Pyruvate Carboxylase Deficiency Research Articles

Clinical, biochemical, and molecular profiles of three Sri Lankan neonates with pyruvate carboxylase deficiency

Abstract Objectives Pyruvate carboxylase, a mitochondrial enzyme, catalyses the conversion of glycolytic end-product pyruvate to tricarboxylic acid cycle intermediate, oxaloacetate. Rare pyruvate carboxylase deficiency manifests in three clinical and biochemical phenotypes: neonatal onset type A, infantile onset type B and a benign C type. The objective of this case series is to expand the knowledge of overlapping clinical and biochemical phenotypes of pyruvate carboxylase deficiency. Case presentation We report three Sri Lankan neonates including two siblings, of two unrelated families with pyruvate carboxylase deficiency. All three developed respiratory distress within the first few hours of birth. Two siblings displayed typical biochemical findings reported in type B. The other proband with normal citrulline, lysine, moderate lactate, paraventricular cystic lesions, bony deformities, and a novel missense, homozygous variant c.2746G>C [p.(Asp916His)] in the PC gene, biochemically favoured type A. Conclusions Our findings indicate the necessity of prompt laboratory investigations in a tachypneic neonate with coexisting metabolic acidosis, as early recognition is essential for patient management and family counselling. Further case studies are required to identify overlapping symptoms and biochemical findings in different types of pyruvate carboxylase deficiency phenotypes.

In silico Analysis of Two Novel Variants in the Pyruvate Carboxylase (PC) Gene Associated with the Severe Form of PC Deficiency

In silico Analysis of Two Novel Variants in the Pyruvate Carboxylase (PC) Gene Associated with the Severe Form of PC Deficiency

Factor V Leiden (FVL), Prothrombin G20210A and MTHFR C677T Mutations among Patients of Budd-Chiari Syndrome

Abstract Background Many studies ask whether screening Factor V Leiden (FVL), Prothrombin G20210A and Methyl Tetra Hydro Folate Reductase (MTHFR) C677T Mutations should be routinely performed in patients with Budd–Chiari syndrome (BCS). However, the prevalence of these mutations in such patients is substantially variable. This is the first study in clinical pathology department in Ain Shams University to evaluate the importance of this mutational screening in patients with Budd-Chiari syndrome to detect occult genetic susceptibility to thrombophilia. Aim of the Work This study aims to detect Factor V Leiden (FVL), Prothrombin G20210A and MTHFR C677T Mutations among Patients with Budd-Chiari Syndrome. Patients and Methods This study was a cross sectional study conducted on 35 newly of Budd Chiari syndrome patients who were attending tropical department at Ain Shams University Hospitals during the period from April 2020 to January 2021. Informed consent was obtained from all patients in the study. Results results of our study revealed that JAK2 mutation it was detected in 17.1% of patients (6 patients), While PGM was detected in 2.9% of our patients. Furthermore Factor V Leiden Mutation was detected in 65.7%of patients and MTHFR mutation was detected in 48.6% of patients. The present study found no significant statistical difference between patients with Factor V Leiden Mutation & patients with normal Factor V Leiden regarding CBC parameters, levels of ANA, ACL IgM, ACL IgG, PC Deficiency, PS Deficiency and AT III Deficiency. In addition, our study revealed that there was no effect of MTHFR Mutation & JAK2 Mutation on levels of ANA, ACL IgM, ACL IgG, PC Deficiency, PS Deficiency and AT III Deficiency. Also there was no effect for MTHFR Mutation & JAK2 Mutation on outcome of patients, survival and response to treatment. Conclusion BCS is associated usually with genetic thrombophilia. Most commonly Factor V Leiden Mutation in 65.7%, followed by MTHFR mutation in 48.6% of our patients. Although, only Factor V Leiden Mutation has an effect on patients Outcome, Survival and Response to treatment through its effect on CBC parameters, levels of ANA, ACL IgM, ACL IgG, PC Deficiency, PS Deficiency and AT III Deficiency. Otherwise, JAK2 Mutation have significant effect on hemopoiesis.

