A Novel Catastrophic Presentation of X-Linked Adrenoleukodystrophy

Abstract

Objective: We report a novel presentation of childhood cerebral X-linked adrenoleukodystrophy: status epilepticus followed by abrupt and catastrophic neurologic deterioration.Methods: A description of the clinical presentation, laboratory evaluation, and imaging findings leading to a diagnosis of X-linked adrenoleukodystrophy.Results: A 3-year-old male with prior history of autism presented with fever, diarrhea, and status epilepticus requiring a pentobarbital coma. Admission labs were notable only for a glucose level of 22 mg/dL, which stabilized after correction. The child never returned to his prior neurologic baseline, with complete loss of gross motor, fine motor, and speech skills. Serial brain magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS) was notable for progressive diffuse cortical signal changes with swelling, diffusion restriction, and ultimately laminar necrosis. Nine months after presentation, CSF (cerebrospinal fluid) protein and MRS lactate were persistently elevated, concerning for a neurodegenerative disorder. This led to testing for mitochondrial disease, followed by lysosomal and peroxisomal disorders. Very long-chain fatty acids were elevated. Identification of a pathogenic ABCD1 mutation confirmed the diagnosis of X-linked adrenoleukodystrophy.Conclusions: Boys with childhood cerebral X-linked adrenoleukodystrophy typically present with gradual behavioral changes. Rare reports of boys presenting with transient altered mental status or status epilepticus describe a recovery to their pre-presentation baseline. To our knowledge this is the first X-ALD patient to present with status epilepticus with abrupt and catastrophic loss of neurologic function. X-linked adrenoleukodystrophy should be suspected in young males presenting with seizures, acute decline in neurologic function, with persistently elevated CSF protein and MRS lactate.

Etiology and treatment of adrenoleukodystrophy: new insights from Drosophila

“…2 ). These data bolster our view that: (1) environmental stress in the form of seizure triggered neurodegeneration in a leukodystrophy patient with a predisposing ACS mutation ( Sivachenko et al, 2016 ), and (2) traumatic brain injury triggered neurodegeneration in patients with catastrophic presentations of ALD ( Raymond et al, 2010 ; Vawter-Lee et al, 2015 ; Weller et al, 1992 ). Moreover, as stress might precipitate a degenerative cellular phenotype when product generation is required to repair damaged or depleted cellular components, our bgm/dbb stress studies suggest that esterified LCFA and VLCFA products of Bgm and Dbb activity are required to prevent neurodegeneration, a hypothesis that contradicts the long-held view that precursor accumulation is causative of neurodegeneration in ALD patients.…”

Neurodegeneration in aDrosophilamodel of Adrenoleukodystrophy: the roles of the bubblegum and double bubble acyl-CoA synthetases

“…Moreover, in addition to revealing severe neurological involvement, activity phenotypes can be monitored in higher-throughput assays, and this opportunity underscores the feasibility of suppression screens for the identification of compounds and/or dietary regimens that alleviate the abnormalities associated with ACS mutation. Finally, highlighting the continuing power of simple invertebrate genetic models, this study has led to our recognition of a new candidate susceptibility gene for catastrophic presentation of leukodystrophy ( Vawter-Lee et al, 2015 ).…”

“…Comparative genotype/phenotype data, coupled with our observation that treatment of the proband with levetiracetam to control seizures unexpectedly stemmed the progression of his neurodegenerative condition, leads us to speculate that, in this patient, seizures are the trigger of a neurodegenerative condition linked to a susceptibility locus, with SLC27a6 being a likely candidate. There is ample evidence for other ALD cases where events such as epileptic seizure or traumatic brain injury have been proposed to precipitate onset of leukodystrophy symptoms in previously asymptomatic individuals ( Weller et al, 1992 ; Raymond et al, 2010 ; Vawter-Lee et al, 2015 ).…”

Fulminating Autoimmune Demyelination with Optic Neuropathy in a Case of Pediatric Cerebral Adrenoleukodystrophy: Case Report and Review of the Literature

“…The inflammatory demyelinating lesion appears to begin at the same site as the original contusion. 5,43,44 Musolino et al reported that an increase in BBB permeability precedes inflammatory demyelination, suggesting that disruption of the BBB may trigger pro-inflammatory demyelination in ALD. 45 It is thus possible that head trauma triggers the inflammatory cerebral ALD presumably due to the BBB disruption.…”