Glutaric aciduria type I: A translational approach to an enigmatic disease

Abstract

Glutaric aciduria type I (GA-I) is an autosomal recessively inherited disorder of L-lysine, L-tryptophan and L-hydroxylysine metabolism which is biochemically characterized by the accumulation of putatively toxic glutaric and 3-hydroxyglutaric acids, and non-toxic glutarylcarnitine due to deficient activity of glutaryl-CoA dehydrogenase. The prognostic relevant event of this disease is the manifestation of a complex movement disorder with predominant dystonia superimposed on axial hypotonia. This movement disorder most often manifests during infancy or early childhood after the precipitation of acute encephalopathic crises by catabolic state but it may also develop insidiously without clinically apparent crises. Advances have been made in the description of the natural disease course and neuroradiological abnormalities demonstrating overlapping episodes of cerebral alterations including (reversible) maturational delay of the brain in utero, (irreversible) acute striatal injury during a vulnerable period of brain development and chronic progressive changes that may continue lifelong and involving extrastriatal brain regions. Neonatal identification of asymptomatic patients by tandem mass spectrometry allowing to start combined metabolic treatment in asymptomatic patients has significantly improved the neurological outcome in countries with such newborn screening programmes. In contrast, therapeutic concepts for symptomatic patients are much less effective. Post mortem studies and investigations in Gcdh-deficient mice, a transgenic mouse model for GA-I, have helped to unravel the pathomechanism. Evidence is increasing that some of the accumulating metabolites in GA-I patients are neurotoxic due to their interference with glutamatergic neurotransmission, inhibition of the 2-oxoglutarate dehydrogenase complex and impairment of the dicarboxylic acid shuttle between astrocytes and neurons. Strikingly, glutaric and 3-hydroxylgutaric acids massively accumulate in the brain of patients due to the low permeability of the blood brain barrier for dicarboxylic acids which may explain the selective neurological phenotype of GA-I. Current therapeutic concepts aim to reduce the cerebral concentrations of neurotoxic metabolites by modulating lysine influx to the brain and stimulating the formation of non-toxic glutarylcarnitine. Despite the outlined progress, the mechanism of current neuroprotective concepts is still quite hypothetical and lack a proof of principle. Our understanding has been hampered by the fact that in affected patients the biochemical effect of metabolic treatment could be determined only by using invasive methods (which would be unethical), whereas the concentrations of these biomarkers in body fluids are unlikely to correlate with the brain tissue. Therefore, a translational approach to this disease is indispensable to further unravel the mechanisms of neurologic disease and to elucidate the major principles of neuroprotective strategies.

Keywords

• organic aciduria, newborn screening, striatum, dystonia, guideline

References

1. Goodman SI, Markey SP, Moe PG, et al. Glutaric aciduria: a new disorder of amino acid metabolism. Biochem Med 1975; 12: 12-21.
2. Lindner M, Kölker S, Schulze A, et al. Neonatal screening for glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 2004; 27: 851-859.
3. Kölker S, Garbade SF, Boy N, et al. Decline of acute encephalopathic crises in children with glutaryl-CoA dehydrogenase deficiency identified by newborn screening in Germany. Pediatr Res 2007; 62: 357-362.
4. Morton DH, Bennett MJ, Seargeant LE, et al. Glutaric aciduria type I: a common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania. Am J Med Genet 1991; 41: 89-95.
5. Haworth JC, Dilling LA, Seargeant LE. Increased prevalence of hereditary metabolic diseases among native Indians in Manitoba and northwestern Ontario. Can Med Assoc J 1991;145:123-129.
6. Basinger AA, Booker JK, Frazier DM, et al: Glutaric acidemia type 1 in patients of Lumbee heritage from North Carolina. Mol Genet Metab 2006;88:90-92.
7. Naughten ER, Mayne PD, Monavari AA, et al: Glutaric aciduria type I: outcome in the Republic of Ireland. J Inherit Metab Dis 2004;27:917-920.
8. Greenberg CR, Duncan AM, Gregory CA, et al: Assignment of human glutaryl-CoA dehydrogenase gene (GCDH) to the short arm of chromosome 19 (19p13.2) by in situ hybridization and somatic cell hybrid analysis. Genomics 1994;21:289-290.

