Rare metabolic disease mimicking COL4A1/COL4A2 fetal brain phenotype.

Pathogenic variants of collagen type IV alpha 1 and 2 (COL4A1/COL4A2) genes cause various phenotypic anomalies, including intracerebral hemorrhage and a wide spectrum of developmental anomalies. Only 20% of fetuses referred for COL4A1/COL4A2 molecular screening (fetuses with a suspected intracerebral hemorrhage) carry a pathogenic variant in these genes, raising questions regarding the causative anomaly in the remaining 80% of these fetuses. We examined, following termination of pregnancy or in-utero fetal death, a series of 113 unrelated fetuses referred for COL4A1/COL4A2 molecular screening, in which targeted sequencing was negative. Using exome sequencing data and a gene-based collapsing test, we searched for enrichment of rare qualifying variants in our fetal cohort in comparison to the Genome Aggregation Database (gnomAD) control cohort (n = 71 702). Qualifying variants in pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) were overrepresented in our cohort, reaching genome-wide significance (P = 2.11 × 10-7 ). Heterozygous PDHA1 loss-of-function variants were identified in three female fetuses. Among these three cases, we observed microcephaly, ventriculomegaly, germinolytic pseudocysts, agenesis/dysgenesis of the corpus callosum and white-matter anomalies that initially suggested cerebral hypoxic-ischemic and hemorrhagic lesions. However, a careful a-posteriori reanalysis of imaging and postmortem data showed that the observed lesions were also consistent with those observed in fetuses carrying PDHA1 pathogenic variants, strongly suggesting that these two phenotypes may overlap. Exome sequencing should therefore be performed in fetuses referred for COL4A1/COL4A2 molecular screening which are screen-negative, with particular attention paid to the PDHA1 gene. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Prognostic value of contrast-enhanced MRI in Guillain-Barré syndrome in children.

BACKGROUND: The aim of this retrospective study is to explore the prognostic value of different contrast enhancement imaging patterns in childhood Guillain-Barré syndrome by comparing the clinical, laboratory, and therapeutic outcomes. METHODS: We included a total of 37 patients who were diagnosed and followed up by a pediatric neurology team at Montpellier University Hospital between 2000 and 2016. All images were reinterpreted by the first author and a senior pediatric neuroradiology staff member in two different sessions; in the case of disagreement, the expert's reading was considered. RESULTS: The study group comprised 22 (59.5%) boys and 15 (40.5%) girls. The age ranged from 1.5 year to 14.8 years. Muscle weakness was present in 33 (89.2%) patients. Cranial nerves involvement was observed in 22 (59.5%) patients, while 29 (78.4%) patients had albuminocytological dissociation. In 27 (73%) patients, contrast enhancement or thickening of the lumbosacral nerve roots was found. Simultaneous spinal nerve root and cranial nerve enhancement was noted in five (17.2%) patients, while isolated cranial nerve enhancement was identified in three (10.3%) patients. Clinical and radiological cranial nerve involvement was found in seven (18.9%) patients, while isolated clinical cranial nerves involvement occurred in 13 (35.1%) patients. No significant correlation between different magnetic resonance imaging (MRI) enhancement patterns and short-term or long-term outcomes was found in our cohort. CONCLUSION: Contrast-enhanced brain and spinal MRI is a sensitive and recommended supportive test for diagnosing acute inflammatory polyradiculopathy in children. Its predictive value for clinical, and therapeutic outcomes in the short or long term has not yet been proved.

Clinical Phenotype in an Early-Onset French Pediatric Population: Charcot-Marie-Tooth's Disease Type 2A.

Charcot-Marie-Tooth's disease type 2A (MCT2A), induced by mutation of the mitofusin 2 (MFN2) gene represents the main cause of MCT2. The aim of this study is to provide details of the clinical and electromyographic phenotype of MCT2A in a pediatric population. We conducted a French multicenter retrospective study, including all children with a genetic diagnosis of MCT2A. Thirteen MCT2A children were included with a beginning of symptoms before the age of 10 years ("early-onset group"). We report two new mutations: c.1070 A → T (p.Lys357.Met) and c.280 C → G (p.Arg94Gly). The evolution of the disease is marked by a fast worsening for three patients with loss of motor autonomy, while the evolution is relatively stable for eight patients. The group of early-onset MCT2A seems more heterogeneous than previously described, with a nonconstant severe phenotype.

Arthrogryposis in children: Etiological assessments and preparation of a protocol for etiological investigations.

