K M Gibson

Washington State University, پولمن، واشینگتن, Washington, United States

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Publications (309)1393.93 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The natural history of succinic semialdehyde dehydrogenase (SSADH) deficiency in adulthood is unknown; we elucidate the clinical manifestations of the disease later in life. A 63-year-old man with long-standing intellectual disability was diagnosed with SSADH deficiency following hospitalization for progressive decline, escalating seizures, and prolonged periods of altered consciousness. We present a detailed review of his clinical course and reviewed our SSADH deficiency database adult cohort to derive natural history information. Of 95 patients in the database for whom age at diagnosis is recorded, there are 40 individuals currently aged 18 years or older. Only 3 patients were diagnosed after age 18 years. Of 25 adults for whom data are available after age 18, 60% have a history of epilepsy. Predominant seizure types are generalized tonic-clonic, absence, and myoclonic. EEGs showed background slowing or generalized epileptiform discharges in two-thirds of adults for whom EEG data were collected. History of psychiatric symptoms was prominent, with frequent anxiety, sleep disturbances, and obsessive-compulsive disorder. We identified patients older than 18 years with SSADH deficiency in our database following identification and review of a patient diagnosed in the seventh decade of life. The illness had a progressive course with escalating seizures in the index case, with fatality at age 63. Diagnosis in adulthood is rare. Epilepsy is more common in the adult than the pediatric SSADH deficiency cohort; neuropsychiatric morbidity remains prominent. © 2015 American Academy of Neurology.
    No preview · Article · Aug 2015 · Neurology
  • Nazmiye B Yapici · Srinivas Mandalapu · K. Michael Gibson · Lanrong Bi
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    ABSTRACT: Mitochondrial oxidative stress has been implicated in aging, neurodegenerative diseases, diabetes, stroke, ischemia/reperfusion injury, age-related macular degeneration (AMD) and cancer. Recently, we developed two new mitochondria-targeting fluorescent probes, MitoProbes I/II, which specifically localize in mitochondria and employed both in vivo and in vitro for detection of mitochondrial oxidative stress. Here, we report the design and synthesis of these agents, as well as their utility for real-time imaging of mitochondrial oxidative stress in cells. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Jul 2015 · Bioorganic & medicinal chemistry letters
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    ABSTRACT: Initial studies on the use of non-physiological amino acids (NPAAs) to block the accretion of Phe in the brain Pah(enu2-/-) mice revealed that 2-aminoisobutyrate (AIB) and N-methyl-2-aminoisobutyrate (MAIB) were promising lead compounds whose pharmacokinetic parameters warranted investigation. Control and Pah(enu2-/-) mice received intraperitoneal NPAA treatments as test compounds (150, 300 and 500 mg/kg, 1 or 7 days;) followed by collection of sera, liver and brain. LC-MS analysis was developed to quantify both AIB and MAIB in all matrices, and pharmacokinetic parameters for distribution, partitioning, accumulation and MAIB demethylation were determined. MAIB was partially converted to AIB in vivo. AIB and MAIB partitioned similarly from sera to brain and liver, with an approximate 10-fold higher accumulation in liver compared to brain. In comparison to MAIB, AIB accumulated to approximately 3 to 7-fold higher concentration in brain. Analysis of brain and liver revealed a trend toward decreased Phe with increased MAIB sera concentration. Our data support further pharmacokinetic characterization of MAIB and AIB in preparation for further preclinical safety, toxicity and tolerability studies of both AIB and MAIB.
