyelinating poly-radiculoneuropathy (AIDP) and 16% with acute motor axonal neuropathy (AMAN).One hundred children received immunoglobulins. At follow-up, 77% were cured,whereas 9% had sequelae, associated with an axonal form (P < .01) and a short inter-val between symptom onset and hospitalization (P < .01). The need for intubationwas correlated with peripheral facial paralysis (P < .01) and dysautonomia (P < .01).Discussion: Although AIDP and AMAN present in a similar way, the axonal form isassociated with a worse outcome

Cerebrospinal fluid YKL‐40 level evolution is associated with autoimmune encephalitis remission

Abstract Objective Because of its heterogeneity in clinical presentation and course, predicting autoimmune encephalitis (AIE) evolution remains challenging. Hence, our aim was to explore the correlation of several biomarkers with the clinical course of disease. Methods Thirty‐seven cases of AIE were selected retrospectively and divided into active (N = 9), improved (N = 12) and remission (N = 16) AIE according to their disease evolution. Nine proteins were tested in both serum and cerebrospinal fluid (CSF) at diagnosis (T0) and during the follow‐up (T1), in particular activated MMP‐9 (MMP‐9A) and YKL‐40 (or chitinase 3‐like 1). Results From diagnosis to revaluation, AIE remission was associated with decreased YKL‐40 and MMP‐9A levels in the CSF, and with decreased NfL and NfH levels in the serum. The changes in YKL‐40 concentrations in the CSF were associated with (1) still active AIE when increasing >10% (P‐value = 0.0093); (2) partial improvement or remission when the changes were between +9% and −20% (P‐value = 0.0173); and remission with a reduction > −20% (P‐value = 0.0072; overall difference between the three groups: P‐value = 0.0088). At T1, the CSF YKL‐40 levels were significantly decreased between active and improved as well as improved and remission AIE groups but with no calculable threshold because of patient heterogeneity. Conclusion The concentration of YKL‐40, a cytokine‐like proinflammatory protein produced by glial cells, is correlated in the CSF with the clinical course of AIE. Its introduction as a biomarker may assist in following disease activity and in evaluating therapeutic response

Paediatric optic neuritis: factors leading to unfavourable outcome and relapses

Objectives To identify prognostic factors associated with poor visual recovery and chronic relapsing diseases, for example, multiple sclerosis (MS), in children with optic neuritis (ON) at onset.Methods This multicentre retrospective study included 102 children with a first ON episode between 1990 and 2012. The primary criterion was poor visual recovery determined by visual acuity, and the secondary was relapses following ON.Results Median age was 11 years, 66% were girls and mean follow-up was 24 months. 58% of children were diagnosed with idiopathic isolated ON, 22% had MS, 5% had Devic's neuromyelitis optica and 6% chronic relapsing inflammatory ON. Complete visual acuity recovery rate was 57% (95% CI=[46%-69%]) at 6 months and 71% (95% CI=[60%-81%]) at 1 and 2 years but was lower in MS (p&lt;0.01), with recovery rate of only 27% (95% CI=[12%-54%]) at 1year. Age 10 years, optic disc pallor at funduscopy and MS were the principal factors associated with poor visual recovery. Age 10 years, abnormal brain MRI at onset and oligoclonal banding were significantly associated with MS (p&lt;0.01).Conclusion Age 10, optic disc pallor and MS were associated with poor recovery. Better identification of these patients may help to adapt treatment and lead to a prospective treatment study

Exonic Deletions of FXN and Early-Onset Friedreich Ataxia.

