Skip to main content

Advertisement

SpringerLink
Log in

Tools for diagnosis of leukodystrophies and other disorders presenting with white matter disease

  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Advances in biochemical techniques, molecular genetics, and neuroimaging, particularly magnetic resonance imaging, have made possible the diagnosis of a significant proportion of leukodystrophies. A specific diagnosis allows the physician to give prognostic information, monitor for known complications, and ultimately may allow disease specific therapeutics. The purpose of this review is to familiarize the reader with pertinent tools in the diagnosis of leukodystrophies and other white matter disorders that may present with white matter disease. The first section discusses conditions that may mimic leukodystrophy and how to exclude them. Although not meant to be an exhaustive summary, several key disorders and their clinical, biochemical, and neuroimaging features are presented. The second section focuses on classically described leukodystrophies and their diagnosis. Finally, a third section provides a diagnostic algorithm to help the clinician in the diagnosis of the patient with leukodystrophy.

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

Access this article

Log in via an institution

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 and Recommended Reading

  1. Pozo-Rosich P, Villoslada P, Canton A, et al.: Reversible white matter alterations in encephalopathy associated with autoimmune thyroid disease. J Neurol 2002, 249:1063–1065.

    Article  PubMed  Google Scholar 

  2. Prayer D, Grois N, Prosch H, et al.: MR imaging presentation of intracranial disease associated with Langerhans cell histiocytosis. Am J Neuroradiol 2004, 25:880–891.

    PubMed  Google Scholar 

  3. Longhi R, Valsasina R, Butte C, et al.: Cranial computerized tomography in dihydropteridine reductase deficiency. J Inherit Metab Dis 1985, 8:109–112.

    Article  PubMed  CAS  Google Scholar 

  4. Kendall BE, Kingsley DP, Leonard JV, et al.: Neurological features and computed tomography of the brain in children with ornithine carbamoyl transferase deficiency. J Neurol Neurosurg Psychiatry 1983, 46:28–34.

    PubMed  CAS  Google Scholar 

  5. Takayanagi M, Ohtake A, Ogura N, et al.: A female case of ornithine transcarbamylase deficiency with marked computed tomographic abnormalities of the brain. Brain Dev 1984, 6:58–60.

    PubMed  CAS  Google Scholar 

  6. Christodoulou J, Qureshi A, McInnes RR, Clarke JT: Ornithine transcarbamylase deficiency presenting with strokelike episodes. J Pediatr 1993, 122:423–425.

    Article  PubMed  CAS  Google Scholar 

  7. Kurihara K, Takanashi J, Tomita M, et al.: Magnetic resonance imagine in late onset ornithine transcarbamylase deficiency. Brain Dev 2003, 25:40–44.

    Article  PubMed  Google Scholar 

  8. Jan W, Zimmerman RA, Wang ZJ, et al.: MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation. Neuroradiology 2003, 45:393–399.

    Article  PubMed  Google Scholar 

  9. Sener RN: Diffusion magnetic resonance imaging in intermediate form of maple syrup urine disease. J Neuroimaging 2002, 12:368–370.

    Article  PubMed  CAS  Google Scholar 

  10. Schonberger S, Schweiger B, Schwahn B, et al.: Dysmyelination in the brain of adolescents and young adults with maple syrup urine disease. Mol Genet Metab 2004, 82:69–75.

    Article  PubMed  CAS  Google Scholar 

  11. Press GA, Barshop BA, Haas RH, et al.: Abnormalities of the brain in nonketotic hyperglycinemia: MR manifestations. Am J Neuroradiol 1989, 10:315–321.

    PubMed  CAS  Google Scholar 

  12. Twomey EL, Naughten ER, Donoghue VB, Ryan S: Neuroimaging findings in glutaric aciduria type 1. Pediatr Radiol 2003, 33:823–830.

