Genetic Leukoencephalopathies in Adults

Abstract

Purpose of review: More than 100 heritable disorders can present with abnormal white matter on neuroimaging. While acquired disorders remain a more common cause of leukoencephalopathy in the adult than genetic causes, the clinician must remain aware of features that suggest a possible genetic etiology.

Recent findings: The differential diagnosis of heritable white matter disorders in adults has been revolutionized by next-generation sequencing approaches and the recent identification of the molecular cause of a series of adult-onset disorders.

Summary: The identification of a heritable etiology of white matter disease will often have important prognostic and family counseling implications. It is thus important to be aware of the most common hereditary disorders of the white matter and to know how to distinguish them from acquired disorders and how to approach their diagnosis.

Figure 12-1

Leukoencephalopathy with brainstem and spinal cord involvement and elevated white matter lactate. T2-weighted images show longitudinally extensive whole cord involvement on sagittal views of the spine (A, C, thin arrows) as well as anterior and posterior tract involvement in the brainstem and cervical cord (B, D, thick arrows) on axial views.

Figure 12-4

Autosomal dominant adult-onset leukodystrophy. T2-weighted MRI images demonstrate classic brainstem and middle cerebellar peduncle signal abnormalities accompanying diffuse central white matter signal abnormalities at a late stage. Images from three unrelated individuals demonstrate the stereotypical brainstem (A) and supratentorial (B) signal abnormalities, such as seen in the patient in Case 12-2.

Figure 12-10

Vanishing white matter disease. T2-weighted images of the pediatric presentation of the disorder show white matter signal that is isointense with CSF spaces, giving the impression that it has “vanished” (A). Fluid-attenuated inversion recovery (FLAIR) imaging documents rarefaction of affected white matter (B). Adult-onset cases show T2 hyperintensity (C), with abnormal signal and loss of white matter volume on FLAIR (D) but without the characteristic rarefaction.

Figure 12-2

Hereditary diffuse leukoencephalopathy with spheroids. Fluid-attenuated inversion recovery (FLAIR) (A, B) and T2-weighted images (C, D) show asymmetric white matter abnormalities and frontal predominance as well as frontal atrophy. The right frontal regions show evidence of the surgical biopsy (D, arrow) that helped establish the diagnosis in this patient.

Figure 12-3

Adult-onset polyglucosan body disease. A, The relatively hypointense normal body of the pons within the affected brainstem on sagittal fluid-attenuated inversion recovery (FLAIR) images is a classic feature of the disease. B, C, D, Confluent white matter disease is seen in this advanced case with significant brainstem and cerebellar signal abnormalities on axial T2-weighted images.

Figure 12-5

Enlarged perivascular spaces in a patient with Lowe syndrome. The areas with decreased T1 signal (A) and increased T2 signal (B) have small nonenhancing cystic regions that are isointense with the CSF, corresponding to increased perivascular spaces.

Figure 12-6

Globoid cell leukodystrophy (Krabbe disease). A, Axial T2-weighted MRI of infantile-onset globoid cell leukodystrophy with diffuse white matter involvement sparing the subcortical fibers, atrophy, and dentate signal abnormality. B, Axial T2-weighted MRI of adult-onset globoid cell leukodystrophy demonstrating selective parietal involvement.

Figure 12-7

Adult-onset Alexander disease. A, In some cases, MRI features resemble early-onset Alexander disease with classic characteristics including frontal preponderance, contrasting T2 signal hypointensity relative to the remainder of the abnormal white matter signal around the periatrial white matter, and basal ganglia signal abnormalities. B, In other cases, MRI abnormalities are predominantly in the posterior fossa, with few supratentorial white matter signal abnormalities.

Figure 12-8

X-linked adrenoleukodystrophy. Axial MRIs show features seen in adult-onset presentations of cerebral adrenoleukodystrophy with frontal rather than parietal signal abnormalities on T2-weighted imaging (A, C), while still having the typical features of callosal involvement on fluid-attenuated inversion recovery (FLAIR) imaging (genu rather than splenium, B) and contrast enhancement of affected white matter on T1 imaging with contrast (D).

Figure 12-9

Kearns-Sayre syndrome. T2-weighted MRIs show cerebellar and globus pallidus involvement. Cerebral white matter is selectively involved in the subcortical regions, with preservation of the periventricular white matter and deep white matter to a lesser degree.