Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Therapy Insight: inborn errors of metabolism in adult neurology—a clinical approach focused on treatable diseases

Nature Clinical Practice Neurology volume 3, pages 279–290 (2007)Cite this article

Abstract

Inborn errors of metabolism (IEMs) are genetic disorders characterized by dysfunction of an enzyme or other protein involved in cellular metabolism. In most cases, IEMs involve the nervous system. The first clinical symptoms of IEMs usually present in infancy, but in an unknown proportion of cases they can appear in adolescence or adulthood. In this Review, we focus on treatable IEMs, presenting acutely or chronically, that can be diagnosed in an adult neurology department. To make our presentation readily usable by clinicians, the Review is subdivided into eight sections according to the main clinical presentations: emergencies (acute encephalopathies and strokes), movement disorders, peripheral neuropathies, spastic paraparesis, cerebellar ataxia, psychiatric disorders, epilepsy and leukoencephalopathies. Our aim is to present simple guidelines to enable neurologists to avoid overlooking a treatable metabolic disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Jimenez-Sanchez G et al. (2001) Human disease genes. Nature 409: 853–855

    Article  CAS  PubMed  Google Scholar 

  2. Gray RG et al. (2000) Inborn errors of metabolism as a cause of neurological disease in adults: an approach to investigation. J Neurol Neurosurg Psychiatry 69: 5–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Saudubray JM et al. (2006) Clinical approach to treatable inborn metabolic diseases: an introduction. J Inherit Metab Dis 29: 261–274

    Article  PubMed  Google Scholar 

  4. Saudubray JM et al. (2006) A clinical approach to inherited metabolic disorders. In Inborn Metabolic Diseases: Diagnosis and Treatment, 3–48 (Eds Saudubray JM et al.) Berlin: Springer-Verlag

    Chapter  Google Scholar 

  5. Saudubray JM and Charpentier C (2001) Clinical phenotypes: Diagnosis/Algorithms. In The Metabolic and Molecular Bases of Inherited Diseases, edn 8, 1327–1407 (Eds Scriver CR et al.) New York: McGraw Hill

    Google Scholar 

  6. DiMagno EP et al. (1986) Ornithine transcarbamylase deficiency—a cause of bizarre behavior in a man. N Engl J Med 315: 744–747

    Article  CAS  PubMed  Google Scholar 

  7. Arn PH et al. (1990) Hyperammonemia in women with a mutation at the ornithine carbamoyltransferase locus: a cause of postpartum coma. N Engl J Med 322: 1652–1655

    Article  CAS  PubMed  Google Scholar 

  8. Bogdanovic MD et al. (2000) Late onset heterozygous ornithine transcarbamylase deficiency mimicking complex partial status epilepticus. J Neurol Neurosurg Psychiatry 69: 813–815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Oechsner M et al. (1998) Hyperammonaemic encephalopathy after initiation of valproate therapy in unrecognised ornithine transcarbamylase deficiency. J Neurol Neurosurg Psychiatry 64: 680–682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nassogne MC et al. (2001) Hereditary metabolic causes of stroke and pseudo-stroke in adulthood. Rev Med Interne 22 (Suppl 3): S338–S346

    Google Scholar 

  11. Eather G et al. (2006) Carbamyl phosphate synthase deficiency: diagnosed during pregnancy in a 41-year-old. J Clin Neurosci 13: 702–706

    Article  CAS  PubMed  Google Scholar 

  12. Cowley DM et al. (1998) Adult-onset arginase deficiency. J Inherit Metab Dis 21: 677–678

    Article  CAS  PubMed  Google Scholar 

  13. Enns GM et al. (2005) Postpartum “psychosis” in mild argininosuccinate synthetase deficiency. Obstet Gynecol 105: 1244–1246

    Article  PubMed  Google Scholar 

  14. Pasquier F et al. (1994) Methylenetetrahydrofolate reductase deficiency revealed by a neuropathy in a psychotic adult. J Neurol Neurosurg Psychiatry 57: 765–766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Freeman JM et al. (1975) Folate-responsive homocystinuria and “schizophrenia”. A defect in methylation due to deficient 5,10-methylenetetrahydrofolate reductase activity. N Engl J Med 292: 491–496

    Article  CAS  PubMed  Google Scholar 

  16. Walk D et al. (1994) Intermittent encephalopathy, reversible nerve conduction slowing, and MRI evidence of cerebral white matter disease in methylenetetrahydrofolate reductase deficiency. Neurology 44: 344–347

    Article  CAS  PubMed  Google Scholar 

  17. Haworth JC et al. (1993) Symptomatic and asymptomatic methylenetetrahydrofolate reductase deficiency in two adult brothers. Am J Med Genet 45: 572–576