9. Goodman SI, Stein DE, Schlesinger S, et al: Glutaryl- CoA dehydrogenase mutations in glutaric acidemia (type I): review and report on thirty novel mutations. Human Mutat 1998;12:141-144.
10. Zschocke J, Quak E, Guldberg P, Hoffmann GF: Mutation analysis in glutaric aciduria type I. J Med Genet 2000;37:177-181.
11. Greenberg CR, Prasad AN, Dilling LA, et al: Outcome of the first 3-years of a DNA-based neonatal screening program for glutaric acidemia type I in Manitoba and northwestern Ontario, Canada. Mol Genet Metab 2002;75:70-78.
12. Strauss KA, Puffenberger EG, Robinson DL, Morton DH: Type I glutaric aciduria, part 1: natural history of 77 patients. Am J Med Genet 2003;121C:38-52.
13. Bijarnia S, Wiley V, Carpenter K, et al: Glutaric aciduria type I: outcome following detection by newborn screening. J Inherit Metab Dis 2008;31:503- 507.
14. Boneh A, Beauchamp M, Humphrey M, et al: Newborn screening for glutaric aciduria type I in Victoria: treatment and outcome. Mol Genet Metab 2008;94:287-291.
15. Baric I, Wagner L, Feyh P, et al: Sensitivity and specificity of free and total glutaric acid and 3- hydroxyglutaric acid measurements by stable-isotope dilution assays for the diagnosis of glutaric aciduria type I. J Inherit Metab Dis 1999;22:867-881.
16. Gallagher RC, Cowan TM, Goodman SI, Enns GM: Glutaryl-CoA dehydrogenase deficiency and newborn screening: Retrospective analysis of a low excretor provides further evidence that some cases may be missed. Mol Genet Metab 2005;86:417-420.
17. Sherman EA, Strauss KA, Tortorelli S, et al: Genetic mapping of glutaric aciduria, type 3, to chromosome 7 and identification of mutations in C7orf10. Am J Hum Genet 2008;83:604-609.
18. Pitt J, Carpenter K, Wilcken B, Boneh A: 3- Hydroxyglutarate excretion is increased in ketotic patients: implications for glutaryl-CoA dehydrogenase deficiency testing. J Inherit Metab Dis 2002;25:83-88.
19. Molven A, Matre GE, Duran M, et al: Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes 2004;53:221-227.
20. Napolitano N, Wiley V, Pitt JJ: Pseudo- glutarylcarnitinaemia in medium-chain acyl-CoA dehydrogenase deficiency detected by tandem mass spectrometry newborn screening. J Inherit Metab Dis 2004;27:465-471.
21. Hoffmann GF, Athanassopoulos S, Burlina AB, et al: Clinical course, early diagnosis, treatment, and prevention of disease in glutaryl-CoA dehydrogenase deficiency. Neuropediatrics 1996;27:115-123.
22. Bjugstad KB, Goodman SI, Freed CR: Age at symptom onset predicts severity of motor impairment and clinical outcome of glutaric acidemia type I. J Pediatr 2000;137:681-686.
23. Harting I, Neumaier-Probst E, Seitz A, et al: Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I. Brain 2009;132:1764-1782.
24. Forstner R, Hoffmann GF, Gassner I, et al: Glutaric aciduria type I: ultrasonographic demonstration of early signs. Pediatr Radiol 1999;29:138-143.
25. Lin SK, Hsu SG, Ho ES, et al: Novel mutations and prenatal sonographic findings of glutaric aciduria (type I) in two Taiwanese families. Prenat Diagn 2005;22:725-729.
26. Kölker S, Garbade SF, Greenberg CR, et al: Natural history, outcome, and treatment efficacy in children and deficiency. Pediatr Res 2006;59:840-847. dehydrogenase
27. Kyllerman M, Skjeldal O, Christensen E, et al: Long- term follow-up, neurological outcome and survival rate in 28 Nordic patients with glutaric aciduria type I. Eur J Paediatr Neurol 2004;8:121-129.
28. Gitiaux C, Roze E, Kinugawa K, et al: Spectrum of movement disorders associated with glutaric aciduria type 1: A study of 16 patients. Mov Disord 2008;23:2392-2397.
