K M Gibson

Washington State University, Pullman, Washington, United States

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Publications (267)1288.36 Total impact

  • [Show abstract] [Hide abstract]
    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.
    43rd Annual Child Neurology Society Meeting, Columbus, OH; 10/2014
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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.
    Gordon's Research Conference - Mechanisms of Epilepsy and Neuronal Synchronization, West Dover, VT; 08/2014
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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.
    Developmental Medicine & Child Neurology 08/2014; · 2.68 Impact Factor
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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.
    Journal of Pediatric Epilepsy. 07/2014; 3(3).
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    ABSTRACT: Conventional therapy for patients with maple syrup urine disease (MSUD) mice 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.
    Orphanet Journal of Rare Diseases 05/2014; 9(1):73. · 4.32 Impact Factor
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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.
    EMBO Molecular Medicine 02/2014; · 7.80 Impact Factor
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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.
    Neurology 02/2014; · 8.30 Impact Factor
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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.
    Journal of Inherited Metabolic Disease 02/2014; · 4.07 Impact Factor
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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.
    Journal of Inherited Metabolic Disease 10/2013; · 4.07 Impact Factor
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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.
    Molecular Genetics and Metabolism 08/2013; · 2.83 Impact Factor
  • Molecular Genetics and Metabolism 07/2013; · 2.83 Impact Factor
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    ABSTRACT: OBJECTIVE: SSADH deficiency, the most prevalent autosomal recessive disorder of GABA degradation, is characterized by elevated gamma-hydroxybutyric acid (GHB). Neurological outcomes may be improved with early intervention and anticipatory guidance. Morbidity has been compounded by complications, e.g. hypotonia, in undiagnosed infants with otherwise routine childhood illnesses. We report pilot methodology on the feasibility of newborn screening for SSADH deficiency. METHOD: Dried blood spot (DBS) cards from patients affected with SSADH deficiency were compared with 2831 archival DBS cards for gamma-hydroxybutyric acid content. Following extraction with methanol, GHB in DBS was separated and analyzed using ultra high-performance liquid chromatography tandem mass spectrometry. RESULTS: Methodology was validated to meet satisfactory accuracy and reproducibility criteria, including intra-day and inter-day validation. Archival refrigerated dried blood spot samples of babies, infants and children (N=2831) were screened for GHB, yielding a mean+/-S.D. of 8±5nM (99.9%-tile 63nM) (Min 0.0 Max 78nM). The measured mean and median concentrations in blood spots derived from seven SSADH deficient patients were 1182nM and 699nM respectively (Min 124, Max 4851nM). CONCLUSIONS: GHB concentration in all 2831 dried blood spot cards was well below the lowest concentration of affected children. These data provide proof-of-principle for screening methodology to detect SSADH deficiency with applicability to newborn screening and earlier diagnosis.
    Molecular Genetics and Metabolism 05/2013; · 2.83 Impact Factor
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    Amy K Goodwin, K Michael Gibson, Elise M Weerts
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    ABSTRACT: BACKGROUND: 1,4-Butanediol (1,4-BD) is a gamma-hydroxybutyrate (GHB) pro-drug, with multiple commercial uses, and a drug of abuse. Although there are case reports of a withdrawal syndrome following 1,4-BD use, no studies have evaluated the physical dependence potential of 1,4-BD and characterized the time course of withdrawal. METHODS: Vehicle and then 1,4-BD were administered continuously 24h/day via intragastric catheters in male baboons (Papio anubis, n=3). Dosing was initiated at 100mg/kg and increased by 100mg/kg/day to 400mg/kg. After a stabilization period, doses of 500 and then 600mg/kg/day were each maintained for 3-4 weeks. Plasma levels of 1,4-BD and GHB were determined for each dose condition. Physical dependence was assessed via administration of a GABA-B antagonist (precipitated withdrawal test) during administration of the 600mg/kg dose and via abrupt termination of chronic 1,4-BD administration (spontaneous withdrawal test). Outcome measures included the number of food pellets earned, performance on a fine-motor task, observed behaviors, and plasma levels of GHB and 1,4-BD. RESULTS: Following maintenance of 1,4-BD 600mg/kg for 3 weeks, the number of food pellets earned was significantly decreased. At the end of chronic 1,4-BD dosing, the levels of GHB in plasma ranged from 1290 to 2300µmol/L and levels of 1,4-BD in plasma ranged from 13.1 to 37.9µmol/L. Signs of physical dependence were observed following precipitated and spontaneous withdrawal tests. Seizures were not observed. CONCLUSIONS: These data indicate chronic 1,4-BD produced physical dependence in baboons and the withdrawal syndrome can be characterized as mild to intermediate.