INTRODUCTION: Arthrogryposis is a descriptive term defining a sign. It describes a set of joint contractures, sometimes identifiable in utero, present from birth and nonprogressive. This term includes a heterogeneous group of diseases, of neurological, neuromuscular, genetic or mechanical origin. The common physiopathological mechanism is fetal immobility syndrome. Two types of classification have been developed: a clinical one (types I, II and III) and an etiological one. The main aim of this study was to define a standardized protocol for etiological investigation based on a descriptive analysis of the various etiologies identified in a population of children followed up for arthrogryposis. Its secondary aim was to assess first the comprehensiveness and relevance of the complementary assessment and second the way in which the classifications proposed by Professor Judith Goslin Hall are applied. MATERIAL AND METHODS: Retrospective multicenter observational study. We enrolled pediatric patients with arthrogryposis being treated at a reference center for neuromuscular diseases, i.e., in three university hospital pediatric neurology units, between February 1997 and January 2017. RESULTS: Forty-two patients (25 boys and 17 girls) were enrolled. According to the clinical classification (Hall et al.), this population consisted of eight cases of type 1 arthrogryposis (19.1%), 14 type II (33.3%) and 20 type III (47.6%). The main etiology was neurological (19.1%), predominantly involving problems with gyration of a polymicrogyria type. Myopathic origin accounted for 9.5% of the population, predominantly involving genotyped distal arthrogryposis (ECEL1 gene). Additional tests produced a diagnosis of 25% type I, 43% type II and 75% type III. CONCLUSION: Arthrogryposis is a sign suggesting multiple etiologies. The main ones are neurological. Several genes have recently been identified, explaining the physiopathological mechanisms. The diagnostic process must be rigorous and coordinated within a multidisciplinary team, following a shared protocol for analysis.

[Bilateral facial nerve palsy associated with Epstein-Barr virus infection in a 3-year-old boy]. / Paralysie faciale bilatérale au cours d'une infection à virus d'Epstein­Barr.

Bilateral facial nerve palsy is a rare and sometimes difficult diagnosis. We describe a case of bilateral simultaneous facial nerve palsy associated with Epstein-Barr virus (EBV) infection in a 3-year-old boy. Several symptoms led to the diagnosis of EBV infection: the clinical situation (fever, stomachache, and throat infection), white blood cell count (5300/mm3 with 70% lymphocyte count), seroconversion with EBV-specific antibodies, lymphocytic meningitis, and a positive blood EBV polymerase chain reaction (9.3×103 copies of EBV-DNA). An MRI brain scan showed bilateral gadolinium enhancement of the facial nerve. A treatment plan with IV antibiotics (ceftriaxone) and corticosteroids was implemented. Antibiotics were stopped after the diagnosis of Lyme disease was ruled out. The patient's facial weakness improved within a few weeks. Bilateral facial nerve palsy is rare and, unlike unilateral facial palsy, it is idiopathic in only 20% of cases. Therefore, it requires further investigation and examination to search for the underlying etiology. Lyme disease is the first infectious disease that should be considered in children, especially in endemic areas. An antibiotic treatment effective against Borrelia burgdorferi should be set up until the diagnosis is negated or confirmed. Further examination should include a blood test (such as immunologic testing, and serologic testing for viruses and bacterium with neurological tropism), a cerebrospinal fluid test, and an MRI brain scan to exclude any serious or curable underlying etiology. Facial bilateral nerve palsy associated with EBV is rarely described in children. Neurological complications have been reported in 7% of all EBV infections. The facial nerve is the most frequently affected of all cranial nerves. Facial palsy described in EBV infections is bilateral in 35% of all cases. The physiopathology is currently unknown. Prognosis is good most of the time.

[Congenital neuromuscular diseases with neonatal respiratory failure excluding myotonic dystrophy type 1 and infantile spinal muscular atrophy. Diagnosis strategy according to a 19-child series]. / Maladies neuromusculaires congénitales à expression respiratoire néonatale à l'exclusion de la dystrophie myotonique de type 1 et de l'amyotrophie spinale infantile. Stratégie d'exploration d'après une série de 19 enfants.

