Mutations in N-acetylglucosamine (O-GlcNAc) transferase in patients with X-linked intellectual disability.

N-Acetylglucosamine (O-GlcNAc) transferase (OGT) regulates protein O-GlcNAcylation, an essential and dynamic post-translational modification. The O-GlcNAc modification is present on numerous nuclear and cytosolic proteins and has been implicated in essential cellular functions such as signaling and gene expression. Accordingly, altered levels of protein O-GlcNAcylation have been associated with developmental defects and neurodegeneration. However, mutations in the OGT gene have not yet been functionally confirmed in humans. Here, we report on two hemizygous mutations in OGT in individuals with X-linked intellectual disability (XLID) and dysmorphic features: one missense mutation (p.Arg284Pro) and one mutation leading to a splicing defect (c.463-6T>G). Both mutations reside in the tetratricopeptide repeats of OGT that are essential for substrate recognition. We observed slightly reduced levels of OGT protein and reduced levels of its opposing enzyme O-GlcNAcase in both patient-derived fibroblasts, but global O-GlcNAc levels appeared to be unaffected. Our data suggest that mutant cells attempt to maintain global O-GlcNAcylation by down-regulating O-GlcNAcase expression. We also found that the c.463-6T>G mutation leads to aberrant mRNA splicing, but no stable truncated protein was detected in the corresponding patient-derived fibroblasts. Recombinant OGT bearing the p.Arg284Pro mutation was prone to unfolding and exhibited reduced glycosylation activity against a complex array of glycosylation substrates and proteolytic processing of the transcription factor host cell factor 1, which is also encoded by an XLID-associated gene. We conclude that defects in O-GlcNAc homeostasis and host cell factor 1 proteolysis may play roles in mediation of XLID in individuals with OGT mutations.

Irreversible Respiratory Failure in a Full-Term Infant with Features of Pulmonary Interstitial Glycogenosis as Well as Bronchopulmonary Dysplasia.

Pulmonary interstitial glycogenosis (PIG) is a rare interstitial lung disease in the newborns. We report on the clinical presentation and pathological findings of a full-term male infant with pulmonary hypertension requiring extracorporeal membrane oxygenation (ECMO). An open lung biopsy demonstrated interstitial changes resembling pulmonary interstitial glycogenosis as well as bronchopulmonary dysplasia (BPD), without convincing evidence of maturational arrest, infection, alveolar proteinosis, or alveolar capillary dysplasia. The boy was treated with glucocorticoids and, after a few days, was weaned from ECMO. A few hours later, the patient died due to acute severe pulmonary hypertension with acute right ventricular failure. The etiology and underlying pathogenic mechanisms of PIG are unknown. The clinical outcomes are quite varied. Deaths have been reported when PIG exists with abnormal lung development and pulmonary vascular growth and congenital heart disease. No mortality has been reported in PIG together with BPD in full-term infants. In this article, we reported on a full-term infant with interstitial changes resembling PIG and BPD who expired despite no convincing evidence of an anatomical maturational arrest or congenital heart disease.

The effect of 3% and 6% hypertonic saline in viral bronchiolitis: a randomised controlled trial.

Bronchiolitis is a common disorder in young children that often results in hospitalisation. Except for a possible effect of nebulised hypertonic saline (sodium chloride), no evidence-based therapy is available. This study investigated the efficacy of nebulised 3% and 6% hypertonic saline compared with 0.9% hypertonic saline in children hospitalised with viral bronchiolitis. In this multicentre, double-blind, randomised, controlled trial, children hospitalised with acute viral bronchiolitis were randomised to receive either nebulised 3%, 6% hypertonic saline or 0.9% normal saline during their entire hospital stay. Salbutamol was added to counteract possible bronchial constriction. The primary endpoint was the length of hospital stay. Secondary outcomes were need for supplemental oxygen and tube feeding. From the 292 children included in the study (median age 3.4 months), 247 completed the study. The median length of hospital stay did not differ between the groups: 69 h (interquartile range 57), 70 h (IQR 69) and 53 h (IQR 52), for 3% (n=84) and 6% (n=83) hypertonic saline and 0.9% (n=80) normal saline, respectively, (p=0.29). The need for supplemental oxygen or tube feeding did not differ significantly. Adverse effects were similar in the three groups. Nebulisation with hypertonic saline (3% or 6% sodium chloride) although safe, did not reduce the length of stay in hospital, duration of supplemental oxygen or tube feeding in children hospitalised with moderate-to-severe viral bronchiolitis.

[A young boy with pulmonary tuberculosis]. / Een jong kind met pulmonale tuberculose.

BACKGROUND: Infectious pulmonary tuberculosis in young children is rare in the Netherlands. Young children with a tuberculosis infection are at high risk of developing miliary tuberculosis or tuberculous meningitis. CASE DESCRIPTION: A 12-month-old boy of Turkish descent was brought to our hospital because of coughing present for a few weeks and fever for 10 days. Nine weeks previously the patient had visited family in western Turkey, where, as far as is known, he did not come into contact with anyone who had tuberculosis. A chest X-ray showed infiltration of the middle lobe. He did not recover with empirical treatment for community-acquired pneumonia. Because of treatment failure, tuberculin skin testing was performed, the result of which was positive. The boy fully recovered during tuberculostatic treatment. Open tuberculosis was subsequently confirmed in a family member in Turkey after the boy's visit. CONCLUSION: In the event of pneumonia with an atypical course, testing for tuberculosis is justified, even if there is no or little likelihood of contact with a tuberculosis patient in the history.

Severe kerion celsi due to Trichophyton mentagrophytes: a case report.

UNLABELLED: We report on a 5-year-old girl with a severe kerion celsi, caused by Trichophyton mentagrophytes, probably acquired from a pet guinea pig. The lesions had started as small irritating squamous lesions that had been accurately diagnosed as skin infection, but had only been treated with local antifungal agents. The lesions progressed and developed into a kerion celsi that had to be treated with long-term systemic griseofulvin. Nevertheless, reinfection occurred and treatment had to be restarted. The girl is left with areas of alopecia, as a result of which she is required to wear a wig. CONCLUSION: Tinea capitis is a common skin infection that should be considered in any type of scalp lesion. It requires systemic treatment, and inappropriate and delayed treatment can result in the development of kerion celsi, with sometimes devastating consequences.