Publications by authors named "Juan M Pascual"

73 Publications

Triheptanoin Mitigates Brain ATP Depletion and Mitochondrial Dysfunction in a Mouse Model of Alzheimer's Disease.

J Alzheimers Dis 2020 ;78(1):425-437

Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.

Background: Brain energy failure is an early pathological event associated with synaptic dysfunction in Alzheimer's disease (AD). Thus, mitigation or enhancement of brain energy metabolism may offer a therapeutic avenue. However, there is uncertainty as to what metabolic process(es) may be more appropriate to support or augment since metabolism is a multiform process such that each of the various metabolic precursors available is utilized via a specific metabolic pathway. In the brain, these pathways sustain not only a robust rate of energy production but also of carbon replenishment.

Objective: Triheptanoin, an edible odd-chain fatty acid triglyceride, is uncommon in that it replenishes metabolites in the tricarboxylic acid cycle (TCA) cycle via anaplerosis in addition to fueling the cycle via oxidation, thus potentially leading to both carbon replenishment and enhanced mitochondrial ATP production.

Methods: To test the hypothesis that triheptanoin is protective in AD, we supplied mice with severe brain amyloidosis (5×FAD mice) with dietary triheptanoin for four and a half months, followed by biological and biochemical experiments to examine mice metabolic as well as synaptic function.

Results: Triheptanoin treatment had minimal impact on systemic metabolism and brain amyloidosis as well as tauopathy while attenuating brain ATP deficiency and mitochondrial dysfunction including respiration and redox balance in 5×FAD mice. Synaptic density, a disease hallmark, was also preserved in hippocampus and neocortex despite profound amyloid deposition. None of these effects took place in treated control mice.

Conclusion: These findings support the energy failure hypothesis of AD and justify investigating the mechanisms in greater depth with ultimate therapeutic intent.
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http://dx.doi.org/10.3233/JAD-200594DOI Listing
January 2020

Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group.

Epilepsia Open 2020 Sep 13;5(3):354-365. Epub 2020 Aug 13.

Department of Neurology and Pediatrics Vagelos College of Physicians and Surgeons at Columbia University New York NY USA.

Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide-ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic variants. KDT represent standard choices with Glut1DS-specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. linical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long-term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle.
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http://dx.doi.org/10.1002/epi4.12414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469861PMC
September 2020

GLUT1 deficiency: Retinal detrimental effects of gliovascular modulation.

Neurol Genet 2020 Aug 25;6(4):e472. Epub 2020 Jun 25.

University of Kentucky College of Medicine (M.H.); Retina Associates of Kentucky (J.K.), Lexington; Rare Brain Disorders Program (J.M.P.), Department of Neurology and Neurotherapeutics, Department of Physiology (J.M.P.), Department of Pediatrics (J.M.P.), Eugene McDermott Center for Human Growth & Development/Center for Human Genetics (J.M.P.), The University of Texas Southwestern Medical Center, Dallas; and Ophthalmic Genetics Program (J.K., R.S.M.), Department of Ophthalmology, University of Kentucky, Lexington.

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http://dx.doi.org/10.1212/NXG.0000000000000472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413606PMC
August 2020

Assessment of Interlaboratory Variation in the Interpretation of Genomic Test Results in Patients With Epilepsy.

JAMA Netw Open 2020 04 1;3(4):e203812. Epub 2020 Apr 1.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas.

Importance: Discordance in the interpretations of genetic test results has occurred with the increased number of laboratories that are performing testing. Differences in diagnostic interpretations may have implications for the treatment of patients.

Objective: To assess the interlaboratory variation in the interpretations of genetic test results with potential therapeutic implications.

Design, Setting, And Participants: In this cross-sectional study, 70 genes that are commonly tested in patients with epilepsy were examined to identify 22 676 genetic variants from an unknown number of patients using the ClinVar public database of clinically annotated variants. Variant annotations submitted to ClinVar (data set version 2019-05) between November 16, 2012, and May 3, 2019, were included in the analysis. Conflicting interpretations of the genetic variants associated with epilepsy were analyzed for clinically substantial discrepancies between May 7 and June 29, 2019. Variants were examined only if they had been interpreted by 2 or more clinical laboratories. A variant with a clinically substantial difference in interpretation was defined as a variant that crossed the threshold between a likely pathogenic variant and a variant of uncertain significance.

Main Outcomes And Measures: The frequency and types of variant interpretation conflicts were analyzed when a conflict was identified.

