Adrenoleukodystrophy as a Cause of Spastic Paraparesis and Hyperpigmentation

Abstract Background: X-linked Adrenoleukodystrophy (X-ALD) is caused by an abnormal gene mutation on the X chromosome which codes for an abnormal ABC transporter, preventing transport of very long chain fatty acids (VLCFAs) into peroxisomes for beta oxidation. These VLCFAs, unable to be broken down, thus accumulate in the CNS, adrenal cortex, and Leydig cells of the testes. The clinical presentation depends upon the anatomical involvement, which most often includes the CNS and adrenal glands, and can be a cause of adrenomyeloneuropathy (AMN) or adrenal insufficiency. Case Report: We report a 44 year old male who presented with 9 years of progressive spastic paraparesis. Physical exam was significant for lower extremity spasticity, 3/5 bilateral lower extremity weakness, and hyperpigmentation. His initial work-up for autoimmune disease, MRI brain, and lumbar puncture were unremarkable, and genetic testing for Hereditary Spastic Paraparesis was negative. However, due to advancing symptoms over the years with progression of spasticity, polyneuropathy, development of erectile dysfunction and significant hyperpigmentation, re-evaluation with MRI brain and EMG revealed diffuse symmetrical cerebral and cerebellar volume loss and axonal motor peripheral neuropathy, respectively. Due to hyperpigmentation, further work-up for VLCFAs was positive and presence of the ABCD1 mutation confirmed the diagnosis of X-ALD. Evaluation of adrenal glands yielded high ACTH of >2000 pg/mL (normal: 7.2–63.3) and low AM cortisol of 2.5 ug/dL (normal: 6.2–19.4). Insignificant increase of cortisol from 2.5 ug/dL to 2.7 ug/dL with cosyntropin confirmed primary adrenal insufficiency as the cause of hyperpigmentation with elevated ACTH. Surprisingly, his testosterone level was normal at 542 (normal: 250–1100 ng/dL) and suggestive of Leydig cell-sparing and neuropathy-induced erectile dysfunction. The patient was started on hydrocortisone for adrenal insufficiency with improvement in his fatigue and feelings of well-being. He received physical therapy and is being monitored closely for progression of AMN by Neurology. Conclusion: Our case suggests that ALD should be considered in the differential diagnosis of unexplained paraparesis with associated hyperpigmentation in males. Moreover, timely diagnosis and medical intervention can prevent life-threatening adrenal crisis in such patients.