Long-term chronic food-derived arsenic exposure induce the urinary system metabolic dysfunction in mice

The consumption of rice contaminated with arsenic on a long-term basis has emerged as a pressing public health issue of global significance. Arsenic-induced urinary injury, particularly kidney damage, has received widespread attention. In this study, mice model under long-term arsenic exposure was established, mouse were exposed to rice arsenic (30 mg/kg) for 14 months. Changes of related metabolites were observed based on kidney metabolomics and lipidomics, and major biomarkers were screened by urine metabolomics. The results showed that phosphatidylethanolamine (PE) was significantly increased and phosphatidycholine (PC) and phosphatidylglycerol (PG) were significantly reduced after arsenic exposure, leading to related downstream lipid metabolism disorders. The metabolic pathways for amino acid and energy were observed to be impacted. In addition, metabolic disorders due to arsenic exposure may be associated with inherited neurometabolic disorders, such as D-2-hydroxyglutaric aciduria (D-2-HGA), and pyruvate carboxylase deficiency (PCD), which is predicted based on significant difference biomarkers (2-oxoglutarate, malic acid, and succinic acid) screened for urine. This study elucidates the mechanism of toxicity in the urinary system induced by arsenic exposure at nearly half life cycle, which furnishes crucial scientific evidence pertaining to the toxicity and risk evaluation associated with chronic exposure to the arsenic.

In silico Analysis of Two Novel Variants in the Pyruvate Carboxylase (PC) Gene Associated with the Severe Form of PC Deficiency.

Inborne errors of metabolism are a common cause of neonatal death. This study evaluated the acute early-onset metabolic derangement and death in two unrelated neonates. WES, Sanger sequencing, homology modeling, and in silico bioinformatics analysis were employed to assess the effects of variants on protein structure and function. WES revealed a novel homozygous variant, p.G303Afs*40 and p.R156P, in the PC gene of each neonate, which both were confirmed by Sanger sequencing. Based on the ACMG guidelines, the p.G303Afs*40 was likely pathogenic, and the p.R156P was a VUS. Nevertheless, a known variant at position 156, the p.R156Q, was also a VUS. Protein secondary structure prediction showed changes in p.R156P and p.R156Q variants compared to the wild-type protein. However, p.G303Afs*40 depicted significant changes at C-terminal. Furthermore, comparing the interaction of wild-type and variant proteins with the ATP ligand during simulations, revealed a decreased affinity to the ATP in all the variants. Moreover, analysis of SNP impacts on PC protein using Polyphen-2, SNAP2, FATHMM, and SNPs&GO servers predicted both R156P and R156Q as damaging variants. Likewise, free energy calculations demonstrated the destabilizing effect of both variants on PC. This study confirmed the pathogenicity of both variants and suggested them as a cause of type B PCD. The results of this study would provide the family with prenatal diagnosis and expand the variant spectrum in the PC gene,which is beneficial for geneticists and endocrinologists.

Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin.

Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive mitochondrial neurometabolic disorder of energy deficit resulting in high morbidity and mortality, with limited therapeutic options. The PC homotetramer has a critical role in gluconeogenesis, anaplerosis, neurotransmitter synthesis, and lipogenesis. The main biochemical and clinical findings in PC deficiency (PCD) include lactic acidosis, ketonuria, failure to thrive, and neurological dysfunction. Use of the anaplerotic agent triheptanoin on a limited number of individuals with PCD has had mixed results. We expand on the potential utility of triheptanoin in PCD by examining the clinical, biochemical, molecular, and health-related quality-of-life (HRQoL) findings in a cohort of 12 individuals with PCD (eight with Type A and two each with Types B and C) treated with triheptanoin ranging for 6days to about 7years. The main endpoints were changes in blood lactate and HRQoL scores, but collection of useful data was limited to about half of subjects. An overall trend of lactate reduction with time on triheptanoin was noted, but with significant variability among subjects and only one subject reaching close to statistical significance for this endpoint. Parent reported HRQoL assessments with treatment showed mixed results, with some subjects showing no change, some improvement, and some worsening of overall scores. Subjects with buried amino acids in the pyruvate carboxyltransferase domain of PC that undergo destabilizing replacements may be more likely to respond (with lactate reduction or HRQoL improvement) to triheptanoin compared to those with replacements that disrupt tetramerization or subunit-subunit interface contacts. The reason for this difference is unclear and requires further validation. We observed significant variability but an overall trend of lactate reduction with time on triheptanoin and mixed parent reported outcome changes by HRQoL assessments for subjects with PCD on long-term triheptanoin. The mixed results noted with triheptanoin therapy in this study could be due to endpoint data limitation, variability of disease severity between subjects, limitation of the parent reported HRQoL tool, or subject genotype variability. Alternative designed trials and more study subjects with PCD will be needed to validate important observations from this work.

