Practical approach to the diagnosis of adult-onset leukodystrophies: an updated guide in the genomic era

Abstract

Adult-onset leukodystrophies and genetic leukoencephalopathies comprise a diverse group of neurodegenerative disorders of white matter with a wide age of onset and phenotypic spectrum. Patients with white matter abnormalities detected on MRI often present a diagnostic challenge to both general and specialist neurologists. Patients typically present with a progressive syndrome including various combinations of cognitive impairment, movement disorders, ataxia and upper motor neuron signs. There are a number of important and treatable acquired causes for this imaging and clinical presentation. There are also a very large number of genetic causes which due to their relative rarity and sometimes variable and overlapping presentations can be difficult to diagnose. In this review, we provide a structured approach to the diagnosis of inherited disorders of white matter in adults. We describe clinical and radiological clues to aid diagnosis, and we present an overview of both common and rare genetic white matter disorders. We provide advice on testing for acquired causes, on excluding small vessel disease mimics, and detailed advice on metabolic and genetic testing available to the practising neurologist. Common genetic leukoencephalopathies discussed in detail include CSF1R, AARS2, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and mitochondrial and metabolic disorders.

Keywords: adrenoleukodystrophy; dementia; movement disorders; neurogenetics; neuroradiology.

Figure 1

Axial T2-weighted MRI of radiotherapy changes (A), as well as axial FLAIR MRI of cerebral Systemic Lupus Eythematosus (SLE) (B) and PRES (C) demonstrating symmetrical and confluent periventricular and subcortical white matter signal hyperintensity (WMH). Axial non-contrast CT demonstrating subcortical volume loss, punctate calcification and confluent hypodensity adjacent to the frontal horns of the lateral ventricles (D). Axial B1000 DWI and FLAIR MRI acquisitions showing DWI avid punctate lesions (E) as well as confluent periventricular hyperintense signal changes (F) in CSF1R leukodystrophy. MRI sagittal T1W acquisition showing diffuse thinning of the corpus callosum (G), as well as axial T1W (H) and FLAIR (I) sequences demonstrating confluent rarefaction of the subcortical and periventricular white matter adjacent to the frontal horns and ventricular trigones of the lateral ventricles in VWM disease. FLAIR, fluid-attenuated inversion recovery; PRES, posterior reversible leukoencephalopathy syndrome; T1W, T1-weighted; VWM, vanishing white matter.

Figure 2

Axial FLAIR MRI sequences demonstrating confluent signal hyperintensity involving the external capsules, posterior limb of the internal capsules, peritrigonal white matter and splenium of the corpus callosum (A), as well as of the subcortical white matter of the temporal poles and central pons (B) in CADASIL. Minimal intensity projection from a susceptibility weighted imaging acquisition MRI demonstrating multiple punctate foci of paramagnetic susceptibility limited within the thalamus, left putamen and subcortical white matter of the left occipital lobe (C), in keeping with multiple microhaemorrhages in CADASIL. Axial T2W MRI sequences demonstrating signal hyperintensity within the trigeminal fascicles and cerebellar white matter (D), as well as within the pyramids, decussation of the medial lemnisci and inferior cerebellar peduncles at the level of the medulla oblongata (E) in LBSL. A sagittal T2W sequence of the upper spinal cord in the same patient demonstrates contiguous longitudinally extensive signal hyperintensity of the dorsal columns and lateral cortical spinal tracts (F). Axial T2W (G) and T1W (H) MRI sequences in a patient with Pelizaeus-Merzbacher disease illustrating the confluent diffuse T2W hyperintense signal within the white matter of the cerebrum, appearing unremarkable on the T1W sequences, suggestive of hypomyelination. Axial T2W sequences demonstrating confluent hyperintense signal change within the pons, middle cerebellar peduncles and dentate nuclei in a patient with a CNCL2 leukodystrophy (I). CADASIL, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy; FLAIR, fluid-attenuated inversion recovery; T1W, T1-weighted; LBSL, leukoencephalopathy with brainstem and spinal cord involvement with elevated lactate; T2W, T2-weighted.

Figure 3

A schematic diagram to illustrate currently available sequencing technologies. Single-gene (Sanger) sequencing is widely available and is performed by amplifying coding regions of the gene of interest by PCR, before sequencing these regions. Introns and promoter regions are not routinely sequenced. Next-generation sequencing-based panel or exome sequencing is becoming more widely available clinically. In this technique, DNA is fragmented, and the exons of multiple genes of interest are selected out for sequencing. Although many genes are sequenced, again only the coding regions are selected. In whole genome sequencing, which is not routinely available to clinicians yet, the DNA is also fragmented, but all the resulting DNA is sequencing, without a selection step. This results in a large amount of data, as the coding regions, intergenic regions, introns and promoters of all human genes are sequenced. Advanced bioinformatics and computing technology are a required part of whole genome sequencing.

Figure 4

A recommended algorithm for the evaluation of adults with suspected inherited white matter disorders. CSF, cerebrospinal fluid; mtDNA, mitochondrial DNA; PML, progressive multifocal leukoencephalopathy; VLCFA, very long chain fatty acids; WCE, White cell enzymes.