Results: A total of 6292 of 22 676 variants related to epilepsy (27.7%) were interpreted by 2 or more clinical laboratories. Many variants (3307 of 6292 [52.6%]) had interpretations that were fully concordant. However, 2985 variants (47.4%) had conflicting interpretations. A clinically substantial conflict was identified in 201 of 6292 variants (3.2%). Furthermore, 117 of 201 variants (58.2%) with differences in interpretation occurred in genes with therapeutic implications.

Conclusions And Relevance: In this cross-sectional study, most interpretations of genetic variants associated with epilepsy were concordant among laboratories, but more than half of the variants with conflicting interpretations occurred in genes that have therapeutic implications. It would be helpful for genetic laboratories to report known diagnostic discordance with other clinical laboratories.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.3812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191323PMC
April 2020

Exosomes in disease: Epigenetic signals from the nervous system to the rest of the organism.

Neurosci Lett 2019 08 13;708:134293. Epub 2019 Jun 13.

Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK. Electronic address:

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http://dx.doi.org/10.1016/j.neulet.2019.134293DOI Listing
August 2019

Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans.

Cell Rep 2019 04;27(5):1376-1386.e6

Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Inborn errors of metabolism (IEMs) link metabolic defects to human phenotypes. Modern genomics has accelerated IEM discovery, but assessing the impact of genomic variants is still challenging. Here, we integrate genomics and metabolomics to identify a cause of lactic acidosis and epilepsy. The proband is a compound heterozygote for variants in LIPT1, which encodes the lipoyltransferase required for 2-ketoacid dehydrogenase (2KDH) function. Metabolomics reveals abnormalities in lipids, amino acids, and 2-hydroxyglutarate consistent with loss of multiple 2KDHs. Homozygous knockin of a LIPT1 mutation reduces 2KDH lipoylation in utero and results in embryonic demise. In patient fibroblasts, defective 2KDH lipoylation and function are corrected by wild-type, but not mutant, LIPT1 alleles. Isotope tracing reveals that LIPT1 supports lipogenesis and balances oxidative and reductive glutamine metabolism. Altogether, the data extend the role of LIPT1 in metabolic regulation and demonstrate how integrating genomics and metabolomics can uncover broader aspects of IEM pathophysiology.
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http://dx.doi.org/10.1016/j.celrep.2019.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351313PMC
April 2019

Brain metabolism modulates neuronal excitability in a mouse model of pyruvate dehydrogenase deficiency.

Sci Transl Med 2019 02;11(480)

Rare Brain Disorders Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Glucose is the ultimate substrate for most brain activities that use carbon, including synthesis of the neurotransmitters glutamate and γ-aminobutyric acid via mitochondrial tricarboxylic acid (TCA) cycle. Brain metabolism and neuronal excitability are thus interdependent. However, the principles that govern their relationship are not always intuitive because heritable defects of brain glucose metabolism are associated with the paradoxical coexistence, in the same individual, of episodic neuronal hyperexcitation (seizures) with reduced basal cerebral electrical activity. One such prototypic disorder is pyruvate dehydrogenase (PDH) deficiency (PDHD). PDH is central to metabolism because it steers most of the glucose-derived flux into the TCA cycle. To better understand the pathophysiology of PDHD, we generated mice with brain-specific reduced PDH activity that paralleled salient human disease features, including cerebral hypotrophy, decreased amplitude electroencephalogram (EEG), and epilepsy. The mice exhibited reductions in cerebral TCA cycle flux, glutamate content, spontaneous, and electrically evoked in vivo cortical field potentials and gamma EEG oscillation amplitude. Episodic decreases in gamma oscillations preceded most epileptiform discharges, facilitating their prediction. Fast-spiking neuron excitability was decreased in brain slices, contributing to in vivo action potential burst prolongation after whisker pad stimulation. These features were partially reversed after systemic administration of acetate, which augmented cerebral TCA cycle flux, glutamate-dependent synaptic transmission, inhibition and gamma oscillations, and reduced epileptiform discharge duration. Thus, our results suggest that dysfunctional excitability in PDHD is consequent to reduced oxidative flux, which leads to decreased neuronal activation and impaired inhibition, and can be mitigated by an alternative metabolic substrate.
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http://dx.doi.org/10.1126/scitranslmed.aan0457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637765PMC
February 2019

Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs.

Cell 2018 09 6;175(1):239-253.e17. Epub 2018 Sep 6.

