Skip to main content
SpringerLink
Log in

Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I)

  • Guideline
  • Published:
Journal of Inherited Metabolic Disease

Summary

Glutaryl-CoA dehydrogenase (GCDH) deficiency is an autosomal recessive disease with an estimated overall prevalence of 1 in 100 000 newborns. Biochemically, the disease is characterized by accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine, which can be detected by gas chromatography–mass spectrometry of organic acids or tandem mass spectrometry of acylcarnitines. Clinically, the disease course is usually determined by acute encephalopathic crises precipitated by infectious diseases, immunizations, and surgery during infancy or childhood. The characteristic neurological sequel is acute striatal injury and, subsequently, dystonia. During the last three decades attempts have been made to establish and optimize therapy for GCDH deficiency. Maintenance treatment consisting of a diet combined with oral supplementation of L-carnitine, and an intensified emergency treatment during acute episodes of intercurrent illness have been applied to the majority of patients. This treatment strategy has significantly reduced the frequency of acute encephalopathic crises in early-diagnosed patients. Therefore, GCDH deficiency is now considered to be a treatable condition. However, significant differences exist in the diagnostic procedure and management of affected patients so that there is a wide variation of the outcome, in particular of pre-symptomatically diagnosed patients. At this time of rapid expansion of neonatal screening for GCDH deficiency, the major aim of this guideline is to re-assess the common practice and to formulate recommendations for diagnosis and management of GCDH deficiency based on the best available evidence.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

3-OH-GA:

3-hydroxyglutaric acid

AA:

amino acid(s)

ADC:

apparent diffusion coefficient

AWMF:

Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften

BT-A:

botulinum toxin A

C5DC:

glutarylcarnitine

CCT:

cranial computed tomography

DBS:

dried blood spots

EPI-SE:

echo-planar imaging spin-echo

GA:

glutaric acid

GCDH:

glutaryl-CoA dehydrogenase

GCP:

good clinical practice

GC-MS:

gas chromatography–mass spectrometry

GDG:

guideline developmental group

HPLC:

high-performance liquid chromatography

Lys:

lysine

MR:

magnetic resonance

MRI:

magnetic resonance imaging

MS/MS:

tandem mass spectrometry

SIGN:

Scottish Intercollegiate Guidelines Network

TE:

echo time

TR:

repetition time

Trp:

tryptophan

References

  • Bähr O, Mader I, Zschocke J, Dichgans J, Schulz JB (2002) Adult onset glutaric aciduria type I presenting with leukoencephalopathy. Neurology 59: 1802–1804.

    PubMed  Google Scholar 

  • Baric I, Wagner L, Feyh P, Liesert M, Buckel W, Hoffmann GF (1999) Sensitivity of free and total glutaric and 3-hydroxyglutaric acid measurement by stable isotope dilution assays for the diagnosis of glutaric aciduria type I. J Inherit Metab Dis 22: 867–882.

    Article  PubMed  CAS  Google Scholar 

  • Bennett MJ, Marlow N, Pollitt RJ, Wales JK (1986) Glutaric aciduria type 1: biochemical investigations and post mortem findings. Eur J Pediatr 145: 403–405.

    Article  PubMed  CAS  Google Scholar 

  • Bjugstad KB, Goodman SI, Freed CR (2000) Age at symptom onset predicts severity of motor impairment and clinical onset of glutaric aciduria type I. J Pediatr 137: 681–686.

    Article  PubMed  CAS  Google Scholar 

  • Brandt NJ, Gregersen N, Christensen E, Gron ICH, Rasmussen K (1979) Treatment of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria). J Pediatr 94: 669–673.

    Article  PubMed  CAS  Google Scholar 

  • Brismar J, Ozand PT (1995) CT and MR of the brain in glutaric aciemia type I: a review of 59 published cases and a report of 5 new patients. Am J Neuroradiol 16: 675–683.

    Google Scholar 

  • Burlina AP, Zara G, Hoffmann GF, Zschocke J, Burlina AB (2004) Management of movement disorders in glutaryl-CoA dehydrogenase deficiency: anticholinergic drugs and botulinum toxin as additional therapeutic options. J Inherit Metab Dis 27: 911–915.

    Article  PubMed  CAS  Google Scholar 

  • Busquets C, Merinero B, Christensen E, et al (2000) Glutaryl-CoA dehydrogenase deficiency in Spain: evidence of two groups of patients, genetically and biochemically distinct. Pediatr Res 48: 315–322.

