Skip to main content
Log in

Leukoencephalopathies associated with inborn errors of metabolism in adults

  • Review
  • Published:
Journal of Inherited Metabolic Disease

Summary

The discovery of a leukoencephalopathy is a frequent situation in neurological practice and the diagnostic approach is often difficult given the numerous possible aetiologies, which include multiple acquired causes and genetic diseases including inborn errors of metabolism (IEMs). It is now clear that IEMs can have their clinical onset from early infancy until late adulthood. These diseases are particularly important to recognize because specific treatments often exist. In this review, illustrated by personal observations, we give an overview of late-onset leukoencephalopathies caused by IEMs.

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

Access this article

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

References

  • Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, et al (1992) Brain MRI and electrophysiologic abnormalities in preclinical and clinical adrenomyeloneuropathy. Neurology 42: 85–91.

    CAS  PubMed  Google Scholar 

  • Bach G (2001) Mucolipidosis type IV. Mol Genet Metab 73: 197–203.

    Article  CAS  PubMed  Google Scholar 

  • Bajaj NPS, Waldmann A, Orrell B, Wood NW, Bhatia KP (2002) Familial adult onset of Krabbe’s disease resembling hereditary spastic paraplegia with normal neuroimaging. J Neurol Neurosurg Psychiatry 72: 635–638.

    Article  CAS  PubMed  Google Scholar 

  • Barkhof F, Verrips A, Wesseling P, et al (2000) Cerebrotendinous xanthomatosis: the spectrum of imaging findings and the correlation with neuropathologic findings. Radiology 217: 869–876.

    CAS  PubMed  Google Scholar 

  • Bataillard M, Richard P, Rumbach L, Vanier MT, Truttmann M (1997) Isolated spastic paraparesis disclosing Krabbe disease in adult age. Rev Neurol (Paris) 153: 347–350.

    CAS  Google Scholar 

  • Baumann N, Turpin JC (2000) Adult-onset leukodystrophies. J Neurol 247: 751–759.

    Article  CAS  PubMed  Google Scholar 

  • Baumann N, Masson M, Carreau V, Lefevre M, Hersckowitz N, Turpin JC (1991) Adult forms of metachromatic leukodystrophy: clinical and biochemical approach. Dev Neurosci 13: 211–215.

    Article  CAS  PubMed  Google Scholar 

  • Baumgartner MR, Poll-The BT, Verhoeven NM, et al (1998) Clinical approach to inherited peroxisomal disorders: a series of 27 patients. Ann Neurol 44: 720–730.

    Article  CAS  PubMed  Google Scholar 

  • Berkhoff M, Weis J, Schroth G, Sturzenegger M (2001) Extensive white-matter changes in case of adult polyglucosan body disease. Neuroradiology 43: 234–236.

    Article  CAS  PubMed  Google Scholar 

  • Bianchi MC, Tosetti M, Battini R (2003) Proton MR spectroscopy of mitochondrial diseases: analysis of brain metabolic abnormalities and their possible diagnostic relevance. Am J Neuroradiol 24: 1958–1966.

    PubMed  Google Scholar 

  • Bischof F, Nagele T, Wanders RJ, Trefz FK, Melms A (2004) 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency in an adult with leukoencephalopathy. Ann Neurol 56: 727–730.

    Article  PubMed  Google Scholar 

  • Bjorkhem I, Muri Boberg K, Leitersdorf E (2001) Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 2961–2988.

    Google Scholar 

  • Bosch EP, Hart MN (1978) Late adult-onset metachromatic leucodystrophy. Dementia and polyneuropathy in a 63-year-old-man. Arch Neurol 35: 475–477.

    CAS  PubMed  Google Scholar 

  • Boxer AL, Kramer JH, Johnston K, Goldman J, Finley R, Miller BL (2005) Executive dysfunction in hyperhomocystinemia responds to homocysteine lowering treatment. Neurology 64: 1431–1434.

    CAS  PubMed  Google Scholar 

  • Brady RO, Schiffmann R (2000) Clinical features of and recent advances in therapy for Fabry disease. JAMA 284: 2771–2775.

