Five Patients with a Recently Described Novel Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Elevated Lactate

Abstract

Recently, a novel leukoencephalopathy syndrome was described in eight patients with a distinct pattern of MRI abnormalities. Here we describe the clinical, laboratory, and MRI findings in five new, unrelated patients. The clinical picture was homogeneous with onset in childhood, a slowly progressive course, variable mental deficits, signs of pyramidal and cerebellar dysfunction and sometimes dorsal column dysfunction. In two patients, a minor head trauma was followed by neurological deterioration and fever. No underlying metabolic defect was found. In two patients serum lactate was elevated, but no evidence of a mitochondrial defect was found. MRI showed variably extensive, diffuse, or spotty cerebral white matter abnormalities and a selective involvement of particular brainstem tracts. The tracts involved included the pyramidal tracts, sensory tracts, superior and inferior cerebellar peduncles, and intraparenchymal trajectories of the trigeminal nerve. In four patients spinal MRI was performed and revealed involvement of tracts over the entire length depicted. Single voxel proton MRS in three patients revealed increased lactate within the abnormal white matter. The uniform and highly characteristic MRI findings, in combination with the similarities in clinical and MRS findings, provide evidence for a distinct nosological entity.

Key words

Leukoencephalopathy - inherited - brainstem tracts - spinal tracts - lactate

References

• 1 Barkhof F, Verrips A, van der Knaap M S, van Engelen B GM, Gabreëls F JM, Keyser A. et al . Cerebrotendinous xanthomatosis: the spectrum of imaging findings and the correlation with neuropathologic findings.  Radiology. 2000;  217 869-876
• 2 Barth P G, Hoffmann G F, Jaeken J, Lehnert W, Hanefeld F, van Gennip A H. et al . L-2-Hydroxyglutaric acidemia: a novel inherited neurometabolic disease.  Ann Neurol. 1992;  32 66-71
• 3 Caro P A, Marks H G. MRI and CT in Pelizaeus-Merzbacher disease.  Magn Reson Im. 1990;  8 791-796
• 4 Grodd W, Krägeloh-Mann I, Klose U, Sauter R. Metabolic and destructive brain disorders in children: findings with localized proton MR spectroscopy.  Radiology. 1991;  181 173-178
• 5 Haataja L, Parkkola R, Sonninen P, Verhanen S-L, Scheutker J, Äärimaa T. et al . Phenotypic variation and magnetic resonance imaging (MRI) in Salla disease, a free sialic acid storage disorder.  Neuropediatrics. 1994;  25 238-244
• 6 Kim T S, Kim I O, Kim W S, Choi Y S, Lee J Y, Kim O W. et al . MR of childhood metachromatic leukodystrophy.  Am J Neuroradiol. 1997;  18 733-738
• 7 Leegwater P AJ, Vermeulen G, Könst A AM, Naidu S, Mulders J, Visser A. et al . Subunits of the translation initiation factor eIF2B are mutated in leukoencephalopathy with vanishing white matter.  Nature Genet. 2001;  29 383-388
• 8 Loes D J, Peters C, Krivit W. Globoid cell leukodystrophy: distinguishing early-onset from late-onset disease using a brain MR imaging scoring method.  Am J Neuroradiol. 1999;  20 316-323
• 9 Loes D J, Hite S, Moser H, Stillman A E, Shapiro E, Lockman L. et al . Adrenoleukodystrophy: a scoring method for brain MR observations.  Am J Neuroradiol. 1994;  15 1761-1766
• 10 Schiffmann R, Moller J R, Trapp B D, Shih H HL, Farrer R G, Katz D A. et al . Childhood ataxia with diffuse central nervous system hypomyelination.  Ann Neurol. 1994;  35 331-340
• 11 Van der Knaap M S, Valk J, de Neeling N, Nauta J JP. Pattern recognition in magnetic resonance imaging of white matter disorders in children and young adults.  Neuroradiology. 1991;  33 478-493
• 12 Van der Knaap M S, Valk J. Magnetic Resonance of Myelin, Myelination, and Myelin Disorders. Heidelberg; Springer 1995
• 13 Van der Knaap M S, Barth P G, Stroink H, Van Nieuwenhuizen O, Arts W FM, Hoogenraad F. et al . Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children.  Ann Neurol. 1995;  37 324-334
• 14 Van der Knaap M S, Barth P G, Gabreëls F JM, Franzoni E, Begeer J H, Stroink H. et al . A new leukoencephalopathy with vanishing white matter.  Neurology. 1997;  48 845-855
• 15 Van der Knaap M S, Breiter S N, Naidu S, Hart A AM, Valk J. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach.  Radiology. 1999;  213 121-133
• 16 Van der Knaap M S, Leegwater P AJ, Könst A AM, Visser A, Naidu S, Oudejans C BM. 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
• 17 Van der Knaap M S, Naidu S, Pouwels P JW, Bonavita S, van Coster R, Lagae L. et al . A new syndrome characterized by hypomyelination with atrophy of basal ganglia and cerebellum.  Am J Neuroradiol. 2002;  23 1466-1474
• 18 Van der Knaap M S, van der Voorn P, Barkhof F, van Coster R, Krägeloh-Mann I, Feigenbaum A. et al . A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate.  Ann Neurol. 2003;  53 252-258
• 19 Van Domburg P HMF, Willemsen M AAP, Rotteveel J J, de Jong J GN, Thijssen H OM, Heerschap A. et al . Sjögren-Larsson syndrome. Clinical and MRI/MRS findings in FALDH-deficient patients.  Neurology. 1999;  52 1345-1352
• 20 Vanhanen S L, Raininko R, Autti T, Santavuori P. MRI evaluation of the brain in infantile neuronal ceroid-lipofuscinosis. Part 2: MRI findings in 21 patients.  J Child Neurol. 1995;  10 444-450