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Background Observational reports suggest that supplementation that increases citric acid cycle intermediates via anaplerosis may have therapeutic advantages over traditional medium-chain triglyceride (MCT) treatment of long-chain fatty acid oxidation disorders (LC-FAODs) but controlled trials have not been reported. The goal of our study was to compare the effects of triheptanoin (C7), an anaplerotic seven-carbon fatty acid triglyceride, to trioctanoin (C8), an eight-carbon fatty acid triglyceride, in patients with LC-FAODs. Methods A double blinded, randomized controlled trial of 32 subjects with LC-FAODs (carnitine palmitoyltransferase-2, very long-chain acylCoA dehydrogenase, trifunctional protein or long-chain 3-hydroxy acylCoA dehydrogenase deficiencies) who were randomly assigned a diet containing 20% of their total daily energy from either C7 or C8 for 4 months was conducted. Primary outcomes included changes in total energy expenditure (TEE), cardiac function by echocardiogram, exercise tolerance, and phosphocreatine recovery following acute exercise. Secondary outcomes included body composition, blood biomarkers, and adverse events, including incidence of rhabdomyolysis. Results Patients in the C7 group increased left ventricular (LV) ejection fraction by 7.4% ( p  = 0.046) while experiencing a 20% ( p  = 0.041) decrease in LV wall mass on their resting echocardiogram. They also required a lower heart rate for the same amount of work during a moderate-intensity exercise stress test when compared to patients taking C8. There was no difference in TEE, phosphocreatine recovery, body composition, incidence of rhabdomyolysis, or any secondary outcome measures between the groups. Conclusions C7 improved LV ejection fraction and reduced LV mass at rest, as well as lowering heart rate during exercise among patients with LC-FAODs. Clinical Trial Registration: Clinicaltrials.gov NCT01379625.

Hyperphagia, Severe Obesity, Impaired Cognitive Function, and Hyperactivity Associated With Functional Loss of One Copy of the Brain-Derived Neurotrophic Factor ( BDNF ) Gene Juliette Gray 1 , Giles S.H. Yeo 1 , James J. Cox 2 , Jenny Morton 3 , Anna-Lynne R. Adlam 4 , Julia M. Keogh 1 , Jack A. Yanovski 5 , Areeg El Gharbawy 5 , Joan C. Han 5 , Y.C. Loraine Tung 1 , John R. Hodges 4 , F. Lucy Raymond 2 , Stephen O’Rahilly 1 and I. Sadaf Farooqi 1 1 University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, U.K 2 University Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, U.K 3 West Midlands Regional Genetics Service, Birmingham Women’s Hospital, Birmingham, U.K 4 Medical Research Council, Cognition and Brain Sciences Unit, and the Department of Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge, U.K 5 Unit on Growth and Obesity, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland Address correspondence and reprint requests to I. Sadaf Farooqi, University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge, CB2 2XY, U.K. E-mail: isf20{at}cam.ac.uk Abstract The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the 5′ end of the BDNF gene. The patient’s genomic DNA was heterozygous for a common coding polymorphism in BDNF , but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared with age- and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyperactivity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior. BAC, bacterial artificial chromosome BDNF, brain-derived neurotrophic factor FISH, fluorescence in situ hybridization TrkB, tropomyosin-related kinase B Footnotes Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted August 21, 2006. Received April 24, 2006. DIABETES

Molybdenum cofactor deficiency (MoCD) is an inborn error of metabolism included in the differential for refractory neonatal seizures. The prognosis is guarded, with a median reported age of death between 2.4 and 3.0 years. Mortality is primarily due to seizures and lower respiratory tract infections. MoCD has a distinct biochemical profile, characterized by elevated urinary S‐sulfocysteine, xanthine, and hypoxanthine, and low or undetectable serum and urine uric acid levels. A disease‐altering treatment is available for MoCD Type A; however, due to the rarity of the condition, its natural history remains poorly understood. We present a patient with neonatal‐onset refractory seizures, whose biochemical testing, performed within 24 h of specimen receipt in the laboratory, revealed a pattern consistent with MoCD. Before the genetics team could disclose the preliminary diagnosis, the patient demised, without evidence of worsening seizures or respiratory infection. Results of genome sequencing, guided by biochemical findings, identified double homozygous pathogenic variants in MOCS1 (associated with MoCD Type A). Although the biochemical genetics laboratory's protocol for analyzing and reporting S‐sulfocysteine levels within 48 h enabled a rapid preliminary diagnosis, the patient's condition deteriorated too quickly to initiate disease‐altering treatment, progressing more rapidly than described in the literature. We discuss potential hypotheses for his rapid decline and the broader implications for the field of biochemical genetics. Take‐Home Message As more disease‐altering treatments emerge for inborn errors of metabolism, this case underscores the urgent need for robust natural history data, faster diagnostics, and more readily available treatments, especially at large academic medical centers.