    Article  CAS  PubMed  Google Scholar 

  18. Roze E et al. (2003) Neuropsychiatric disturbances in presumed late-onset cobalamin C disease. Arch Neurol 60: 1457–1462

    Article  PubMed  Google Scholar 

  19. Kauppinen R (2005) Porphyrias. Lancet 365: 241–252

    Article  CAS  PubMed  Google Scholar 

  20. Crimlisk HL (1997) The little imitator—porphyria: a neuropsychiatric disorder. J Neurol Neurosurg Psychiatry 62: 319–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Asola MR (1995) A diver unconscious after gastroenteritis. Lancet 346: 1338

    Article  CAS  PubMed  Google Scholar 

  22. Hall DA and Ringel SP (2004) Adult nonketotic hyperglycinemia (NKH) crisis presenting as severe chorea and encephalopathy. Mov Disord 19: 485–486

    Article  PubMed  Google Scholar 

  23. Livingstone IR et al. (1984) Familial intermittent ataxia with possible X-linked recessive inheritance: two patients with abnormal pyruvate metabolism and a response to acetazolamide. J Neurol Sci 64: 89–97

    Article  CAS  PubMed  Google Scholar 

  24. Feillet F et al. (2003) Adult presentation of MCAD deficiency revealed by coma and severe arrythmias. Intensive Care Med 29: 1594–1597

    Article  CAS  PubMed  Google Scholar 

  25. Ozand PT et al. (1998) Biotin-responsive basal ganglia disease: a novel entity. Brain 121: 1267–1279

    Article  PubMed  Google Scholar 

  26. Pendlebury ST et al. (2004) Strokelike presentation of Wilson disease with homozygosity for a novel T766R mutation. Neurology 63: 1982–1983

    Article  CAS  PubMed  Google Scholar 

  27. Mudd SH et al. (1985) The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 37: 1–31

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kelly PJ et al. (2003) Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency. Neurology 60: 275–279

    Article  CAS  PubMed  Google Scholar 

  29. Visy JM et al. (1991) Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency revealed by stroke in adult siblings. Neurology 41: 1313–1315

    Article  CAS  PubMed  Google Scholar 

  30. Mitsias P and Levine SR (1996) Cerebrovascular complications of Fabry's disease. Ann Neurol 40: 8–17

    Article  CAS  PubMed  Google Scholar 

  31. Rolfs A et al. (2005) Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet 366: 1794–1796

    Article  PubMed  Google Scholar 

  32. Fellgiebel A et al. (2006) CNS manifestations of Fabry's disease. Lancet Neurol 5: 791–795

    Article  PubMed  Google Scholar 

  33. Dinopoulos A et al. (2005) Atypical variants of non-ketotic hyperglycinemia. Mol Genet Metab 86: 61–69

    Article  CAS  PubMed  Google Scholar 

  34. Zeng WQ et al. (2005) Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet 77: 16–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kitzberger R et al. (2005) Wilson disease. Metab Brain Dis 20: 295–302

    Article  PubMed  Google Scholar 

  36. Mellick G et al. (2004) Late-onset presentation of pyruvate dehydrogenase deficiency. Mov Disord 19: 727–729

    Article  PubMed  Google Scholar 

  37. Van Maldergem L et al. (2002) Coenzyme Q-responsive Leigh's encephalopathy in two sisters. Ann Neurol 52: 750–754

    Article  CAS  PubMed  Google Scholar 

  38. Lopez LC et al. (2006) Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. Am J Hum Genet 79: 1125–1129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ramaekers VT et al. (2005) Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med 352: 1985–1991

    Article  CAS  PubMed  Google Scholar 

  40. Berg D and Hochstrasser H (2006) Iron metabolism in Parkinsonian syndromes. Mov Disord 21: 1299–1310

    Article  PubMed  Google Scholar 

  41. Segawa M et al. (2003) Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease). Ann Neurol 54 (Suppl 6): S32–S45

    Article  CAS  PubMed  Google Scholar 

  42. Schiller A et al. (2004) Long-term course of L-dopa-responsive dystonia caused by tyrosine hydroxylase deficiency. Neurology 63: 1524–1526

    Article  CAS  PubMed  Google Scholar 

  43. Friedman J et al. (2006) Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Neurology 67: 2032–2035

    Article  PubMed  Google Scholar 

  44. Tanaka K et al. (1987) Dihydrobiopterin synthesis defect: an adult with diurnal fluctuation of symptoms. Neurology 37: 519–522

    Article  CAS  PubMed  Google Scholar 

  45. Pogson D (1997) Issues for consideration in dihydropteridine reductase (DHPR) deficiency: a variant form of hyperphenylalaninaemia. J Intellect Disabil Res 41: 208–214

    Article  PubMed  Google Scholar 

  46. Sedel F et al. (2006) Dihydropteridine reductase deficiency: levodopa's long-term effectiveness without dyskinesia. Neurology 67: 2243–2245