    Article  CAS  PubMed  Google Scholar 

  • Deconinck N, Messaaoui A, Ziereisen F, et al (2007) Metachromatic leukodystrophy without arylsulfatase A deficiency: a new case of saposin-B deficiency. Eur J Paediatr Neurol [E-pub ahead of print].

  • Eichler F, Mahmood A, Loes D, et al (2007) Magnetic resonance imaging detection of lesion progression in adult patients with X-linked adrenoleukodystrophy. Arch Neurol 64: 659–664.

    Article  PubMed  Google Scholar 

  • Eriguchi M, Mizuta H, Kurohara K, et al (2006) 3-Methylglutaconic aciduria type I causes leukoencephalopathy of adult onset. Neurology 67: 1895–1896.

    Article  CAS  PubMed  Google Scholar 

  • Farina L, Bizzi A, Finocchiaro G, et al (2000) MR imaging and proton MR spectroscopy in adult Krabbe disease. Am J Neuroradiol 21: 1478–1482.

    CAS  PubMed  Google Scholar 

  • Fellgiebel A, Muller MJ, Mazanek M, Baron K, Beck M, Stoeter P (2005) White matter lesion severity in male and female patients with Fabry disease. Neurology 23: 65: 600–602.

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Finsterer J (2006) Central nervous system manifestations of mitochondrial disorders. Acta Neurol Scand 114: 217–238.

    Article  CAS  PubMed  Google Scholar 

  • Fontaine B, Thenin JP, Viader F (2003) Gait disorders with insidious progression in a 60-year old woman. Rev Neurol (Paris) 159: 695–699.

    CAS  Google Scholar 

  • Frei KP, Patronas NJ, Crutchfield KE, Altarescu G, Schiffmann R (1998) Mucolipidosis type IV: characteristic MRI findings. Neurology 51: 565–569.

    CAS  PubMed  Google Scholar 

  • Grunewald S, Champion MP, Leonard JV, Schaper J, Morris AA (2004) Biotinidase deficiency: a treatable leukoencephalopathy. Neuropediatrics 35: 211–216.

    Article  CAS  PubMed  Google Scholar 

  • Harzer K, Knoblich R, Rolfs A, Bauer P, Eggers J (2002) Residual galactosylsphingosine (psychosine) beta-galactosidase activities and associated GALC mutations in late and very late onset Krabbe disease. Clin Chim Acta 317: 77–84.

    Article  CAS  PubMed  Google Scholar 

  • Henderson RD, MacMillan JC, Bradfield JM (2003) Adult onset Krabbe disease may mimic motor neurone disease. J Clin Neurosci 10: 638–639.

    Article  CAS  PubMed  Google Scholar 

  • Hirano M, Silvestri G, Blake DM, et al (1994) Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology 44: 721–727.

    CAS  PubMed  Google Scholar 

  • Hörster F, Surtees R, Hoffmann GF (2005) Disorders of intermediary metabolism: toxic leukoencephalopathies. J Inherit Metab Dis 28: 345–356.

    Article  PubMed  CAS  Google Scholar 

  • Huck JH, Verhoeven NM, Struys EA, Salomons GS, Jakobs C, van der Knaap MS (2004) Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy. Am J Hum Genet 74: 745–751.

    Article  CAS  PubMed  Google Scholar 

  • Janson CG, Kolodny EH, Zeng BJ, et al (2006) Mild-onset presentation of Canavan’s disease associated with novel G212A point mutation in aspartoacylase gene. Ann Neurol 59: 428–431.

    Article  CAS  PubMed  Google Scholar 

  • Jaros E, Mahad DJ, Hudson G, et al (2007) Primary spinal cord neurodegeneration in Leber hereditary optic neuropathy. Neurology 69: 214–216.

    Article  CAS  PubMed  Google Scholar 

  • Kasim S, Moo LR, Zschocke J, Jinnah HA (2001) Phenylketonuria presenting in adulthood as progressive spastic paraparesis with dementia. J Neurol Neurosurg Psychiatry 71: 795–797.

    Article  CAS  PubMed  Google Scholar 

  • Kidd D, Nelson J, Jones F, et al (1998) Long-term stabilization after bone marrow transplantation in juvenile metachromatic leukodystrophy. Arch Neurol 55: 98–99.