Proteome Dynamics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125 Berlin, Germany; Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany. Electronic address:

Many disease-causing missense mutations affect intrinsically disordered regions (IDRs) of proteins, but the molecular mechanism of their pathogenicity is enigmatic. Here, we employ a peptide-based proteomic screen to investigate the impact of mutations in IDRs on protein-protein interactions. We find that mutations in disordered cytosolic regions of three transmembrane proteins (GLUT1, ITPR1, and CACNA1H) lead to an increased clathrin binding. All three mutations create dileucine motifs known to mediate clathrin-dependent trafficking. Follow-up experiments on GLUT1 (SLC2A1), the glucose transporter causative of GLUT1 deficiency syndrome, revealed that the mutated protein mislocalizes to intracellular compartments. Mutant GLUT1 interacts with adaptor proteins (APs) in vitro, and knocking down AP-2 reverts the cellular mislocalization and restores glucose transport. A systematic analysis of other known disease-causing variants revealed a significant and specific overrepresentation of gained dileucine motifs in structurally disordered cytosolic domains of transmembrane proteins. Thus, several mutations in disordered regions appear to cause "dileucineopathies."
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http://dx.doi.org/10.1016/j.cell.2018.08.019DOI Listing
September 2018

Author Correction: Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice.

Nat Neurosci 2018 Jul;21(7):1016

The Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

In the version of this article initially published, the Simons Foundation was missing from the list of sources of support to P.T.T. in the Acknowledgments. The error has been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41593-018-0096-2DOI Listing
July 2018

Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice.

Nat Neurosci 2017 Dec 30;20(12):1744-1751. Epub 2017 Oct 30.

The Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Cerebellar abnormalities, particularly in Right Crus I (RCrusI), are consistently reported in autism spectrum disorders (ASD). Although RCrusI is functionally connected with ASD-implicated circuits, the contribution of RCrusI dysfunction to ASD remains unclear. Here neuromodulation of RCrusI in neurotypical humans resulted in altered functional connectivity with the inferior parietal lobule, and children with ASD showed atypical functional connectivity in this circuit. Atypical RCrusI-inferior parietal lobule structural connectivity was also evident in the Purkinje neuron (PN) TscI ASD mouse model. Additionally, chemogenetically mediated inhibition of RCrusI PN activity in mice was sufficient to generate ASD-related social, repetitive, and restricted behaviors, while stimulation of RCrusI PNs rescued social impairment in the PN TscI ASD mouse model. Together, these studies reveal important roles for RCrusI in ASD-related behaviors. Further, the rescue of social behaviors in an ASD mouse model suggests that investigation of the therapeutic potential of cerebellar neuromodulation in ASD may be warranted.
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http://dx.doi.org/10.1038/s41593-017-0004-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867894PMC
December 2017

Intramyocellular lipid excess in the mitochondrial disorder MELAS: MRS determination at 7T.

Neurol Genet 2017 Jun 25;3(3):e160. Epub 2017 May 25.

Rare Brain Disorders Program (S.G., J.M.P.), Department of Neurology and Neurotherapeutics, Department of Pediatrics (S.G., J.M.P.), Advanced Imaging Research Center (J.R., C.R.M.), Department of Radiology (J.R., C.R.M.), Department of Internal Medicine (C.R.M.), Department of Physiology (J.M.P.), and Eugene McDermott Center for Human Growth & Development/Center for Human Genetics (J.M.P.), The University of Texas Southwestern Medical Center, Dallas.

Objective: There is a paucity of objective, quantifiable indicators of mitochondrial disease available for clinical and scientific investigation.

Methods: To this end, we explore intramyocellular lipid (IMCL) accumulation noninvasively by 7T magnetic resonance spectroscopy (MRS) as a reporter of metabolic dysfunction in MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). We reasoned that mitochondrial dysfunction may impair muscle fat metabolism, resulting in lipid deposition (as is sometimes observed in biopsies), and that MRS is well suited to quantify these lipids.

Results: In 10 MELAS participants and relatives, IMCL abundance correlates with percent mitochondrial DNA mutation abundance and with disease severity.

Conclusions: These results indicate that IMCL accumulation is a novel potential disease hallmark in MELAS.
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http://dx.doi.org/10.1212/NXG.0000000000000160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444911PMC
June 2017

Frontotemporal Degeneration in a Child.

Pediatr Neurol 2017 Jul 12;72:62-64. Epub 2017 Apr 12.

Rare Brain Disorders Program, Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas; Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas; Eugene McDermott Center for Human Growth & Development/Center for Human Genetics, The University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

Background: There is a predilection for the frontal and temporal lobes in certain cases of dementia in the adult, leading to the syndrome of frontotemporal dementia. However, this syndrome has seemed to elude the developing brain until now.

