Early-Onset LBSL: How Severe Does It Get?

M. E. Steenweg; L. van Berge; C. G. M. van Berkel; I. F. M. de Coo; I. K. Temple; K. Brockmann; C. I. P. Mendonça; S. Vojta; A. Kolk; D. Peck; L. Carr; G. Uziel; A. Feigenbaum; S. Blaser; G. C. Scheper; M. S. van der Knaap

doi:10.1055/s-0032-1329395

Neuropediatrics, Table of Contents

Neuropediatrics 2012; 43(06): 332-338
DOI: 10.1055/s-0032-1329395

Original Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Early-Onset LBSL: How Severe Does It Get?

Authors

M. E. Steenweg

¹Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands
L. van Berge

¹Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands
C. G. M. van Berkel

¹Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands
I. F. M. de Coo

²Department of Child Neurology, Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands
I. K. Temple

³Department of Medical Genetics, School of Medicine, Princess Anne Hospital, University of Southampton, Southampton, United Kingdom
K. Brockmann

⁴Department of Pediatrics and Pediatric Neurology, Georg August University, Göttingen, Germany
C. I. P. Mendonça

⁵Department of Pediatric Neurology, Hospital de Faro, Faro, Portugal
S. Vojta

⁶Department of Pediatrics, Kinderzentrum München, München, Germany
A. Kolk

⁷Department of Pediatrics, Children's Clinic of Tartu, University Hospital, Tartu, Estonia
D. Peck

⁸Department of Genetics, Children's Hospital, University of Missouri Health Care, Columbia, Missouri, United States
L. Carr

⁹Department of Paediatric Neurology, Great Ormond Street Hospital for Children, London, United Kingdom
G. Uziel

¹⁰Department of Child Neurology, National Institute for Neurology “Carlo Besta,” Milan, Italy
A. Feigenbaum

¹¹Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Canada
S. Blaser

¹²Division of Pediatric Neuroradiology, Hospital for Sick Children, Toronto, Canada
G. C. Scheper

¹Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands
M. S. van der Knaap

¹Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands

Abstract

Aim Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is known as a relatively mild leukoencephalopathy. We investigated the occurrence of severe variants of LBSL with extensive brain magnetic resonance imaging (MRI) abnormalities.

Method MRIs of approximately 3,000 patients with an unknown leukoencephalopathy were retrospectively reviewed for extensive signal abnormalities of the cerebral and cerebellar white matter, posterior limb of the internal capsule, cerebellar peduncles, pyramids, and medial lemniscus. Clinical data were retrospectively collected.

Results Eleven patients fulfilled the MRI criteria (six males); six had DARS2 mutations. Clinical and laboratory findings did not distinguish between patients with and without DARS2 mutations, but MRI did. Patients with DARS2 mutations more often had involvement of structures typically affected in LBSL, including decussatio of the medial lemniscus, anterior spinocerebellar tracts, and superior and inferior cerebellar peduncles. Also, involvement of the globus pallidus was associated with DARS2 mutations. Earliest disease onset was neonatal; earliest death at 20 months.

Interpretation This study confirms the occurrence of early infantile, severe LBSL, extending the known phenotypic range of LBSL. Abnormality of specific brainstem tracts and cerebellar peduncles are MRI findings that point to the correct diagnosis.

Keywords

childhood white matter disorder - MRI pattern recognition - phenotypic variation

Full Text

References

References
1 van der Knaap MS, van der Voorn P, Barkhof F , et al. A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate. Ann Neurol 2003; 53 (2) 252-258
2 Labauge P, Roullet E, Boespflug-Tanguy O , et al. Familial, adult onset form of leukoencephalopathy with brain stem and spinal cord involvement: inconstant high brain lactate and very slow disease progression. Eur Neurol 2007; 58 (1) 59-61
3 Petzold GC, Bohner G, Klingebiel R, Amberger N, van der Knaap MS, Zschenderlein R. Adult onset leucoencephalopathy with brain stem and spinal cord involvement and normal lactate. J Neurol Neurosurg Psychiatry 2006; 77 (7) 889-891
4 Scheper GC, van der Klok T, van Andel RJ , et al. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet 2007; 39 (4) 534-539
5 Miyake N, Yamashita S, Kurosawa K , et al. A novel homozygous mutation of DARS2 may cause a severe LBSL variant. Clin Genet 2011; 80 (3) 293-296
6 Synofzik M, Schicks J, Lindig T , et al. Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation. J Med Genet 2011; 48 (10) 713-715
7 Yamashita S, Miyake N, Matsumoto N , et al. Neuropathology of leukoencephalopathy with brainstem and spinal cord involvement and high lactate caused by a homozygous mutation of DARS2. Brain Dev 2012; ; epub ahead of print
8 Steenweg ME, Pouwels PJW, Wolf NI, van Wieringen WN, Barkhof F, van der Knaap MS. Leucoencephalopathy with brainstem and spinal cord involvement and high lactate: quantitative magnetic resonance imaging. Brain 2011; 134 (Pt 11) 3333-3341
9 van der Knaap MS, Breiter SN, Naidu S, Hart AA, Valk J. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology 1999; 213 (1) 121-133