    Full-text · Article · Jun 2015 · Molecular Genetics and Metabolism Reports
  • Lance H. Rodan · K. Michael Gibson · Phillip L. Pearl
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    ABSTRACT: Cerebrospinal fluid neurotransmitter collection, analysis, and follow-up are integral to the diagnosis and management of multiple inborn metabolic errors, some of which require prompt identification and intervention to improve outcome. Cerebrospinal fluid pterins and monoamine metabolites are diagnostic in a range of primary neurotransmitter disorders, including disorders of biogenic amine synthesis, metabolism, and transport. Recently described mutations of the human dopamine transporter are associated with an elevated cerebrospinal fluid homovanillic acid:hydroxyindoleacetic acid ratio. Disorders of pyridoxine metabolism are also detectable via cerebrospinal fluid quantification of bioamines, amino acids, and pyridoxal-5-phosphate levels. Cerebrospinal fluid amino acids are diagnostic in disorders of gamma aminobutyric acid, glycine, and serine metabolism. A wide range of acquired and genetic disorders has also been associated with secondary alterations in cerebrospinal fluid levels of monoamine metabolites, glycine, and neopterin. Lumbar puncture is required to detect abnormal cerebrospinal fluid metabolites in a significant proportion of these disorders, including treatable entities such as dopa-responsive deficiencies of guanosine-5'-triphosphate cyclohydrolase I (Segawa disease), sepiapterin reductase, and tyrosine hydroxylase. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · Pediatric Neurology
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    ABSTRACT: Recent findings in mice with targeted deletion of the GABA-metabolic enzyme succinic semialdehyde dehydrogenase revealed a new role for supraphysiological GABA (4-aminobutyric acid) in the activation of the mechanistic target of rapamycin (mTOR) that results in disruption of endogenous mitophagy. Employing biochemical and electron microscopic methodology, we examined the hypothesis that similar outcomes would be observed during intervention with vigabatrin, whose antiepileptic capacity hinges on central nervous system GABA elevation. Vigabatrin intervention was associated with significantly enhanced mitochondrial numbers and areas in normal mice that could be selectively normalized with the rapalog and mechanistic target of rapamycin inhibitor, Torin 1. Moreover, short-term administration of vigabatrin induced apoptosis and enhanced phosphorylation of mechanistic target of rapamycin Ser 2448 in liver. Our results provide new insight into adverse outcomes associated with vigabatrin intervention, and the first evidence that its administration is associated with increased mitochondrial number in central and peripheral tissues that may associate with mechanistic target of rapamycin function and enhanced cell death.
    Full-text · Article · Apr 2015
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    ABSTRACT: Intracellular pH plays an important role in the response to cancer invasion. We have designed and synthesized a series of new fluorescent probes (Superior LysoProbes) with the capacity to label acidic organelles and monitor lysosomal pH. Unlike commercially available fluorescent dyes, Superior LysoProbes are lysosome-specific and are highly stable. The use of Superior LysoProbes facilitates the direct visualization of the lysosomal response to lobaplatin elicited in human chloangiocarcinoma (CCA) RBE cells, using confocal laser scanning microscopy. Additionally, we have characterized the role of lysosomes in autophagy, the correlation between lysosome function and microtubule strength, and the alteration of lysosomal morphology during apoptosis. Our findings indicate that Superior LysoProbes offer numerous advantages over previous reagents to examine the intracellular activities of lysosomes.
    Preview · Article · Mar 2015 · Scientific Reports
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    ABSTRACT: We report the design, synthesis and application of several new fluorescent probes (LysoProbes I-VI) that facilitate lysosomal pH monitoring and characterization of lysosome-dependent apoptosis. LysoProbes are superior to commercially available lysosome markers since the fluorescent signals are both stable and highly selective, and they will aid in characterization of lysosome morphology and trafficking. We predict that labeling of cancer cells and solid tumor tissues with LysoProbes will provide an important new tool for monitoring the role of lysosome trafficking in cancer invasion and metastasis.
    Full-text · Article · Feb 2015 · Scientific Reports
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    Mahsa Parviz · Kara Vogel · K. Michael Gibson · Phillip L. Pearl
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    ABSTRACT: Clinical disorders known to affect inherited gamma-amino butyric acid (GABA) metabolism are autosomal reces-sively inherited succinic semialdehyde dehydrogenase and GABA-transaminase deficiency. The clinical presentation of succinic semialdehyde dehydrogenase deficiency includes intellectual disability, ataxia, obsessive-compulsive disorder and epilepsy with a nonprogressive course in typical cases, although a progressive form in early childhood as well as deterioration in adulthood with worsening epilepsy are reported. GABA-transaminase deficiency is associated with a severe neonatal-infantile epileptic encephalopathy.