Methods And Results: We describe an example of apparently selective neurodegeneration of the frontal and temporal regions during development associated with some of the clinical, magnetic resonance imaging, and fludeoxyglucose positron emission tomography (FDG PET) scan features of canonical frontotemporal dementia in the adult. This patient does not have any of the common frontotemporal dementia-causing mutations or known progressive brain disorders of children.

Conclusion: This patient illustrates that symptomatic, selective, and progressive vulnerability of the frontal and temporal lobes is not restricted to adulthood, expanding the phenotype of frontotemporal degeneration.
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http://dx.doi.org/10.1016/j.pediatrneurol.2017.04.001DOI Listing
July 2017

Clinical Aspects of Glucose Transporter Type 1 Deficiency: Information From a Global Registry.

JAMA Neurol 2017 06;74(6):727-732

Rare Brain Disorders Program, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas3Department of Physiology, University of Texas Southwestern Medical Center, Dallas4Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas5Eugene McDermott Center for Human Growth & Development/Center for Human Genetics, University of Texas Southwestern Medical Center, Dallas.

Importance: Case reports regularly document unique or unusual aspects of glucose transporter type 1 deficiency (G1D). In contrast, population studies from which to draw global inferences are lacking. Twenty-five years after the earliest case reports, this deficiency still particularly affects treatment and prognostic counseling.

Objective: To examine the most common features of G1D.

Design, Setting, And Participants: In this study, data were collected electronically from 181 patients with G1D through a web-based, worldwide patient registry from December 1, 2013, through December 1, 2016. The study used several statistical methods tailored to address the age at onset of various forms of G1D, associated manifestations, natural history, treatment efficacy, and diagnostic procedures. These factors were correlated in a predictive mathematical model designed to guide prognosis on the basis of clinical features present at diagnosis.

Results: A total of 181 patients with G1D were included in the study (92 [50.8%] male and 89 female [49.2%]; median age, 9 years; age range, 0-65 years). As previously known, a relatively large variety of common phenotypes are characteristic of the G1D syndrome, including movement disorders, absence epilepsy (typical and atypical), and myoclonic and generalized epilepsies. The 3 main novel results are (1) the feasibility of effective dietary therapies (such as the modified Atkins diet) other than the ketogenic diet, (2) the relatively frequent occurrence (one-fourth of cases) of white matter magnetic resonance imaging abnormalities, and (3) the favorable effect of early diagnosis and treatment regardless of treatment modality and mutation type. In fact, the most important factor that determines outcome is age at diagnosis, as reflected in a predictive mathematical model.

Conclusions And Relevance: The results reveal several changing notions in the approach to G1D syndrome diagnosis and treatment, such as the perceived absolute requirement for a ketogenic diet, the assumed lack of structural brain defects, and the potential existence of genotype-phenotype correlations, all of which are contested by the registry data.
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http://dx.doi.org/10.1001/jamaneurol.2017.0298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822202PMC
June 2017

Age-dependent changes of cerebral copper metabolism in Atp7b knockout mouse model of Wilson's disease by [Cu]CuCl-PET/CT.

Metab Brain Dis 2017 06 27;32(3):717-726. Epub 2017 Jan 27.

Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9140, USA.

Copper is a nutritional metal required for brain development and function. Wilson's disease (WD), or hepatolenticular degeneration, is an inherited human copper metabolism disorder caused by a mutation of the ATP7B gene. Many WD patients present with variable neurological and psychiatric symptoms, which may be related to neurodegeneration secondary to copper metabolism imbalance. The objective of this study was to explore the feasibility and use of copper-64 chloride ([C]CuCl) as a tracer for noninvasive assessment of age-dependent changes of cerebral copper metabolism in WD using an Atp7b knockout mouse model of WD and positron emission tomography/computed tomography (PET/CT) imaging. Continuing from our recent study of biodistribution and radiation dosimetry of [C]CuCl in Atp7b knockout mice, PET quantitative analysis revealed low Cu radioactivity in the brains of Atp7b knockout mice at 7th weeks of age, compared with Cu radioactivity in the brains of age- and gender-matched wild type C57BL/6 mice, at 24 h (h) post intravenous injection of [C]CuCl as a tracer. Furthermore, age-dependent increase of Cu radioactivity was detected in the brains of Atp7b knockout mice from the 13th to 21th weeks of age, based on the data derived from a longitudinal [C]CuCl-PET/CT study of Atp7b knockout mice with orally administered [Cu]CuCl as a tracer. The findings of this study support clinical use of [Cu]CuCl-PET/CT imaging as a tool for noninvasive assessment of age-dependent changes of cerebral copper metabolism in WD patients presenting with variable neurological and psychiatric symptoms.
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http://dx.doi.org/10.1007/s11011-017-9956-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573586PMC
June 2017

Oxidation of [U- C]glucose in the human brain at 7T under steady state conditions.

