A large number of cases with Dravet syndrome (DS) has been attributed to SCN1A loss of function (LOF), whereas SCN1A gain-of-function (GOF) causes early infantile developmental and epileptic encephalopathy (EIDEE) and familial hemiplegic migraine 3. We retrospectively analyzed 37 individuals with SCN1A pathogenic variants at our institute between January 2012 and October 2024 to investigate phenotype-function correlations. Variant functions were classified as LOF, GOF, or mixed, based on existing patch-clamp data, paralog sodium channel experimental findings, and in silico prediction tools. Clinical characteristics, antiseizure medication (ASM) responses, and variant location were compared. Nine variants were novel. One variant with insufficient data for functional prediction was excluded. Of the 36 cases with predictable functions, five cases (14%) were classified as GOF/mixed (DS = 4, EIDEE = 1) and 31 (86%) as LOF (DS = 31). GOF/mixed-DS had earlier epilepsy onset but otherwise resembled LOF-DS. Sodium channel blocking ASMs (SCB-ASMs) did not exacerbate seizures in GOF/mixed DS cases, with carbamazepine reducing seizures in one case. GOF/mixed variants clustered in the intracellular S6 segment, whereas LOF variants clustered in the S5-S6 pore loop. These findings highlight a potential GOF effect for certain DS cases, suggesting that SCB-ASMs may be effective for GOF/mixed DS. This underscores the importance of functional characterization for tailored therapy, warranting further research to confirm and extend these results. PLAIN LANGUAGE SUMMARY: Dravet syndrome is a severe epilepsy that usually begins in infancy and is linked to changes in a gene called SCN1A. Most cases are caused by gene changes that reduce function, but in some cases, the gene may become overactive. In this study, we found that some patients with Dravet syndrome had these overactive changes and still showed typical symptoms. We found that people with overactive SCN1A function might respond differently to certain medications.

Heterozygous transmembrane protein 63A (TMEM63A) variants cause transient infantile hypomyelinating leukodystrophy-19, which features remarkable natural resolution of clinical and imaging findings during childhood. Previous reports have mainly described de novo variants lacking detailed familial cases. Herein, we describe the clinical course of familial cases with a TMEM63A variant. A 5-month-old girl presented with nystagmus, global hypotonia, and difficulty swallowing since birth. Brain magnetic resonance imaging at 1.5 and 5 months revealed diffuse hypomyelination. Her mother, maternal aunt, and grandfather had nystagmus and motor developmental delays in infancy, which resolved spontaneously during childhood. Compared with these cases, the proband's motor developmental delay was profound, and she was the only one with feeding difficulties, necessitating nasogastric tube feeding. Genetic testing revealed a heterozygous TMEM63A variant (NM_014698.3:c.1658G>A, p.(Gly553Asp)) in the proband and her family. This is the first three-generation familial report of a TMEM63A variant that provides insight into its history and heterogeneity.

Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan Department of Pediatrics, Kagoshima City Hospital, Kagoshima, Japan Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan Department of Pediatrics, Jichi Medical University, Tochigi, Japan Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Tokyo Women's Medical University Institute of Integrated Medical Sciences, Tokyo, Japan Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

Introduction: Food-induced anaphylaxis among infants shows an increasing prevalence; however, the prescription of epinephrine auto-injectors (EAIs) for children weighing <15 kg is associated with issues of the needle length and the epinephrine dose. Several studies have shown age-related differences in food-induced anaphylaxis, although little is known about the weight-related differences in food-induced anaphylaxis. This study aimed to reveal the incidence, clinical characteristics, and management of food-induced anaphylaxis in children weighing <15 kg. Methods: This chart review included children who visited the pediatric emergency department (ED) of the National Center for Child Health and Development (Tokyo, Japan) from January 2014 to December 2016 and were diagnosed with food-induced anaphylaxis. The severity of anaphylaxis was evaluated using the Sampson Grading Scale. Results: Of 89,232 ED visits, 444 visits included patients with food-induced anaphylaxis, after excluding cases of food-induced anaphylaxis related to oral desensitization therapy. The incidence was 4.98 per 1,000 visits. More than half of the children (n = 247/444, 55.6%) weighed <15 kg. The proportion of grade 3 and higher severity anaphylactic symptoms was 74.5% (184/247) in children weighing <15 kg and 79.2% (156/197) in children weighing 15 kg or more. The recurrence rate of food-induced anaphylaxis was 22.3% (55/247) in children weighing <15 kg and 48.7% (96/197) in children weighing 15 kg or more. Among the children weighing <15 kg, the proportion of those with recurrent food-induced anaphylaxis was 4 times higher in children weighing 10–15 kg than in those weighing <10 kg (32.2% [47/146] vs. 7.9% [8/101]). The proportion of patients who were prescribed EAIs before each visit was 25.5% (14/55) in children weighing <15 kg with a history of food-induced anaphylaxis. Conclusion: Food-induced anaphylaxis among children weighing <15 kg occurred as frequently and was as severe as that among children weighing 15 kg or more. However, the proportion of patients prescribed EAIs was very low in children weighing <15 kg with food-induced anaphylaxis. The potential need for EAIs is suggested among children weighing <15 kg, especially among children weighing 10 kg or more but <15 kg.