    Article  CAS  PubMed  Google Scholar 

  47. Kempster PA et al. (1988) Dystonia in homocystinuria. J Neurol Neurosurg Psychiatry 51: 859–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tayebi N et al. (2003) Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol Genet Metab 79: 104–109

    Article  CAS  PubMed  Google Scholar 

  49. Verrips A et al. (2000) Cerebrotendinous xanthomatosis: controversies about nerve and muscle: observations in ten patients. Neuromuscul Disord 10: 407–414

    Article  CAS  PubMed  Google Scholar 

  50. Illingworth DR et al. (1980) Abetalipoproteinemia: report of two cases and review of therapy. Arch Neurol 37: 659–662

    Article  CAS  PubMed  Google Scholar 

  51. Jung KH et al. (2005) Wilson disease with an initial manifestation of polyneuropathy. Arch Neurol 62: 1628–1631

    Article  PubMed  Google Scholar 

  52. Wolf B et al. (1998) Delayed-onset profound biotinidase deficiency. J Pediatr 132: 362–365

    Article  CAS  PubMed  Google Scholar 

  53. Mitchell G et al. (1990) Neurologic crises in hereditary tyrosinemia. N Engl J Med 322: 432–437

    Article  CAS  PubMed  Google Scholar 

  54. Debray FG et al. (2006) Intermittent peripheral weakness as the presenting feature of pyruvate dehydrogenase deficiency. Eur J Pediatr 165: 462–466

    Article  PubMed  Google Scholar 

  55. Wills AJ et al. (2001) Refsum's disease. QJM 94: 403–406

    Article  CAS  PubMed  Google Scholar 

  56. Ibdah JA et al. (1998) Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype–phenotype correlation. J Clin Invest 102: 1193–1199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. De Koning TJ et al. (1999) Continuing education in neurometabolic disorders—serine deficiency disorders. Neuropediatrics 30: 1–4

    Article  CAS  PubMed  Google Scholar 

  58. Baumgartner MR et al. (1998) Clinical approach to inherited peroxisomal disorders: a series of 27 patients. Ann Neurol 44: 720–730

    Article  CAS  PubMed  Google Scholar 

  59. Ferdinandusse S et al. (2000) Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Genet 24: 188–191

    Article  CAS  PubMed  Google Scholar 

  60. Powers JM et al. (2001) Neurological and neuropathologic heterogeneity in two brothers with cobalamin C deficiency. Ann Neurol 49: 396–400

    Article  CAS  PubMed  Google Scholar 

  61. Salvi FM et al. (2001) Clinical and molecular findings in hyperornithinemia–hyperammonemia–homocitrullinuria syndrome. Neurology 57: 911–914

    Article  CAS  PubMed  Google Scholar 

  62. Kasim S et al. (2001) Phenylketonuria presenting in adulthood as progressive spastic paraparesis with dementia. J Neurol Neurosurg Psychiatry 71: 795–797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. McCombe PA et al. (1992) Spasticity and white matter abnormalities in adult phenylketonuria. J Neurol Neurosurg Psychiatry 55: 359–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hansen FJ and Blau N (2005) Cerebral folate deficiency: life-changing supplementation with folinic acid. Mol Genet Metab 84: 371–373

    Article  CAS  PubMed  Google Scholar 

  65. Verrips A et al. (1999) Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis. Brain 122: 1589–1595

    Article  PubMed  Google Scholar 

  66. Tokatli A et al. (1997) Biotinidase deficiency with neurological features resembling multiple sclerosis. J Inherit Metab Dis 20: 707–708

    Article  CAS  PubMed  Google Scholar 

  67. Patel K et al. (1995) Dopa responsive dystonia. Arch Dis Child 73: 256–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Furukawa Y et al. (2001) Dopa-responsive dystonia simulating spastic paraplegia due to tyrosine hydroxylase (TH) gene mutations. Neurology 56: 260–263

    Article  CAS  PubMed  Google Scholar 

  69. Martinello F et al. (1998) Supplemental therapy in isolated vitamin E deficiency improves the peripheral neuropathy and prevents the progression of ataxia. J Neurol Sci 156: 177–179

    Article  CAS  PubMed  Google Scholar 

  70. Homer VM et al. (2005) Mental retardation and ataxia due to normotriglyceridemic hypobetalipoproteinemia. Ann Neurol 58: 160–163

    Article  PubMed  Google Scholar 

  71. Verrips A et al. (2000) Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain 123: 908–919

    Article  PubMed  Google Scholar 

  72. Lamperti C et al. (2003) Cerebellar ataxia and coenzyme Q10 deficiency. Neurology 60: 1206–1208

    Article  CAS  PubMed  Google Scholar 

  73. Bressman S et al. (1986) Biotin-responsive encephalopathy with myoclonus, ataxia, and seizures. Adv Neurol 43: 119–125