    Full-text · Article · Nov 2014
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    ABSTRACT: Pearl PL, Lewis E, Lapalme-Remis S, Schreiber J, Parviz M, Barrios ES, Theodore WH, Gibson KM. Natural History of SSADH Deficiency throughout Adulthood, in 43rd Annual Child Neurology Society Meeting. Columbus, OH; 2014.
    No preview · Conference Paper · Oct 2014
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    ABSTRACT: INTRODUCTION SSADH deficiency, or gamma-hydroxybutyric aciduria, has been identified in approximately 450 persons worldwide and typically has a phenotype with developmental delay, hypotonia, severe expressive language impairment, and epilepsy. The longterm outcome in adulthood has not been described. The murine model, induced by genetic degradative techniques, is associated with a transition from absence to convulsive seizures in the third week, with fatal status epilepticus. METHODS We review a) our database of SSADH deficiency patients to determine the natural history, and b) clinical trials informed by the murine model. RESULTS Of 112 patients in the database, there are 35 of age 18+ years (stratification: 25 patients age 18-29 years, 9 age 30-39, one age 45, and one deceased at age 63). While epilepsy is reported overall in 47 (42%), 22 adults (63%) have epilepsy and seizure exacerbation appears to be a pattern. EEGs in adulthood were normal in 40%, showed background slowing or disorganization in 35%, and interictal epileptiform discharges in 30%. SUDEP has occurred and the associated neuropathology is consistent with chronic excitotoxic injury in globus pallidus. MRIs reveal a dentatopallidoluysian pattern of signal hyperintensity. There is evidence of GABA-dependent down-regulation of GABA(A) and GABA(B) receptors in the animal model using electrocorticography, single cell electrophysiology, and radioligand binding studies, and in patients using flumazenil-PET and transcranial magnetic stimulation. Therapeutic trials have been undertaken using taurine and the experimental GABA(B) receptor antagonist SGS742 based on improved survival in the murine mutant. Further metabolic disruptions include accumulation of dihydrohexanoic acid, D-2-hydroxyglutaric acid, and homocarnosine, disrupted glutamine homeostasis, and enhanced oxidative damage. GABAergic effects on autophagy with enhanced activation of the mTOR pathway suggest a potential role for antioxidant agents or mTOR inhibitors. CONCLUSIONS Generalized epilepsy and epileptiform discharges are characteristic of SSADH deficiency. Spontaneous absence seizures appear in null mice by the third week, which may be induced by GHB or GABA(B) activity. Subsequent overuse dependent downregulation of GABA(A) and GABA(B) receptor activity may be associated with hyperexcitability concomitant with the transition to generalized seizures. Extended animal survival using taurine and an experimental GABA(B) receptor antagonist have led to clinical trials, and further therapeutic strategies are informed by evidence of oxidative stress and mTOR stimulation in the murine model.
    No preview · Conference Paper · Aug 2014
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    ABSTRACT: BACKGROUND AND OBJECTIVES: Inherited disorders of GABA metabolism include SSADH and GABA-transaminase deficiencies. The clinical features, pathophysiology, diagnosis, and management of both are discussed, including an updated list of ALDH5A1 mutations causing SSADH deficiency. METHODS: Our SSADH patient database was analyzed and murine and translational studies leading to clinical trials are reviewed. RESULTS: The database containing 112 SSADH-deficient patients (71 pediatric and adolescent subjects, 41 adults) indicates that developmental delay and hypotonia are the most common presenting symptoms. Epilepsy is present in 2/3 of patients by adulthood. Murine genetic model, and human studies using flumazenil-PET and transcranial magnetic stimulation, have led to therapeutic trials and identified additional metabolic disruptions. Suggestions for new therapies have arisen from findings of GABAergic effects on autophagy with enhanced activation of the mTor pathway. A total of 45 pathogenic mutations have been reported in SSADH deficiency including the discovery of three previously unreported. CONCLUSIONS: Investigations into the disorders of GABA metabolism provide fundamental insights into mechanisms underlying epilepsy and support the development of biomarkers and clinical trials. Comprehensive definition of the phenotypes of both SSADH and GABA-T deficiencies may increase our knowledge of the neurophysiological consequences of a hyperGABAergic state.