International audienceBACKGROUND: Friedreich ataxia (FA) is the most frequent type of autosomal recessive cerebellar ataxia, occurring at a mean age of 16 years. Nearly 98% of patients with FA present with homozygous GAA expansions in the FXN gene. The remaining patients are compound heterozygous for an expansion and a point mutation. Patients who are compound heterozygous for an exonic deletion and an expansion are exquisitely rare. OBJECTIVES: To describe 6 patients affected with FA due to an exonic deletion mutation (FAexdel) and to compare these 6 patients with FAexdel with 46 patients consecutively diagnosed with typical FA due to homozygous GAA expansion and whose small expansions were within the same range as that of the expansions of the patients with FAexdel. DESIGN: Description of a series. SETTING: Academic research. Patients Six patients with FAexdel and 46 patients with typical FA. Intervention FXN gene analysis, including assessments of GAA expansion and exon sequencing and determination of exonic copy numbers using multiplex ligation-dependent probe amplification. RESULTS: We identified 6 patients with FA who presented with the combination of 1 GAA expansion and 1 FXN exonic deletion. The mean (SD) age at onset of the disease was earlier for patients with FAexdel (7 [4] years [range, 3-12 years]) than for patients with typical FA (15 [5] years [range, 6-30 years]) (P = .001), and the median time to confinement to wheelchair was shorter for patients with FAexdel (20 years) than for patients with typical FA (28 years) (P = .002). There was no difference between the mean (SD) size of the expansion for the patients with FAexdel (780 [256] GAA triplet repeat sequences [range, 340-1070 GAA triplet repeat sequences]) and the mean (SD) size of the short expansion for the patients with typical FA (634 [163] GAA triplet repeat sequences [range, 367-1000 GAA triplet repeat sequences]) (P = .10). The mean disease duration before becoming wheelchair bound was shorter for patients with FAexdel (9 years) than for patients with typical FA (13 years), and the incidence of cardiomyopathy was higher for patients with FAexdel (84%) than for patients with typical FA (68%). However, these differences were not significant, probably owing to the small size of the FAexdel group. The other extraneurological signs, such as scoliosis or diabetes mellitus, were particularly frequently observed in the FAexdel group. One patient presented at 9 years of age with severe angina and marked cardiomyopathy that confined her to a wheelchair. Three patients had disabling autonomic disturbances. It appears that exonic deletion significantly contributes to the clinical picture of patients with FA. CONCLUSIONS: Friedreich ataxia due to an exonic deletion mutation corresponds to an early onset and severe variant of FA. FXN should be investigated for exonic deletion in patients with early-onset FA in which only 1 GAA expansion without a point mutation is found. Patients with FAexdel have to be carefully observed using cardiological, orthopaedic, endocrinological, gastroenterological, and ophthalmological data. Friedreich ataxia due to an exonic deletion mutation should be suspected in young patients presenting with severe scoliosis

Cognitive impairment in children with CACNA 1A mutations

International audienceAim: To describe the clinico‐radiological phenotype of children with a CACNA 1A mutation and to precisely evaluate their learning ability and cognitive status.Method: Children between the ages of 3 and 18 years harboring a pathogenic CACNA 1A mutation associated with episodic ataxia, hemiplegic migraine, benign paroxysmal torticollis, benign paroxysmal vertigo, or benign paroxysmal tonic upgaze, were enrolled in this cross‐sectional study. Data concerning psychomotor development, academic performance, educational management, clinical examination at inclusion, and brain imaging were collected. Cognitive assessment was performed using age‐standardized scales.Results: Eighteen patients (nine males, nine females; mean age at inclusion: 11y 7mo [SD 4y 5mo; range 3y–17y 11mo]) from 14 families were enrolled. Eleven patients displayed the coexistence or consecutive occurrence of more than one type of episodic event. Nine patients exhibited abnormal neurological examination at inclusion. Brain magnetic resonance imaging (MRI ) showed cerebellar atrophy in five patients. Psychomotor development was delayed in nine patients and academic difficulties were reported by the parents in 15 patients; nine patients were in special education. Impairment of intellectual function was assessed in six of the 12 patients with interpretable Full‐scale IQ scores and was more frequent when cerebellar atrophy was present on MRI .Interpretation: Cognitive impairment is commonly associated with CACNA 1A mutations. We suggest that CACNA 1A ‐associated phenotype should be considered a neurodevelopmental disorder