Magn Reson Med 2017 Dec 23;78(6):2065-2071. Epub 2017 Jan 23.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Purpose: Disorders of brain energy metabolism and neurotransmitter recycling have been implicated in multiple neurological conditions. C magnetic resonance spectroscopy ( C MRS) during intravenous administration of C-labeled compounds has been used to measure turnover rates of brain metabolites. This approach, however, requires prolonged infusion inside the magnet. Proton decoupling is typically required but may be difficult to implement with standard equipment. We examined an alternative approach to monitor glucose metabolism in the human brain.

Methods: C-enriched glucose was infused in healthy subjects outside the magnet to a steady-state level of C enrichment. Subsequently, the subjects were scanned at 7T for 60 min without H decoupling. Metabolic modeling was used to calculate anaplerosis.

Results: Biomarkers of energy metabolism and anaplerosis were detected. The glutamate C5 doublet provided information about glucose-derived acetyl-coenzyme A flux into the tricarboxylic acid (TCA) cycle via pyruvate dehydrogenase, and the bicarbonate signal reflected overall TCA cycle activity. The glutamate C1/C5 ratio is sensitive to anaplerosis.

Conclusion: Brain C MRS at 7T provides information about glucose oxidation and anaplerosis without the need of prolonged C infusions inside the scanner and without technical challenges of H decoupling, making it a feasible approach for clinical research. Magn Reson Med 78:2065-2071, 2017. © 2017 International Society for Magnetic Resonance in Medicine.
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http://dx.doi.org/10.1002/mrm.26603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522773PMC
December 2017

The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations.

Genet Med 2016 11 17;18(11):1143-1150. Epub 2016 Mar 17.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

Purpose: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder characterized by optic atrophy and intellectual disability caused by loss-of-function mutations in NR2F1. We report 20 new individuals with BBSOAS, exploring the spectrum of clinical phenotypes and assessing potential genotype-phenotype correlations.

Methods: Clinical features of individuals with pathogenic NR2F1 variants were evaluated by review of medical records. The functional relevance of coding nonsynonymous NR2F1 variants was assessed with a luciferase assay measuring the impact on transcriptional activity. The effects of two start codon variants on protein expression were evaluated by western blot analysis.

Results: We recruited 20 individuals with novel pathogenic NR2F1 variants (seven missense variants, five translation initiation variants, two frameshifting insertions/deletions, one nonframeshifting insertion/deletion, and five whole-gene deletions). All the missense variants were found to impair transcriptional activity. In addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%).

Conclusion: BBSOAS encompasses a broad range of clinical phenotypes. Functional studies help determine the severity of novel NR2F1 variants. Some genotype-phenotype correlations seem to exist, with missense mutations in the DNA-binding domain causing the most severe phenotypes.Genet Med 18 11, 1143-1150.
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http://dx.doi.org/10.1038/gim.2016.18DOI Listing
November 2016

The life, times and work of Charles R. Roe, M.D.

Authors:
Juan M Pascual

Neurosci Lett 2017 01 18;637:1-3. Epub 2016 Aug 18.

The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Mail Code 8813, Dallas, TX 75390-8813, United States. Electronic address:

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http://dx.doi.org/10.1016/j.neulet.2016.08.030DOI Listing
January 2017

Genetic Gradients in Epileptic Brain Malformations.

Authors:
Juan M Pascual

JAMA Neurol 2016 07;73(7):787

Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center at Dallas2Department of Pediatrics, The University of Texas Southwestern Medical Center at Dallas.

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http://dx.doi.org/10.1001/jamaneurol.2016.1039DOI Listing
July 2016

Deregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer's disease.

Nat Commun 2016 05 6;7:11483. Epub 2016 May 6.

Department of Biological Sciences, The University of Texas at Dallas, 800W. Campbell Road, Richardson, Texas 75080, USA.

