Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome.

Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harbouring different homozygous loss-of-function variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intra-uterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 loss-of-function in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility. Our findings define an ABCC9 loss-of-function-related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction.

HINT1 neuropathy in Norway: clinical, genetic and functional profiling.

BACKGROUND: Autosomal recessive axonal neuropathy with neuromyotonia has been linked to loss of functional HINT1. The disease is particularly prevalent in Central and South-East Europe, Turkey and Russia due to the high carrier frequency of the c.110G > C (p.Arg37Pro) founder variant. RESULTS: In a cohort of 748 Norwegian patients with suspected peripheral neuropathy, we identified two seemingly unrelated individuals, compound heterozygous for a new variant (c.284G > A, p.Arg95Gln) and the most common pathogenic founder variant (c.110G > C, p.Arg37Pro) in the HINT1 gene. Probands presented with motor greater than sensory neuropathy of various onset, accompanied by muscle stiffness and cramps in the limbs. Furthermore, they displayed non-classical symptoms, including pain in the extremities and signs of central nervous system involvement. Haplotype analysis in both patients revealed a common chromosomal background for p.Arg95Gln; moreover, the variant was identified in Swedish carriers. Functional characterization in HINT1-knockout and patient-derived cellular models, and in HNT1-knockout yeast, suggested that the new variant is deleterious for the function of HINT1 and provided mechanistic insights allowing patient stratification for future treatment strategies. CONCLUSION: Our findings broaden the genetic epidemiology of HINT1-neuropathy and have implications for molecular diagnostics of inherited peripheral neuropathies in Scandinavia.

Community-acquired pneumonia (CAP) in children in Oslo, Norway.

AIM: To investigate the epidemiology and clinical characteristics of community acquired pneumonia (CAP) in children before the introduction of the 7-valent pneumococcal vaccine in the national vaccination programme. METHODS: For the period 21 May 2003 to 20 May 2005 hospitalization rates for pneumonia in children were obtained from retrospective studies of medical journals. Pneumonia was also studied prospectively in children less than sixteen years old referred to Ullevål University Hospital (Oslo) in the same time period. RESULTS: The overall observed hospitalization rate of pneumonia was 14.7/10 000 (95% CI: 12.2-17.1), for children under five it was 32.8/10 000 (95% CI: 26.8-38.8), and for children under two 42.1/10 000 (95% CI: 32.0-52.3). In the clinical study 123 children, of whom 59% (73) were boys, met the inclusion criteria and were enrolled. Only 2.4% (3) had pneumonia complicated with pleural effusion and in general few complications were observed. No patients required assisted ventilation, and none were transferred to the intensive care unit. Penicillin was effective as treatment for pneumonia. CONCLUSION: Pneumonia, seen in a paediatric department in Oslo, is a common but benign disease. Penicillin is effective as treatment for pneumonia in Norwegian children.

[Invasive pneumoccal disease in children in Oslo 1998-2004]. / Invasiv pneumokokkinfeksjon hos barn i Oslo 1998-2004.

BACKGROUND: Invasive pneumococcal disease (IPD) is an important cause of morbidity and mortality in Norwegian children. MATERIAL AND METHODS: This retrospective study included all children (under 16 years) with isolates of Streptococcus pneumoniae from a normally sterile site admitted to the Department of Paediatrics at Ullevaal University Hospital in the period 1998 to 2004. We studied the epidemiology, predisposing factors, clinical picture, antimicrobial resistance, outcome of IPD and the theoretical coverage of the 7-valent conjugate pneumococcal vaccine (PCV7) in these children. The isolates were tested for antimicrobial susceptibility, serogrouped and serotyped. RESULTS: 68 children were identified; 31 of them had one or more predisposing factors. Six children died, all of them had a predisposing factor. Six of the seven children who survived with sequelae were previously healthy. 67 of 68 isolates were fully susceptible to benzyl penicillin and 13 isolates showed intermediate susceptibility or resistance to erythromycin. Serogroups or serotypes were obtained in 66 children. 24 (36.8%) children fulfilled the criteria for PCV7. 35 (51.1%) children had serotypes covered by the vaccine. Only 12 (17.6%) fulfilled the criteria for PCV7 and had serotypes covered by it. Four of the six children who died had serotypes covered by PCV7. INTERPRETATION: Invasive pneumococcal disease is a serious condition in children and vaccination can prevent disease in many children.