    Drug and alcohol dependence 03/2013; · 3.60 Impact Factor
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    ABSTRACT: Orthotopic liver transplant (OLT) significantly improves patient outcomes in maple syrup urine disease (MSUD; OMIM: 248600), yet organ shortages point to the need for alternative therapies. Hepatocyte transplantation has shown both clinical and preclinical efficacy as an intervention for metabolic liver diseases, yet the availability of suitable livers for hepatocyte isolation is also limited. Conversely, human amnion epithelial cells (hAEC) may have utility as a hepatocyte substitute, and they share many of the characteristics of pluripotent embryonic stem cells while lacking their safety and ethical concerns. We reported that like hepatocytes, transplantation of hAEC significantly improved survival and lifespan, normalized body weight, and significantly improved branched-chain amino acid (BCAA) levels in sera and brain in a transgenic murine model of intermediate maple syrup urine disease (imsud). In the current report, we detail the neural and peripheral metabolic improvements associated with hAEC transplant in imsud mice, including amino acids associated with bioenergetics, the urea cycle, as well as the neurotransmitter systems for serotonin, dopamine, and gamma-aminobutyric acid (GABA). This stem cell therapy results in significant global correction of the metabolic profile that characterizes the disease, both in the periphery and the central nervous system, the target organ for toxicity in iMSUD. The significant correction of the disease phenotype, coupled with the theoretical benefits of hAEC, particularly their lack of immunogenicity and tumorigenicity, suggests that human amnion epithelial cells deserve serious consideration for clinical application to treat metabolic liver diseases.
    Molecular Genetics and Metabolism 02/2013; · 2.83 Impact Factor
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    ABSTRACT: OBJECTIVE: To examine essential fatty acids (EFAs) in hyper-IgD syndrome (HIDS) and Familial Mediterranean Fever (FMF). METHODS: EFAs were determined in sera derived from an archival, cross-sectional group of HIDS/FMF patients, stratified for presence and absence of fever. Control populations included healthy afebrile adults, and individuals with non-periodic fever (septic shock). EFAs were quantified using isotope dilution gas chromatography-mass spectrometry and data analyzed employing a Kruskal-Wallis non-parametric ANOVA with Dunn's post-hoc test. RESULTS: Sera samples derived from HIDS patients showed significantly decreased C20, C26, phytanic and pristanic acids during febrile crises that normalized in the afebrile state, and a significantly increased afebrile C22_4ω6 level that normalized with fever. Samples derived from FMF patients revealed increased ω-oxidized LCFAs as compared to controls, and the trend was for these same species to be increased in comparison to febrile, but not afebrile, HIDS patients. Individuals with non-periodic fever demonstrated global decreases in C10-C24 fatty acids, both saturated and unsaturated, accompanied by an elevated triene/tetraene ratio. CONCLUSIONS: Our results suggest that different mechanisms are active in hereditary periodic fever syndromes that appear unrelated to fever, including depletion of very long chain fatty acids (VLCFAs) in febrile HIDS patients and increased ω-oxidized LCFAs in patients with FMF. These findings underscore new roles for EFAs in the potential production of inflammatory species in patients with hereditary periodic fever.
    Molecular Genetics and Metabolism 01/2013; · 2.83 Impact Factor
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    ABSTRACT: Succinic semialdehyde dehydrogenase deficiency (SSADHD), a disorder of γ-aminobutyric acid (GABA) metabolism, manifests typically as a nonprogressive neurodevelopmental disorder with cognitive deficiency, neuropsychiatric morbidity and epilepsy. Therapy targets symptomatic seizures and neurobehavioral disturbances. We report an adolescent female with SSADHD whose unresponsiveness to a broad spectrum of antiepileptics was circumvented with magnesium valproate (MgVPA). Epilepsy remains well controlled in our patient, with concomitant improvements in behavioral symptoms and an absence of adverse symptoms. MgVPA intervention may have utility in SSADHD.
    JIMD reports. 01/2013; 8:133-7.
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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.