F1FO-ATP synthase is critical for mitochondrial functions. The deregulation of this enzyme results in dampened mitochondrial oxidative phosphorylation (OXPHOS) and activated mitochondrial permeability transition (mPT), defects which accompany Alzheimer's disease (AD). However, the molecular mechanisms that connect F1FO-ATP synthase dysfunction and AD remain unclear. Here, we observe selective loss of the oligomycin sensitivity conferring protein (OSCP) subunit of the F1FO-ATP synthase and the physical interaction of OSCP with amyloid beta (Aβ) in the brains of AD individuals and in an AD mouse model. Changes in OSCP levels are more pronounced in neuronal mitochondria. OSCP loss and its interplay with Aβ disrupt F1FO-ATP synthase, leading to reduced ATP production, elevated oxidative stress and activated mPT. The restoration of OSCP ameliorates Aβ-mediated mouse and human neuronal mitochondrial impairments and the resultant synaptic injury. Therefore, mitochondrial F1FO-ATP synthase dysfunction associated with AD progression could potentially be prevented by OSCP stabilization.
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http://dx.doi.org/10.1038/ncomms11483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494197PMC
May 2016

Understanding Atomic Interactions to Achieve Well-being.

Authors:
Juan M Pascual

JAMA Neurol 2016 06;73(6):626-7

Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas2Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas3Department of Pediatrics, Universi.

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http://dx.doi.org/10.1001/jamaneurol.2016.0546DOI Listing
June 2016

IKBKG Mutation With Incontinentia Pigmenti and Ring-Enhancing Encephalopathy.

JAMA Neurol 2015 Dec;72(12):1533-5

Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas2Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas6Eugene McDermott Center for Human Growth & Development/Center.

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http://dx.doi.org/10.1001/jamaneurol.2015.2795DOI Listing
December 2015

Glucose Transporter Type I Deficiency (G1D) at 25 (1990-2015): Presumptions, Facts, and the Lives of Persons With This Rare Disease.

Pediatr Neurol 2015 Nov 10;53(5):379-93. Epub 2015 Aug 10.

Department of Pediatrics, McMaster Child Health Research Institute, McMaster University, Hamilton, Ontario, Canada.

Background: As is often the case for rare diseases, the number of published reviews and case reports of glucose transporter type I deficiency (G1D) approaches or exceeds that of original research. This can indicate medical interest, but also scientific stagnation.

Methods: In assessing this state of affairs here, we focus not on what is peculiar or disparate about G1D, but on the assumptions that have reigned thus far undisputed, and critique them as a potential impediment to progress. To summarize the most common G1D phenotype, we trace the 25-year story of G1D in parallel with the natural history of one of two index patients, identified in 1990 by one of us (G.M.R.) and brought up to date by the other (J.M.P.) while later examining widely repeated but little-scrutinized statements. Among them are those that pertain to assumptions about brain fuels; energy failure; cerebrospinal glucose concentration; the purpose of ketogenic diet; the role of the defective blood-brain barrier; genotype-phenotype correlations; a bewildering array of phenotypes; ictogenesis, seizures, and the electroencephalograph; the use of mice to model the disorder; and what treatments may and may not be expected to accomplish.

Results: We reach the forgone conclusion that the proper study of mankind-and of one of its ailments (G1D) -is man itself (rather than mice, isolated cells, or extrapolated inferences) and propose a framework for rigorous investigation that we hope will lead to a better understanding and to better treatments for this and for rare disorders in general.

Conclusions: These considerations, together with experience drawn from other disorders, lead, as a logical consequence, to the nullification of the view that therapeutic development (i.e., trials) for rare diseases could or should be accelerated without the most vigorous scientific scrutiny: trial and error constitute an inseparable couple, such that, at the present time, hastening the former is bound to precipitate the latter.
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http://dx.doi.org/10.1016/j.pediatrneurol.2015.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609610PMC
November 2015

Metabolic plasticity maintains proliferation in pyruvate dehydrogenase deficient cells.

Cancer Metab 2015 29;3. Epub 2015 Jun 29.

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA ; Departments of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA ; McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390-8502 USA.

Background: Pyruvate dehydrogenase (PDH) occupies a central node of intermediary metabolism, converting pyruvate to acetyl-CoA, thus committing carbon derived from glucose to an aerobic fate rather than an anaerobic one. Rapidly proliferating tissues, including human tumors, use PDH to generate energy and macromolecular precursors. However, evidence supports the benefits of constraining maximal PDH activity under certain contexts, including hypoxia and oncogene-induced cell growth. Although PDH is one of the most widely studied enzyme complexes in mammals, its requirement for cell growth is unknown. In this study, we directly addressed whether PDH is required for mammalian cells to proliferate.

