Early-onset Infantile Spasms Research Articles

Characterisation of CDKL5 Transcript Isoforms in Human and Mouse.

Mutations in the X-linked Cyclin-Dependent Kinase-Like 5 gene (CDKL5) cause early onset infantile spasms and subsequent severe developmental delay in affected children. Deleterious mutations have been reported to occur throughout the CDKL5 coding region. Several studies point to a complex CDKL5 gene structure in terms of exon usage and transcript expression. Improvements in molecular diagnosis and more extensive research into the neurobiology of CDKL5 and pathophysiology of CDKL5 disorders necessitate an updated analysis of the gene. In this study, we have analysed human and mouse CDKL5 transcript patterns both bioinformatically and experimentally. We have characterised the predominant brain isoform of CDKL5, a 9.7 kb transcript comprised of 18 exons with a large 6.6 kb 3’-untranslated region (UTR), which we name hCDKL5_1. In addition we describe new exonic regions and a range of novel splice and UTR isoforms. This has enabled the description of an updated gene model in both species and a standardised nomenclature system for CDKL5 transcripts. Profiling revealed tissue- and brain development stage-specific differences in expression between transcript isoforms. These findings provide an essential backdrop for the diagnosis of CDKL5-related disorders, for investigations into the basic biology of this gene and its protein products, and for the rational design of gene-based and molecular therapies for these disorders.

PP13.2 – 3042: Infantile spasms in an infant with anti-NMDA receptor encephalitis secondary to HSV-1 encephalitis

Objective The recent identification of NMDAR antibodies causing choreoatethosis post-herpes simplex encephalitis (HSE) has provided a proof of principle that relapsing symptoms post-HSE are immune mediated. We report the first patient with anti-NMDAR encephalitis post-HSE and infantile spasms. Methods Review of patient's clinical information. Immunological studies as previously reported. Results An 11-month-old boy was admitted to our Pediatric Intensive Care Unit for status epilepticus and fever. The CSF showed 25 WBC/uL and the PCR was positive for HSV1. Intravenous acyclovir was started and over the next days 3 days he developed simple partial seizures that were initially well controlled with valproate (VPA). On day 19th after HSE onset he was readmitted for irritability, impaired interaction, involuntary movements (head shaking and facial twitching), and spasms with EEG hypsarrhythmia. The CSF revealed mild pleocytosis, negative HSV-1 PCR and high titers of NMDAR antibodies. Repeated MRI showed progression of T2/FLAIR abnormalities and intense contrast enhancement that was not present in previous studies. He was treated with midazolam, VPA, vigabatrin and immunotherapy (iv methylprednisolone, IVIg, rituximab, cyclophosphamide) without symptom improvement. Spasms and EEG paroxysmal activity progressively worsened and evolved towards a super-refractory status epilepticus, which was eventually controlled with barbiturate coma, lacosamide and ketogenic diet (KD). Seventy days after HSE onset he underwent plasma exchange for persisting coma and generalized choreoathetosis with partial clinical improvement of symptoms. KD was discontinued after 3 months of seizure control and EEG activity improvement. Conclusion Early onset infantile spasms post-HSE can be caused by anti-NMDAR encephalitis. Recent advances in the genetics of West syndrome (GRIN2B mutations – encoding the NR2B subunit of the NMDA receptor) and the animal model for West syndrome (induced by NMDA) support this hypothesis. Plasma exchange and KD were the most effective treatments in our patient.

Un syndrome d’Aicardi associé à un ptosis congénital sévère

Aicardi syndrome is a rare neurodevelopmental disorder characterized by corpus callosum agenesis, chorioretinal lacunae and early-onset infantile spasms. We report a particular case of Aicardi syndrome characterized by the association of the classical triad of severe bilateral ptosis, pontocerebellar hypoplasia, and perisylvian polymicrogyria in a girl born to non-consanguineous parents, but whose mother suffered from idiopathic generalized epilepsy.

