Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.

DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mammalian target of rapamycin (mTOR) pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5. Cases were identified clinically. Available records, including magnetic resonance imaging and electroencephalography, were reviewed. Genetic testing was performed by whole exome and whole-genome sequencing and cascade screening. In addition, immunohistochemistry was performed on skin biopsy. The phenotype was identified in nine children, eight of which are described in detail herein. Six of the children were of Irish Traveller, two of Tunisian and one of Lebanese origin. The Irish Traveller children shared the same DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese and Tunisian children shared a different germline homozygous variant (p.Arg806Cys). Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies. Eye and cardiac involvement and severe neutropenia were also observed in one or more patients. Five of the children died in infancy or childhood; the other four are currently aged between 5 months and 6 years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway. The clinical, histopathological and genetic evidence supports a causal role for the homozygous DEPDC5 variants, expanding our understanding of the biology of this gene.

Pediatric Neurotuberculosis: A cases series and review of the literature.

Neurotuberculosis or central nervous system tuberculosis is a form of tuberculous infection that affects any part of the nervous system. Although it is more frequent in adults, pediatric cases have been reported in endemic countries and it is potentially a deadly affection. Therefore, any unusual neurological manifestation in a formerly healthy child, independently of their vaccination status, must bring suspicion of CNS tuberculosis among other diagnoses. We report four cases of pediatric neurotuberculosis with various clinical presentations and outcome and a brief review of the litterature. We conclude that clinical manifestations of pediatric neurotuberculosis are extremely variable and could be misleading. Extra-neurological sites are a key element for diagnosis especially in the pediatric population. A diagnosis and clinical outcome score, especially designed for children might help personalize the therapeutic approach and outcome measures.

Autoimmune Encephalitis in Tunisia: Report of a Pediatric Cohort.

BACKGROUND: Autoimmune encephalitis (AE) is a rapidly progressive encephalopathy caused by antibodies targeting neurons in the central nervous system generating specific immune responses. It is increasingly recognized in children. OBJECTIVE: To describe clinical, neuroimaging, and laboratory features, treatment, and outcome in a cohort of Tunisian children with AE. METHODS: We conducted a retrospective review of the medical records of all children attending the Department of Child and Adolescent Neurology (Tunis) with autoimmune encephalitis between 2004 and 2020. Clinical, neuroimaging, laboratory features, therapeutic data, and outcome were analyzed. RESULTS: Nineteen children were included in the study (12 girls and 7 boys). The median age at diagnosis was 7.68 years (range: 10 months-13 years). The most frequent manifestations were seizures and behavioral disorders. Eleven cases were diagnosed with anti-NMDA receptor encephalitis, 4 cases with anti-Ma2 encephalitis, 3 cases with anti-GAD encephalitis, and 1 case with anti-SOX1 encephalitis. Brain MRI showed increased T2 and fluid-attenuated inversion recovery (FLAIR) signal of the temporal lobe in 5 patients. Eighteen patients showed improvement following first-line immunotherapy (high-dose corticosteroids, intravenous immunoglobulin). One patient with anti-GAD encephalitis died despite escalating immunotherapy. CONCLUSION: Diagnosis of autoimmune encephalitis is challenging in children, because of misleading presentations. An early and accurate diagnosis is important to enable proper therapeutic interventions.