    No preview · Article · Aug 2014 · Developmental Medicine & Child Neurology
  • Mahsa Parviz · Kara Vogel · K. Michael Gibson · Phillip L. Pearl
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    ABSTRACT: Clinical disorders known to affect inherited gamma-amino butyric acid (GABA) metabolism are autosomal recessively inherited succinic semialdehyde dehydrogenase (SSADH) and GABA-transaminase (GABA-T) deficiency. The clinical presentation of SSADH deficiency includes intellectual disability, ataxia, obsessive-compulsive disorder and epilepsy with a nonprogressive course in typical cases, although a progressive form in early childhood as well as deterioration in adulthood with worsening epilepsy are reported. GABA-transaminase deficiency is associated with a severe neonatal-infantile epileptic encephalopathy.
    No preview · Article · Jul 2014
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    ABSTRACT: Background Conventional therapy for patients with maple syrup urine disease (MSUD) entails restriction of protein intake to maintain acceptable levels of the branched chain amino acid, leucine (LEU), monitored in blood. However, no data exists on the correlation between brain and blood LEU with protein restriction, and whether correction in blood is reflected in brain. Methods To address this question, we fed intermediate MSUD mice diets of 19% (standard) and 6% protein, with collection of sera (SE), striata (STR), cerebellum (CE) and cortex (CTX) for quantitative amino acid analyses. Results LEU and valine (VAL) levels in all brain regions improved on average 28% when shifting from 19% to 6% protein, whereas the same improvements in SE were on average 60%. Isoleucine (ILE) in brain regions did not improve, while the SE level improved 24% with low-protein consumption. Blood-branched chain amino acids (LEU, ILE, and VAL in sera (SE)) were 362-434 μM, consistent with human values considered within control. Nonetheless, numerous amino acids in brain regions remained abnormal despite protein restriction, including glutamine (GLN), aspartate (ASP), glutamate (GLU), gamma-aminobutyric acid (GABA), asparagine (ASN), citrulline (CIT) and serine (SER). To assess the specificity of these anomalies, we piloted preliminary studies in hyperphenylalaninemic mice, modeling another large neutral aminoacidopathy. Employing an identical dietary regimen, we found remarkably consistent abnormalities in GLN, ASP, and GLU. Conclusions Our results suggest that blood amino acid analysis may be a poor surrogate for assessing the outcomes of protein restriction in the large neutral amino acidopathies, and further indicate that chronic neurotransmitter disruptions (GLU, GABA, ASP) may contribute to long-term neurocognitive dysfunction in these disorders.
    Preview · Article · May 2014 · Orphanet Journal of Rare Diseases
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    ABSTRACT: In addition to key roles in embryonic neurogenesis and myelinogenesis, γ-aminobutyric acid (GABA) serves as the primary inhibitory mammalian neurotransmitter. In yeast, we have identified a new role for GABA that augments activity of the pivotal kinase, Tor1. GABA inhibits the selective autophagy pathways, mitophagy and pexophagy, through Sch9, the homolog of the mammalian kinase, S6K1, leading to oxidative stress, all of which can be mitigated by the Tor1 inhibitor, rapamycin. To confirm these processes in mammals, we examined the succinic semialdehyde dehydrogenase (SSADH)-deficient mouse model that accumulates supraphysiological GABA in the central nervous system and other tissues. Mutant mice displayed increased mitochondrial numbers in the brain and liver, expected with a defect in mitophagy, and morphologically abnormal mitochondria. Administration of rapamycin to these mice reduced mTOR activity, reduced the elevated mitochondrial numbers, and normalized aberrant antioxidant levels. These results confirm a novel role for GABA in cell signaling and highlight potential pathomechanisms and treatments in various human pathologies, including SSADH deficiency, as well as other diseases characterized by elevated levels of GABA.