29. McClelland VM, Bakalinova DB, Hendriksz C, Singh RP: Glutaric aciduria type 1 presenting with epilepsy. Dev Med Child Neurol 2009;51:235-239.
30. Cerisola A, Campistol J, Pérez-Duenas B, et al: Seizures versus dystonia in encephalopathic crisis of glutaric aciduria type I. Pediatr Neurol 2009;40:426- 431.
31. Beauchamp MH, Boneh A, Anderson V: Cognitive, behavioural and adaptive profiles of children with glutaric aciduria type I detected through newborn screening. J Inherit Metab Dis 2009 May 23 [Epub ahead of print].
32. Brismar J, Ozand PT: CT and MR of the brain in glutaric acidemia type I: a review of 59 published cases and a report of 5 new patients. Am J Neuroradiol 1995;16:675-683.
33. Strauss KA, Lazovic J, Wintermark M, Morton DH: Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency. Brain 2007;130:1905-1920. 34. Funk CB, Neuropathological, findings in a glutaric acidemia type 1 cohort. Brain 2005;128:711-722. AN, biochemical, et al: and molecular aciduria type I presenting with a
34. Kulkens S, Harting I, Sauer S, et al: Late-onset neurologic disease in glutaryl-CoA dehydrogenase deficiency. Neurology 2005;64:2142-2144.
35. Twomey EL, Naughten ER, Donoghue VB, Ryan S: Neuroimaging findings in glutaric aciduria type 1. Pediatr Radiol 2003;33:823-830.
36. Chow CW, Haan EA, Goodman SI, et al: Neuropathology in glutaric acidaemia type 1. Acta Neuropathol 1988;76:590-594.
37. Soffer D, Amir N, Elpeleg ON, et al: Striatal degeneration and spongy myelinopathy in glutaric acidemia. J Neurol Sci 1992;107:199-204.
38. Collins J, Leonard JV: Natural history of glutaric aciduria type 1. Arch Dis Child 2000; 83: 87.
39. Heidenreich R, Natowicz M, Hainline BE, et al: Acute extrapyramidal syndrome in methylmalonic acidemia: “metabolic stroke” involving the globus pallidus. J Pediatr 1988; 113: 1022-1027.
40. Ullrich K, Flott-Rahmel B, Schluff P, et al: Glutaric aciduria neurodegeneration. J Inherit Metab Dis 1999; 22: 392- 403. pathomechanisms of
41. Kölker S, Koeller DM, Okun JG, Hoffmann GF: Pathomechanisms of neurodegeneration in glutaryl- CoA dehydrogenase deficiency. Ann Neurol 2004; 55: 7-12.
42. Sauer SW, Okun JG, Schwab MA, et al: Bioenergetics in glutaryl-coenzyme A dehydrogenase deficiency, a role for glutaryl-coenzyme A. J Biol Chem 2005; 280: 21830-21836.
43. Zinnanti WJ, Lazovic J, Wolpert EB, et al: A diet- induced mouse model for glutaric aciduria type I. Brain 2006; 129: 899-910.
44. Porciuncula LO, Dal-Pizzol Jr A, Coitinho AS, et al: Inhibition of synaptosomal [³H]glutamate uptake and [³H]glutamate binding to plasma membranes from brain of young rats by glutaric acid in vitro. J Neurol Science 2000; 173: 93-96.
45. Stokke O, Goodman SI, Moe PG: Inhibition of brain glutamate decarboxylase by glutarate, glutaconate, and
46. beta-hydroxyglutarate: explanation of the symptoms in glutaric aciduria? Clin Chim Acta 1976;66:411-415.
47. Yodoya E, Wada M, Shimada A, et al: Functional and molecular dicarboxylate transporters in rat primary cultured cerebrocortical astrocytes and neurons. J Neurochem 2006;97:162-173. of sodium-coupled
48. Stellmer F, Keyser B, Burckhardt BC, et al: 3- Hydroxyglutaric acid is transported via the sodium- dependent dicarboxylate transporter NaDC3. J Mol Med 2007;85:763-770.
49. Mühlhausen C, Ott N, Chalajour F, et al: Endothelial effects of 3-hydroxyglutaric acid: implications for glutaric aciduria type I. Pediatr Res 2006;59:196-202.
