A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies

Abstract

Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison's disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive--many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders.

Keywords: Glia; Leukodystrophy; Myelin.

Fig. 1

Recommended molecular diagnostic workflow. Note emphasis on identification of treatable disorders to enable rapid changes in care as appropriate. For a complete description of this figure please see the main text. Abbreviations: P = pathogenic; LP = likely pathogenic.

Fig. 2

MRI pattern recognition in the LD and gLE (reprinted with permission from Genereviews). Three major MRI characteristics help to discriminate between the different types of LD and gLE. The first discriminator is the presence or absence of hypomyelination (Fig. 2a). Within this subset, the presence of improvement of myelination or atrophy directs the clinician towards a series of gLEs. Within the true hypomyelinating LDs, the presence of basal ganglia and cerebellar involvement further helps refine the diagnosis. If the pattern is not one of hypomyelination, then the second discriminator is whether the white matter abnormalities are confluent or isolated and multifocal (Fig. 2b). If the white matter abnormalities are confluent, then the third discriminator is the predominant localization of the abnormalities (Fig. 2b).

Fig. 2

MRI pattern recognition in the LD and gLE (reprinted with permission from Genereviews). Three major MRI characteristics help to discriminate between the different types of LD and gLE. The first discriminator is the presence or absence of hypomyelination (Fig. 2a). Within this subset, the presence of improvement of myelination or atrophy directs the clinician towards a series of gLEs. Within the true hypomyelinating LDs, the presence of basal ganglia and cerebellar involvement further helps refine the diagnosis. If the pattern is not one of hypomyelination, then the second discriminator is whether the white matter abnormalities are confluent or isolated and multifocal (Fig. 2b). If the white matter abnormalities are confluent, then the third discriminator is the predominant localization of the abnormalities (Fig. 2b).