    Article  PubMed  Google Scholar 

  13. Uziel G, Garavaglia B, Ciceri E, et al.: Riboflavin-responsive glutaric aciduria type II presenting as a leukodystrophy. Pediatr Neurol 1995, 13:333–335.

    Article  PubMed  CAS  Google Scholar 

  14. van Domburg PH, Willemsen MA, Rotteveel JJ, et al.: Sjogren-Larsson syndrome: clinical and MRI/MRS findings in FALDH-deficient patients. Neurology 1999, 52:1345–1352.

    PubMed  Google Scholar 

  15. Feliz B, Witt DR, Harris BT: Propionic academia: a neuropathology case report and review of prior cases. Arch Pathol Lab Med 2003, 127:e325-e328.

    PubMed  Google Scholar 

  16. Darin N, Oldfors A, Moslemi AR, et al.: The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol 2001, 49:377–383.

    Article  PubMed  CAS  Google Scholar 

  17. Barkhof F, Verrips A, Wesseling P, et al.: Cerebrotendinous xanthomatosis: the spectrum of imaging findings and the correlation with neuropathologic findings. Radiology 2000, 7:869–876.

    Google Scholar 

  18. Poll-The BT, Gootjes J, Duran M, et al.: Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients. Am J Med Genet 2004, 126A:333–338.

    Article  PubMed  Google Scholar 

  19. Barth PG, Gootjes J, Bode H, et al.: Late onset white matter disease in peroxisome biogenesis disorder. Neurology 2001, 57:1949–1955. This is an excellent review of these underdiagnosed disorders

    PubMed  CAS  Google Scholar 

  20. Sylvain M, Arnold DL, Scriver CR, et al.: Magnetic resonance spectroscopy in Niemann-Pick disease type C: correlation with diagnosis and clinical response to cholestyramine and lovastatin. Pediatr Neurol 1994, 10:228–232.

    Article  PubMed  CAS  Google Scholar 

  21. Grau AJ, Brandt T, Weisbrod M, et al.: Adult Niemann-Pick disease type C mimicking features of multiple sclerosis. J Neurol Neurosurg Psychiatry 1997, 63:552.

    PubMed  CAS  Google Scholar 

  22. Chen CY, Zimmerman RA, Lee CC, et al.: Neuroimaging findings in late infantile GM1 gangliosidosis. Am J Neuroradiol 1998, 19:1628–1630.

    PubMed  CAS  Google Scholar 

  23. Campdelacreu J, Munoz E, Gomez B, et al.: Generalised dystonia with an abnormal magnetic resonance imaging signal in the basal ganglia: a case of adult-onset GM1 gangliosidosis. Mov Disord 2002, 17:1095–1097.

    Article  PubMed  Google Scholar 

  24. Mugikura S, Takahashi S, Higano S, et al.: MR findings in Tay-Sachs disease. J Comput Assist Tomogr 1996, 20:551–555.

    Article  PubMed  CAS  Google Scholar 

  25. Nassogne MC, Commare MC, Lellouch-Tubiana A, et al.: Unusual presentation of GM2 gangliosidosis mimicking a brain stem tumor in a 3-year-old girl. Am J Neuroradiol 2003, 24:840–842.

    PubMed  Google Scholar 

  26. Barone R, Parano E, Trifiletti RR, et al.: White matter changes mimicking a leukodystrophy in a patient with mucopolysaccharidosis: characterization by MRI. J Neurol Sci 2002, 195:171–175.

    Article  PubMed  Google Scholar 

  27. Matheus MG, Castillo M, Smith JK, et al.: Brain MRI findings in patients with mucopolysaccharidosis types I and II and mild clinical presentation. Neuroradiology 2004, 46:666–672.