    Article  PubMed  CAS  Google Scholar 

  • Chace DH, Kalas TA, Naylor EW (2003) Use of tandem mass spectrometry for multianalyte screening of dried blood specimens from newborns. Clin Chem 40: 1797–1817.

    Article  CAS  Google Scholar 

  • Chalmers RA, Bain MD, Zschocke J (2006) Riboflavin-responsive glutaryl-CoA dehydrogenase deficiency. Mol Genet Metab 29: 162–172.

    CAS  Google Scholar 

  • Christensen E (1983) Improved assay of glutaryl-CoA dehydrogenase in cultured cells and liver: application to glutaric aciduria type I. Clin Chim Acta 129: 91–97.

    Article  PubMed  CAS  Google Scholar 

  • Christensen E, Ribes A, Merinero B, Zschocke J (2004) Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27: 861–868.

    Article  PubMed  CAS  Google Scholar 

  • Desai NK, Runge VM, Crisp DE, Crisp MB, Naul LG (2003) Magnetic resonance imaging of the brain in glutaric aciduria type I. Invest Radiol 38: 489–496.

    Article  PubMed  Google Scholar 

  • Dewey KG, Beaton G, Fjeld C, Lonnerdal B, Reeds P (1996) Protein requirements of infants and children. Eur J Clin Nutr 50: 119–147.

    Google Scholar 

  • Dixon M, Leonard JV (1992) Intercurrent illness in inborn errors of intermediary metabolism. Arch Dis Child 67: 1387–1391.

    Article  PubMed  CAS  Google Scholar 

  • Elster AW (2004) Value of diffusion-weighted resonance imaging for diagnosing acute striatal necrosis. J Comput Assist Tomogr 28: 98–100.

    Article  PubMed  Google Scholar 

  • Forstner R, Hoffmann GF, Gassner I, et al (1999) Glutaric aciduria type I: ultrasonographic demonstration of early signs. Pediatr Radiol 29: 138–143.

    Article  PubMed  CAS  Google Scholar 

  • Fu Z, Wang M, Paschke R, Rao S, Frerman FE, Kim JJP (2004) Crystal structures of human glutaryl-CoA dehydrogenase with and without an alternate substrate: structural bases of dehydrogenation and decarboxylation reactions. Biochemistry 43: 9674–9684.

    Article  PubMed  CAS  Google Scholar 

  • Funk CB, Prasad AN, Frosk P, et al (2005) Neuropathological, biochemical, and molecular findings in a glutaric aciduria type 1 cohort. Brain 128: 711–722.

    Article  PubMed  Google Scholar 

  • Gallagher RC, Cowan TM, Goodman SI, Enns GM (2005) Glutaryl-CoA dehydrogenase deficiency and newborn screening: Retrospective analysis of a low excretor provides further evidence that some cases may be missed. Mol Genet Metabol 86: 417–420.

    Article  CAS  Google Scholar 

  • Goodman SI, Markey SP, Moe PG, Miles BS, Teng CC (1975) Glutaric aciduria: a ‘new’ inborn error of amino acid metabolism. Biochem Med 12: 12–21.

    Article  PubMed  CAS  Google Scholar 

  • Goodman SI, Norenberg MD, Shikes RH, Breslich DJ, Moe PG (1977) Glutaric aciduria: biochemical and morphologic considerations. J Pediatr 90: 746–750.

    Article  PubMed  CAS  Google Scholar 

  • Goodman SI, Stein DE, Schlesinger S, et al (1998) Glutaryl-CoA dehydrogenase mutations in glutaric acidemia (type I): review and report of thirty novel mutations. Hum Mutat 12: 141–144.

    Google Scholar 

  • Greenberg CR, Reimer D, Singal R, et al (1995) A G-to-T transversion at the +5 position of intron 1 in the glutaryl-CoA dehydrogenase gene is associated with the Island Lake variant of glutaric acidemia type I. Hum Mol Genet 4: 493–495.

    Article  PubMed  CAS  Google Scholar 

  • Greenberg CR, Prasad AN, Dilling LA, et al (2002) Outcome of the three years of a DNA-based neonatal screening program for glutaric aciduria type I in Manitoba and Northwestern Ontaria, Canada. Mol Gen Metab 75: 70–78.

    Article  CAS  Google Scholar 

  • Hald JK, Nakstad PH, Skjeldal OH, Stromme P (1991) Bilateral arachnoid cysts of the temporal fossa in four children with glutaric aciduria type I. Am J Neuroradiol 12: 407–409.