Aicardi Syndrome in a Male Patient

Aicardi syndrome ( OMIM 304050) is defined by the clinical triad of early-onset infantile spasms, agenesis of the corpus callosum and chorioretinal lacunae. Almost all patients are females showing severe cognitive and physical disabilities, and early onset seizures. Astrocytic inclusions containing filamin have been found, but the molecular defect in Aicardi syndrome is not yet known. We report a male patient with Aicardi syndrome characterised by agenesis of the corpus callosum, infantile spasms, chorioretinal lacunae, severe psychomotor retardation, periventricular heterotopias, and patent ductus arteriosus. As the latter two symptoms are suggestive of a mutation in the FLNA gene encoding filamin A, this gene was sequenced, but the sequence did not reveal a disease-causing mutation.

CEREBELLAR MIGRATION DEFECTS IN AICARDI SYNDROME: AN EXTENSION OF THE NEUROPATHOLOGICAL SPECTRUM

The Aicardi syndrome is characterized by infantile spasms, corpus callosum agenesis, and chorioretinal lacunae and almost exclusively affects females (very rarely, 47, XXY males). The crucial genetic mishap likely occurs in the postzygotic stage, but the variable clinical phenotype among the ∼ 450 known cases has not been explained. No consistent mutations or deletions exist among patients. We encountered a baby girl with early onset infantile spasms. She had left-sided cleft lip/palate, costovertebral defects, scoliosis, callosal agenesis, and microphthalmia. She expired at the age of 3 months of respiratory infection. On autopsy she had thoracic hemivertebrae with rib defects, bilateral microphthalmia, microcornea, posterior colobomata, abnormalities of the retinal pigment epithelium, absence of normal ganglion cells in the retina, gross asymmetry of the brain with cerebral polymicrogyria, total callosal agenesis, cerebral subcortical and subependymal nodular heterotopias, cerebellar nodular heterotopias, and tegmental/basal unilateral brainstem hypoplasia. Cerebellar and retinal migration defects have not been described before in Aicardi syndrome and may have had a bearing on this patient's eventual outcome.

Aicardi syndrome with favorable outcome: Case report and review

Aicardi syndrome is a congenital disorder characterized by severe psychomotor retardation, corpus callosum agenesis, chorioretinal lacunae, and early-onset infantile spasms. The prognosis is generally poor for children with the classical form. We report a peculiar case of Aicardi syndrome characterized by corpus callosum hypoplasia, brain malformations with subependymal heterotopias, extensive chorioretinal lacunae, seizures, and normal cognitive functions. Therefore, the clinical picture of the syndrome is broader than originally described. Cognitive disorders should not be considered inevitable and the prognosis not ineludibly poor.

Mutations in the X-Linked Cyclin-Dependent Kinase–Like 5 ( CDKL5/STK9) Gene Are Associated with Severe Neurodevelopmental Retardation

Recently, we showed that truncation of the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene caused mental retardation and severe neurological symptoms in two female patients. Here, we report that de novo missense mutations in CDKL5 are associated with a severe phenotype of early-onset infantile spasms and clinical features that overlap those of other neurodevelopmental disorders, such as Rett syndrome and Angelman syndrome. The mutations are located within the protein kinase domain and affect highly conserved amino acids; this strongly suggests that impaired CDKL5 catalytic activity plays an important role in the pathogenesis of this neurodevelopmental disorder. In view of the overlapping phenotypic spectrum of CDKL5 and MECP2 mutations, it is tempting to speculate that these two genes play a role in a common pathogenic process.

Neuroepileptic correlates of autistic symptomatology in tuberous sclerosis.

Tuberous sclerosis is a genetic condition that is strongly associated with the development of an autism spectrum disorder. However, there is marked variability in expression, and only a subset of children with tuberous sclerosis develop autism spectrum disorder. Clarification of the mechanisms that underlie the association and variability in expression will potentially throw light on the biological processes involved in the etiology of idiopathic forms of autism spectrum disorder. Current evidence indicates that the likelihood of a child with tuberous sclerosis developing an autism spectrum disorder is greater if the child has a mutation in the TSC2 gene, although autism can and does develop in children with TSC1 mutations. The likelihood is also greater if the child has early-onset infantile spasms that are difficult to control, especially if there is an epileptiform focus in the temporal lobes. The emerging evidence is consistent with the notion that early onset electrophysiological disturbances within the temporal lobes (and perhaps other locations) has a deleterious effect on the development and establishment of key social cognitive representations concerned with processing social information, perhaps especially from faces. However, alternative mechanisms to account for the findings cannot yet be ruled out. Future research will have to employ prospective longitudinal designs and treatment trials to clarify the processes involved.