Prevalence of Inherited Thrombophilia in Women with Recurrent Pregnancy Loss During the First Trimester of Pregnancy.

This study aims to investigate the prevalence of inherited thrombophilia in women with recurrent pregnancy loss during the first trimester of pregnancy. The study was assessed the potential role of inherited thrombophilia in recurrent miscarriages and evaluate the consequences of this condition on the reproductive outcomes of affected women. This study was an analytical descriptive carried out in Khartoum, Sudan. The research comprised 98 controls who had given birth twice or more without experiencing a miscarriage and 120 patients. Each patient had done more than two miscarriages especially when the pregnancy is at its beginning trimester. (APCR), and (PS) were investigated using the clotting approach. There was an assessment of biological activities of (ATIII), (PC), and (PS) for both groups using the chromogenic method. The average age of the patients was 34, which was higher than the average age of the controls (33.5). The patient group had a much higher rate of multiple miscarriages among the women.: 35 (29.17%), 45 (37.50%), and 40 (33.33%). The incidence of PC deficiencies was determined to be 1.02% (1/98), whereas neither ATIII nor PS deficiencies were seen in the control group (0/98). APCR was more prevalent in the control group (4.10% or 4/98). Despite contradicting evidence to the contrary in the literature, our findings imply that most miscarriages occur when pregnancy is at the first trimester when a woman is pregnant and they are all caused by thrombophilia.

Polycystic kidney disease: novel insights into polycystin function.

Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening monogenic disease caused by mutations in PKD1 and PKD2 that encode polycystin 1 (PC1) and polycystin 2 (PC2). PC1/2 localize to cilia of renal epithelial cells, and their function is believed to embody an inhibitory activity that suppresses the cilia-dependent cyst activation (CDCA) signal. Consequently, PC deficiency results in activation of CDCA and stimulates cyst growth. Recently, re-expression of PCs in established cysts has been shown to reverse PKD. Thus, the mode of action of PCs resembles a 'counterbalance in cruise control' to maintain lumen diameter within a designated range. Herein we review recent studies that point to novel arenas for future PC research with therapeutic potential for ADPKD.

Generation of an induced pluripotent stem cell line (SHCDNi007-A) from a patient with pyruvate carboxylase deficiency carrying compound heterozygous (c.182 T > C/ c.2581G > A) variants in PC

Pyruvate carboxylase (PC) deficiency (PCD), due to biallelic PC variants, is a rare inherited metabolic disease, which is characterized by seizures, global developmental delay, as well as lactic acidosis, and elevated plasma pyruvate and alanine levels in affected individuals. In the present study, a new induced pluripotent stem cell line (SHCDNi007-A) was generated from the peripheral blood mononuclear cells of a 2-month-old male infant with biallelic PC mutations c.(182 T > C;2581G > A), i.e. p.(Ile61Thr;Val861Met). This cell line is expected to facilitate the in vitro modeling of the disease pathophysiology and the development of future therapeutics for PCD.

Analysis of child with pyruvate carboxylase deficiency type A due to compound heterozygous variants of the PC gene

To analyze the clinical features and genetic basis for a child with pyruvate carboxylase deficiency type A (PCD-A). Clinical data of the child was retrospectively analyzed. The child and his parents were subjected to trio-whole exome sequencing, and candidate variants were verified by bioinformatics analysis. The child was admitted due to fever with vomiting and disturbance of consciousness. His clinical manifestations included severe decompensated acidosis, hypotension and intractable shock. Cranial MRI showed abnormal signal in the brain, and chest X-ray revealed acute pulmonary edema. DNA sequencing revealed that he has harbored compound heterozygous variants of the PC gene, namely c.182T>C (p.I61T) and c.2581G>A (p.V861M), which were respectively inherited from his father and mother. Neither variant was retrievable in the ClinVar and HGMD databases. Through prediction of protein structure, both variants may affect the functional stability of the protein product. The compound heterozygous variants of the PC gene probably underlay the PCD-A in this child. Combined with the clinical features, the child was ultimately diagnosed as PCD-A. Above finding has enriched the spectrum of PC gene variation underlying PCD-A.