    Article  PubMed  Google Scholar 

  28. Cheon JE, Kim IO, Hwang YS, et al.: Leukodystrophy in children: a pictoral review of MR Imaging Features. Radiographics 2002, 22:461–476. This is a good primer for recognition of MRI characteristics of common leukodystrophies and leukoencephalopathies

    PubMed  Google Scholar 

  29. Mackay MT, Kornberg AJ, Shield L, et al.: Congenital muscular dystrophy, white-matter abnormalities, and neuronal migration disorders: the expanding concept. J Child Neurol 1998, 13:481–487.

    PubMed  CAS  Google Scholar 

  30. Sugita K, Takanashi J, Ishii M, Niimi H: Comparison of MRI white matter changes with neuropsychologic impairment in Cockayne syndrome. Pediatr Neurol 1992, 8:295–298.

    Article  PubMed  CAS  Google Scholar 

  31. Thompson JE, Smith M, Castillo M, et al.: MR in children with L-carnitine deficiency. Am J Neuroradiol 1996, 17:1585–1588.

    PubMed  CAS  Google Scholar 

  32. Huck JH, Verhoeven NM, Struys EA, et al.: Ribose-5-phosphate isomerase deficiency: new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy. Am J Hum Genet 2004, 74:745–751.

    Article  PubMed  CAS  Google Scholar 

  33. Kim TS, Kim IO, Kim WS, et al.: MR of childhood metachromatic leukodystrophy. Am J Neuroradiol 1997, 18:733–738.

    PubMed  CAS  Google Scholar 

  34. Faerber EN, Melvin J, Smergel EM: MRI appearances of metachromatic leukodystrophy. Pediatr Radiol 1999, 29:669–672.

    Article  PubMed  CAS  Google Scholar 

  35. Jones BV, Barron TF, Towfighi J: Optic nerve enlargement in Krabbe’s disease. Am J Neuroradiol 1999, 20:1228–1231.

    PubMed  CAS  Google Scholar 

  36. Vasconcellos E, Smith M: MRI nerve root enhancement in Krabbe disease. Pediatr Neurol 1998, 19:151–152.

    Article  PubMed  CAS  Google Scholar 

  37. Given CA, Santos CC, Durden DD: Intracranial and spinal MR imaging findings associated with Krabbe’s disease: case report. Am J Neuroradiol 2001, 22:1782–1785.

    PubMed  Google Scholar 

  38. Loes DJ, Hite S, Moser H, et al.: Adrenoleukodystrophy: a scoring method for brain MR observations. Am J Neuroradiol 1994, 15:1761–1766.

    PubMed  CAS  Google Scholar 

  39. Toft PB, Geiss-Holtorff R, Rolland MO, et al.: Magnetic resonance imaging in juvenile Canavan disease. Eur J Pediatr 1993, 152:750–753.

    Article  PubMed  CAS  Google Scholar 

  40. van der Knaap MS, Naidu S, Breiter SN, et al.: Alexander disease: diagnosis with MR imaging. Am J Neuroradiol 2001, 22:541–552. This is the best overview of the MRI diagnosis of this common leukodystrophy.

    PubMed  Google Scholar 

  41. Hanefeld F, Holzbach U, Kruse B, et al.: Diffuse white matter disease in three children: an encephalopathy with unique features on magnetic resonance imaging and proton magnetic resonance spectroscopy. Neuropediatrics 1993, 24:244–248.

    PubMed  CAS  Google Scholar 

  42. Schiffmann R, Moller JR, Trapp BD, et al.: Childhood ataxia with diffuse central nervous system hypomyelination. Ann Neurol 1994, 35:331–340.

    Article  PubMed  CAS  Google Scholar 

  43. van der Knaap MS, Barth PG, Gabreels FJ, et al.: A new leukoencephalopathy with vanishing white matter. Neurology 1997, 48:845–855.

    PubMed  Google Scholar 

  44. van der Knaap MS, Wevers RA, Kure S, et al.: Increased cerebrospinal fluid glycine: a biochemical marker for a leukoencephalopathy with vanishing white matter. Ann Neurol 1999, 14:728–731.

