A novel heterozygous TMEM63A variant in a familial case with early onset nystagmus, severe hypomyelination, and a favorable adult prognosis.

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.

A familial 2p14 microdeletion disrupting actin-related protein 2 and Ras-related protein Rab-1A genes with intellectual disability and language impairment.

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.

Food-Induced Anaphylaxis among Children Weighing <15 kg: A Single-Center Case Series of the Pediatric Emergency Department.

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.