    Full-text · Article · Apr 2014 · EMBO Molecular Medicine
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    ABSTRACT: The objective of this open-label study was primarily to assess the effect of taurine on adaptive behavior and secondarily to collect safety and tolerability data in patients with succinic semialdehyde dehydrogenase deficiency. In the current study, subjects were titrated weekly from a starting dose of 50 mg/kg/d to a target 200 mg/kg/d, and assessed for safety, tolerability, and adaptive functioning using age-normalized Adaptive Behavior Assessment Scales. Eighteen patients (8 males/10 females, aged 0.5-28 years, mean 12 years) were recruited. Three subjects withdrew because of perceived lack of efficacy. One serious adverse event occurred (hospitalization for hypersomnia) on 16 g/d (200 mg/kg/d), leading to a dose-lowering paradigm with a maximum dose of 10 g/d. Results did not show clinically meaningful improvement in the adaptive domains after taurine therapy. Pre- and posttherapy adaptive scores also demonstrated no statistically significant difference (p > 0.18). Adaptive behavior did not improve significantly with taurine intervention. Further therapeutic clinical trials including an on-off paradigm using biomarkers are planned. This study provides Class IV evidence that for patients with succinic semialdehyde dehydrogenase deficiency, taurine does not significantly improve adaptive behavior. The study is rated Class IV because of the absence of a control group.
    No preview · Article · Feb 2014 · Neurology
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    ABSTRACT: Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU.
    Full-text · Article · Feb 2014 · Journal of Inherited Metabolic Disease
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    ABSTRACT: We screened for the presence of inborn errors of metabolism (IEM) in 187 children (105 males; 82 females, ages 4-14 years old) who presented with confirmed features of autism spectrum disorder (ASD). Twelve patients (7%) manifested increased 3-hydroxyisovaleric acid (3-OH-IVA) excretion in urine, and minor to significant improvement in autistic features was observed in seven patients following supplementation with biotin. Five diagnoses included: Lesch Nyhan syndrome (2), succinic semialdehyde dehydrogenase (SSADH) deficiency (2), and phenylketonuria (1) (2.7%). Additional metabolic disturbances suggestive of IEMs included two patients whose increased urine 3-OH-IVA was accompanied by elevated methylcitrate and lactate in sera, and 30 patients that showed abnormal glucose-loading tests. In the latter group, 16/30 patients manifested increased sera beta hydroxybutyrate (b-OH-b) production and 18/30 had a paradoxical increase of sera lactate. Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet (KD). Five patients showed decreased serum ketone body production with glucose loading. Twelve of 187 patients demonstrated non-specific MRI pathology, while 25/187 had abnormal electroencephalogram (EEG) findings. Finally, family history was positive for 22/187 patients (1st or 2nd degree relative with comparable symptomatology) and consanguinity was documented for 12/187 patients. Our data provide evidence for a new biomarker (3-OH-IVA) and novel treatment approaches in ASD patients. Concise 1 sentence take-home message: Detailed metabolic screening in a Greek cohort of ASD patients revealed biomarkers (urine 3-hydroxyisovaleric acid and serum b-OH-b) in 7% (13/187) of patients for whom biotin supplementation or institution of a KD resulted in mild to significant clinical improvement in autistic features.
    Full-text · Article · Dec 2013 · Frontiers in Human Neuroscience
  • Kara R Vogel · Andrew A Kennedy · Luke A Whitehouse · K Michael Gibson
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    ABSTRACT: The applications, outcomes and future strategies of hepatocyte transplantation (HTx) as a corrective intervention for inherited metabolic disease (IMD) are described. An overview of HTx in IMDs, as well as preclinical evaluations in rodent and other mammalian models, is summarized. Current treatments for IMDs are highlighted, along with short- and long-term outcomes and the potential for HTx to supplement or supplant these treatments. Finally, the advantages and disadvantages of HTx are presented, highlighted by long-term challenges with interorgan engraftment and expansion of transplanted cells, in addition to the future prospects of stem cell transplants. At present, the utility of HTx is represented by the potential to bridge patients with life-threatening liver disease to organ transplantation, especially as an adjuvant intervention where severe organ shortages continue to pose challenges.