    PubMed  CAS  Google Scholar 

  • Hartley LM, Khwaja OS, Verity CM (2001) Glutaric aciduria type 1 and nonaccidental head injury. Pediatrics 107: 174–175.

    Article  PubMed  CAS  Google Scholar 

  • Haworth JC, Booth FA, Chudley AE, et al (1991) Phenotypic variability in glutaric aciduria type I: report of fourteen cases in five Canadian Indian kindreds. J Pediatr 118: 52–58.

    Google Scholar 

  • Hoffmann GF, Trefz FK, Barth PG, et al (1991) Glutaryl-CoA dehydrogenase deficiency: A distinct encephalopathy. Pediatrics 88: 1194–1203.

    PubMed  CAS  Google Scholar 

  • Hoffmann GF, Athanassopoulos S, Burlina AB, et al (1996) Clinical course, early diagnosis, treatment, and prevention of disease in glutaryl-CoA dehydrogenase deficiency. Neuropediatrics 27: 115–123.

    Article  PubMed  CAS  Google Scholar 

  • Jamjoom ZA, Okamoto E, Jamjoom AH, Al-Hajery O, Abu-Melha A (1995) Bilateral arachnoid cysts of the sylvian region in female siblings with glutaric aciduria type I. Report of two cases. J Neurosurg 82: 1078–1081.

    Google Scholar 

  • Köhler M, Hoffmann GF (1998) Subdural haematoma in a child with glutaric aciduria type I. Pediatr Radiol 28: 582.

    Article  PubMed  Google Scholar 

  • Kölker S, Hoffmann GF, Schor DS, et al (2003) Glutaryl-CoA dehydrogenase deficiency: regional-specific analysis of organic acids and acylcarnitines in post mortem brain predicts vulnerability of the putamen. Neuropediatrics 34: 253–260.

    Article  PubMed  Google Scholar 

  • Kölker S, Greenberg CR, Lindner M, Müller E, Naughten ER, Hoffmann GF (2004) Emergency treatment in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27: 893–902.

    Article  PubMed  Google Scholar 

  • Kölker S, Garbade S, Greenberg CR, et al (2006) Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res 59: 840–847.

    Article  PubMed  Google Scholar 

  • Külkens S, Harting I, Sauer S, et al (2005) Late-onset neurologic disease in glutaryl-CoA dehydrogenase deficiency. Neurology 64: 2142–2144.

    Article  PubMed  Google Scholar 

  • Kyllerman M, Skjeldal OH, Lundberg M, et al (1994) Dystonia and dyskinesia in glutaric aciduria type I: Clinical heterogeneity and therapeutic considerations. Mov Disord 9: 22–30.

    Article  PubMed  CAS  Google Scholar 

  • Kyllerman M, Skjeldal O, Christensen E, et al (2004) Long-term follow-up, neurological outcome and survival rate in 28 Nordic patients with glutaric aciduria type 1. Eur J Paediatr Neurol 8: 121–129.

    Article  PubMed  Google Scholar 

  • Leibel RL, Shih VE, Goodman SI, et al (1980) Glutaric aciduria type I: A metabolic disorder causing progressive choreoathetosis. Neurology 30: 1163–1168.

    PubMed  CAS  Google Scholar 

  • Lin SK, Hsu SG, Ho ES, et al (2002) Novel mutations and prenatal sonographic findings of glutaric aciduria (type I) in two Taiwanese families. Prenat Diagn 22: 725–729.

    Article  PubMed  CAS  Google Scholar 

  • Lindner M, Kölker S, Schulze A, Christensen E, Greenberg CR, Hoffmann GF (2004) Neonatal screening for glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27: 851–859.

    Article  PubMed  CAS  Google Scholar 

  • Lipkin PH, Roe CR, Goodman SI, Batshaw ML (1988) A case of glutaric aciduria type I: effect of riboflavin and carnitine. J Pediatr 112: 62–65.

    Article  PubMed  CAS  Google Scholar 

  • Lütcherath V, Waaler PE, Jellum E, Wester K (2000) Children with bilateral temporal arachnoid cysts may have glutaric aciduria type 1 (GAT1); operation without knowing that may be harmful. Acta Neurochir (Wien) 142: 1025–1030.

    Article  Google Scholar 

  • Martinez-Lage JF, Casas C, Fernandez MA, Puche A, Rodriguez Costa T, Poza M (1994) Macrocephaly, dystonia, and bilateral temporal arachnoid cysts: glutaric aciduria type 1. Childs Nerv Syst 10: 198–203.