Microdeletions encompassing the 2p14 region have been reported to cause a novel microdeletion syndrome, characterised by mild intellectual disability (ID) and language impairment (LI), usually showing no congenital malformations or severe dysmorphisms. Actin-related protein 2 (ACTR2) and Ras-related protein Rab-1A (RAB1A) genes present in this region have been suggested to be associated with ID and/or LI pathogenesis on the basis of a few singleton cases with 2p14 microdeletions, although the effects of other deleted genes could not be ruled out. Here, we describe the clinical and molecular cytogenetic characterisation of a three-generation Japanese family comprising six individuals carrying a 144-kb microdeletion at the 2p14 locus, which disrupted two genes, ACTR2 and RAB1A, and co-segregated with ID and LI. The 5'- and 3'-deletion breakpoints were mapped within two flanking Alu repeat elements at 30-bp perfect homology, and thus suggested homologous recombination between the Alu elements as an underlying mechanism for the deletion event. Since ACTR2 is the only gene located in the minimal overlapping interval among the cases reported in the present study and those reported previously with 2p14 microdeletions, and ACTR2 exhibits strong intolerance for loss-of-function, our findings further support the notion that ACTR2, a key component involved in the branching of cytoskeletal actin networks, is probably responsible for the aetiology of LI in 2p14 microdeletion syndrome.