    CAS  PubMed  Google Scholar 

  74. Ryan MM et al. (2002) Homocystinuria presenting as psychosis in an adolescent. J Child Neurol 17: 859–860

    Article  PubMed  Google Scholar 

  75. Akil M et al. (1991) The psychiatric presentations of Wilson's disease. J Neuropsychiatry Clin Neurosci 3: 377–382

    Article  CAS  PubMed  Google Scholar 

  76. Berginer VM et al. (1988) Psychiatric disorders in patients with cerebrotendinous xanthomatosis. Am J Psychiatry 145: 354–357

    Article  CAS  PubMed  Google Scholar 

  77. Abbott MH et al. (1987) Psychiatric manifestations of homocystinuria due to cystathionine beta-synthase deficiency: prevalence, natural history, and relationship to neurologic impairment and vitamin B6-responsiveness. Am J Med Genet 26: 959–969

    Article  CAS  PubMed  Google Scholar 

  78. Turpin JC and Baumann N (2003) Presenting psychiatric and cognitive disorders in adult neurolipidoses. Rev Neurol (Paris) 159: 637–647

    Google Scholar 

  79. Brockmann K et al. (2001) Autosomal dominant glut-1 deficiency syndrome and familial epilepsy. Ann Neurol 50: 476–485

    Article  CAS  PubMed  Google Scholar 

  80. Klepper J et al. (2001) Autosomal dominant transmission of GLUT1 deficiency. Hum Mol Genet 10: 63–68

    Article  CAS  PubMed  Google Scholar 

  81. Winkelman MD et al. (1983) Non-infantile neuronopathic Gaucher's disease: a clinicopathologic study. Neurology 33: 994–1008

    Article  CAS  PubMed  Google Scholar 

  82. Winkler AS et al. (2005) Neuropsychiatric porphyria in patients with refractory epilepsy: report of three cases. J Neurol Neurosurg Psychiatry 76: 380–383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Dening TR et al. (1988) Wilson's disease and epilepsy. Brain 111: 1139–1155

    Article  PubMed  Google Scholar 

  84. Arlazoroff A et al. (1991) Epileptic seizure as a presenting symptom of cerebrotendinous xanthomatosis. Epilepsia 32: 657–661

    Article  CAS  PubMed  Google Scholar 

  85. Clayton PT (2006) B6-responsive disorders: a model of vitamin dependency. J Inherit Metab Dis 29: 317–326

    Article  CAS  PubMed  Google Scholar 

  86. Filley CM and Kleinschmidt-DeMasters BK (2001) Toxic leukoencephalopathy. N Engl J Med 345: 425–432

    Article  CAS  PubMed  Google Scholar 

  87. Barkhof F et al. (2000) Cerebrotendinous xanthomatosis: the spectrum of imaging findings and the correlation with neuropathologic findings. Radiology 217: 869–876

    Article  CAS  PubMed  Google Scholar 

  88. Boxer AL et al. (2005) Executive dysfunction in hyperhomocystinemia responds to homocysteine-lowering treatment. Neurology 64: 1431–1434

    Article  CAS  PubMed  Google Scholar 

  89. Bahr O et al. (2002) Adult onset glutaric aciduria type I presenting with a leukoencephalopathy. Neurology 59: 1802–1804

    Article  CAS  PubMed  Google Scholar 

  90. Kulkens S et al. (2005) Late-onset neurologic disease in glutaryl-CoA dehydrogenase deficiency. Neurology 64: 2142–2144.

    Article  CAS  PubMed  Google Scholar 

  91. Thompson AJ et al. (1993) Brain MRI changes in phenylketonuria: associations with dietary status. Brain 116: 811–821.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. F Sedel is a Hospital Practitioner in the Department of Neurology at Salpêtrière Hospital, O Lyon-Caen is Head of the Department of Neurology at Salpêtrière Hospital and Professor of Neurology at the Pierre et Marie Curie University, Paris VI, and J-M Saudubray is Full Professor of Pediatrics and Genetics at the Necker Enfants Malades Hospital and the René Descartes University Paris V, Paris, France.,

    Frédéric Sedel, Olivier Lyon-Caen & Jean-Marie Saudubray

Authors
  1. Frédéric Sedel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Olivier Lyon-Caen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean-Marie Saudubray
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frédéric Sedel.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Proposed treatments in adult neurometabolic diseases (DOC 102 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sedel, F., Lyon-Caen, O. & Saudubray, JM. Therapy Insight: inborn errors of metabolism in adult neurology—a clinical approach focused on treatable diseases. Nat Rev Neurol 3, 279–290 (2007). https://doi.org/10.1038/ncpneuro0494

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpneuro0494

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing