Summary
Sir Archibald Garrod's concept of chemical individuality introduced a century ago provided the basis for the entire discipline of inborn errors of metabolism. Human disorders are defined by variation in disease-causing mutations, environmental influences, genetic factors other than the primary genetic defect, and evolution itself. Myriad examples support the prescience of Garrod with respect to these issues, each of which has therapeutic implications. Just as Garrod predicted that the future of biochemical genetics would be intertwined with the concept of chemical variability, we might forecast that variation will influence emotions, dreams, and the human thinking process itself.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Anikster Y, Shotelersuk V, Gahl WA (1999) CTNS mutations in patients with cystinosis. Hum Mutat 14: 454–458. doi:10.1002/(SICI)1098-1004(199912)14:6<454::AID-HUMU2>3.0.CO;2-H.
Anikster Y, Lucero C, Guo J, et al (2000) Ocular, non-nephropathic cystinosis: Clinical, biochemical and molecular correlations. Pediatr Res 47: 17–23. doi:10.1203/00006450-200001000-00007.
Capell BC, Collins FS (2006) Human laminopathies: nuclei gone genetically awry. Nat Rev Genet 7: 940–952.
Delgado MR (2008) Fool me once, shame on you; fool me twice, shame on oxytocin. Neuron 58: 470–471. doi:10.1016/j.neuron.2008.05.005.
Eisenberg I, Avidan N, Potikha T, et al (2001) The UDP-N-acetylglucosamine 2-epimerase/-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 29: 83–89. doi:10.1038/ng718.
Gahl WA, Tietze F (1987) Lysosomal cystine transport in cystinosis variants and their parents. Pediatr Res 21: 193–196. doi:10.1203/00006450-198702000-00016.
Gahl WA, Bashan N, Tietze F, Bernardini I, Schulman JD (1982) Lysosomal cystine transport is defective in cystinosis. Science 217: 1263–1265. doi:10.1126/science.7112129.
Gahl WA, Reed GF, Thoene JG, et al (1987). Cysteamine therapy for children with nephropathic cystinosis. N Engl J Med 316: 971–977.
Gahl WA, Kuehl EM, Iwata F, Lindblad A, Kaiser-Kupfer MI (2000) Corneal crystals in nephropathic cystinosis: Natural history and treatment with cysteamine eyedrops. Mol Genet Metab 71: 100–121. doi:10.1006/mgme.2000.3062.
Gahl WA, Thoene JG, Schneider JA (2002) Cystinosis. N Engl J Med 347: 111–121. doi:10.1056/NEJMra020552.
Gahl WA, Balog JZ, Kleta R (2007) Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy. Ann Intern Med 147: 242–250.
Galeano B, Klootwijk R, Manoli I, et al (2007) Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine. J Clin Invest 117: 1585–1594. doi:10.1172/JCI30954.
Garrod AE (1901) About alkaptonuria. Lancet 158(4083): 1484–1486. doi:10.1016/S0140-6736(01)74537-0.
Garrod AE (1902) The incidence of alkaptonuria: A study in chemical individuality. Lancet 160(4137): 1616–1620. doi:10.1016/S0140-6736(01)41972-6.
Hinderlich S, Stasche R, Zeitler R, Reutter W (1997) A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver. Purification and characterization of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. J Biol Chem 272: 24313–24318. doi:10.1074/jbc.272.39.24313.
Huizing M, Rakocevic G, Sparks SE, et al (2004) Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations. Mol Genet Metab 81: 196–202. doi:10.1016/j.ymgme.2003.11.012.
Introne W, Boissy RE, Gahl WA (1999) Clinical, molecular, and cell biological aspects of Chediak–Higashi syndrome. Mol Genet Metab 68: 283–303. doi:10.1006/mgme.1999.2927.
Introne WJ, Phornphutkul C, Bernardini I, McLaughlin K, Fitzpatrick D, Gahl WA (2002) Exacerbation of the ochronosis of alkaptonuria due to renal insufficiency. Mol Genet Metab 77: 136–142. doi:10.1016/S1096-7192(02)00121-X.
Kaiser-Kupfer MI, Fujikawa L, Kuwabara T, Gahl WA (1987) Removal of corneal crystals by topical cysteamine in nephropathic cystinosis. N Engl J Med 316: 775–779.
