Spinal cord atrophy as a measure of severity of myelopathy in adrenoleukodystrophy

Abstract

All men and most women with X‐linked adrenoleukodystrophy (ALD) develop myelopathy in adulthood. As clinical trials with new potential disease‐modifying therapies are emerging, sensitive outcome measures for quantifying myelopathy are needed. This prospective cohort study evaluated spinal cord size (cross‐sectional area ‐ CSA) and shape (eccentricity) as potential new quantitative outcome measures for myelopathy in ALD. Seventy‐four baseline magnetic resonance imaging (MRI) scans, acquired in 42 male ALD patients and 32 age‐matched healthy controls, and 26 follow‐up scans of ALD patients were included in the study. We used routine T 1 ‐weighted MRI sequences to measure mean CSA, eccentricity, right‐left and anteroposterior diameters in the cervical spinal cord. We compared MRI measurements between groups and correlated CSA with clinical outcome measures of disease severity. Longitudinally, we compared MRI measurements between baseline and 1‐year follow‐up. CSA was significantly smaller in patients compared to controls on all measured spinal cord levels ( P < .001). The difference was completely explained by the effect of the symptomatic subgroup. Furthermore, the spinal cord showed flattening (higher eccentricity and smaller anteroposterior diameters) in patients. CSA correlated strongly with all clinical measures of severity of myelopathy. There was no detectable change in CSA after 1‐year follow‐up. The cervical spinal cord in symptomatic ALD patients is smaller and flattened compared to controls, possibly due to atrophy of the dorsal columns. CSA is a reliable marker of disease severity and can be a valuable outcome measure in long‐term follow‐up studies in ALD. Synopsis A prospective cohort study in 42 adrenoleukodystrophy (ALD) patients and 32 controls demonstrated that the spinal cord cross‐sectional area of patients is smaller compared to healthy controls and correlates with severity of myelopathy in patients, hence it could be valuable as a much needed surrogate outcome measure.

Spinal Cord Involvement in Pediatric-Onset Metabolic Disorders With Mendelian and Mitochondrial Inheritance

“…Spinal cord involvement, either clinical and/or radiological, in pediatric-onset metabolic disorders with Mendelian and mitochondrial inheritance is likely more frequent than anticipated and requires special attention. In inherited metabolic diseases, spinal cord involvement is most frequently reported in adrenoleukodystrophy, biotinidase deficiency, arginase deficiency, and cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ, and MTHFR deficiency ( 9 , 32 – 34 , 41 ). In mitochondrial disorders, spinal cord involvement is most frequently reported in leukoencephalopathy with brainstem, spinal cord involvement and lactate elevation, Leigh syndrome, and multiple mitochondrial dysfunction syndrome ( 4 ).…”

“…Spinal cord imaging in ALD mainly reveals atrophy; however, other anomalies can be observed, including the involvement of the corticospinal and corticopontine tracts. Van de Stadt et al showed that the cervical spinal cord in patients with ALD is smaller and flattened compared to that in controls, possibly due to atrophy of the dorsal columns, and can be a marker of disease severity ( 9 ). The treatment of X-ALD remains mainly supportive.…”

Plasma NfL and GFAP as biomarkers of spinal cord degeneration in adrenoleukodystrophy

“…There is an important difference between molecular biomarkers such as NfL and GFAP and other (surrogate) outcomes used for myelopathy in ALD. Most outcomes – for example clinical parameters (EDSS, SSPROM, timed walking activities) or imaging biomarkers (spinal cord atrophy, diffusion tensor imaging) – represent disability or accumulated spinal cord damage resulting from years of spinal cord degeneration 1,30‐32 . NfL and GFAP – with an estimated half‐life of a number of days and months respectively – reflect current or recent neurodegeneration and are therefore the markers of ongoing or recent disease activity 33,34 .…”

Leukodystrophies

“…In adulthood, the predominant form is adrenomyeloneuropathy, which affects both men and women 17 . Adrenomyeloneuropathy is characterized by chronic progression of demyelination and atrophy within the spinal cord, particularly in the corticospinal tracts.…”