    Article  CAS  PubMed  Google Scholar 

  • Kiselyov K, Soyombo A, Muallem S (2007) TRPpathies. J Physiol 578: 641–653.

    Article  CAS  PubMed  Google Scholar 

  • Krivit W, Shapiro EG, Peters C, et al (1998) Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy. N Engl J Med 338: 1119–1126.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kuriyama M, Fujiyama J, Yoshidome H, et al (1991) Cerebrotendinous xanthomatosis: clinical and biochemical evaluation of eight patients and review of the literature. J Neurol Sci 102: 225–232.

    Article  CAS  PubMed  Google Scholar 

  • Lerman-Sagie T, Leshinsky-Silver E, Watemberg N, Luckman Y, Lev D (2005) White matter involvement in mitochondrial diseases. Mol Genet Metab 84: 127–136.

    Article  CAS  PubMed  Google Scholar 

  • Lin DD, Crawford TO, Barker PB (2003) Proton MR spectroscopy in the diagnostic evaluation of suspected mitochondrial disease. AJNR Am J Neuroradiol 24: 33–41.

    PubMed  Google Scholar 

  • Lorincz MT, Rainier S, Thomas D, Fink JK (2005) Cerebrotendinous xanthomatosis. Possible higher prevalence than previously recognized. Arch Neurol 62: 1459–1463.

    Article  PubMed  Google Scholar 

  • McCombe PA, McLaughlin DB, Chalk JB, Brown NN, McGill JJ, Pender MP (1992) Spasticity and white matter abnormalities in adult phenylketonuria. J Neurol Neurosurg Psychiatry 55: 359–361.

    Article  CAS  PubMed  Google Scholar 

  • Menage P, Carreau V, Tourbah A, et al (1993) [Symptomatic heterozygotic adrenoleukodystrophy in adults. 10 cases] [In French]. Rev Neurol (Paris) 149: 445–454.

    CAS  Google Scholar 

  • Mitsias P, Levine SR (1996) Cerebrovascular complications of Fabry’s disease. Ann Neurol 40: 8–17.

    Article  CAS  PubMed  Google Scholar 

  • Moser AB, Rasmussen M, Naidu S, et al (1995) Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups. J Pediatr 127: 13–22.

    Article  CAS  PubMed  Google Scholar 

  • Moser HW, Mahmood A, Raymond GV (2007) X-linked adrenoleukodystrophy. Nat Clin Pract Neurol 3: 140–151.

    Article  PubMed  Google Scholar 

  • Ogier de Baulny H, Gerard M, Saudubray JM, Zittoun J (1998) Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr 157(Supplement 2): S77–83.

    Article  PubMed  Google Scholar 

  • Owens WE, Okun MS (2004) Dystonia, tremor, and parkinsonism in a 54 year old man with 2-hydroxyglutaric aciduria. J Neurol Neurosurg Psychiatry 75: 1362–1363.

    Article  CAS  PubMed  Google Scholar 

  • Rauschka H, Colsch B, Baumann N, et al (2006) Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype. Neurology 67: 859–863.

    Article  CAS  PubMed  Google Scholar 

  • Reis S, Sheffer RN, Merin S, Luder AS, Bach G (1993) Mucolipidosis type IV: a mild form with late onset. Am J Med Genet 47: 392–394.

    Article  CAS  PubMed  Google Scholar 

  • Sabatelli M, Quaranta L, Madia F, et al (2002) Peripheral neuropathy with hypomyelinating features in adult-onset Krabbe’s disease. Neuromuscul Disord 12: 386–391.

    Article  CAS  PubMed  Google Scholar 

  • Sakakibara R, Fukutake T, Arai K, Katayama K, Mori M, Hattori T (2001) Unilateral caudate head lesion stimulating brain tumour in X-linked adult onset adrenoleukodystrophy. J Neurol Neurosurg Psychiatry 70: 414–415.

    Article  CAS  PubMed  Google Scholar 

  • Schiffmann R, van der Knaap MS (2004) The latest on leukodystrophies. Curr Opin Neurol 17: 187–192.

    Article  CAS  PubMed  Google Scholar 

  • Schiffmann R, Dwyer NK, Lubensky IA, et al (1998) Constitutive achlorhydria in mucolipidosis type IV. Proc Natl Acad Sci U S A 95: 1207–1212.