Results: We genetically suppressed expression of the PDHA1 gene encoding an essential subunit of the PDH complex and characterized the effects on intermediary metabolism and cell proliferation using a combination of stable isotope tracing and growth assays. Surprisingly, rapidly dividing cells tolerated loss of PDH activity without major effects on proliferative rates in complete medium. PDH suppression increased reliance on extracellular lipids, and in some cell lines, reducing lipid availability uncovered a modest growth defect that could be completely reversed by providing exogenous-free fatty acids. PDH suppression also shifted the source of lipogenic acetyl-CoA from glucose to glutamine, and this compensatory pathway required a net reductive isocitrate dehydrogenase (IDH) flux to produce a source of glutamine-derived acetyl-CoA for fatty acids. By deleting the cytosolic isoform of IDH (IDH1), the enhanced contribution of glutamine to the lipogenic acetyl-CoA pool during PDHA1 suppression was eliminated, and growth was modestly suppressed.

Conclusions: Although PDH suppression substantially alters central carbon metabolism, the data indicate that rapid cell proliferation occurs independently of PDH activity. Our findings reveal that this central enzyme is essentially dispensable for growth and proliferation of both primary cells and established cell lines. We also identify the compensatory mechanisms that are activated under PDH deficiency, namely scavenging of extracellular lipids and lipogenic acetyl-CoA production from reductive glutamine metabolism through IDH1.
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http://dx.doi.org/10.1186/s40170-015-0134-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487196PMC
July 2015

A Protein Kinase C Phosphorylation Motif in GLUT1 Affects Glucose Transport and is Mutated in GLUT1 Deficiency Syndrome.

Mol Cell 2015 Jun 14;58(5):845-53. Epub 2015 May 14.

Department of Dermatology, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Protein kinase C has been implicated in the phosphorylation of the erythrocyte/brain glucose transporter, GLUT1, without a clear understanding of the site(s) of phosphorylation and the possible effects on glucose transport. Through in vitro kinase assays, mass spectrometry, and phosphospecific antibodies, we identify serine 226 in GLUT1 as a PKC phosphorylation site. Phosphorylation of S226 is required for the rapid increase in glucose uptake and enhanced cell surface localization of GLUT1 induced by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Endogenous GLUT1 is phosphorylated on S226 in primary endothelial cells in response to TPA or VEGF. Several naturally occurring, pathogenic mutations that cause GLUT1 deficiency syndrome disrupt this PKC phosphomotif, impair the phosphorylation of S226 in vitro, and block TPA-mediated increases in glucose uptake. We demonstrate that the phosphorylation of GLUT1 on S226 regulates glucose transport and propose that this modification is important in the physiological regulation of glucose transport.
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http://dx.doi.org/10.1016/j.molcel.2015.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458224PMC
June 2015

Acute effect of glucose on cerebral blood flow, blood oxygenation, and oxidative metabolism.

Hum Brain Mapp 2015 Feb 16;36(2):707-16. Epub 2014 Oct 16.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas.

While it is known that specific nuclei of the brain, for example hypothalamus, contain glucose-sensing neurons thus their activity is affected by blood glucose level, the effect of glucose modulation on whole-brain metabolism is not completely understood. Several recent reports have elucidated the long-term impact of caloric restriction on the brain, showing that animals under caloric restriction had enhanced rate of tricarboxylic acid cycle (TCA) cycle flux accompanied by extended life span. However, acute effect of postprandial blood glucose increase has not been addressed in detail, partly due to a scarcity and complexity of measurement techniques. In this study, using a recently developed noninvasive MR technique, we measured dynamic changes in global cerebral metabolic rate of O2 (CMRO2 ) following a 50 g glucose ingestion (N = 10). A time dependent decrease in CMRO2 was observed, which was accompanied by a reduction in oxygen extraction fraction (OEF) with unaltered cerebral blood flow (CBF). At 40 min post-ingestion, the amount of CMRO2 reduction was 7.8 ± 1.6%. A control study without glucose ingestion was performed (N = 10), which revealed no changes in CMRO2 , CBF, or OEF, suggesting that the observations in the glucose study was not due to subject drowsiness or fatigue after staying inside the scanner. These findings suggest that ingestion of glucose may alter the rate of cerebral metabolism of oxygen in an acute setting.
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http://dx.doi.org/10.1002/hbm.22658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6869447PMC
February 2015

Triheptanoin for glucose transporter type I deficiency (G1D): modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement.

JAMA Neurol 2014 Oct;71(10):1255-65

Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas10Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas.