    Article  PubMed  CAS  Google Scholar 

  • Monavari AA, Naughten ER (2000) Prevention of cerebral palsy in glutaric aciduria type I by dietary management. Arch Dis Child 82: 67–70.

    Article  PubMed  CAS  Google Scholar 

  • Morris AAM, Hoffmann GF, Naughten ER, Monavari AA, Collins JE, Leonard JV (1999) Glutaric aciduria and suspected child abuse. Arch Dis Child 80: 404–405.

    PubMed  CAS  Google Scholar 

  • Morton DH, Bennett MJ, Seargeant LE, Nichter CA, Kelley RI (1991) A common cause of episodic encephalopathy an spastic paralysis in the Amish of Lancaster County, Pennsylvania. Am J Med Genet 41: 89–95.

    Article  PubMed  CAS  Google Scholar 

  • Mühlhausen C, Christensen E, Schwartz M, Muschol N, Ullrich K, Lukacz Z (2003) Severe phenotype despite high residual glutaryl-CoA dehydrogenase activity: a novel mutation in a Turkish patient with glutaric aciduria type I. J Inherit Metab Dis 26: 713–714.

    Article  PubMed  Google Scholar 

  • Mühlhausen C, Hoffmann GF, Strauss KA, et al (2004) Maintenance treatment of glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27: 885–892.

    Article  PubMed  Google Scholar 

  • Müller E, Kölker S (2004) Reduction of lysine intake while avoiding malnutrition—major goals and major problems in dietary treatment of glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 27: 903–910.

    Article  PubMed  Google Scholar 

  • Napolitano N, Wiley V, Pitt JJ (2004) Pseudo-glutarylcarnitinaemia in medium-chain acyl-CoA dehydrogenase deficiency detected by tandem mass spectrometry newborn screening. J Inherit Metab Dis 27: 465–471.

    Article  PubMed  CAS  Google Scholar 

  • Naughten ER, Mayne PD, Monavari AA, Goodman SI, Sulaiman G, Croke DT (2004) Glutaric aciduria type I, outcome in the Republic of Ireland. J Inherit Metab Dis 27: 917–920.

    Google Scholar 

  • Neumaier-Probst E, Harting I, Seitz A, Ding C, Kölker S (2004) Neuroradiological findings in glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency). J Inherit Metab Dis 27: 869–876.

    Article  PubMed  CAS  Google Scholar 

  • Oguz KK, Ozturk A, Cila A (2005) Diffusion-weighted MR imaging and MR spectroscopy in glutaric aciduria type I. Neuroradiology 47: 229–234.

    Article  PubMed  CAS  Google Scholar 

  • Prietsch V, Lindner M, Zschocke J, Nyhan WL, Hoffmann GF (2002) Emergency management of inherited metabolic diseases. J Inherit Metab Dis 25: 531–546.

    Article  PubMed  CAS  Google Scholar 

  • Rakocevic G, Lyons KE, Wilkinson SB, Overman JW, Pahwa R (2004) Bilateral pallidotomy for severe dystonia in an 18-month-old child with glutaric aciduria. Stereotact Funct Neurosurg 82: 80–83.

    Article  PubMed  Google Scholar 

  • Schulze-Bergkamen A, Okun JG, et al (2005) Quantitative acylcarnitine profiling in peripheral blood mononuclear cells using in vitro loading with palmitic and 2-oxoadipic acids: biochemical confirmation of fatty acid oxidation and organic acid disorders. Pediatr Res 58: 873–880.

    Article  PubMed  CAS  Google Scholar 

  • Seccombe DW, James L, Booth F (1986) L-Carnitine treatment in glutaric aciduria type I. Neurology 36: 264–267.

    PubMed  CAS  Google Scholar 

  • Smith WE, Millington DS, Koeberl DD, Lesser PS (2001) Glutaric academia, type I, missed by newborn screening in an infant with dystonia following promethazine administration. Pediatrics 107: 1184–1187.

    Google Scholar 

  • Strauss KA, Puffenberger EG, Robinson DL, Morton DH (2003) Type I glutaric aciduria, part 1: Natural history of 77 patients. Am J Med Genet 121C: 38–52.

    Article  Google Scholar 

  • Tortorelli S, Hahn SH, Cowan TM, Brewster TG, Rinaldo P, Matern D (2005) The urinary excretion of glutarylcarnitine is an informative tool in the biochemical diagnosis of glutaric aciduria type I. Mol Genet Metab 84: 137–143.

