Journal of Child Neurology

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Peripheral Neuropathy in a Child With Cree Leukodystrophy R.J. Huntsman, S. Seshia, N. Lowry, E.G. Lemire and S.L. Harder J Child Neurol 2007; 22; 766 DOI: 10.1177/0883073807304010 The online version of this article can be found at: http://jcn.sagepub.com/cgi/content/abstract/22/6/766

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Brief Communication

Peripheral Neuropathy in a Child With Cree Leukodystrophy

Journal of Child Neurology Volume 22 Number 6 June 2007 766-768 © 2007 Sage Publications 10.1177/0883073807304010 http://jcn.sagepub.com hosted at http://online.sagepub.com

R. J. Huntsman, MD, S. Seshia, MD, N. Lowry, MD, E. G. Lemire, MD, PhD, and S. L. Harder, MD The authors describe peripheral nerve involvement in a 12month-old boy with Cree leukodystrophy. Nerve conduction and genetic studies were performed during investigation of his leukodystrophy. Mutation analysis of the eukaryotic initiation factor 2B5 gene detected homozygosity of the R195 mutation, confirming the diagnosis of Cree leukodystrophy. Median and posterior tibial motor nerve conduction study results were normal, but sensory responses in the median nerves were unobtainable bilaterally, in keeping with a sensory axonal neuropathy. Somatosensory-evoked potentials were absent in the

upper extremities and delayed in the lower extremities, confirming sensory nerve involvement. This degree of sensory nerve involvement has not been previously reported in patients with eukaryotic initiation factor 2B5–related disorders. Peripheral neuropathy should be looked for both clinically and with electrodiagnostic studies in patients with eukaryotic initiation factor 2B–related disorders.

Case History

increased T2 signal throughout the white matter (Figure 1A), with attenuation on the fluid-attenuated inversion recovery sequence, in keeping with a leukodystrophy (Figure 1B). Magnetic resonance spectroscopy demonstrated diminished N-acetylaspartate, in keeping with neuronal loss or dysfunction; elevated choline, in keeping with demyelination; and lactate peaks, in keeping with metabolic stress in regions of demyelination (Figure 2A,B). A full metabolic workup, including cerebrospinal fluid analysis, had normal results. Motor nerve conduction velocities within the right median and right posterior tibial nerves were 34 and 35 m/s, respectively. Amplitude of motor responses was normal. On sensory nerve studies of the median nerves bilaterally and the left sural nerve, no responses were obtained. Somatosensory-evoked responses revealed no reproducible waveforms from right and left median nerve stimulation and a delayed P37 response of 50 ms from the right tibial nerve. These findings were in keeping with an axonal sensory neuropathy. Genetic analysis revealed homozygosity for G584A mutation within the eukaryotic initiation factor 2B5 (EIF2B5) gene on chromosome 3q, confirming the diagnosis of Cree leukodystrophy. Over the next 3 months, he became increasingly spastic and developed difficult-to-control seizures. He died at 14 months of age from complications arising from prolonged seizures. A request for autopsy was denied by the family.

The patient presented at 11 months of age for assessment of increasing irritability and motor impairment. Symptoms first began 3 months earlier following a mild upper respiratory tract infection that required admission at his local hospital. After an uncomplicated course in the hospital, he was discharged home in good health. However, within a few days of discharge, he became lethargic and demonstrated developmental regression. He had become increasingly spastic in all 4 limbs and was no longer ambulatory. At the time of our assessment, he was unable to sit unsupported, had lost the ability to grasp objects with his hands, and had ceased vocalizing. On examination, spasticity with increased deep tendon reflexes and clonus were seen in the extremities. The patient was admitted to our hospital for investigation immediately following his initial presentation. Magnetic resonance imaging at 11 months of age showed From the Division of Pediatric Neurology (RJH, SS, NL), Division of Medical Genetics (EGL), and Department of Radiology (SLH), University Of Saskatchewan, Saskatoon, Canada. Address correspondence to: R. J. Huntsman, MD, Division of Pediatric Neurology, Department of Pediatrics, University of Saskatchewan, 103 Hospital Drive, Saskatoon, Saskatchewan, Canada S7N-0W8; e-mail: [email protected]. Huntsman RJ, Seshia S, Lowry N, Lemire EG, Harder SL. Peripheral neuropathy in a child with Cree leukodystrophy. J Child Neurol. 2007;22:766-768.

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Keywords: strophy

peripheral neuropathy; EIF2B5; Cree leukody-


Peripheral Neuropathy in Cree Leukodystrophy / Huntsman et al

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Figure 1. (A) Axial T2 magnetic resonance image demonstrates bilateral, symmetric T2 hyperintensity of the white matter and globus pallidi. (B) Axial fluid-attenuated inversion recovery image demonstrates hypointense white matter with scattered linear foci of increased signal in a tigroid pattern.