Importance: Disorders of brain metabolism are multiform in their mechanisms and manifestations, many of which remain insufficiently understood and are thus similarly treated. Glucose transporter type I deficiency (G1D) is commonly associated with seizures and with electrographic spike-waves. The G1D syndrome has long been attributed to energy (ie, adenosine triphosphate synthetic) failure such as that consequent to tricarboxylic acid (TCA) cycle intermediate depletion. Indeed, glucose and other substrates generate TCAs via anaplerosis. However, TCAs are preserved in murine G1D, rendering energy-failure inferences premature and suggesting a different hypothesis, also grounded on our work, that consumption of alternate TCA precursors is stimulated and may be detrimental. Second, common ketogenic diets lead to a therapeutically counterintuitive reduction in blood glucose available to the G1D brain and prove ineffective in one-third of patients.

Objective: To identify the most helpful outcomes for treatment evaluation and to uphold (rather than diminish) blood glucose concentration and stimulate the TCA cycle, including anaplerosis, in G1D using the medium-chain, food-grade triglyceride triheptanoin.

Design, Setting, And Participants: Unsponsored, open-label cases series conducted in an academic setting. Fourteen children and adults with G1D who were not receiving a ketogenic diet were selected on a first-come, first-enrolled basis.

Intervention: Supplementation of the regular diet with food-grade triheptanoin.

Main Outcomes And Measures: First, we show that, regardless of electroencephalographic spike-waves, most seizures are rarely visible, such that perceptions by patients or others are inadequate for treatment evaluation. Thus, we used quantitative electroencephalographic, neuropsychological, blood analytical, and magnetic resonance imaging cerebral metabolic rate measurements.

Results: One participant (7%) did not manifest spike-waves; however, spike-waves promptly decreased by 70% (P = .001) in the other participants after consumption of triheptanoin. In addition, the neuropsychological performance and cerebral metabolic rate increased in most patients. Eleven patients (78%) had no adverse effects after prolonged use of triheptanoin. Three patients (21%) experienced gastrointestinal symptoms, and 1 (7%) discontinued the use of triheptanoin.

Conclusions And Relevance: Triheptanoin can favorably influence cardinal aspects of neural function in G1D. In addition, our outcome measures constitute an important framework for the evaluation of therapies for encephalopathies associated with impaired intermediary metabolism.
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http://dx.doi.org/10.1001/jamaneurol.2014.1584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376124PMC
October 2014

Diagnostic yield of clinical next-generation sequencing panels for epilepsy.

JAMA Neurol 2014 May;71(5):650-1

Department of Pathology, Children's Medical Center, University of Texas Southwestern Medical Center, Dallas.

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http://dx.doi.org/10.1001/jamaneurol.2014.405DOI Listing
May 2014

A novel de novo KIF21A mutation in a patient with congenital fibrosis of the extraocular muscles and Möbius syndrome.

Mol Vis 2014 28;20:368-75. Epub 2014 Mar 28.

University of Texas Southwestern Medical Center, Department of Ophthalmology, Dallas, TX ; University of Texas Southwestern Medical Center, McDermott Center for Human Growth and Development / Center for Human Genetics, Dallas, TX.

Purpose: To describe the phenotypic characteristics and clinical course of a sporadic case of congenital fibrosis of the extraocular muscles (CFEOM) and Möbius syndrome with a de novo mutation in the KIF21A gene encoding a kinesin motor protein.

Methods: An individual with the rare combination of CFEOM and Möbius syndrome underwent comprehensive ophthalmologic and neurological evaluations. Magnetic resonance imaging (MRI) including diffusion tensor imaging (DTI) tractigraphy at 3T field strength was used to evaluate orbital, encephalic, and intracranial nerve integrity. The proband and her healthy parents underwent screening for mutations in the KIF21A, PHOX2A, and TUBB3 genes.

Results: The patient exhibited congenital, nonprogressive, bilateral external ophthalmoplegia, bilateral ptosis, bilateral facial palsy, and developmental delay. Her inability to blink resulted in severe exposure keratopathy and subsequent corneal perforation requiring a penetrating keratoplasty. MRI revealed an unremarkable configuration of the axial central nervous system and preservation of the intracranial portion of cranial nerves I, II, III, V, VI, VII, and VIII (cranial nerve IV is not normally visualized by MRI). A novel and de novo heterozygous KIF21A mutation (c.1056C>G, p.Asp352Glu) in a highly conserved region of the gene was present in the proband.

Conclusions: The reported KIF21A D352E mutation and associated phenotype further expand the clinical and mutational spectrum of CFEOM and Möbius syndrome.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976685PMC
September 2014