    Frontiers in Human Neuroscience 01/2013; 7:858. · 2.91 Impact Factor
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    ABSTRACT: We previously reported improved survival and partial metabolic correction of a mouse intermediate maple syrup urine disease (iMSUD) model post allogenic hepatocyte transplant, confirming that a small number of enzyme proficient liver-engrafted cells can improve phenotype. However, clinical shortages of suitable livers for hepatocyte isolation indicate a need for alternative cell sources. Human amnion epithelial cells (hAEC) share stem cell characteristics while lacking many safety and ethical concerns, and differentiate to hepatocyte-like cells. Eight direct hepatic hAEC transplants were administered to iMSUD mice over the first 35 days beginning at birth; animals were provided a normal protein diet and sacrificed at days 35 and 100. Treatment at the neonatal stage is clinically relevant for MSUD, and may offer a donor cell engraftment advantage. Survival was significantly extended and body weight was normalized in iMSUD mice receiving hAEC transplants compared to iMSUD (severely cachectic; dead ≤28 days). Branched chain α-keto acid dehydrogenase enzyme activity was significantly increased in transplanted livers. Branched chain amino acids leucine, isoleucine, valine, and alloisoleucine were significantly improved in the sera and brain, as were other large neutral amino acids. Conclusion: Placental-derived stem cell transplantation lengthened survival and corrected many amino acid imbalances in a mouse model of iMSUD. This highlights the potential for their use as a viable alternative clinical therapy for MSUD and other liver-based metabolic diseases. (HEPATOLOGY 2012.).
    Hepatology 11/2012; · 12.00 Impact Factor
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    ABSTRACT: Dolichols, polyisoprene alcohols derived from the mevalonate pathway of cholesterol synthesis, serve as carriers of glycan precursors for the formation of oligosaccharides important in protein glycosylation. Seven autosomal-recessively inherited disorders in the metabolism (synthesis, utilization, recycling) of the dolichols have recently been described, and all are associated with decreased lipid-linked oligosaccharides leading to underglycosylated proteins or lipids which facilitate their detection in the diagnostic laboratory. Multisystem pathology encompasses developmental delays and eye, heart, skin and muscle abnormalities; outcomes range from death in infancy to mild, late-onset disease. © 2012 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 10/2012; 160C(4):322-8. · 4.44 Impact Factor
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    ABSTRACT: Transport of large neutral amino acids (LNAA) across the blood brain barrier (BBB) is facilitated by the L-type amino acid transporter, LAT1. Peripheral accumulation of one LNAA (e.g., phenylalanine (phe) in PKU) is predicted to increase uptake of the offending amino acid to the detriment of others, resulting in disruption of brain amino acid homeostasis. We hypothesized that selected non-physiological amino acids (NPAAs) such as DL-norleucine (NL), 2-aminonorbornane (NB; 2-aminobicyclo-(2,1,1)-heptane-2-carboxylic acid), 2-aminoisobutyrate (AIB), and N-methyl-aminoisobutyrate (MAIB), acting as competitive inhibitors of various brain amino acid transporters, could reduce brain phe in Pah ( enu2 ) mice, a relevant murine model of PKU. Oral feeding of 5 % NL, 5 % AIB, 0.5 % NB and 3 % MAIB reduced brain phe by 56 % (p < 0.01), -1 % (p = NS), 27 % (p < 0.05) and 14 % (p < 0.01), respectively, compared to untreated subjects. Significant effects on other LNAAs (tyrosine, methionine, branched chain amino acids) were also observed, however, with MAIB displaying the mildest effects. Of interest, MAIB represents an inhibitor of the system A (alanine) transporter that primarily traffics small amino acids and not LNAAs. Our studies represent the first in vivo use of these NPAAs in Pah ( enu2 ) mice, and provide proof-of-principle for their further preclinical development, with the long-term objective of identifying NPAA combinations and concentrations that selectively restrict brain phe transport while minimally impacting other LNAAs and downstream intermediates.