Kalatzis V, Cherqui S, Antignac C, Gasnier B (2001) Cystinosin, the protein defective in cystinosis, is a H+-driven lysosomal cystine transporter. EMBO J 20: 5940–5949. doi:10.1093/emboj/20.21.5940.
Kleta R, Gahl W (2005). Cystinosis. In: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle. 1997–2007. Available at www.genetests.org.
Mallal S, Phillips E, Carosi G, et al (2008) HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 358: 568–579. doi:10.1056/NEJMoa0706135.
Markello TC, Bernardini IM, Gahl WA. (1993) Improved renal function in children with cystinosis treated with cysteamine. N Engl J Med 328: 1157–1162. doi:10.1056/NEJM199304223281604.
Merideth MA, Gordon LB, Clauss S, et al (2008) Phenotype and course of Hutchinson–Gilford progeria syndrome. N Engl J Med 358: 592–604. doi:10.1056/NEJMoa0706898.
Nachman MW, Crowell SL (2000) Estimate of the mutation rate per nucleotide in humans. Genetics 156: 297–304.
Phornphutkul C, Introne WJ, Perry MB, et al (2002) Natural history of alkaptonuria. N Engl J Med 347: 2111–2121. doi:10.1056/NEJMoa021736.
Pisoni RL, Thoene JG, Christensen HN (1985) Detection and characterization of carrier-mediated cationic amino acid transport in lysosomes of normal and cystinotic human fibroblasts: role in therapeutic cystine removal. J Biol Chem 260: 4791–4798.
Schwarz UI, Ritchie MD, Bradford Y, et al (2008) Genetic determinants of reponse to warfarin during initial anticoagulation. N Engl J Med 358: 999–1008. doi:10.1056/NEJMoa0708078.
Scriver CR (2001) Garrod’s foresight; our hindsight. J Inherit Metab Dis 24: 93–116. doi:10.1023/A:1010351630856.
Shotelersuk V, Larson D, Anikster Y, et al (1998) CTNS mutations in an American-based population of cystinosis patients. Am J Hum Genet 63: 1352-1362.
Suwannarat P, Phornphutkul C, Bernardini I, Turner M, Gahl WA (2004) Minocycline-induced hyperpigmentation misdiagnosed as alkaptonuria in individuals with joint pain. Arthritis Rheum 50: 3698–3701. doi:10.1002/art.20606.
Suwannarat P, O’Brien K, Perry MB, et al (2005) Use of nitisinone in patients with alkaptonuria. Metabolism 54: 719–728.
Thoene JG, Oshima RG, Crawhall JC, Olson DL, Schneider JA (1976) Cystinosis. Intracellular cystine depletion by aminothiols in vitro and in vivo. J Clin Invest 58: 180–189. doi:10.1172/JCI108448.
Thoene J, Lemons R, Anikster Y, et al (1999) Mutations of CTNS causing intermediate cystinosis. Mol Genet Metab 67: 283–293. doi:10.1006/mgme.1999.2876.
Touchman JW, Anikster Y, Dietrich NL, et al (2000) The genomic region encompassing the nephropathic cystinosis gene (CTNS): Complete sequencing of a 200-kb segment and discovery of a novel gene within the common cystinosis-causing deletion. Genome Res 10: 165–173. doi:10.1101/gr.10.2.165.
Town M, Jean G, Cherqui S, et al (1998) Novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet 18: 319–324. doi:10.1038/ng0498-319.
Valle D (2004) Genetics, individuality, and medicine in the 21st century. Am J Hum Genet 74: 374–381. doi:10.1086/382790.
Westbroek W, Adams D, Huizing M, et al (2007) Cellular defects in Chediak–Higashi syndrome correlate with the molecular genotype and clinical phenotype. J Invest Dermatol 127: 2674–2677. doi:10.1038/sj.jid.5700899.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicating editor: Verena Peters
Competing interests: None declared
Rights and permissions
About this article
Cite this article
Gahl, W.A. Chemical individuality: Concept and outlook. J Inherit Metab Dis 31, 630–640 (2008). https://doi.org/10.1007/s10545-008-0995-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-008-0995-6