Leukodystrophies

Abstract

Purpose of review: This article reviews the most common leukodystrophies and is focused on diagnosis, clinical features, and emerging therapeutic options.

Recent findings: In the past decade, the recognition of leukodystrophies has exponentially increased, and now this class includes more than 30 distinct disorders. Classically recognized as progressive and fatal disorders affecting young children, it is now understood that leukodystrophies are associated with an increasing spectrum of neurologic trajectories and can affect all ages. Next-generation sequencing and newborn screening allow the opportunity for the recognition of presymptomatic and atypical cases. These new testing opportunities, in combination with growing numbers of natural history studies and clinical consensus guidelines, have helped improve diagnosis and clinical care. Additionally, a more granular understanding of disease outcomes informs clinical trial design and has led to several recent therapeutic advances. This review summarizes the current understanding of the clinical manifestations of disease and treatment options for the most common leukodystrophies.

Summary: As early testing becomes more readily available through next-generation sequencing and newborn screening, neurologists will better understand the true incidence of the leukodystrophies and be able to diagnose children within the therapeutic window. As targeted therapies are developed, it becomes increasingly imperative that this broad spectrum of disorders is recognized and diagnosed. This work summarizes key advances in the leukodystrophy field.

FIGURE 9-1. Imaging patterns of the leukodystrophies. The imaging findings of the leukodystrophies can be broadly divided into demyelinating (A) and hypomyelinating (B). Within each category, often distinguishing features or areas of most prominent abnormality can aid in narrowing the differential diagnosis.

4H = 4H syndrome; − = negative; + = positive; AGS = Aicardi-Goutières syndrome; ALD = adrenoleukodystrophy; AxD = Alexander disease; CTX = cerebrotendinous xanthomatosis; HABC = hypomyelination with atrophy of the basal ganglia and cerebellum; LD = leukodystrophy; MLD = metachromatic leukodystrophy; PMD = Pelizaeus-Merzbacher disease; VWM = vanishing white matter disease; X-ALD = X-linked adrenoleukodystrophy.

FIGURE 9-2

MRI from the patient in CASE 9-1. A, Axial T2-weighted image shows posterior, confluent hyperintensity with corpus callosuminvolvement. B, Axial postcontrast T1-weighted image shows a rim of contrast enhancement surrounding the regions of T2 abnormality.

FIGURE 9-3

MRI from the patient in CASE 9-2. A, Axial fluid-attenuated inversion recovery (FLAIR) image showing confluent hyperintense signal within the periventricular and subcortical white matter with tigroid striping, which are classic in metachromatic leukodystrophy. B, On axial postcontrast T1-weighted image, bilateral cranial nerve III enhancement can be observed.

FIGURE 9-4

Imaging from the patients in CASE 9-3. A, Axial noncontrast head CT showing atrophy and calcifications. B, Axial T2-weighted MRI showing patchy hyperintensity of the white matter involving the U fibers.

FIGURE 9-5

Imaging from the patient in CASE 9-4. Axial fluid-attenuated inversion recovery (FLAIR) image showing diffuse, symmetric white matter signal abnormality predominantly involving the frontal lobes.

FIGURE 9-6

Imaging from the patient in CASE 9-5. Symmetrical white matter signal alteration (A) is shown in axial T2-weighted image, and symmetrical lesions can be seen in the brainstem with cranial nerve VIII enhancement (arrows) in axial postcontrast T1-weighted image (B).

FIGURE 9-7

Axial MRI from the patient in CASE 9-6. Imaging is notable for diffuse abnormal white matter signal intensity with high T2 signal intensity (A) and T1 hypointensity (B) throughout the white matter regions. Minimal myelination can be seen along the optic radiations and the posterior limb of the internal capsules.

FIGURE 9-8

Axial fluid-attenuated inversion recovery (FLAIR) MRI from the patient in CASE 9-7 is notable for diffuse abnormal white matter signal intensity with high signal intensity and rarefaction. The inner leaflet of the corpus callosum (arrow) is notably affected.

FIGURE 9-9

MRI from the patient in CASE 9-8. Longitudinal axial fluid-attenuated inversion recovery (FLAIR) (top row) and sagittal T1-weighted (bottom row) imaging obtained when the patient was 5 years, 10 years, and 13 years old reveals diffuse hypomyelination with progressive basal ganglia and cerebellar atrophy. The arrows indicate the location of the putamen (top row) and cerebellum (bottom row).