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Amino Acid Transport Defects

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Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases

Abstract

Disorders associated with the malfunction of amino acid transporters mainly affect the function of the intestine, kidney, brain, and liver. Mutations of brain amino acid transporters, for example, alter neuronal excitability. Examples presented in this chapter are episodic ataxia due to EAAT3 defect, hyperekplexia due to GLYT2 deficiency, global cerebral hypomyelination due to AGC1 deficiency, and neonatal myoclonic epilepsy due to GC1 deficiency. Mutations of renal and intestinal amino acid transporters cause renal problems (cystinuria and dicarboxylic aminoaciduria) and malabsorption that can affect whole-body homoeostasis (Hartnup disorder, lysinuric protein intolerance, and hyperdibasic aminoaciduria type 1). Inborn errors associated with the mitochondrial SLC25 family with a liver phenotype such as the ones affecting SLC25A13 (aspartate/glutamate transporter 2), citrin deficiency and SLC25A15 (ornithine–citrulline carrier 2), homocitrullinuria, hyperornithinemia, and hyperammonemia will be dealt with in Chap. 4.

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References

  • Bailey CG, Ryan RM, Thoeng AD et al (2011) Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. J Clin Invest 121:446–453

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bakker MJ, van Dijk JG, van den Maagdenberg AM, Tijssen MA (2006) Startle syndromes. Lancet Neurol 5:513–524

    Article  PubMed  Google Scholar 

  • Borsani G, Bassi MT, Sperandeo MP et al (1999) SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance. Nat Genet 21:297–301

    Article  CAS  PubMed  Google Scholar 

  • Bröer S, Palacín M (2011) The role of amino acid transporters in inherited and acquired diseases. Biochem J 436:193–211

    Article  PubMed  Google Scholar 

  • Bröer S, Bailey CG, Kowalczuk S, Ng C, Vanslambrouck JM, Rodgers H, Auray-Blais C, Cavanaugh JA, Bröer A, Rasko JE (2008) Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters. J Clin Invest 118:3881–3892

    Article  PubMed Central  PubMed  Google Scholar 

  • Calonge MJ, Gasparini P, Chillarón J et al (1994) Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nat Genet 6:420–425

    Article  CAS  PubMed  Google Scholar 

  • Chillarón J, Font-Llitjós M, Fort J, Zorzano A, Goldfarb DS, Nunes V, Palacín M (2010) Pathophysiology and treatment of cystinuria. Nat Rev Nephrol 6:424–434

    Article  PubMed  Google Scholar 

  • Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105

    Article  CAS  PubMed  Google Scholar 

  • de Koning-Tijssen MAJ, Rees MI (2007) Hyperekplexia. In: Pagon RA, Bird TD, Dolan CR (eds) GeneReviews. University of Washington, Seattle

    Google Scholar 

  • de Vries B, Mamsa H, Stam AH, Wan J, Bakker SL, Vanmolkot KR, Haan J, Terwindt GM, Boon EM, Howard BD, Frants RR, Baloh RW, Ferrari MD, Jen JC, van den Maagdenberg AM (2009) Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake. Arch Neurol 66:97–101

    Article  PubMed  Google Scholar 

  • Douda DN, Farmakovski N, Dell S, Grasemann H, Palaniyar N (2009) SP-D counteracts GM-CSF-mediated increase of granuloma formation by alveolar macrophages in lysinuric protein intolerance. Orphanet J Rare 4:29

    Article  Google Scholar 

  • Eggermann T, Elbracht M, Haverkamp F, Schmidt C, Zerres K (2007) Isolated cystinuria (OMIM 238200) is not a separate entity but is caused by a mutation in the cystinuria gene SLC7A9. Clin Genet 71:597–598

    Article  CAS  PubMed  Google Scholar 

  • Feliubadaló L, Font M, Purroy J et al (International Cystinuria Consortium) (1999) Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT. Nat Genet 23:52–57

    Google Scholar 

  • Font-Llitjós M, Jiménez-Vidal M, Bisceglia L, Di Perna M, de Sanctis L, Rousaud F, Zelante L, Palacín M, Nunes V (2005) New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype. J Med Genet 42:58–68

    Article  PubMed Central  PubMed  Google Scholar 

  • Gómez L, García-Cazorla A, Gutiérrez A, Artuch R, Varea V, Martín J, Pinillos S, Vilaseca MA (2006) Treatment of severe osteoporosis with alendronate in a patient with lysinuric protein intolerance. J Inherit Metab Dis 29:687

    Article  PubMed  Google Scholar 

  • Jen JC, Wan J, Palos TP, Howard BD, Baloh RW (2005) Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology 65:529–534

    Article  CAS  PubMed  Google Scholar 

  • Jen JC, Graves TD, Hess EJ, Hanna MG, Griggs RC, Baloh RW, CINCH Investigators (2007) Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain 130:2484–2493

    Article  CAS  PubMed  Google Scholar 

  • Kihara H, Valente M, Porter MT, Fluharty AL (1973) Hyperdibasicaminoaciduria in a mentally retarded homozygote with a peculiar response to phenothiazines. Pediatrics 51:223–229

    CAS  PubMed  Google Scholar 

  • Kleta R, Romeo E, Ristic Z et al (2004) Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder. Nat Genet 36:999–1002

    Article  CAS  PubMed  Google Scholar 

  • Knoll T, Zöllner A, Wendt-Nordahl G, Michel MS, Alken P (2005) Cystinuria in childhood and adolescence: recommendations for diagnosis, treatment, and follow-up. Pediatr Nephrol 20:19–24

    Article  PubMed  Google Scholar 

  • Kowalczuk S, Bröer A, Tietze N, Vanslambrouck JM, Rasko JE, Bröer S (2008) A protein complex in the brush-border membrane explains a Hartnup disorder allele. FASEB J 22:2880–2887