    Google Scholar 

  45. van der Knaap MS, Leegwater PA, Konst AA, et al.: Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann Neurol 2002, 51:264–270. The authors provide a comprehensive review of this disorder and its genetic basis.

    Article  PubMed  CAS  Google Scholar 

  46. Hobson GM, Davis AP, Stowell NC, et al.: Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease. Neurology 2000, 55:1089–1096.

    PubMed  CAS  Google Scholar 

  47. Uhlenberg B, Schuelke M, Ruschendorf F, et al.: Mutations in the gene encoding gap junction protein alpha 12 (Connexin 46.6) cause pelizaeus-merzbacher-like disease. Am J Hum Genet 2004, 75:251–260.

    Article  PubMed  CAS  Google Scholar 

  48. Plecko B, Stockler-Ipsiroglu S, Gruber S, et al.: Degree of hypomyelination and magnetic resonance spectroscopy findings in patients with Pelizaeus Merzbacher phenotype. Neuropediatrics 2003, 34:127–136.

    Article  PubMed  CAS  Google Scholar 

  49. van der Knaap MS, Barth PG, Stroink H, et al.: Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol 1995, 37:324–334.

    Article  PubMed  Google Scholar 

  50. Leegwater PA, Yuan BQ, van der Steen J, et al.: Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet 2001, 68:831–838.

    Article  PubMed  CAS  Google Scholar 

  51. Tolmie JL, Shillito P, Hughes-Benzie R, Stephenson JB: TheAicardi-Goutieres syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis). J Med Genet 1995, 32:881–884.

    Article  PubMed  CAS  Google Scholar 

  52. Lebon P, Badoual J, Ponsot G, et al.: Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J Neurol Sci 1988, 84:201–208.

    Article  PubMed  CAS  Google Scholar 

  53. Crow YJ, Jackson AP, Roberts E, et al.: Aicardi-Goutieres syndrome displays genetic heterogeneity with one locus (AGS1) on chromosome 3p21. Am J Hum Genet 2000, 67:213–221.

    Article  PubMed  CAS  Google Scholar 

  54. Blau N, Bonafe L, Krageloh-Mann I, et al.: Cerebrospinal fluid pterins and folates in Aicardi-Goutieres syndrome: a new phenotype. Neurology 2003, 61:642–647.

    PubMed  CAS  Google Scholar 

  55. Polizzi A, Pavone P, Parano E, et al.: Lack of progression of brain atrophy in Aicardi-Goutieres syndrome. Pediatr Neurol 2001, 24:300–302.

    Article  PubMed  CAS  Google Scholar 

  56. van der Knaap MS, Naidu S, Pouwels PJ, et al.: New syndrome characterized by hypomyelination with atrophy of the basal ganglia and cerebellum. Am J Neuroradiol 2002, 23:1466–1474. The authors describe this new disorder.

    PubMed  Google Scholar 

  57. van der Knaap MS, van der Voom P, Barkof F, et al.: Anew leukoencephalopathy with brainstem and spinal cord involvement and high lactate. Ann Neurol 2003, 53:252–258. The authors describe this new disorder.

    Article  PubMed  Google Scholar 

  58. Linnankiviv T, Lundbom N, Autti T, et al.: Five new cases of a recently described leukoencephalopathy with brain lactate. Neurology 2004, 63:688–692.

    Google Scholar 

  59. Serko SV, Pronin IN, Bykova OV, et al.: Five patients with a recently described novel leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate. Neuropediatrics 2004, 35:1–5.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Children’s National Medical Center, 111 Michigan Avenue, NW, 20010, Washington, DC, USA

    Adeline Vanderver MD

Authors
  1. Adeline Vanderver MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vanderver, A. Tools for diagnosis of leukodystrophies and other disorders presenting with white matter disease. Curr Neurol Neurosci Rep 5, 110–118 (2005). https://doi.org/10.1007/s11910-005-0008-1

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-005-0008-1

Keywords

Search

Navigation