Newborn Screening for Adrenoleukodystrophy Is the First Step to a Cure

Presentation Number: SUN 372
Date of Presentation: April 2nd, 2017

Jeremy Taylor*, Brian Kirmse, Shema R Ahmad and Jose S. Subauste
University of Mississippi Medical Center, Jackson, MS

Abstract

Introduction:X-linked adrenoleukodystrophy (X-ALD) is a neurogenetic disorder that affects cerebral white matter as well as adrenal cortical function and has at least 3 distinctive phenotypic variants that can manifest at any point during development. No clear genotype-phenotype correlations exist. While hemopoietic stem cell transplant (HSCT) is now used to treat affected males early in the course, Lorenzo’s oil (LO, a 4:1 mix of oleic acid and erucic acid) is an investigational therapy that may delay progression of neurologic symptoms in some patients and is offered to affected patients aged 18 months to 18 years. Here we report a case of X-ALD in which the development of neurodegenerative symptoms appeared 3 years after Lorenzo’s oil was stopped.

Clinical Case: Our patient, now a male 23 years of age, was diagnosed at birth with X-ALD after an uncle with the disorder died. DNA sequence analysis of the ABCD1gene revealed the familial nonsense mutation, c.1815 G>T (p.E477X), which was a known pathogenic variant (1). His parents opted to treat him with restriction of dietary very long chain fatty acids and administered Lorenzo’s oil nightly. He was started on hydrocortisone and fludrocortisone at age 5 for primary adrenal insufficiency confirmed by lab testing: ACTH 281.6 pg/mL, cortisol <0.5 mcg/dL, aldosterone <1.0 ng/dL, renin 2.12 ng/dL, DHEA-S 5.6 μg/dL. Periodic MRI of the brain, EEG and EMG documented stability as he developed normally throughout adolescence and successfully completed high school.

Since open label trials had not shown any significant benefit in mortality or preventing the development of neurodegenerative sequelae when LO is continued beyond age 18, treatment was stopped. At age 21 the patient began exhibiting signs of lethargy that evolved into an emotionally lability with disinhibited behavior that was initially attributed to his abuse of alcohol and marijuana. Symptoms worsened over the following months and progressed further to include incontinence, slurred speech and ataxia leading to frequent falls. MRI of the brain showed significant white matter disease progression which has worsened on subsequent imaging. Most recent brain MRI staged his disease 8/9 and therefore he was not deemed an appropriate candidate for bone marrow transplantation.

Conclusion: X-ALD is a complex genetic disorder that affects both the nervous and endocrine systems for which there is no cure. LO continues to be used in young patients and may reduce the risk of cerebral disease; HSCT is used in pediatric patients in early symptomatic stages of the disease. This case highlights the need for more studies of LO and HSCT in adults with X-ALD especially since newborn screening for the disorder is currently under way in some states and likely to identify more patients with later adult-onset variants.

 

Nothing to Disclose: JT, BK, SRA, JSS