Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

Centronuclear myopathies are characterized by muscle weakness and abnormal centralization of nuclei in muscle fibers not secondary to regeneration. The severe neonatal X-linked form (myotubular myopathy) is due to mutations in the phosphoinositide phosphatase myotubularin (MTM1), whereas mutations in dynamin 2 (DNM2) have been found in some autosomal dominant cases. By direct sequencing of functional candidate genes, we identified homozygous mutations in amphiphysin 2 (BIN1) in three families with autosomal recessive inheritance. Two missense mutations affecting the BAR (Bin1/amphiphysin/RVS167) domain disrupt its membrane tubulation properties in transfected cells, and a partial truncation of the C-terminal SH3 domain abrogates the interaction with DNM2 and its recruitment to the membrane tubules. Our results suggest that mutations in BIN1 cause centronuclear myopathy by interfering with remodeling of T tubules and/or endocytic membranes, and that the functional interaction between BIN1 and DNM2 is necessary for normal muscle function and positioning of nuclei.

BackgroundReducing emergency admissions to hospital has been a cornerstone of healthcare policy. Little evidence exists to show that systematic interventions across a population have achieved this aim. The authors report the impact of a complex intervention over a 44-month period in Frome, Somerset, on unplanned admissions to hospital.AimTo evaluate a population health complex intervention of an enhanced model of primary care and compassionate communities on population health improvement and reduction of emergency admissions to hospital.Design and settingA cohort retrospective study of a complex intervention on all emergency admissions in Frome Medical Practice, Somerset, compared with the remainder of Somerset, from April 2013 to December 2017.MethodPatients were identified using broad criteria, including anyone giving cause for concern. Patient-centred goal setting and care planning combined with a compassionate community social approach was implemented broadly across the population of Frome.ResultsThere was a progressive reduction, by 7.9 cases per quarter (95% confidence interval [CI] = 2.8 to 13.1, P = 0.006), in unplanned hospital admissions across the whole population of Frome during the study period from April 2013 to December 2017, a decrease of 14.0%. At the same time, there was a 28.5% increase in admissions per quarter within Somerset, with a rise in the number of unplanned admissions of 236 per quarter (95% CI = 152 to 320, P<0.001).ConclusionThe complex intervention in Frome was associated with highly significant reductions in unplanned admissions to hospital, with a decrease in healthcare costs across the whole population of Frome.

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