UNLABELLED: Apart from spinal muscular atrophy (SMA) and myotonic dystrophy type 1 (DM1), congenital neuromuscular diseases with early neonatal symptoms mean diagnostic and prognostic challenges mainly when infants require ventilatory support. OBJECTIVES: Consider a standardized strategy for infants suspected of congenital neuromuscular disease from analysis of the literature and retrospective experience with floppy and ventilatory support-dependent infants, after exclusion of well-known diseases (DM1, SMA). PATIENTS AND METHODS: Floppy infants requiring ventilatory support in their 1st month of life, but showing no evidence of DM1, SMA, Prader-Willi syndrome, or encephalopathy. The retrospective multicenter study was based on the response of regional referent neuropediatricians in the Reference Centre for Neuromuscular Diseases of Greater Southwest France to an inquiry about prenatal and perinatal history, investigations, diagnosis, and outcome of the child and family. It was conducted between 2007 and 2012. RESULTS: Among the 19 newborns studied, all had severe hypotonia. Prenatal and perinatal features were similar. Their outcome was generally severe: the median survival as measured by the Kaplan-Meier method was 6.9 months. Thirteen children died at a median age of 61 days; ten of them were treated with a palliative procedure. Five children had achieved respiratory independence but suffered from a small delay in motor development. Among the three children who continuously required ventilatory support, only one survived (follow-up period: 23 months); he was the only one undergoing tracheostomy in the cohort. Diagnostic processes were different, leading to pathological and genetic diagnosis for only six infants. There was only histological orientation for seven and no specific diagnostic orientation for the last six. These difficulties have led us to propose an exploration process based on the literature. CONCLUSION: This study highlights difficulties in obtaining a diagnosis and a precise prognosis for floppy ventilated infants. An exploration-standardized process for infants suspected of congenital neuromuscular diseases was made in order to standardize procedures. It could be used as a tool for all professionals involved.

Bilateral idiopathic calf muscle hypertrophy: an exceptional cause of unsightly leg curvature.

The authors present the management of a young female patient who presented with longstanding bilateral calf muscle hypertrophy, with no known cause. Taking into account the patient's wishes and the fact that the hypertrophy was mainly located in the posteromedial compartment, we chose to carry out a subtotal bilateral resection of medial gastrocnemius muscles. This procedure was performed with an harmonic scalpel, permitting a excellent cosmetic result while avoiding complications or functional impairment. After a reviewing of the commonly used techniques, the authors discuss the chosen surgical approach taking into account its clinical particularity.

[Central manifestations of dystrophinopathies]. / Manifestations centrales des dystrophinopathies.

The dystrophin gene involved in Duchenne and Becker muscular dystrophy is expressed in three main tissues resulting in clinical manifestations: skeletal muscle, heart and central nervous system. The 6 different existing dystrophins in the brain may play a role in the maturation and plasticity of neuronal synapses in particular by their functions in clustering and stabilization of different receptors at the post synaptic membrane. The possibility of an intellectual deficiency in Duchenne muscular dystrophy is known from the original description by Duchenne himself. Current data are in line with a constant cognitive impairment with a Gaussian curve shifted intellectual quotient (IQ) at -1 standard deviation from the standard population with an average IQ around 80. Clinical manifestations suggestive of a central nervous system involvement can affect all dystrophinopathies, including isolated central presentations without myopathic sign. The phenotypic spectrum appears broader and more subtle than non specific intellectual deficiency. The isolated or shared involvement of specific cognitive functions is possible (memory functions, executive functions, attention) with or without intellectual deficiency. Autism spectrum disorders are also among the encountered events. In clinical practice, it seems worth to ask for a measurement of serum creatine kinase (CK) in these different situations, keeping in mind that pure forms of central dystrophinopathies with a normal CK level have been recently reported.

[Mitochondrial neurogastrointestinal encephalopathy disease]. / L'encéphalomyopathie neuro-gastro-intestinale mitochondriale : un tableau d'anorexie mentale atypique.

Mitochondrial neurogastrointestinal encephalopathy disease (MNGIE) is a rare autosomal-recessive syndrome, resulting from mutations in the TYMP gene, located at 22q13. The mutation induces a thymidine phosphorylase (TP) deficit, which leads to a nucleotide pool imbalance and to instability of the mitochondrial DNA. The clinical picture regroups gastrointestinal dysmotility, cachexia, ptosis, ophthalmoplegia, peripheral neuropathy, and asymptomatic leukoencephalopathy. The prognosis is unfavorable. We present the case of a 14-year-old Caucasian female whose symptoms started in early childhood. The diagnosis was suspected after magnetic resonance imaging (MRI), performed given the atypical features of mental anorexia, which revealed white matter abnormalities. She presented chronic vomiting, postprandial abdominal pain, and problems gaining weight accompanied by cachexia. This diagnosis led to establishing proper care, in particular an enteral and parenteral nutrition program. There is no known specific effective treatment, but numerous studies are in progress. In this article, after reviewing the existing studies, we discuss the main diagnostic and therapeutic aspects of the disease. We argue for the necessity of performing a cerebral MRI given the atypical features of a patient with suspected mental anorexia (or when the clinical pattern of a patient with mental anorexia seems atypical), so that MNGIE can be ruled out.

