Le pouvoir diagnostique de l'exome dans les troubles du développement et/ou les épilepsies : étude de 100 cas

Les troubles du développement et les épilepsies d'origine monogénique sont en lien avec des variants pathogéniques d'impact fort, qui suivent une hérédité mendélienne. Ils sont hautement hétérogènes génétiquement et peuvent être expliqués par certains CNVs (Copy Number Variant) ou SNVs (Single Nucleotide Variant). Alors que la mise en évidence des CNVs a été facilitée par l'utilisation des techniques d'array-CGH, la détection des SNVs a connu un extraordinaire essor grâce à la technologie de séquençage à haut-débit (SHD), qui a rendu possible l'analyse simultanée d'un grand nombre de gènes, pour un coût et un temps d'analyse réduits, augmentant ainsi drastiquement le rendement diagnostique. Grâce à l'étude rétrospective d'une cohorte de 100 patients, dont 39% ont bénéficié d'un diagnostic moléculaire après analyse par cette nouvelle technologie, ce travail reprend les aspects importants théoriques, techniques et pratiques du séquençage à haut-débit appliqué au diagnostic des troubles du développement et épilepsies

GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects

We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine

Pure Progressive Ataxia and Palatal Tremor (PAPT) Associated with a New Polymerase Gamma (POLG) Mutation

Progressive ataxia with palatal tremor (PAPT) is a syndrome caused by cerebellar and brainstem lesions involving the dentato-rubro-olivary tract and associated with hypertrophic olivary degeneration. Etiologies include acquired posterior fossa lesions (e.g. tumors, superficial siderosis, and inflammatory diseases) and genetic disorders, such as glial fibrillary acidic protein (GFAP) and polymerase gamma (POLG) mutations. We describe the case of a 52-year-old man who developed pure progressive ataxia and palatal tremor. Genetic analysis has shown that he is compound heterozygote for a known pathogenic (W748S) and a novel POLG variant (I1185N). Patients with POLG recessive mutations usually manifest a more complex clinical picture, including polyneuropathy and epilepsy; our case emphasizes the need to consider a genetic origin in a seemingly sporadic and pure PAPT

A triad of infantile spasms, nystagmus and a focal tonic seizure

Epileptic spasms represent a subcategory of motor seizures that have been extensively documented and recently re-classified by the International League Against Epilepsy as either generalized, focal or of unknown onset. Atypical characteristics continue to be reported in case studies, emphasizing the divergent morphological traits and putting into question the underlying aetiopathophysiology. Here, we report the findings of an infant with a triad of clinical manifestations during a single ictal event, comprising a cluster of epileptic spasms, vertical binocular nystagmus, and a focal tonic seizure. A video recording is presented that enabled clinical data to be correlated with EEG modifications. To date, a focal lesion has not been identified on brain imaging. The co-occurrence of these ictal paroxysms provides insight into the anatomical localization of seizure onset and complex epileptic networks involved, and challenges the pathophysiological hypothesis for epileptic spasms, implicating cortical-subcortical dysfunction and the implication of structures deep within the sulcus. Furthermore, the focal components both clinically and electrographically implicate involvement of the frontal eye field in the generation of vertical ictal nystagmus. [Published with video sequence on www.epilepticdisorders.com]

Génétique des troubles auditifs chez l’enfant

The majority of early hearing disorders are of genetic origin. In view of the genetic heterogeneity, high-throughput sequencing analysis of a panel of genes involved in hearing loss is the most effective and economical approach, providing a diagnostic yield of around 40 % today. The determination of a molecular diagnosis makes it possible to: i) adapt the audiological care; ii) to search for possible somatic problems associated with so-called syndromic hearing loss; (iii) to avoid unnecessary additional examinations in isolated hearing loss; (iv) to establish accurate genetic counseling for relatives, or even to provide early diagnosis; and (v) to lay the foundation for potential future molecular hearing loss therapies in selected cases

Case Report: Persistent Hypogammaglobulinemia More Than 10 Years After Rituximab Given Post-HSCT

Rituximab (RTX) is an anti-CD20 monoclonal antibody that targets B cells-from the immature pre-B-cell stage in the bone marrow to mature circulating B cells-while preserving stem cells and plasma cells. It is used to treat autoimmune diseases, hematological malignancies, or complications after hematopoietic stem cell transplantation (HSCT). Its safety profile is acceptable; however, a subset of patients can develop persistent hypogammaglobulinemia and associated severe complications, especially in pediatric populations. We report the unrelated cases of two young men aged 17 and 22, presenting with persistent hypogammaglobulinemia more than 7 and 10 years after treatment with RTX, respectively, and administered after HSCT for hemolytic anemia and Epstein-Barr virus reactivation, respectively. Both patients' immunological workups showed low levels of total immunoglobulin, vaccine antibodies, and class switched-memory B cells but an increase in naive B cells, which can also be observed in primary immunodeficiencies such as those making up common variable immunodeficiency. Whole exome sequencing for one of the patients failed to detect a pathogenic variant causing a Mendelian immunological disorder. Annual assessments involving interruption of immunoglobulin replacement therapy each summer failed to demonstrate the recovery of endogenous immunoglobulin production or normal numbers of class switched-memory B cells 7 and 10 years after the patients' respective treatments with RTX. Although the factors that may lead to prolonged hypogammaglobulinemia after rituximab treatment (if necessary) remain unclear, a comprehensive immunological workup before treatment and long-term follow-up are mandatory to assess long-term complications, especially in children

Hyperinsulinism associated with GLUD1 mutation: allosteric regulation and functional characterization of p.G446V glutamate dehydrogenase

Gain-of-function mutations in the GLUD1 gene, encoding for glutamate dehydrogenase (GDH), result in the hyperinsulinism/hyperammonemia HI/HA syndrome. HI/HA patients present with harmful hypoglycemia secondary to protein-induced HI and elevated plasma ammonia levels. These symptoms may be accompanied by seizures and mental retardation. GDH is a mitochondrial enzyme that catalyzes the oxidative deamination of glutamate to α-ketoglutarate, under allosteric regulations mediated by its inhibitor GTP and its activator ADP. The present study investigated the functional properties of the GDH-G446V variant (alias c.1496G > T, p.(Gly499Val) (NM_005271.4)) in patient-derived lymphoblastoid cells

Activated Phosphoinositide 3 Kinase Delta Syndrome (APDS): A Primary Immunodeficiency Mimicking Lymphoma

Malignant or nonmalignant lymphoproliferative disorders together with repeated ear, nose, and throat infections should strongly motivate immunologic investigations. Indeed, we report a 7-year-old patient with a history of persistent abdominal symptoms along with recurrent ear, nose, and throat infections, who presented with intra-abdominal masses highly suggestive of a diagnostic of lymphoma, and who was diagnosed with activated-PI3K-delta syndrome, a recently described primary immunodeficiency prone to lymphoproliferation