Reduced phosphatidylcholine synthesis suppresses the embryonic lethality of seipin deficiency

AbstractSeipin plays a vital role in lipid droplet homeostasis, and its deficiency causes congenital generalized lipodystrophy type II in humans. It is not known whether the physiological defects are all caused by cellular lipid droplet defects. Loss-of-function mutation of seip-1, the Caenorhabditis elegans seipin ortholog, causes embryonic lethality and lipid droplet abnormality. We uncover nhr-114 and spin-4 as two suppressors of seip-1 embryonic lethality. Mechanistically, nhr-114 and spin-4 act in the “B12-one-carbon cycle-phosphatidylcholine (PC)” axis, and reducing PC synthesis suppresses the embryonic lethality of seip-1 mutants. Conversely, PC deficiency enhances the lipid droplet abnormality of seip-1 mutants. The suppression of seip-1 embryonic lethality by PC reduction requires polyunsaturated fatty acid. In addition, the suppression is enhanced by the knockdown of phospholipid scramblase epg-3. Therefore, seipin and PC exhibit opposite actions in embryogenesis, while they function similarly in lipid droplet homeostasis. Our results demonstrate that seipin-mediated embryogenesis is independent of lipid droplet homeostasis.

Study on the Correlation between the Prevalence of Venous Thromboembolism in Kazak Pregnant and Lying-In Women in Xinjiang.

In order to reveal the correlation between the prevalence of venous thromboembolism in Kazak pregnant and lying-in women in Xinjiang, the polymorphisms in the promoter region and coding region of the TAFI gene and the interaction of environmental factors are investigated. In this study, determination and analysis of anticoagulation indexes are conducted. The activity of antithrombin III and protein C is measured by chromogenic substrate method, and the activity of protein S is measured by coagulation method. Besides, the detection of APC-R is performed by APC-APTT method. The experimental results show that the prevalence rate of hereditary thrombophilia + DVT among Kazak pregnant women in Xinjiang is 33.8%, and the prevalence rates of AT-III deficiency, PC deficiency, PS deficiency, APCR, and Hcy are 17.5%, 16.7%, 22.0%, 23.7%, and 26.8%, respectively. Also, the genotype frequency and allele frequency distribution of each group are in line with Hardy–Weinberg equilibrium (P > 0.05). The comparison result indicates that the gene frequency has reached a genetic balance and is representative of the population. It is clearly evident that the polymorphisms of prothrombin gene rs3136447 and rs5896 may be associated with hereditary thrombophilia in Xinjiang Kazaks.

Expanding the genetic spectrum of the pyruvate carboxylase deficiency with novel missense, deep intronic and structural variants

IntroductionPathogenic variants in the pyruvate carboxylase (PC) gene cause a wide spectrum of recessive phenotypes, ranging from the early-onset fatal encephalopathy to the adult-onset benign form. ResultsPatient 1 is a 6 y.o. boy with ataxia, hypoglycemia and episodes of lactic acidosis. WGS revealed the novel heterozygous missense variant c.1372A > G (p.Asn458Asp) in the PC gene. Additional analysis revealed discordant reads mapped to chromosomes 11 and 1, so a reciprocal translocation disrupted the PC gene was suspected. The translocation was validated via FISH-analysis and Sanger sequencing of its boundaries.Patient 2 is a 13 y.o. girl with psychomotor delay, episodes of lactic acidosis and ketonuria. WES revealed the novel homozygous intronic variant c.1983-116C > T. The PC's mRNA analysis demonstrated the exonization of several intron 16 sequences and some residual amount of WT mRNA isoform.Two other patients had more severe course of the disease. Their genotype represents missense variants in compound heterozygous and homozygous state (c.1876C > T (p.Arg626Trp), c.2606G > C (p.Gly869Ala), c.2435C > A (p.Ala812Asp). ConclusionIn patients with metabolic crises, lactic acidosis and hypoglycemia analysis of PC gene is recommended. WGS with deep bioinformatic analysis should be taken into consideration when none or the only one pathogenic variant in the PC gene is found.

Screening of the protein C pathway abnormality-related thrombophilia by using thrombomodulin-mediated tissue factor-triggered clot waveform analysis.

