Practical Approach to Longitudinal Neurologic Care of Adults With X-Linked Adrenoleukodystrophy and Adrenomyeloneuropathy

Abstract

Although X-linked adrenoleukodystrophy (ALD) has historically been considered a childhood disease managed by pediatric neurologists, it is one of the most common leukodystrophies diagnosed in adulthood. An increase in both male and female adults reaching diagnosis due to familial cases identified by state newborn screening panels and more widespread use of genetic testing results in a large cohort of presymptomatic or early symptomatic adults. This population is in urgent need of standardized assessments and follow-up care. Adults with ALD/adrenomyeloneuropathy (AMN) may be diagnosed in a variety of ways, including after another family member is identified via genetic testing or newborn screening, presenting for symptomatic evaluation, or following diagnosis with primary adrenal insufficiency. Significant provider, patient, and systems-based barriers prevent adult patients with ALD/AMN from receiving appropriate care, including lack of awareness of the importance of longitudinal neurologic management. Confirmation of and education about the diagnosis should be coordinated in conjunction with a genetic counselor. Routine surveillance for adrenal insufficiency and onset of cerebral ALD (CALD) in men should be performed systematically to avoid preventable morbidity and mortality. While women with ALD do not usually develop cerebral demyelination or adrenal insufficiency, they remain at risk for myeloneuropathy and are no longer considered "carriers." After diagnosis, patients should be connected to the robust support networks, foundations, and research organizations available for ALD/AMN. Core principles of neurologic symptom management parallel those for patients with other etiologies of progressive spastic paraplegia. Appropriate patient candidates for hematopoietic stem cell transplant (HSCT) and other investigational disease-modifying strategies require early identification to achieve optimal outcomes. All patients with ALD/AMN, regardless of sex, age, or symptom severity, benefit from a multidisciplinary approach to longitudinal care spearheaded by the neurologist. This review proposes key strategies for diagnostic confirmation, laboratory and imaging surveillance, approach to symptom management, and guidance for identification of appropriate candidates for HSCT and investigational treatments.

Figure 1. Types of ALD/AMN Phenotypes Identified by Surveillance in Adult Patients

Adults with X-linked ALD can present with myeloneuropathy, adrenal insufficiency, or they may remain asymptomatic. As time progresses, adult patients with ALD can develop overlapping phenotypes, and all adults with ALD remain at risk for developing cerebral ALD thus requiring long-term surveillance. Although the neurologist caring for adult patients with ALD/AMN is likely to be more familiar with surveilling for neurologic complications of disease, monitoring adrenal function is also necessary. ALD = adrenoleukodystrophy; AMN = adrenomyeloneuropathy.

Figure 2. MRI of Adult Patients With X-Linked Adrenoleukodystrophy

(A) Patient 1: axial FLAIR sequences (A.a, A.b) and T1 postgadolinium images (A.c, A.d) from a man in his mid-40s with ALD/AMN with EDSS of 4 who was found to have T2/FLAIR hyperintense (orange arrows) and enhancing (green arrows) lesions in the corticospinal tract extending to the pons and brainstem. He developed frontal disinhibition and worsening gait, requiring a wheelchair within 1 year after the images presented. (B) Patient 2: axial FLAIR (B.a, B.b, B.c) and T1 postgadolinium images (B.d, B.e) of a man in his mid-40s with rapidly progressive cerebral ALD involving multiple brain regions, including the corticospinal tract (B.a, blue arrows), cerebellar white matter (B.b, B.c, pink brackets) and cerebellar peduncles (B.b, B.e, white arrows). Note the subtle FLAIR signal increase also in the genu of corpus callosum (B.a, green arrow) associated with gadolinium enhancement (B.d, green arrows). Follow-up imaging after 1 year showed bright signal hyperintensity in the genu on FLAIR sequences (B.f, green bracket). (C) Patient 3: axial FLAIR sequences (C.a and C.b) from a man in his late 40s with cerebral ALD demonstrating symmetric periventricular T2/FLAIR hyperintensities (white bracket and arrows). There is associated gadolinium enhancement on axial T1 postcontrast images in the periventricular white matter and splenium (C.c, yellow arrows). (D) Patients 4 and 5: sagittal short tau inversion recovery (STIR) images demonstrating mild spinal cord atrophy of the cervical spine (D.a) in a man in his late 60s and lower thoracic spine (D.b) in a man in his late 30s with AMN. There are no parenchymal lesions in the spinal cord and no gadolinium enhancement (not shown). ALD = adrenoleukodystrophy; AMN = adrenomyeloneuropathy; EDSS = Expanded Disability Status Scale; FLAIR = fluid-attenuated inversion recovery.