    Article  CAS  PubMed  Google Scholar 

  • Molinari F, Raas-Rothschild A, Rio M, Fiermonte G, Encha-Razavi F, Palmieri L, Palmieri F, Ben-Neriah Z, Kadhom N, Vekemans M, Attie-Bitach T, Munnich A, Rustin P, Colleaux L (2005) Impaired mitochondrial glutamate transport in autosomal recessive neonatal myoclonic epilepsy. Am J Hum Genet 76:334–339

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Molinari F, Kaminska A, Fiermonte G, Boddaert N, Raas-Rothschild A, Plouin P, Palmieri L, Brunelle F, Palmieri F, Dulac O, Munnich A, Colleaux L (2009) Mutations in the mitochondrial glutamate carrier SLC25A22 in neonatal epileptic encephalopathy with suppression bursts. Clin Genet 76:188–194

    Article  CAS  PubMed  Google Scholar 

  • Pessia M, Hanna MG (2010) Episodic ataxia type 1. In: Pagon RA, Bird TD, Dolan CR (eds) GeneReviews [Online]. University of Washington, Seattle

    Google Scholar 

  • Plecko B, Karl P, Mills Ph, et al Pyridoxine responsiveness in novel PNPO mutations. Neurology in press

    Google Scholar 

  • Potter SJ, Lu A, Wilcken B, Green K, Rasko JE (2002) Hartnup disorder: polymorphisms identified in the neutral amino acid transporter SLC1A5. J Inherit Metab Dis 25:437–448

    Article  CAS  PubMed  Google Scholar 

  • Rees MI, Harvey K, Pearce BR et al (2006) Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nat Genet 38:801–806

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rimer JD, An Z, Zhu Z, Lee MH, Goldfarb DS, Wesson JA, Ward MD (2010) Crystal growth inhibitors for the prevention of L-cystine kidney stones through molecular design. Science 330:337–341

    Article  CAS  PubMed  Google Scholar 

  • Santamaria F, Brancaccio G, Parenti G, Francalanci P, Squitieri C, Sebastio G, Dionisi-Vici C, D’argenio P, Andria G, Parisi F (2004) Recurrent fatal pulmonary alveolar proteinosis after heart-lung transplantation in a child with lysinuric protein intolerance. J Pediatr 145:268–272

    Article  PubMed  Google Scholar 

  • Sebastio G, Sperandeo MP, Andria G (2011) Lysinuric protein intolerance: reviewing concepts of a multisystem disease. Am J Med Genet 157:54–62

    Article  CAS  Google Scholar 

  • Seow HF, Bröer S, Bröer A et al (2004) Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. Nat Genet 36:1003–1007

    Article  CAS  PubMed  Google Scholar 

  • Simell O (2001) Lysinuric protein intolerance and another cationic aminoacidurias. In: Scriver CR et al (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York

    Google Scholar 

  • Torrents D, Mykkänen J, Pineda M et al (1999) Identification of SLC7A7, encoding y + LAT-1, as the lysinuric protein intolerance gene. Nat Genet 21:293–296

    CAS  PubMed  Google Scholar 

  • Vigevano F, Di Capua M, Dalla Bernardina B (1989) Startle disease: an avoidable cause of sudden infant death. Lancet 1:216

    Article  CAS  PubMed  Google Scholar 

  • Whelan DT, Scriver CR (1968) Hyperdibasicaminoaciduria: an inherited disorder of amino acid transport. Pediatr Res 2:525–534

    Article  CAS  PubMed  Google Scholar 

  • Wibom R, Lasorsa FM, Töhönen V, Barbaro M, Sterky FH, Kucinski T, Naess K, Jonsson M, Pierri CL, Palmieri F, Wedell A (2009) AGC1 deficiency associated with global cerebral hypomyelination. N Engl J Med 361:489–495

    Article  PubMed  Google Scholar 

  • Zhou L, Chillag KL, Nigro MA (2002) Hyperekplexia: a treatable neurogenetic disease. Brain Dev 24:669–674

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Christian Lueck (Canberra Hospital) for clarification of differential diagnosis in cases of episodic ataxia. The authors thank Dr. Rafael Artuch (Hospital San Joan de Deu, Barcelona) for reference values of plasma amino acid concentration.

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Authors and Affiliations

  1. Institute for Research in Biomedicine (IRB Barcelona), Centre for Biomedical Network Research on Rare Diseases (CIBERER, U731) and University of Barcelona, Baldiri i Reixac 12, Barcelona, 08028, Spain

    Manuel Palacín

  2. Research School of Biology, Australian National University, Canberra, ACT 0200, Australia

    Stefan Broer

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  1. Manuel Palacín
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  2. Stefan Broer
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Correspondence to Manuel Palacín .

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Editors and Affiliations

  1. Department of General Pediatrics, University Children's Hospital, Division of Inborn Metabolic Diseases, Heidelberg, Germany

    Nenad Blau

  2. Laboratory Genetic Metabolic Diseases, University of Amsterdam Academic Medical Centre, Amsterdam, The Netherlands

    Marinus Duran

  3. Section of Clinical Pharmacology, Washington State University, Spokane, Washington, USA

    K Michael Gibson

  4. Division of Metabolism, Department of Pediatric Medicine, Bambino Gesù Children’s Research Hospital, Rome, Italy

    Carlo Dionisi Vici

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Palacín, M., Broer, S. (2014). Amino Acid Transport Defects. In: Blau, N., Duran, M., Gibson, K., Dionisi Vici, C. (eds) Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40337-8_6

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  • DOI: https://doi.org/10.1007/978-3-642-40337-8_6

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  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-40336-1

  • Online ISBN: 978-3-642-40337-8

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