    No preview · Article · Oct 2013 · Journal of Inherited Metabolic Disease
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    ABSTRACT: Our laboratory seeks a pharmacotherapeutic intervention for PKU that utilizes non-physiological amino acids (NPAAs) to block the accumulation of phenylalanine (Phe) in the brain. In previous studies (Vogel et al. 2013), methylation of the amino group of 2-aminoisobutyrate (AIB) provided an enhanced degree of selectivity for Phe restriction into the brain of Pah(enu2) mice in comparison to unmethylated AIB, leading to the hypothesis that 2-(methylamino)alkanoic acid analogs of AIB might represent targeted inhibitors of Phe accretion into the brain. Pah(enu2) and control mice were intraperitoneally administered (500-750mg/kg body weight, once daily; standard 19% protein diet) AIB, methyl AIB (MAIB), isovaline, and two MAIB analogs, 2-methyl-2-(methylamino)butanoic (MeVal) and 3-methyl-2-(methylamino)pentanoic (MePent) acids for one week, followed by brain and blood isolation for amino acid analyses using UPLC. In the brain, AIB significantly reduced Phe accretion in Pah(enu2) mice, while MeVal significantly improved glutamine and aspartic acids. Four of five test compounds improved brain threonine and arginine levels. AIB, MAIB and IsoVal significantly reduced blood Phe, with no effect of any drug intervention on other sera amino acids. Further evaluation of AIB and the 2-(methylamino)alkanoic acids as inhibitors of brain Phe accumulation in Pah(enu2) mice is warranted, with more detailed evaluations of route of administration, combinatorial intervention, and detailed toxicity studies.
    No preview · Article · Aug 2013 · Molecular Genetics and Metabolism

  • No preview · Article · Jul 2013 · Molecular Genetics and Metabolism

Publication Stats

7k Citations
1,393.93 Total Impact Points


  • 2012-2015
    • Washington State University
      • College of Pharmacy
      پولمن، واشینگتن, Washington, United States
    • Emory University
      Atlanta, Georgia, United States
  • 2009-2013
    • Michigan Technological University
      • Department of Biological Sciences
      Houghton, Michigan, United States
    • University of Rome Tor Vergata
      • Dipartimento di Biologia
      Roma, Latium, Italy
  • 1992-2012
    • Baylor University
      Waco, Texas, United States
    • Universität Heidelberg
      • General pediatrics, pediatric neurology, metabolism, gastroenterology, nephrology
      Heidelburg, Baden-Württemberg, Germany
  • 2006-2011
    • University of Pittsburgh
      • • Department of Medicine
      • • Department of Pathology
      • • Department of Pediatrics
      • • Division of Medical Genetics
      Pittsburgh, Pennsylvania, United States
  • 2009-2010
    • VU University Medical Center
      • Department of Clinical Chemistry
      Amsterdamo, North Holland, Netherlands
  • 2006-2008
    • Childrens Hospital of Pittsburgh
      • • Division of Medical Genetics
      • • Department of Pediatrics
      • • Division of Pediatric Pathology
      Pittsburgh, Pennsylvania, United States
  • 1984-2008
    • SickKids
      • Division of Neurology
      Toronto, Ontario, Canada
  • 1998-2006
    • Oregon Health and Science University
      • Department of Molecular & Medical Genetics
      Portland, Oregon, United States
  • 2005
    • University of Chicago
      • Department of Pediatrics
      Chicago, Illinois, United States
  • 2004
    • University of Portland
      Portland, Oregon, United States
    • University of Toronto
      • Institute of Medical Sciences
      Toronto, Ontario, Canada
  • 2000
    • The Portland Hospital
      Londinium, England, United Kingdom
  • 1997-1998
    • University of Texas at Dallas
      Richardson, Texas, United States
  • 1996-1998
    • University of Texas Southwestern Medical Center
      • Division of Neuro-oncology
      Dallas, Texas, United States
  • 1990-1998
    • Baylor Health Care System
      • Institute of Metabolic Disease (IMD)
      Dallas, Texas, United States
  • 1995
    • Hackensack University Medical Center
      Хакенсак, New Jersey, United States
  • 1994
    • Shaare Zedek Medical Center
      Yerushalayim, Jerusalem District, Israel
  • 1993
    • Medical College of Wisconsin
      • Department of Biochemistry
      Milwaukee, Wisconsin, United States
    • University of Amsterdam
      • Department of Paediatrics
      Amsterdamo, North Holland, Netherlands
  • 1989
    • CSU Mentor
      Long Beach, California, United States
  • 1982-1989
    • University of California, San Diego
      • Department of Pediatrics
      San Diego, CA, United States
  • 1986
    • University of Hamburg
      Hamburg, Hamburg, Germany