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.
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Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, et al (1992) Brain MRI and electrophysiologic abnormalities in preclinical and clinical adrenomyeloneuropathy. Neurology 42: 85–91.
Bach G (2001) Mucolipidosis type IV. Mol Genet Metab 73: 197–203.
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.
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.
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.
Baumann N, Turpin JC (2000) Adult-onset leukodystrophies. J Neurol 247: 751–759.
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.
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.
Berkhoff M, Weis J, Schroth G, Sturzenegger M (2001) Extensive white-matter changes in case of adult polyglucosan body disease. Neuroradiology 43: 234–236.
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.
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.
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.
Bosch EP, Hart MN (1978) Late adult-onset metachromatic leucodystrophy. Dementia and polyneuropathy in a 63-year-old-man. Arch Neurol 35: 475–477.
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.
Brady RO, Schiffmann R (2000) Clinical features of and recent advances in therapy for Fabry disease. JAMA 284: 2771–2775.
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.
Eriguchi M, Mizuta H, Kurohara K, et al (2006) 3-Methylglutaconic aciduria type I causes leukoencephalopathy of adult onset. Neurology 67: 1895–1896.
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.
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.
Filley CM, Kleinschmidt-DeMasters BK (2001) Toxic leukoencephalopathy. N Engl J Med 345: 425–432.
Finsterer J (2006) Central nervous system manifestations of mitochondrial disorders. Acta Neurol Scand 114: 217–238.
Fontaine B, Thenin JP, Viader F (2003) Gait disorders with insidious progression in a 60-year old woman. Rev Neurol (Paris) 159: 695–699.
Frei KP, Patronas NJ, Crutchfield KE, Altarescu G, Schiffmann R (1998) Mucolipidosis type IV: characteristic MRI findings. Neurology 51: 565–569.
Grunewald S, Champion MP, Leonard JV, Schaper J, Morris AA (2004) Biotinidase deficiency: a treatable leukoencephalopathy. Neuropediatrics 35: 211–216.
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.
Henderson RD, MacMillan JC, Bradfield JM (2003) Adult onset Krabbe disease may mimic motor neurone disease. J Clin Neurosci 10: 638–639.
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.
Hörster F, Surtees R, Hoffmann GF (2005) Disorders of intermediary metabolism: toxic leukoencephalopathies. J Inherit Metab Dis 28: 345–356.
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.
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.
Jaros E, Mahad DJ, Hudson G, et al (2007) Primary spinal cord neurodegeneration in Leber hereditary optic neuropathy. Neurology 69: 214–216.
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.
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.
Kiselyov K, Soyombo A, Muallem S (2007) TRPpathies. J Physiol 578: 641–653.
Krivit W, Shapiro EG, Peters C, et al (1998) Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy. N Engl J Med 338: 1119–1126.
Kulkens S, Harting I, Sauer S, et al (2005) Late-onset neurologic disease in glutaryl-CoA dehydrogenase deficiency. Neurology 64: 2142–2144.
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.
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.
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.
Lorincz MT, Rainier S, Thomas D, Fink JK (2005) Cerebrotendinous xanthomatosis. Possible higher prevalence than previously recognized. Arch Neurol 62: 1459–1463.
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.
Menage P, Carreau V, Tourbah A, et al (1993) [Symptomatic heterozygotic adrenoleukodystrophy in adults. 10 cases] [In French]. Rev Neurol (Paris) 149: 445–454.
Mitsias P, Levine SR (1996) Cerebrovascular complications of Fabry’s disease. Ann Neurol 40: 8–17.
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.
Moser HW, Mahmood A, Raymond GV (2007) X-linked adrenoleukodystrophy. Nat Clin Pract Neurol 3: 140–151.
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.
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.
Rauschka H, Colsch B, Baumann N, et al (2006) Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype. Neurology 67: 859–863.
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.
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.
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.
Schiffmann R, van der Knaap MS (2004) The latest on leukodystrophies. Curr Opin Neurol 17: 187–192.
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.
Sedel F, Tourbah A, Baumann N, et al (2005) Adult onset leukodystrophies. Rev Neurol (Paris) 161: 916–931.
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.
Tészas A, Pfund Z, Morava E, et al (2006) Presenile cataract: consider cholestanol. Arch Ophthalmol 124: 1490–1492.
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.
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.
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.
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.
Verrips A, Hoefsloot LH, Steenbergen GC, et al (2000) Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain 123: 908–919.
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.
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.
Weglage J, Oberwittler C, Marquardt T (2000) Neurological deterioration in adult phenylketonuria. J Inherit Metab Dis 23: 83–84.
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.
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.
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.
Wray SH, Provenzale JM, Johns DR, Thulborn KR (1995) MR of the brain in mitochondrial myopathy. AJNR Am J Neuroradiol 16: 1167–1173.
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.
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Communicating editor: John Walter
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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
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DOI: https://doi.org/10.1007/s10545-008-0778-0