Fatty acid receptors have been recognized as important players in glycaemic control. This study is the first to describe a role for the medium‐chain fatty acid (MCFA) receptor G‐protein‐coupled receptor (Gpr) 84 in skeletal muscle mitochondrial function and insulin secretion. We are able to show that Gpr84 is highly expressed in skeletal muscle and adipose tissue. Mice with global deletion of Gpr84 [Gpr84 knockout (KO)] exhibit a mild impairment in glucose tolerance when fed a MCFA‐enriched diet. Studies in mice and pancreatic islets suggest that glucose intolerance is accompanied by a defect in insulin secretion. MCFA‐fed KO mice also exhibit a significant impairment in the intrinsic respiratory capacity of their skeletal muscle mitochondria, but at the same time also exhibit a substantial increase in mitochondrial content. Changes in canonical pathways of mitochondrial biogenesis and turnover are unable to explain these mitochondrial differences. Our results show that Gpr84 plays a crucial role in regulating mitochondrial function and quality control.—Montgomery, M. K., Osborne, B., Brandon, A. E., O'Reilly, L., Fiveash, C. E., Brown, S. H. J., Wilkins, B. P., Samsudeen, A., Yu, J., Devanapalli, B., Hertzog, A., Tolun, A. A., Kavanagh, T., Cooper, A. A., Mitchell, T. W., Biden, T. J., Smith, N. J., Cooney, G. J., Turner, N. Regulation of mitochondrial metabolism in murine skeletal muscle by the medium‐chain fatty acid receptor Gpr84. FASEB J. 33, 12264‐12276 (2019). http://www.fasebj.org

Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder characterised by reduced or absent OTC enzyme activity, resulting in the accumulation of neurotoxic ammonia. Approximately 80%-90% of the causative variants are identified by Sanger sequencing or multiplex ligationdependent probe amplification (MLPA) of the OTC gene. A 23-year-old male with biochemical evidence of OTCD was referred for molecular analysis. Initial Sanger sequencing yielded no pathogenic variants. MLPA testing raised suspicion of a mosaic deletion of exon 1; however, high-resolution microarray did not identify a copy number variant on the X chromosome. Sequencing over

3‐Methylglutaconyl‐CoA hydratase deficiency (MGA1) is a defect in leucine catabolism, which causes the accumulation of urinary 3‐methylglutaconate, with or without 3‐hydroxyisovalerate and 3‐methylglutarate. It is an ultra‐rare condition, with <30 cases published in the literature. It is unclear whether the clinical features seen in reported patients are caused by the biochemical abnormalities, or whether they simply represent an ascertainment bias in patients that come to clinical attention. We reviewed the collective Australian experience of patients with confirmed MGA1, four of whom were diagnosed when asymptomatic through newborn screening (NBS). When our cohort is considered alongside the broader literature, there is no clear evidence of a specific childhood‐onset clinical phenotype associated with this disorder. Some patients have non‐specific clinical features (such as autism spectrum disorder [ASD]); however, there are also other family members with ASD in the absence of MGA1, suggesting a multifactorial aetiology. Importantly, all four patients diagnosed through NBS (including three with over 18 years of clinical follow‐up) remain asymptomatic in the absence of treatment. Based on the available literature, we suggest that MGA1 represents a biochemical phenotype, with an absence of a childhood clinical phenotype. The burdens of sustained treatment (particularly with intensive dietary leucine restriction) in asymptomatic individuals may be of little benefit, and likely to result in poor compliance. Longer‐term follow‐up of patients detected via NBS (or biochemical screening of large cohorts of asymptomatic adult individuals) will be required to conclusively prove or disprove the association with adult‐onset leukoencephalopathy.

Background and Objective: Traditional targeted metabolomic investigations identify a pre-defined list of analytes in samples and have been widely used for decades in the diagnosis and monitoring of inborn errors of metabolism (IEMs). Recent technological advances have resulted in the development and maturation of untargeted metabolomics: a holistic, unbiased, analytical approach to detecting metabolic disturbances in human disease. We aim to provide a summary of untargeted metabolomics [focusing on tandem mass spectrometry (MS-MS)] and its application in the field of IEMs.Methods: Data for this review was identified through a literature search using PubMed, Google Scholar, and personal repositories of articles collected by the authors. Findings are presented within several sections describing the metabolome, the current use of targeted metabolomics in the diagnostic pathway of patients with IEMs, the more recent integration of untargeted metabolomics into clinical care, and the limitations of this newly employed analytical technique.