Purpose Glycogen storage disease (GSD) types VI and IX are rare diseases of variable clinical severity affecting primarily the liver. GSD VI is caused by deficient activity of hepatic glycogen phosphorylase, an enzyme encoded by the PYGL gene. GSD IX is caused by deficient activity of phosphorylase kinase (PhK), the enzyme subunits of which are encoded by various genes: ɑ ( PHKA1 , PHKA2 ), β ( PHKB ), ɣ ( PHKG1 , PHKG2 ), and δ ( CALM1 , CALM2 , CALM3 ). Glycogen storage disease types VI and IX have a wide spectrum of clinical manifestations and often cannot be distinguished from each other, or from other liver GSDs, on clinical presentation alone. Individuals with GSDs VI and IX can present with hepatomegaly with elevated serum transaminases, ketotic hypoglycemia, hyperlipidemia, and poor growth. This guideline for the management of GSDs VI and IX was developed as an educational resource for health-care providers to facilitate prompt and accurate diagnosis and appropriate management of patients. Methods A national group of experts in various aspects of GSDs VI and IX met to review the limited evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management. Evidence bases for these rare disorders are largely based on expert opinion, particularly when targeted therapeutics that have to clear the US Food and Drug Administration (FDA) remain unavailable. Results This management guideline specifically addresses evaluation and diagnosis across multiple organ systems involved in GSDs VI and IX. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, and prenatal diagnosis are addressed. Conclusion A guideline that will facilitate the accurate diagnosis and optimal management of patients with GSDs VI and IX was developed. This guideline will help health-care providers recognize patients with GSDs VI and IX, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.

Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid β-oxidation. Mutations in HADHA and HADHB, which encode the TFP α and β subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase deficiency. TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. We explored the effect of mutations in TFP subunits on CL and other phospholipid content and composition and the consequences of these changes on mitochondrial bioenergetics in patient-derived fibroblasts. Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls. Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. Response to new potential drugs targeting CL metabolism might be dependent on patient genotype.

Key Clinical Message Clinical features are variable in patients with Cornelia de Lange syndrome (CdLS). Milder forms exist with structural maintenance of chromosomes 3 (SMC3) mutations. Inherited milder forms of CdLS are uncommon and may be missed if genetic testing is limited to Nipped‐B‐like protein (NIPBL) and SMC1A. Parental studies should be pursued if there is a history of learning disabilities and/or dysmorphic features. Clinical features are variable in patients with Cornelia de Lange syndrome (CdLS). Milder forms exist with structural maintenance of chromosomes 3 (SMC3) mutations. Inherited milder forms of CdLS are uncommon and may be missed if genetic testing is limited to Nipped‐B‐like protein (NIPBL) and SMC1A. Parental studies should be pursued if there is a history of learning disabilities and/or dysmorphic features.

Combined D‐2‐ and L‐2‐hydroxyglutaric aciduria (D/L‐2‐HGA) is a devastating neurometabolic disorder, usually lethal in the first years of life. Autosomal recessive mutations in the SLC25A1 gene, which encodes the mitochondrial citrate carrier (CIC), were previously detected in patients affected with combined D/L‐2‐HGA. We showed that transfection of deficient fibroblasts with wild‐type SLC25A1 restored citrate efflux and decreased intracellular 2‐hydroxyglutarate levels, confirming that deficient CIC is the cause of D/L‐2‐HGA. We developed and implemented a functional assay and applied it to all 17 missense variants detected in a total of 26 CIC‐deficient patients, including eight novel cases, showing reduced activities of varying degrees. In addition, we analyzed the importance of residues affected by these missense variants using our existing scoring system. This allowed not only a clinical and biochemical overview of the D/L‐2‐HGA patients but also phenotype–genotype correlation studies.

Leptin may be a link in the relationship of obesity with hypertension. We evaluated associations of leptin with blood pressure (BP) in 54 normotensive and 114 hypertensive African American individuals. Plasma leptin was higher ( P < .03) in hypertensive women than in normotensive women, although body mass index did not differ (30.5 ± 0.5 v 30.2 ± 0.8 kg/m 2). After adjusting for obesity and insulin resistance, there were no significant relationships between leptin and BP; however, leptin independently predicted 28% of the variability of heart rate in hypertensive men ( P < .01) and 18% of the variability of lithium clearance in hypertensive women ( P < .01). Thus, in these obese hypertensive African American women, there is no direct or independent association of leptin with BP. However, leptin may contribute to hypertension in these women by increasing renal tubular sodium reabsorption.

Inherited disorders of anerobic glycolysis can be categorized essentially into two types of clinical presentation: hemolytic or myopathic. The specific presentation relates to the presence of multiple isoforms for the glycolytic enzymes, such that activity for a specific enzyme might be defective in erythrocytes, myofibers, or both tissues. The basic mechanism for pathogenesis relates to the deficiency of adenosine triphosphate synthesis and resultant membrane instability. A deficiency of phosphofructokinase has been associated with an increased risk for insulin resistance and diabetes mellitus and enhanced glycolysis compensated for diabetes in rodent models. Furthermore, increased glycolysis is a hallmark for cancer cells that could provide insights for new cancer therapies. The critical role of glycolysis in the cellular metabolism explains the clinical severity of glycolytic defects, as well as profound effects of altered glycolysis on other metabolic pathways and common diseases such as cancer and diabetes.