Partial acute transverse myelitis is a predictor of multiple sclerosis in children.

BACKGROUND: Acute transverse myelitis (ATM) in children is a rare and often severe disease for which there are few known prognostic factors, particularly the subsequent risk of multiple sclerosis (MS) diagnosis. OBJECTIVES: To determine the clinical course and prognostic factors after a first episode of ATM in children. METHODS: Thirty children below 16 years of age diagnosed with a first neurological episode of ATM were included retrospectively. Clinical evaluation, treatment, laboratory, and MRI data were collected. RESULTS: Median age at onset was 11 years (range 3-15 years). Follow-up data were available for a median of 4 years (range 0.5-16.7 years). Five patients subsequently had a diagnosis of MS (17%), which was associated with acute partial transverse myelitis (odds ratio 5; 95% confidence interval 2.3-11), with a 60% probability of having a relapse at five years (p < 0.01). The 2011 Verhey criteria correctly identified MS in children with the highest specificity (96%) and sensitivity (80%). CONCLUSION: Acute partial transverse myelitis and brain MRI abnormalities at initial presentation are significantly predictive of a subsequent diagnosis of MS in children with ATM. These findings suggest that closer brain MRI monitoring after acute partial transverse myelitis might make the earlier introduction of disease-modifying therapies possible.

[Phenotypic heterogeneity and phenotype-genotype correlations in dystrophinopathies: Contribution of genetic and clinical databases]. / Variabilité phénotypique et corrélations génotype-phénotype des dystrophinopathies : contribution des banques de données.

The objective of this work was to study the natural history of dystrophinopathies and the genotype-phenotype correlations made possible by the development of the clinical part of the French DMD database. The collection of 70,000 clinical data for 600 patients with an average longitudinal follow-up of 12years enabled clarification of the natural history of Duchenne and Becker muscular dystrophies and clinical presentations in symptomatic females. We were able to specify the phenotypic heterogeneity of motor, orthopedic and respiratory involvements (severe, standard and intermediary form), of the cardiac disorder (severe, standard or absent cardiomyopathy, absence of correlation between motor and cardiac involvements), and of brain function (mental deficiency in the patients with Becker muscular dystrophy, psychopathological disorders in dystrophinopathies). Phenotypic variability did not correlate with a specific mutational spectrum. We propose a model of phenotypic analysis based on the presence or not of muscular and cardiac involvements (described by age at onset and rate of progression) and brain involvement (described by the type and the severity of the cognitive impairment and of the psychological disorders). The methodology developed for the DMD gene can be generalized and used for other databases dedicated to genetic diseases. Application of this model of phenotypic analysis for each patient and further development of the database should contribute substantially to clinical research providing useful tools for future clinical trials.

[Childhood parvovirus B19 encephalitis]. / Encéphalite à parvovirus B19 de l'enfant.

INTRODUCTION: Human parvovirus B19 (PVB19) causes erythema infectiosum or 5(th) disease in childhood, which mainly affects children between 3 and 15 years of age. PVB19 infections have also been described in association with a variety of neurologic manifestations including encephalitis. CASE REPORT: This 3-year 8-month-old boy developed febrile encephalitis (mental status change with seizures and left limb hypertonia) associated with a rash. The electroencephalographs revealed focal slowing with some spikes in front of the left centro-temporo-occipital areas ; bacteriological and biochemical cerebrospinal fluid (CSF) analysis were normal, brain radiologic studies (tomography and magnetic resonance imaging) were normal. The diagnosis of encephalitis associated with PVB19 primo infection was based on viral DNA detection in the serum and CSF using PCR and on the specific immunoglobulin M (without immunoglobulin G) detection in the serum. DISCUSSION: In France, encephalitis etiology is unknown in 48% of the cases. PVB19 accounts for 4.3% of undiagnosed meningoencephalitis in children. Although there is no specific sign, seizures and rash are reported in about one-half and one-quarter of cases, respectively. CONCLUSION: Even if PVB19 research is not cited in the French or American infectious disease society recommendations on the diagnosis and management of infectious encephalitis, this virus may be responsible, especially in cases of child febrile rash. Therefore, PVB19 research seems reasonable if the clinical presentation is concordant in children due to its diagnostic simplicity and efficacy.

[Genetic syndromes that mimic congenital infections: report of 2 cases]. / Syndromes génétiques mimant les infections congénitales : à propos de 2 cas.