    Article  PubMed  CAS  Google Scholar 

  • Treacy EP, Lee-Chong A, Roche G, Lynch B, Ryan S, Goodman SI (2003) Profound neurological presentation resulting from homozygosity for a mild glutaryl-CoA dehydrogenase mutation with a minimal biochemical phenotype. J Inherit Metab Dis 26: 72–74.

    Article  PubMed  CAS  Google Scholar 

  • Twomey EL, Naughten ER, Donoghue VB, Ryan S (2003) Neuroimaging findings in glutaric aciduria type I. Pediatr Radiol 33: 823–830.

    Article  PubMed  Google Scholar 

  • Wilcken B, Wiley V, Hammond J, Carpenter K (2003) Screening newborns for inborn errors of metabolism by tandem mass spectrometry. N Engl J Med 348: 2304–2312.

    Article  PubMed  CAS  Google Scholar 

  • Woelfle J, Kreft B, Emons D, Haverkamp F (1996) Subdural hematoma and glutaric aciduria type I. Pediatr Radiol 26: 779–781.

    Article  PubMed  CAS  Google Scholar 

  • Yannicelli S, Rohr F, Warman FL (1994) Nutrition support for glutaric acidemia type I. J Am Diet Assoc 94: 183–191.

    Article  PubMed  CAS  Google Scholar 

  • Zschocke J, Quak E, Guldberg P, Hoffmann GF (2000) Mutation analysis in glutaric aciduria type I. J Med Genet 37: 177–181.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    S. Kölker, E. Müller, J. G. Okun, G. F. Hoffmann & P. Burgard

  2. Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark

    E. Christensen

  3. Biochemistry, Endocrinology and Metabolism, and Neurosciences Units, Institute of Child Health, London, UK

    J. V. Leonard

  4. Department of Biochemical and Medical Genetics, Winnipeg Children’s Hospital, University of Manitoba, Winnipeg, Manitoba, Canada

    C. R. Greenberg

  5. Metabolic Unit, Department of Pediatrics, University Hospital of Padova, Padua, Italy

    A. B. Burlina

  6. Department of Neuroscience, Neurological Clinic, University Hospital, Padua, Italy

    A. P. Burlina

  7. Dietetic Department, Great Ormond Street Hospital for Children NHS Trust, London, UK

    M. Dixon

  8. Academic Medical Centre, Laboratory of Genetic Metabolic Diseases FO-224, Amsterdam, The Netherlands

    M. Duran

  9. Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado, USA

    S. I. Goodman

  10. Departments of Pediatrics, Molecular and Medical Genetics, Doernbecher Children’s Hospital, Oregon Health and Science University, Portland Oregon, USA

    D. M. Koeller

  11. The National Centre of Inherited Metabolic Disorders, Children’s University Hospital, Dublin, Ireland

    E. R. Naughten

  12. Department of Neuroradiology, University Hospital Mannheim, University of Heidelberg Medical School, Mannheim, Germany

    E. Neumaier-Probst

  13. Department of Paediatric Neurology, Queen Silvia Children’s Hospital, Göteborg, Sweden

    M. Kyllerman

  14. Department of Neurology, Great Ormond Street Hospital for Children NHS Trust, London, UK

    R. A. Surtees

  15. Biochemical Genetics and Newborn Screening Service, The Children’s Hospital at Westmead, University of Sydney, Westmead, New South Wales, Australia

    B. Wilcken

Authors
  1. S. Kölker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Christensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. V. Leonard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. R. Greenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. B. Burlina
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. P. Burlina
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Dixon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. Duran
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S. I. Goodman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D. M. Koeller
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. E. Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. E. R. Naughten
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. E. Neumaier-Probst
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. J. G. Okun
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M. Kyllerman
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. R. A. Surtees
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. B. Wilcken
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. G. F. Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. P. Burgard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Kölker.

Additional information

Communicating editor: Rodney Pollitt

Competing interests: A statement of competing interests is provided in the electronic supplementary material available online.

Contributions of authors: Full details are provided in the electronic supplementary material available online.

References to electronic databases: Glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I): OMIM # 231670 Glutaryl-CoA dehydrogenase: EC 1.3.99.7

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kölker, S., Christensen, E., Leonard, J.V. et al. Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I). J Inherit Metab Dis 30, 5–22 (2007). https://doi.org/10.1007/s10545-006-0451-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-006-0451-4

Keywords

Search

Navigation