Figure 2. (A) Multivoxel PRESS acquisitions (TR/TE = 3000/144 ms). A voxel in the region of the splenium of the corpus callosum demonstrates diminished N-acetylaspartate (NAA), elevated choline, and a lactate peak. (B) Multivoxel PRESS acquisitions (TR/TE = 3000/144 ms) within a selected voxel in the adjacent cortex demonstrates a normal metabolite profile.

Discussion Cree leukodystrophy, first described by Black et al1 in 1988, is a fatal, rapidly progressive, neurodegenerative disorder affecting infants and young children of Cree and Chippewayan descent. Affected children present with hypotonia or spasticity followed by seizures and abnormal

posturing often in the setting of an intercurrent infection typically between 6 and 12 months of age. Although most reported cases are from northern Quebec and Manitoba, this disease can be seen as far west as Saskatchewan. In 2002, Fogli et al2 reported that patients with Cree leukodystrophy were homozygous for a mutation within the ε subunit of the eukaryotic initiation factor 2B (EIF2B)


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gene on chromosome 3q. The G584A mutation leads to an arginine to histidine amino acid substitution at position 195 in the polypeptide chain. The identical mutation was found in a Scottish patient with a severe form of central hypomyelination syndrome. The ancestry of children affected with Cree leukodystrophy was traced to a Scottish fur trader who came to North America in the 1770s.2 The eukaryotic initiating factor 2 (EIF2) is thought to regulate the translation of messenger ribonucleic acid (RNA) into proteins by controlling ribosomal binding to the messenger RNA. For EIF2 to be recycled and therefore initiate the production of more protein, it needs to be phosphorylated, achieved in part by the requirement for guanosine diphosphate to be phosphorylated to an active triphosphate form. This is catalyzed by EIF2B, a heteropentameric guanine nucleotide exchange factor.3 During times of cellular stress such as fever, protein synthesis normally decreases. It is postulated that a mutation in the EIF2B gene results in the loss of this decreased protein synthesis, resulting in an accumulation of denatured proteins within the cell and premature cell death.4 How this results in the marked and rapid loss of myelin in the otherwise normal brains of affected children is uncertain. Dietrich et al5 reported that in cell cultures of patients with vanishing white matter disease, there were normal-appearing oligodendrocytes despite marked demyelination. There was, however, a paucity of glial fibrillary acidic protein-positive astrocytes. These astrocytes showed abnormal morphology and an inability to be induced. Peripheral nerve involvement is a recognized feature of many of the leukodystrophies such as metachromatic leukodystrophy and Krabbe disease. A Medline review of the literature of central hypomyelination syndrome and vanishing white matter disease does not identify any patients with peripheral nerve involvement. Other organs can be involved outside of the central nervous system, such as seen in EIF2B5-related ovarioleukodystrophy.6 Although Black et al1 reported mild abnormalities of peripheral motor nerve involvement in 1 of their patients with Cree leukodystrophy, sensory nerve dysfunction was not described. The severity of peripheral nerve involvement seen in our patient was not reported in their cohort. The presence of peripheral nerve involvement in our patient certainly raises the possibility of the same in patients with central hypomyelination syndrome and vanishing white matter disease. The fact that motor

nerve involvement was not seen while sensory nerve abnormalities were prominent may indicate a preferential involvement of the large myelinated sensory fibers, the pattern of peripheral nerve involvement typically seen in patients with metachromatic leukodystrophy. The presence of peripheral nerve involvement may shed some understanding of the exact mechanism by which a mutation in the EIF2B gene causes the marked loss of myelin in patients with Cree leukodystrophy and other EIF2B-related disorders, thereby enabling curative or preventative treatments to be found. As well, because peripheral neuropathy may cause disability and discomfort in affected patients, its recognition and treatment with physiotherapy and orthopedic measures may provide some benefit in those affected.

Acknowledgment The work for this article was done at the University of Saskatchewan. No competing interests are identified. This work was also presented as a poster presentation at the 10th International Child Neurology Congress, June 2006.

References 1. Black DN, Booth F, Watters GV, et al. Leukoencephalopathy among native Indian infants in northern Quebec and Manitoba. Ann Neurol. 1988;24:490-496. 2. Fogli A, Wong K, Eymard-Pierre E, et al. Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus. Ann Neurol. 2002;52:506-510. 3. Online Mendelian Inheritance in Man, OMIM. Baltimore, Md: John Hopkins University. Available at: http://www.ncbi.nlm.nih .gov/omim/. 4. Leegwater PA, Vermeulen G, Konst AA, et al. Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat Genet. 2001; 29:383-388. 5. Dietrich J, Lacagnina M, Gass D, et al. EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy. Nat Med. 2005;11:277-283. 6. van der Knaap M, van Berkel CGM, Herms J, et al. EIF2Brelated disorders: antenatal onset and involvement of multiple organs. Am J Hum Genet. 2003;73:1199-1207.
