Late adult-onset adrenomyeloneuropathy evolving with atypical severe frontal lobe syndrome: Importance of neuroimaging

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a rare inherited metabolic disease affecting the nervous system and the adrenal glands. It is caused by a mutation of the ABCD1 gene, resulting in the impaired degradation of very long-chain fatty acids and their subsequent accumulation in several organs and tissues. X-ALD is notable for its high phenotypical variability, that includes isolated adrenocortical insufficiency, slowly progressive myelopathy with paraparesis, ataxia, and peripheral neuropathy to severe childhood cerebral forms. Here, we describe the case of an X-ALD patient with a p.Gly343Val mutation in ABCD1 gene, who presented in adulthood with a spinal syndrome of mild severity, and later developed a progressive cognitive and behavioral syndrome. Our patient showed a striking correlation between clinical phenotype and neuroimaging, including a brain fluoro-2-deoxy-d-glucose positron emission tomography that displayed an atypical cerebral glucose metabolism.

Keywords: Brain FDG-PET; Cortical and subcortical atrophy; Frontal lobe dysfunction; Missense mutation; X-linked adrenoleukodystrophy (X-ALD).

Fig. 1

Family tree. The presented case is marked with an arrow. Subject II,4; II,8; III,2; III,9 were affected by ALD/AMN; II,1 and II,3 are female carriers. ALD = adrenoleukodystrophy; AMN = adrenomyeloneuropath.

Fig. 2

(A-D) Brain MRI. Axial turbo spin-echo (TSE) T2-weighted image (A) well depicts bilateral and confluent white matter fronto-parietal hyperintensities more extensive and characterized by a higher signal in the frontal lobes. The anterior limb of the internal capsule is also clearly affected, bilaterally. The ventricular system and the fronto-insular subarachnoid spaces are enlarged. Axial diffusion-weighted imaging (DWI) eADC map (B) shows a marked hypointensity of the deep frontal white matter, rather than the parietal one. Axial TSE T2-weighted image at subtentorial level (C) reveals a bilateral hyperintense signal of the middle cerebellar peduncles associated to a subtle hyperintensity of the ventral pons that results quite atrophic. Sagittal TSE T2-weighted image shows thinning of the entire corpus callosum with abnormal hyperintense signal of the isthmus, the genu and the anterior part of the body (D). eADC = exponential Apparent Diffusion Coefficient; MRI = magnetic resonance imaging.

Fig. 3

Spine MRI. Sagittal TSE T2-weighted image shows thinning of the dorsal spinal cord, with relative sparing of the conus medullaris. MRI = magnetic resonance imaging.

Fig. 4

Positron emission tomography (PET) transaxial images of [18F]FDG uptake in the patient at 4 different sections (A) show a clear relative hypometabolism involving the associative cerebral cortex, mostly the frontal lobe and the anterior cingulate region, and the cerebellar hemispheres (azure color). To a lesser extent, [18F]FDG uptake appears also reduced in the thalamus and the striatum, bilaterally. These findings are highlighted by the results of single subject statistical parametric mapping (SPM) analysis obtained in our patient in comparison to a group of controls (age range of controls: 27-70, age was considered in the statistical model of SPM as nuisance covariate) and rendered as clusters of reduced relative metabolism (P < .01 uncorrected) onto the sagittal (B), coronal (C) and transaxial (D, E) T1-MRI SPM images spatially normalized to the Montreal Neurological Institute (MNI) space. FDG = fluoro-2-deoxy-d-glucose; MRI = magnetic resonance imaging.