Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.

Infantile tremor syndrome (ITS) is characterized by anaemia, skin depigmentation, tremors and developmental delay. The lack of sufficient literature on ITS and its conflicting association with vitamin B12 deficiency made us present this article. The objective of this study is to describe demographic, clinical and laboratory profile and outcome of ITS. This is a retrospective chart review of all children presenting with typical features of ITS attending a tertiary paediatric centre in southern India between January 2014 and January 2017. All children with pallor, skin depigmentation and developmental delay, with/without tremors, were included. Anaemia, developmental delay and tremors secondary to non-nutritional causes like metabolic causes were excluded. Of 70 children, 66 were exclusively breastfed and 46 mothers were vegetarians. Mean age of presentation was 13.2 months. Developmental delay was noted in 64, regression in 6 and tremors in 40. Vitamin B₁₂ levels were low in 62 cases. ITS should be considered in children <3 years with anaemia, developmental delay/regression and skin depigmentation, with/without tremors. ITS can be seen in < 3 months of age and in high socio-economic status.

Introduction: In children, health-related quality of life (HRQOL) includes parental impact and family functioning along with concepts of illness, functional status, mental health, and comfort. We are focusing on the impact of cerebral palsy (CP) on children's HRQOL and their families, and its relationship with gross motor dysfunction. Subjects and Methods: CP children aged 3–10 years under regular neurology follow-up were enrolled. The HRQOL and motor severity were prospectively assessed using lifestyle assessment questionnaire-CP and gross motor function classification systems, respectively. Results: One hundred children participated in this study. Thirty-three percent of children had good, 22% had mildly affected, whereas 45% had moderately to severely affected HRQOL. A significant association is present between gross motor function classification system and HRQOL. Conclusion: HRQOL in CP and their caregivers is highly impaired. The degree of impairment is associated with physical independence, mobility, clinical burden, and social integration dimensions. Therapies targeting these dimensions and associated comorbidities will improve the HRQOL. Gross motor function classification system is a good indicator of HRQOL.