Clinical and genetic characterization of leukoencephalopathies in adults

Abstract

Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carried out whole exome sequencing on the remaining negative cases including four family trios, but could not identify any further potentially disease-causing mutations, confirming the equivalence of focused and whole exome sequencing in the diagnosis of genetic leukoencephalopathies. Here we provide an overview of the clinical and genetic features of these disorders in adults.

Keywords: imaging; leukodystrophy; neurodegeneration; white matter lesion.

Figure 1

Pathogenic and likely pathogenic variants identified in known leukodystrophy/genetic leukoencephalopathy genes and coverage metrics for focused exome and WES.

Figure 2

CADASIL and CARASAL imaging appearance. (A) Typical imaging appearance of CADASIL in axial FLAIR MRI images. There is symmetric subcortical high signal in the anterior temporal lobes, internal and external capsules and scattered asymmetric involvement of the periventricular cerebral white matter and pons. (B) CARASAL in T₂ axial images. There was no involvement of the anterior temporal lobes (left) but there was extensive involvement of the internal and external capsules, the basal ganglia and thalami (middle) and the periventricular and deep white matter (right).

Figure 3

AARS2, DARS2 and RNF216 imaging appearance. (A) Typical imaging appearance of AARS2-related leukoencephalopathy. There is an extensive, symmetric white matter abnormality in the frontal, parietal and occipital lobes on the FLAIR imaging (left), with evidence of restricted diffusion on diffusion weighted imaging (middle) and apparent diffusion coefficient (right). (B) DARS2-related leukoencephalopathy. Axial FLAIR MRI image (top left) discloses bilateral deep and periventricular cerebral white matter involvement. Axial and sagittal T₂-weighted MRI images show hyperintensity in the medullary pyramids (red arrows), the posterior columns of the spinal cord (white arrow), the deep white matter of the cerebellum and along the intraparenchymal tracts of the trigeminal nerves bilaterally (blue arrows), in addition to a lactate peak on short echo time magnetic resonance spectroscopy (yellow arrow). (C) RNF216-related leukoencephalopathy with diffuse supratentorial white matter signal abnormality appreciated in axial FLAIR MRI images.