Genetic syndromes that mimic congenital infections must be recognized because of the associated risk of recurrence. We describe a male infant who was born with the association of intra-uterine growth retardation, microcephaly, intracranial calcifications, white matter abnormalities, microphtalmy, bilateral cataract, and hearing loss. Congenital cytomegalovirus (CMV) infection was suspected, but serologic CMV markers were not decisive (IgG+/IgM-). His half-sister (same father) presented a similar phenotype. Therefore, the diagnosis of congenital CMV infection was questioned and a genetic hypothesis was suggested. In 1983, Baraitser et al. first described two brothers with microcephaly and intracranial calcifications and negative TORCH analysis. Later, a number of authors reported children in whom detailed investigation failed to objectively confirm an intra-uterine infective agent. Clinical features include severe postnatal microcephaly, seizures, and pronounced developmental arrest. These cases have been considered to define a distinct autosomal recessive disorder first named pseudo-Torch syndrome. The family described herein is different from the cases previously described with a suspected autosomal dominant inheritance, severe ophtalmological abnormalities, and unusual brain imaging.

[Acute inflammatory polyradiculoneuropathy and membranous glomerulonephritis following Epbstein-Barr virus primary infection in a 12-year-old girl]. / Polyradiculonévrite aiguë et glomérulonéphrite extramembraneuse au décours d'une primo-infection à Epstein-Barr virus chez une patiente de 12 ans.

Acute inflammatory polyradiculoneuropathy, or Guillain-Barré syndrome (GBS), is characterized by peripheral nerve demyelination, which leads to rapidly progressive weakness, loss of sensation, and loss of deep tendon reflexes. It is a prototype of postinfectious autoimmune disease, whose pathophysiology is well described in the forms provoked by certain bacteria (molecular mimicry with Campylobacter jejuni), but remains unclear for the forms related to other organisms (cytomegalovirus, Epstein-Barr virus and other herpes group viruses, Mycoplasma pneumoniae). Glomerular lesions can be associated with the neurological symptoms and have also been described after various infections, independently of any signs of polyradiculoneuropathy. We report the observation of a 12-year-old girl who presented with Guillain-Barré syndrome with facial diplegia, ataxia, and intracranial hypertension following Epstein-Barr virus (EBV) primary infection. During the course of the neurological disease, membranous glomerulonephritis (MGN) was diagnosed. The neurological impairment was regressive within 6 months after intravenous immunoglobulin treatment followed by intravenous then oral corticosteroid administration. Viremia remained high more than 6 months after the onset of symptoms. Glomerulopathy progressed independently and finally required immunosuppressant medication with cyclosporine. EBV might be the factor that triggered the autoimmune disorders, as previously reported for systemic lupus erythematosus and multiple sclerosis in children. To the best of our knowledge, this association of 3 conditions (GBS, MGN, and EBV primary infection) has never been reported in the literature.

[Acute motor deficit in childhood: diagnosis management]. / Déficit moteur aigu non traumatique de l'enfant : orientations diagnostiques.

Acute motor deficit is not uncommon in childhood, with various neurological etiologies. Pertinent semiological analysis allows correct diagnosis management, with adequate paraclinical investigations. The authors describe this clinical diagnosis strategy. The most common clinical situations and various etiologies are presented; paraclinical investigations confirming the diagnosis are discribed, with specific attention to central nervous system imaging according to the most recent sequences.

Unexpected neurological sequelae following propofol anesthesia in infants: Three case reports.

UNLABELLED: Propofol is a widely used hypnotic agent for induction and maintenance of pediatric anesthesia with a well known safety profile. Experimental in vitro studies suggest that propofol may be toxic to developing neurons. We report the cases of three infants who underwent surgery before 2 months of age for different benign pathologies. Propofol was used for induction and maintenance of anesthesia in all cases. The three patients developed convulsions with similar clinical characteristics (cluster of recurrent clinical and subclinical seizures) between the 23th and 30th hours following anesthesia. Clinical and electroencephalographic improvement was obtained between the third and fourth day of management in pediatric intensive care unit. The seizures never recurred, and the three patients underwent further uneventful general anesthesia without propofol. Follow-up of the three patients disclosed unexpected neurological dysfunction: progressive microcephaly (head circumferences were normal at birth), developmental impairment with cognitive and behavioural disturbances in two cases, and bilateral symmetrical white-matter abnormalities on cerebral magnetic resonance imaging. CONCLUSION: The causal relationship between propofol anesthesia and the neurological symptoms of our patients remains difficult to ascertain, but we believe that pediatricians, anesthetists and intensive care-givers should be aware of this possible adverse reaction that has never been described before.