Case of the Week
Section Editors: Matylda Machnowska1 and Anvita Pauranik2
1University of Toronto, Toronto, Ontario, Canada
2BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
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December 12, 2024
Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation (LBSL)
- Background:
- Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is caused by recessive mutations in the DARS2 gene.
- DARS2 encodes for mitochondrial aspartyl-tRNA synthetase (mtAspRS), an enzyme that is essential for life.
- MtAspRS attaches the amino acid aspartate to the correct mitochondrial transfer RNA, which is necessary for the translation of mitochondrial messenger RNA into protein.
- Clinical Presentation:
- Childhood or young adulthood onset of slowly progressive ataxia, spasticity, and dorsal column dysfunction.
- Key Diagnostic Features:
- Highly distinct MRI pattern, characterized by inhomogeneous signal abnormalities in the periventricular and deep cerebral white matter with relative sparing of the subcortical U-fibers, combined with abnormalities of the pyramids at the level of medulla oblongata or decussation of the medial lemniscus, mesencephalic trigeminal tracts, intraparenchymal parts of the trigeminal nerves, and superior and inferior cerebellar peduncles. In the spinal cord, signal abnormalities are confined to the dorsal columns and lateral corticospinal tracts over the entire length of the spinal cord.
- Brain MR spectroscopy characteristically shows lactate elevation in the abnormal white matter, but this is not always the case.
- Genetic testing is helpful to confirm the diagnosis. In the presented case, the diagnosis was confirmed by clinical exome sequencing that revealed a heterozygous variant of rs142433332 splicing in the DARS2 gene (c.492+2T>C).
- Differential Diagnosis:
- Progressive multiple sclerosis: lesions seen in MS are juxtacortical or perpendicular to the lateral ventricles in a triangular configuration, with asymmetrical pattern of white matter involvement
- X-linked adrenoleukodystrophy: frontal or parieto-occipital pattern of white matter involvement, and involvement of the splenium or genu of the corpus callosum
- Krabbe disease: parieto-occipital predominant or diffuse periventricular white matter involvement; MR spectroscopy may show abnormal choline elevation in the centrum semiovale
- Phenylketonuria: occurs first in the periventricular/parieto-occipital white matter; MR spectroscopy shows phenylalanine peak
- Vanishing white matter disease: the lesions are multifocal and cystic; cerebellar atrophy typically involves the vermis
- Alexander disease: Adult onset predominantly affects the medulla and upper cervical cord
- Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS): predominant lesions of gray matter structures
- Leigh syndrome: involvement of cerebral or cerebellar white matter is unusual; MR spectroscopy shows elevated choline, occasionally elevated lactate
- Kearns-Sayre syndrome: subcortical calcifications, sometimes with bilateral basal ganglia siderocalcific deposits
- Succinate dehydrogenase (complex 2) deficiency: white matter lesions of the transverse pontine fibers, the middle cerebellar peduncles, and thalami, with a succinate peak in MR spectroscopy
- Treatment:
- Not currently available. Physical therapy and counseling are the cornerstones of management.
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