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Purpose: Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND., Methods: We describe 19 patients with congenital CACNA1G-variants including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity., Results: We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics, and increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity., Conclusion: This detailed description of several de novo missense pathogenic variants in CACNA1G, including 13 previously reported cases, supports a clinical spectrum of congenital CACNA1G syndrome beyond spinocerebellar ataxia., (Copyright © 2024. Published by Elsevier Inc.)

Background: Moyamoya disease is a progressive, occlusive arteriopathy of the intracranial vessels causing an increased risk of stroke. It often results in functional impairment and decrease in quality of life, both in the presence and absence of stroke. Revascularization is the accepted treatment for patients with symptomatic moyamoya disease, preventing further stroke. At Leeds Children's Hospital we use the encephalo-duro-arterio-myo-synangiosis (EDAMS) technique to facilitate revascularization. We aim to assess the quality of life outcomes of patients who have undergone operative intervention at our unit for moyamoya disease., Methods: Pediatric patients with operated moyamoya disease from Leeds Children Hospital between February 2009 and January 2019 were included. Patients awaiting primary surgery were excluded. Patients were contacted via telephone and the Pediatric Quality of Life Inventory 4.0 (PedsQL) questionnaire administered via parent proxy. Quality of life outcomes were assessed using the PedsQL questionnaire score, which measures physical, emotional social and school functioning domains. This score was then converted to a health-related quality of life score. Scores in each domain and mean scores were compared with normative data., Results: This study included 11 children (5 boys), median age 6.8 years (range: 22 months to 15.5 years), and 9 children underwent bilateral operations. Mean parent proxy PedsQL score was 66 (range: 12.5-98.4), with a mean score of 61.9 in physical function, 88.9 in emotional function, 70.9 in social function, and 58.7 in school function. This was lower than healthy controls overall and in each individual domain except emotional function, which was similar to normative data., Conclusions: Children with moyamoya disease have a lower quality of life than healthy controls within this series. This suggests that children with moyamoya should be offered additional psychosocial support within the community., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Mitochondrial DNA (mtDNA) depletion syndrome (MDDS) encompasses a group of genetic disorders of mtDNA maintenance. Mutation of RRM2B is an uncommon cause of infantile-onset encephalomyopathic MDDS. Here we describe the natural history of this disease., Methods: Multinational series of new genetically confirmed cases from six pediatric centers., Results: Nine new cases of infantile-onset RRM2B deficiency, and 22 previously published cases comprised a total cohort of 31 patients. Infants presented at a mean of 1.95 months with truncal hypotonia, generalized weakness, and faltering growth. Seizures evolved in 39% at a mean of 3.1 months. Non-neurological manifestations included respiratory distress/failure (58%), renal tubulopathy (55%), sensorineural hearing loss (36%), gastrointestinal disturbance (32%), eye abnormalities (13%), and anemia (13%). Laboratory features included elevated lactate (blood, cerebrospinal fluid (CSF), urine, magnetic resonance (MR), spectroscopy), ragged-red and cytochrome c oxidase-deficient fibers, lipid myopathy, and multiple oxidative phosphorylation enzyme deficiencies in skeletal muscle. Eight new RRM2B variants were identified. Patients with biallelic truncating variants had the worst survival. Overall survival was 29% at 6 months and 16% at 1 year., Conclusions: Infantile-onset MDDS due to RRM2B deficiency is a severe disorder with characteristic clinical features and extremely poor prognosis. Presently management is supportive as there is no effective treatment. Novel treatments are urgently needed.