To define how the C9orf72 GGGGCC expansion mutation causes ALS/FTD and to facilitate therapy development, a mouse model that recapitulates the molecular and phenotypic features of the disease is urgently needed. Two groups recently reported BAC mouse models that produce RNA foci and RAN proteins but, surprisingly, do not develop the neurodegenerative or behavioral features of ALS/FTD. We now report a BAC mouse model of C9orf72 ALS/FTD that shows decreased survival, paralysis, muscle denervation, motor neuron loss, anxiety-like behavior, and cortical and hippocampal neurodegeneration. These mice express C9orf72 sense transcripts and upregulated antisense transcripts. In contrast to sense RNA foci, antisense foci preferentially accumulate in ALS/FTD-vulnerable cell populations. RAN protein accumulation increases with age and disease, and TDP-43 inclusions are found in degenerating brain regions in end-stage animals. The ALS/FTD phenotypes in our mice provide a unique tool that will facilitate developing therapies targeting pathways that prevent neurodegeneration and increase survival.

Myotonic dystrophy type 1 (DM1) is a CTG microsatellite expansion (CTG exp ) disorder caused by expression of CUG exp RNAs. These mutant RNAs alter the activities of RNA processing factors, including MBNL proteins, leading to re-expression of fetal isoforms in adult tissues and DM1 pathology. While this pathogenesis model accounts for adult-onset disease, the molecular basis of congenital DM (CDM) is unknown. Here, we test the hypothesis that disruption of developmentally regulated RNA alternative processing pathways contributes to CDM disease. We identify prominent alternative splicing and polyadenylation abnormalities in infant CDM muscle, and, although most are also misregulated in adult-onset DM1, dysregulation is significantly more severe in CDM. Furthermore, analysis of alternative splicing during human myogenesis reveals that CDM-relevant exons undergo prenatal RNA isoform transitions and are predicted to be disrupted by CUG exp -associated mechanisms in utero. To test this possibility and the contribution of MBNLs to CDM pathogenesis, we generated mouse Mbnl double (Mbnl1; Mbnl2) and triple (Mbnl1; Mbnl2; Mbnl3) muscle-specific knockout models that recapitulate the congenital myopathy, gene expression, and spliceopathy defects characteristic of CDM. This study demonstrates that RNA misprocessing is a major pathogenic factor in CDM and provides novel mouse models to further examine roles for cotranscriptional/post-transcriptional gene regulation during development.

Repeat associated non-AUG (RAN) translation is found in a growing number of microsatellite expansion diseases, but the mechanisms remain unclear. We show that RAN translation is highly regulated by the double-stranded RNA-dependent protein kinase (PKR). In cells, structured CAG, CCUG, CAGG, and G4C2 expansion RNAs activate PKR, which leads to increased levels of multiple RAN proteins. Blocking PKR using PKR-K296R, the TAR RNA binding protein or PKR-KO cells, reduces RAN protein levels. p-PKR is elevated in C9orf72 ALS/FTD human and mouse brains, and inhibiting PKR in C9orf72 BAC transgenic mice using AAV-PKR-K296R or the Food and Drug Administration (FDA)-approved drug metformin, decreases RAN proteins, and improves behavior and pathology. In summary, targeting PKR, including by use of metformin, is a promising therapeutic approach for C9orf72 ALS/FTD and other expansion diseases.

Highlights d Human antibodies recognize GA or GP RAN proteins with high affinity and selectivity d Human antibodies cross the blood-brain barrier and engage RAN protein targets in vivo d a-GA 1 antibody reduces GA, GP, and GR levels in C9 models d a-GA 1 improves behavior and survival and decreases neurodegeneration in C9-BAC mice

Sodium glucose cotransporter-2 (SGLT2) inhibitors are glucose-lowering drugs with proven efficacy in treating type 2 diabetes mellitus, and more recently, have been shown to improve heart failure outcomes in patients without diabetes. A rare complication of SGLT2 inhibitor use is the development of euglycaemic diabetic ketoacidosis (EDKA), characterised by euglycaemia (blood glucose level <250 mg/dL), metabolic acidosis (arterial pH <7.3 and serum bicarbonate <18 mEq/L), and ketonaemia. Given patients with EDKA do not present with the typical manifestations of diabetic ketoacidosis, including marked hyperglycaemia and dehydration, the diagnosis of EDKA may be missed and initiation of treatment delayed. We present the case of a man with recent SGLT2 inhibitor use and multiple other risk factors who developed EDKA.

Oestrogens are sex steroid hormones that have gained prominence over the years owing to their crucial roles in human health and reproduction functions which have been preserved throughout evolution. One of oestrogens actions, and the focus of this review, is their ability to determine adipose tissue distribution, function and adipose tissue ‘health’. Body fat distribution is sexually dimorphic, affecting males and females differently. These differences are also apparent in the development of the metabolic syndrome and other chronic conditions where oestrogens are critical. In this review, we summarize the different molecular mechanisms, pathways and resulting pathophysiology which are a result of oestrogens actions in and on adipose tissues. This article is part of a discussion meeting issue ‘Causes of obesity: theories, conjectures and evidence (Part I)’.

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Background: Cervical myelopathy in an adult is typically the result of degenerative disease or trauma. Dysraphism is rarely the cause. Case Description: The authors report the case of a 35-year-old male drywall installer who presented with 2 years of progressive left upper extremity weakness, numbness, and hand clumsiness. Only upon detailed questioning did he mention that he had neck surgery just after birth, but he did not know what was done. He then also reported that he routinely shaved a patch of lower back hair, but denied bowel, bladder, or lower extremity dysfunction. Magnetic resonance imaging of the cervical spine demonstrated T2 hyperintensity at C4-C5 with dorsal projection of the neural elements into the subcutaneous tissues concerning for a retethered cervical myelomeningocele. Lumbar imaging revealed a diastematomyelia at L4. He underwent surgical intervention for detethering and repaired of the cervical myelomeningocele. Four months postoperatively, he had almost complete resolution of symptoms, and imaging showed a satisfactory detethering. The diastematomyelia remained asymptomatic and is being observed. Conclusion: Tethered cervical cord is a rare cause for myelopathy in the adult patient. In the symptomatic patient, surgical repair with detethering is indicated to prevent disease progression and often results in clinical improvement.