50. Gerstner B, Gratopp A, Marcinkowski M, et al: Glutaric acid and its metabolites cause apoptosis in immature oligodendrocytes: a novel mechanism of white dehydrogenase deficiency. Pediatr Res 2005;57:771- 776. in glutaryl-CoA
51. Christensen E, Ribes A, Merinero B, Zschocke J: Correlation of genotype and phenotype in glutaryl- CoA dehydrogenase deficiency. J Inherit Metab Dis 2004;27:861-868.
52. Goodman SI, Norenberg MD, Shikes RH, et al: Glutaric aciduria: biochemical and morphological considerations. J Pediatr 1977;90:746-750.
53. Leibel RL, Shih VE, Goodman SI, et al: Glutaric acidemia: a metabolic disorder causing progressive choreoathetosis. Neurology 1980;30:1163-1168.
54. Koeller DM, Woontner M, Crnic LS, et al: Biochemical, pathological and behavioral analysis of a mouse model of glutaric aciduria type I. Hum Mol Genet 2002; 11: 347-357.
55. Sauer SW, Okun JG, Fricker G, et al: Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood-brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency. J Neurochem 2006; 97: 899-910. 58. Hassel B, Brathe A, Petersen D: Cerebral dicarboxylate transport and metabolism studied with isotopically labelled fumarate, malate and malonate. J Neurochem 2002; 82: 410-419.
56. Sweet DH, Chan LM, Walden R, et al: Organic anion transporter 3 (Slc22a8) is a dicarboxylate exchanger indirectly coupled to the Na+ gradient. Am J Physiol Renal Physiol 2003; 284: F763-769.
57. Sauer SW, Opp S, Mahringer A, et al: Glutaric aciduria aciduria:stimulation of cerbebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus.Biochem Biophys Acta 2010;1802:551-560.
58. Hagos Y, Krick W, Braulke T, et al: Organic anion transporter OAT1 and OAT4 mediate the high affinity transport of glutarate derivates accumulating in patients with glutaric aciduria. Pflugers Arch 2008;457:223-231. 62. Zinnanti WJ, Lazovic J, Housman C, et al.:Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I. J Clin Invest 2007;117:3258-3270.
59. Bennett MJ, Marlow N, Pollitt RJ, Wales JK: Glutaric aciduria type 1: biochemical investigations and postmortem findings. Eur J Pediatr 1986;145: 403- 405.
60. Kölker S, Hoffmann GF, Schor DSM, et al: Glutaryl- CoA dehydrogenase deficiency: Regional-specific analysis of organic acids and acylcarnitines in post mortem brain predicts vulnerability of the putamen. Neuropediatrics 2003;34: 253-260.
61. Kölker S, Sauer SW, Surtees RA, Leonard JV: The aetiology of neurological complications of organic acidaemias – a role for the blood-brain barrier. J Inherit Metab Dis 2003; 29: 701-704.
62. Strauss KA, Donnelly P, Wintermark M: Cerebral haemodynamics in patients with glutaryl-coenzyme A dehydrogenase deficiency. Brain 2010; 133: 76-92.
63. Roy CS, Sherrington CS: On the regulation of the blood-supply of the Brain. J Physiol 1890; 11: 85-185.
64. Kölker S, Christensen E, Leonard JV, et al: Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I). J Inherit Metab Dis 2007; 30: 5-22.
65. Monavari AA, Naughten ER: Prevention of cerebral palsy in glutaric aciduria type 1 by dietary management. Arch Dis Child 2000; 82: 67-70.
66. Heringer J, Boy NPS, Ensenauer R, et al: Use of guidelines imprives the neurological outcome in glutaric aciduria type I. Ann Neurol 2010; 68:743-52.
67. Nasser M, Javaheri H, Fedorowicz Z, Noorani Z: Carnitine supplementation for inborn errors of metabolism. Cochrane Database Sys Rev 2009; 15: CD006659.
68. Chalmers RA, Bain MD, Zschocke J: Riboflavin- responsive glutaryl-CoA dehydrogenase deficiency. Mol Genet Metab 2006; 88: 29-37.