Malan syndrome (MIM# 614753; also known as Sotos syndrome 2) is a disorder characterized by postnatal overgrowth, macrocephaly, advanced bone age, long narrow face, high forehead, and intellectual disability. It results from heterozygous variants or microdeletions of nuclear factor I/X (NFIX; MIM# 164005) on chromosome 19p13.2 [ [1] Priolo M. Schanze D. Tatton-Brown K. Mulder P.A. Tenorio J. Kooblall K. Acero I.H. Alkuraya F.S. Arias P. Bernardini L. Bijlsma E.K. Cole T. Coubes C. Dapia I. Davies S. Di Donato N. Elcioglu N.H. Fahrner J.A. Foster A. Gonzalez N.G. Huber I. Iascone M. Kaiser A.S. Kamath A. Liebelt J. Lynch S.A. Maas S.M. Mammi C. Mathijssen I.B. McKee S. Menke L.A. Mirzaa G.M. Montgomery T. Neubauer D. Neumann T.E. Pintomalli L. Pisanti M.A. Plomp A.S. Price S. Salter C. Santos-Simarro F. Sarda P. Segovia M. Shaw-Smith C. Smithson S. Suri M. Valdez R.M. Van Haeringen A. Van Hagen J.M. Zollino M. Lapunzina P. Thakker R.V. Zenker M. Hennekam R.C. Further delineation of Malan syndrome. Hum. Mutat. 2018; 39: 1226-1237https://doi.org/10.1002/humu.23563 Crossref PubMed Scopus (27) Google Scholar ]. Although distinguishing Malan syndrome from two similar overgrowth disorders—Sotos (MIM# 117550) and Weaver syndromes (MIM# 277590)—is possible by clinical evaluation [ [1] Priolo M. Schanze D. Tatton-Brown K. Mulder P.A. Tenorio J. Kooblall K. Acero I.H. Alkuraya F.S. Arias P. Bernardini L. Bijlsma E.K. Cole T. Coubes C. Dapia I. Davies S. Di Donato N. Elcioglu N.H. Fahrner J.A. Foster A. Gonzalez N.G. Huber I. Iascone M. Kaiser A.S. Kamath A. Liebelt J. Lynch S.A. Maas S.M. Mammi C. Mathijssen I.B. McKee S. Menke L.A. Mirzaa G.M. Montgomery T. Neubauer D. Neumann T.E. Pintomalli L. Pisanti M.A. Plomp A.S. Price S. Salter C. Santos-Simarro F. Sarda P. Segovia M. Shaw-Smith C. Smithson S. Suri M. Valdez R.M. Van Haeringen A. Van Hagen J.M. Zollino M. Lapunzina P. Thakker R.V. Zenker M. Hennekam R.C. Further delineation of Malan syndrome. Hum. Mutat. 2018; 39: 1226-1237https://doi.org/10.1002/humu.23563 Crossref PubMed Scopus (27) Google Scholar ], these are symptomatically similar and share several clinical features. Shimojima et al. [ [2] Shimojima K. Okamoto N. Tamasaki A. Sangu N. Shimada S. Yamamoto T. An association of 19p13.2 microdeletions with Malan syndrome and Chiari malformation. Am. J. Med. Genet. A. 2015; 167: 724-730https://doi.org/10.1002/ajmg.a.36959 Crossref Scopus (17) Google Scholar ] identified three patients with Malan syndrome due to 19p13.2 microdeletion as having Chiari malformation type I (CMI), including two of their own patients and one reported by Dolan et al. [ [3] Dolan M. Mendelsohn N.J. Pierpont M.E. Schimmenti L.A. Berry S.A. Hirsch B. A novel microdeletion/microduplication syndrome of 19p13.13. Genet. Med. 2010; 12: 503-511https://doi.org/10.1097/GIM.0b013e3181e59291 Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar ] and stated that the incidence of CMI in patients with 19p13.2 deletions involving NFIX is 15.8% [ [2] Shimojima K. Okamoto N. Tamasaki A. Sangu N. Shimada S. Yamamoto T. An association of 19p13.2 microdeletions with Malan syndrome and Chiari malformation. Am. J. Med. Genet. A. 2015; 167: 724-730https://doi.org/10.1002/ajmg.a.36959 Crossref Scopus (17) Google Scholar ]. The authors speculated that NFIX or its neighboring genes may be associated with CMI and suggested that the presence of CMI may help differentiate 19p13.2 deletion syndrome from the NSD1-related Sotos syndrome. Following this study, a large cohort of Malan syndrome patients with NFIX mutations was reported and three of 44 cases showed Chiari malformation by imaging studies [ [1] Priolo M. Schanze D. Tatton-Brown K. Mulder P.A. Tenorio J. Kooblall K. Acero I.H. Alkuraya F.S. Arias P. Bernardini L. Bijlsma E.K. Cole T. Coubes C. Dapia I. Davies S. Di Donato N. Elcioglu N.H. Fahrner J.A. Foster A. Gonzalez N.G. Huber I. Iascone M. Kaiser A.S. Kamath A. Liebelt J. Lynch S.A. Maas S.M. Mammi C. Mathijssen I.B. McKee S. Menke L.A. Mirzaa G.M. Montgomery T. Neubauer D. Neumann T.E. Pintomalli L. Pisanti M.A. Plomp A.S. Price S. Salter C. Santos-Simarro F. Sarda P. Segovia M. Shaw-Smith C. Smithson S. Suri M. Valdez R.M. Van Haeringen A. Van Hagen J.M. Zollino M. Lapunzina P. Thakker R.V. Zenker M. Hennekam R.C. Further delineation of Malan syndrome. Hum. Mutat. 2018; 39: 1226-1237https://doi.org/10.1002/humu.23563 Crossref PubMed Scopus (27) Google Scholar ]. However, the underlying mechanism by which CMI develops in Malan syndrome patients remains uncertain. Here we report a novel NFIX variant in a subject with Malan syndrome accompanying hindbrain overcrowding reminiscent of CMI.