Absolute or relative protein (P)C pathway abnormalities (PC deficiency, PS deficiency, antiphospholipid syndrome (APS), factor (F)V-abnormality, and high FVIII level) cause thrombophilia. Although screening assays for these thrombophilias are available, one utilizing clot waveform analysis (CWA) remains unknown. We aimed to establish a CWA-based screening assay to distinguish PC pathway abnormality-related thrombophilia. Samples were reacted with tissue factor (TF)/phospholipids and recombinant thrombomodulin (rTM; optimal 20 nM), followed by CWA measurement. The peak ratio (with/without rTM) of the first derivative curve of clot waveform was calculated. The peak ratio in healthy plasmas (n=35) was 0.36 ± 0.13; hence, the cutoff value was set to 0.49. The peak ratios in plasmas with PC deficiency, PS deficiency, high-FVIII (spiked 300 IU/dl), and APS were higher than the cutoff values (0.79/0.97/0.50/0.93, respectively). PC-deficient plasma or PS-deficient plasma mixed with normal plasma (25%/50%/75%/100% PC or PS level) showed dose-dependent decreases in the peak ratios (PC deficient: 0.85/0.64/0.44/0.28; PS deficient: 0.69/0.53/0.40/0.25), suggesting that the peak ratio at ≤50% of PC or PS level exceeded the cutoff value. The peak ratio in FV deficiency with FV ≤25% was higher than the cutoff value. FV-deficient plasma spiked with 40 IU/dl rFV-R506Q (FVLeiden ) or rFV-W1920R (FVNara ) showed >90% peak ratios. rTM-mediated TF-triggered CWA might be useful for screening PC pathway abnormality-related thrombophilia.

Abstract #1184551: Hypertriglyceridemic pancreatitis in a rare case of type A pyruvate carboxylase deficiency

Pyruvate carboxylase (PC) deficiency is a spectrum of rare autosomal recessive disorders that can have significant metabolic consequences. Decreases of PC activity limits utilization of lactate and alanine for anaplerotic and synthetic fluxes. PC deficiency can lead to hypoglycemia, lactic acidosis, and hyperammonemia. Patients can develop central nervous system disease (via glial damage and demyelination leading to hydrocephalus), hepatotoxicity and insulinopenia. The latter can result in hypertriglyceridemia, though not a hallmark of PC deficiency.

A Case of Pyruvate Carboxylase Deficiency With Longer Survival and Normal Laboratory Findings

Pyruvate carboxylase deficiency (PCD) is a rare autosomal recessive defect in a biotin-containing enzyme, Pyruvate carboxylase, which is considered as an enzyme of TCA-cycle regulation, gluconeogenesis, lipogenesis, and biosynthesis of neurotransmitters. Increased lactate to pyruvate ratio and decreased three hydroxybutyrates to acetoacetate are the main biochemical features of PCD. The elevated level of Citrulline, Proline, and Lysine with a short life span has been reported previously. Patients’ survival in almost all cases is below three months. Here, the authors aimed to report a girl with manifestations of Type B of PCD and longer survival (two-year and four-month-old). This patient did not have any changes in amino acid level, which was a unique case of Type B of PCD.

INHERITED PROTEIN C AND PROTEIN S DEFICIENCY IN RENAL TRANSPLANT CANDIDATES OF SINDH PROVINCE, PAKISTAN

Background: Thrombophilia is a common risk factor for venous thromboembolism. The objective of this study was to determine prevalence of inherited protein C and protein S deficiency in renal transplant candidates of Sindh Province, Pakistan. Material & Methods: This cross-sectional study was conducted in Department of Pathology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan from 16-10-2010 to 15-4-2011. 300 renal transplant candidates were selected. Candidates with acquired thrombotic disorders, women taking oral contraceptives and patients taking anti-coagulants during previous one week were excluded. Venous blood samples were collected before starting dialysis procedure or at least two days after last dialysis session. Platelet-poor plasma (PPP) was parted using plastic pipettes and protein C and protein S were processed on coagulation analyzer. Sex, age groups (<40 and ≥ 40years), presence of protein C deficiency and presence of protein S deficiency were nominal variables and analyzed by count and percentage along with population parameters. Results: 300 renal transplant candidates included 199 (66.33%) men and 101 (33.67%) women and 238 (79.33%) in age group <40 years and 62 (20.67%) cases in age group ≥40 years. Prevalence of protein C deficiency was 6.66% (20/300) and of protein S deficiency was 4% (12/300). Prevalence of PC deficiency was higher in men 5.33% than women 1.33%. Also prevalence of PS deficiency was higher in men 3.0% than women 1.0%. Prevalence of PC deficiency was higher in age group <40 years 5.67% than ≥40 years 1.0%. Also prevalence of PS deficiency was higher in age group <40 years 3.33% than ≥40 years 0.66%. Conclusion: More prolonged and follow-up studies are needed to define the true significance of deficiency of protein C and S (coagulation inhibitors) in post-transplant settings.

