Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency

Impaired proteasome activity due to genetic variants of certain subunits might lead to proteasome-associated autoinflammatory syndromes (PRAAS). Here we report a de novo heterozygous missense variant of the PSMB9 proteasome subunit gene in two unrelated Japanese infants resulting in amino acid substitution of the glycine (G) by aspartic acid (D) at position 156 of the encoded protein β1i. In addition to PRAAS-like manifestations, these individuals suffer from pulmonary hypertension and immunodeficiency, which are distinct from typical PRAAS symptoms. The missense variant results in impaired immunoproteasome maturation and activity, yet ubiquitin accumulation is hardly detectable in the patients. A mouse model of the heterozygous human genetic variant (Psmb9G156D/+) recapitulates the proteasome defects and the immunodeficiency phenotype of patients. Structurally, PSMB9 G156D interferes with the β-ring-βring interaction of the wild type protein that is necessary for 20S proteasome formation. We propose the term, proteasome-associated autoinflammatory syndrome with immunodeficiency (PRAAS-ID), to indicate a separate category of autoinflammatory diseases, similar to, but distinct from PRAAS, that describes the patients in this study.

Segmentation of Rhythmic Units in Word Speech by Japanese Infants and Toddlers

When infants and toddlers are confronted with sequences of sounds, they are required to segment the sounds into meaningful units to achieve sufficient understanding. Rhythm has been regarded as a crucial cue for segmentation of speech sounds. Although previous intermodal methods indicated that infants and toddlers could detect differences in speech sounds based on stress-timed and syllable-timed units, these methods could not clearly indicate how infants and toddlers perform sound segmentation. Thus, the present study examined whether Japanese infants and toddlers could segment word speech sounds comprising basic morae (i.e., rhythm units similar to syllables), on the basis of concurrent basic mora units within syllable units, using the new intermodal matching procedure. The results indicated that, regardless of their ages and linguistic abilities, Japanese infants and toddlers aged 6–25 months tended to segment Japanese words comprising basic morae sounds on the basis of concurrent basic mora units within syllable units. This implies that infants' and toddlers' use of syllable units for segmentation of speech sounds at an early age could be evident among many infants and toddlers learning various languages. Although this finding should be interpreted carefully, the present study demonstrated the utility of the new intermodal matching procedure for examining segmentation of speech sounds and word sounds by infants and toddlers, on the basis of specific rhythm units.

Adult-onset Kawasaki disease: A great masquerader

Kawasaki disease is a necrotising small-to-medium vessel vasculitis affecting children between age groups of 6 months and 5 years. Following the first description in Japanese infants, it has been recognised as the single most common cause of non-infectious vasculitis in children worldwide. Presentation in adult age groups, although described, is rare. Herein, we report a case about a 19-year-old female Indian patient diagnosed with Kawasaki disease and managed with antiplatelets and intravenous immunoglobulin, without further sequalae. We aim to highlight the importance of recognising this entity in adult age groups in day-to-day clinical practice.

Evaluating the seasonality of growth in infants using a mobile phone application

It has been observed that growth velocity of toddlers and school children shows seasonal variation, while such seasonality is unknown in infants. The aim of this study was to examine whether growth velocity (length and weight) of infants differs by seasons. We assessed longitudinal measurement data obtained for 9,409 Japanese infants whose parents used the mobile phone application, “Papatto Ikuji”, during the period from January 2014 to October 2017. On average, each infant had 4.8 entries for length and 5.4 entries for weight. The mean daily change in sex- and age-adjusted z-scores between two time points was estimated as the growth velocity during that period: ΔLAZ/day and ΔWAZ/day for length and weight, respectively. We analyzed 20,007 ΔLAZ/day (mean, −0.0022) and 33,236 ΔWAZ/day (mean, 0.0005) measurements, and found that ΔLAZ/day showed seasonal differences with increases during summer. We conducted a multilevel linear regression analysis, in which effects of age, sex, nutrition and season of birth were adjusted, showing significant difference in ΔLAZ/day between winter and summer with a mean ΔLAZ/day difference of 0.0026 (95%CI 0.0015 to 0.0036; P < 0.001). This seasonal difference corresponded to 13% of the average linear growth velocity in 6-month-old infants. A modest effect of nutrition on linear growth was observed with a mean ΔLAZ/day difference of 0.0015 (95%CI 0.0006 to 0.0025; P < 0.001) between predominantly formula-fed infants and breastfed infants. In conclusion, we observed that linear growth, but not weight gain, of Japanese infants showed significant seasonality effects represented by increases in summer and decreases in winter.

Staphylococcus Agr virulence is critical for epidermal colonization and associates with atopic dermatitis development

Atopic dermatitis (AD) is commonly associated with colonization by Staphylococcus aureus in the affected skin. To understand the role of S. aureus in the development of AD, we performed whole-genome sequencing of S. aureus strains isolated from the cheek skin of 268 Japanese infants 1 and 6 months after birth. About 45% of infants were colonized with S. aureus at 1 month regardless of AD outcome. In contrast, skin colonization by S. aureus at 6 months of age increased the risk of developing AD. Acquisition of dysfunctional mutations in the S. aureus Agr quorum-sensing (QS) system was primarily observed in strains from 6-month-old infants who did not develop AD. Expression of a functional Agr system in S. aureus was required for epidermal colonization and the induction of AD-like inflammation in mice. Thus, retention of functional S. aureus agr virulence during infancy is associated with pathogen skin colonization and the development of AD.