    Article  CAS  PubMed  Google Scholar 

  • Sedel F, Tourbah A, Baumann N, et al (2005) Adult onset leukodystrophies. Rev Neurol (Paris) 161: 916–931.

    CAS  Google Scholar 

  • Sedel F, Lyon-Caen O, Saudubray JM (2007) Inborn errors of metabolism in adult neurology—a clinical approach focused on treatable diseases. Nat Clin Pract Neurol 3: 279–290.

    Article  CAS  PubMed  Google Scholar 

  • Tészas A, Pfund Z, Morava E, et al (2006) Presenile cataract: consider cholestanol. Arch Ophthalmol 124: 1490–1492.

    Article  PubMed  Google Scholar 

  • Thompson AJ, Tillotson S, Smith I, Kendall B, Moore SG, Brenton DP (1993) Brain MRI changes in phenylketonuria. Associations with dietary status. Brain 116: 811–821.

    Article  PubMed  Google Scholar 

  • Tourbah A, Stievenart JL, Iba-Zizen MT, et al (1997) Localized proton magnetic resonance spectroscopy in patients with adult adrenoleukodystrophy. Increase of choline compounds in normal appearing white matter. Arch Neurol 54: 586–592.

    CAS  PubMed  Google Scholar 

  • Turpin JC, Paturneau-Jouas M, Sereni C, Pluot M, Baumann N (1985) Adult disclosure of a case of familial adrenoleukodystrophy. Rev Neurol (Paris) 141: 289–295.

    CAS  Google Scholar 

  • Van Geel BM, Bezman L, Loes DJ, Moser HW, Raymond GV (2001) Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy. Ann Neurol 49: 186–194.

    Article  PubMed  Google Scholar 

  • Verrips A, Hoefsloot LH, Steenbergen GC, et al (2000) Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain 123: 908–919.

    Article  PubMed  Google Scholar 

  • Von Figura K, Gieselmann V, Jaeken J (2001) Metachromatic leukodystrophy. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 3695–3724.

    Google Scholar 

  • Walk D, Kang SS, Horwitz A (1994) Intermittent encephalopathy, reversible nerve conduction slowing, and MRI evidence of cerebral white matter disease in methylenetetrahydrofolate reductase deficiency. Neurology 44: 344–347.

    CAS  PubMed  Google Scholar 

  • Weglage J, Oberwittler C, Marquardt T (2000) Neurological deterioration in adult phenylketonuria. J Inherit Metab Dis 23: 83–84.

    Article  CAS  PubMed  Google Scholar 

  • Wenger DA, Suzuki K, Suzuki Y, Suzuki K (2001) Galactosylceramide lipidosis: globoid cell leukodystrophy (Krabbe disease). In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 3669–3694.

    Google Scholar 

  • Willemsen MA, Ijlst L, Steijlen PM, et al (2001) Clinical, biochemical and molecular genetic characteristics of 19 patients with the Sjögren–Larsson syndrome. Brain 124: 1426–1437.

    Article  CAS  PubMed  Google Scholar 

  • Willemsen MA, Van Der Graaf M, Van Der Knaap MS, et al (2004) MR imaging and proton MR spectroscopic studies in Sjögren–Larsson syndrome: characterization of the leukoencephalopathy. Am J Neuroradiol 25: 649–657.

    PubMed  Google Scholar 

  • Wray SH, Provenzale JM, Johns DR, Thulborn KR (1995) MR of the brain in mitochondrial myopathy. AJNR Am J Neuroradiol 16: 1167–1173.

    CAS  PubMed  Google Scholar 

  • Ziemssen F, Sindern E, Schroder JM, et al (2000) Novel missense mutations in the glycogen-branching enzyme gene in adult polyglucosan body disease. Ann Neurol 47: 536–540.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to F. Sedel.

Additional information

Communicating editor: John Walter

Competing interests: None declared

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sedel, F., Tourbah, A., Fontaine, B. et al. Leukoencephalopathies associated with inborn errors of metabolism in adults. J Inherit Metab Dis 31, 295–307 (2008). https://doi.org/10.1007/s10545-008-0778-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-008-0778-0

Keywords

Navigation