Pyruvate carboxylase deficiency type A and type C: Characterization of five novel pathogenic variants in PC and analysis of the genotype-phenotype correlation.

Pyruvate carboxylase deficiency (PCD) is caused by biallelic mutations of the PC gene. The reported clinical spectrum includes a neonatal form with early death (type B), an infantile fatal form (type A), and a late-onset form with isolated mild intellectual delay (type C). Apart from homozygous stop-codon mutations leading to type B PCD, a genotype-phenotype correlation has not otherwise been discernible. Indeed, patients harboring biallelic heterozygous variants leading to PC activity near zero can present either with a fatal infantile type A or with a benign late onset type C form. In this study, we analyzed six novel patients with type A (three) and type C (three) PCD, and compared them with previously reported cases. First, we observed that type C PCD is not associated to homozygous variants in PC. In silico modeling was used to map former and novel variants associated to type A and C PCD, and to predict their potential effects on the enzyme structure and function. We found that variants lead to type A or type C phenotype based on the destabilization between the two major enzyme conformers. In general, our study on novel and previously reported patients improves the overall understanding on type A and C PCD.

Prenatal sonographic description of fetuses affected by pyruvate dehydrogenase or pyruvate carboxylase deficiency.

Pyruvate dehydrogenase deficiency (PDHD) and pyruvate carboxylase deficiency (PCD) are diseases with severe neonatal forms, and their low prevalence makes them difficult to diagnose during pregnancy. Our objective was to describe prenatal ultrasound features that may be suggestive of these diagnoses. We analyzed 3 cases from our institution and reviewed 12 published cases of PDHD and 6 cases of PCD, recording all of the ultrasound signs, as well as magnetic resonance findings when available. Because of the small number of cases of PCD, we also included postnatal signs that could have been observed during imaging during pregnancy, for a total of 11 cases of PCD. We conclude that PDHD can be suggested in the presence of ventriculomegaly or paraventricular cysts, associated with an abnormality of the cerebral parenchyma such as abnormal gyration or involvement of the corpus callosum. Pyruvate carboxylase deficiency can be suggested in the presence of ventriculomegaly, frontal horn impairment associated with subependymal, and paraventricular cysts. When confronted to the ultrasound abnormalities we described, and after eliminating the most frequent etiologies, a metabolic deficiency should be considered. Furthermore, the hereditary character of these diseases makes that it is important to send the family with genetic advice in particular in case of history of a fetal death in utero or a death neonatal unexplained.

Triheptanoin for the treatment of brain energy deficit: A 14‐year experience

Triheptanoin is an odd-chain triglyceride with anaplerotic properties-that is, replenishing the pool of metabolic intermediates in the Krebs cycle. Unlike even-chain fatty acids metabolized to acetyl-CoA only, triheptanoin can indeed provide both acetyl-CoA and propionyl-CoA, two key carbon sources for the Krebs cycle. Triheptanoin was initially used in patients with long-chain fatty acid oxidation disorders. The first demonstration of the possible benefit of triheptanoin for brain energy deficit came from a patient with pyruvate carboxylase deficiency, a severe metabolic disease that affects anaplerosis in the brain. In an open-label study, triheptanoin was then shown to decrease nonepileptic paroxysmal manifestations by 90% in patients with glucose transporter 1 deficiency syndrome, a disease that affects glucose transport into the brain. 31 P magnetic resonance spectroscopy studies also indicated that triheptanoin was able to correct bioenergetics in the brain of patients with Huntington disease, a neurodegenerative disease associated with brain energy deficit. Altogether, these studies indicate that triheptanoin can be a treatment for brain energy deficit related to altered anaplerosis and/or glucose metabolism. © 2017 Wiley Periodicals, Inc.