    Journal of Inherited Metabolic Disease 09/2012; · 4.07 Impact Factor

Publication Stats

4k Citations
1,288.36 Total Impact Points


  • 2012–2014
    • Washington State University
      Pullman, Washington, United States
    • National Institutes of Health
      Maryland, United States
  • 2013
    • Radboud University Nijmegen
      • Department of General Internal Medicine
      Nijmegen, Provincie Gelderland, Netherlands
  • 2006–2013
    • University of Pittsburgh
      • • Department of Pathology
      • • Division of Medical Genetics
      Pittsburgh, PA, United States
    • Barrow Neurological Institute
      Phoenix, Arizona, United States
  • 2009–2012
    • Michigan Technological University
      • • Department of Biological Sciences
      • • Department of Chemistry
      Houghton, Michigan, United States
    • Università degli Studi di Messina
      • Dipartimento di Scienze Pediatriche, Ginecologiche, Microbiologiche e Biomediche
      Messina, Sicily, Italy
  • 2005–2012
    • VU University Medical Center
      • • Department of Clinical Genetics
      • • Department of Clinical Chemistry
      Amsterdam, North Holland, Netherlands
    • Johns Hopkins University
      • Department of Psychiatry and Behavioral Sciences
      Baltimore, MD, United States
  • 2011
    • Charité Universitätsmedizin Berlin
      Berlín, Berlin, Germany
    • Hebei Medical University
      • School of Basic Medical Sciences
      Chentow, Hebei, China
  • 2004–2011
    • University of Washington Seattle
      • Department of Neurology
      Seattle, WA, United States
    • Emory University
      Atlanta, Georgia, United States
  • 2010
    • Pohang University of Science and Technology
      • Pohang Accelerator Laboratory
      Andong, North Gyeongsang, South Korea
  • 2006–2010
    • Childrens Hospital of Pittsburgh
      • • Division of Medical Genetics
      • • Department of Pediatrics
      • • Division of Pediatric Pathology
      Pittsburgh, Pennsylvania, United States
  • 1999–2010
    • Oregon Health and Science University
      • Department of Molecular & Medical Genetics
      Portland, OR, United States
    • IRCCS Istituto G. Gaslini
      Genova, Liguria, Italy
    • University of Padova
      • Department of Pediatrics
      Padova, Veneto, Italy
  • 2004–2009
    • University of Toronto
      • • Hospital for Sick Children
      • • Faculty of Medicine
      • • Institute of Medical Sciences
      Toronto, Ontario, Canada
  • 1997–2009
    • University of Rome Tor Vergata
      • Dipartimento di Biologia
      Roma, Latium, Italy
    • University of South Florida
      • Morsani College of Medicine
      Tampa, FL, United States
  • 2008
    • Mayo Clinic - Rochester
      Rochester, Minnesota, United States
  • 2005–2008
    • SickKids
      • Division of Neurology
      Toronto, Ontario, Canada
  • 1983–2008
    • University of California, San Diego
      • • Department of Neurosciences
      • • Department of Pediatrics
      San Diego, CA, United States
    • Stanford University
      • Department of Pediatrics
      Palo Alto, CA, United States
  • 2007
    • University of North Dakota
      • Department of Pharmacology, Physiology & Therapeutics
      Grand Forks, ND, United States
  • 2004–2006
    • Children's National Medical Center
      • Department of Neurology
      Washington, D. C., DC, United States
  • 2001
    • VU University Amsterdam
      • Metabolic Unit
      Amsterdam, North Holland, Netherlands
    • Istanbul University
      • Department of Family Medicine (Cerrahpasa Faculty of Medicine)
      İstanbul, Istanbul, Turkey
  • 2000
    • University of Freiburg
      • Department of Pediatrics
      Freiburg, Baden-Württemberg, Germany
    • The Portland Hospital
      Londinium, England, United Kingdom
  • 1994–2000
    • University of Texas Southwestern Medical Center
      • • Department of Pediatrics
      • • Division of Neuro-oncology
      • • Department of Pathology
      Dallas, TX, United States
    • Shaare Zedek Medical Center
      Yerushalayim, Jerusalem District, Israel
  • 1995–1999
    • University of California, Los Angeles
      • Molecular Biology Institute
      Los Angeles, California, United States
  • 1990–1999
    • Baylor Health Care System
      • • Institute of Metabolic Disease (IMD)
      • • Baylor Research Institute (BRI)
      Dallas, Texas, United States
  • 1998
    • Geron Corporation
      Menlo Park, California, United States
  • 1993
    • Medical College of Wisconsin
      • Department of Biochemistry
      Milwaukee, Wisconsin, United States
    • University Hospital München
      München, Bavaria, Germany
  • 1990–1993
    • University of Amsterdam
      • Department of Paediatrics
      Amsterdam, North Holland, Netherlands
  • 1992
    • Universität Heidelberg
      • General pediatrics, pediatric neurology, metabolism, gastroenterology, nephrology
      Heidelberg, Baden-Wuerttemberg, Germany
  • 1989
    • CSU Mentor
      Long Beach, California, United States