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The two most common phenotypes of X-linked adrenoleucodystrophy are the childhood cerebral form and adrenomyeloneuropathy, which occurs mainly in adults and affects the long tracts in the spinal cord most severely.1 Most patients with the cerebral forms have an inflammatory demyelinating process, while the principal pathology of adrenomyeloneuropathy is a non-inflammatory distal axonopathy, although 30% of patients with adrenomyeloneuropathy also develop some degree of inflammatory brain pathology.2 All forms of X-linked adrenoleucodystrophy are caused by a defect in the gene ABCD1 which codes for the peroxisomal membrane protein ALDP and is associated with the abnormal accumulation of very long chain fatty acids. Most patients with X-linked adrenoleucodystrophy have primary adrenocortical insufficiency. Although adrenal hormone treatment is considered mandatory and may be life saving, most investigators have expressed the opinion that it does not alter neurological status. We report a patient with a variant of adrenomyeloneuropathy in whom adrenal hormone replacement therapy improved neurophysiological function and clinical status.
A 39 year old man was evaluated for adrenoleucodystrophy at the Kennedy–Krieger Institute (KKI) in 1985, because his nephew had been diagnosed with childhood onset adrenoleucodystrophy. The nephew died aged nine years and had necropsy confirmation of the diagnosis. Our patient had no neurological symptoms at that time. In 1996, he returned to KKI with complaints of “leg stiffness” and “being off balance.” His plasma adrenocorticotrophic hormone (ACTH) level and serum very long chain fatty acids were both raised. Brain magnetic resonance imaging (MRI) showed “subtle white matter changes in the posterior periventricular region that were either at the upper limit of normal or minimally abnormal” (not shown).
In July 2000, he presented to the Buffalo VA Medical Center with complaints of leg stiffness and balance problems. Physical examination showed mild hyperpigmentation, especially in the palmar skinfolds. On neurological examination there was increased tone and decreased vibratory and positional sensation in the lower extremities only. His gait was spastic, with hyperactive deep tendon reflexes and extensor plantar responses.
Before steroid treatment was begun, brain MRI and evoked potential testing were undertaken, as follows:
visual evoked response: OS/OD, P100 = 166.0/159.6 ms;
brain stem auditory evoked response: AS, wave I, 2.00 ms; II–V absent; AD, wave I, 1.94 ms; II, 2.88 ms, III–V absent;
peroneal nerve somatosensory evoked response: left/right, L3 = 8.64/9.44 ms, P27 = 54.60 ms (delayed)/absent;
median somatosensory evoked response and upper and lower extremity peripheral nerve conduction velocities: normal.
Brain MRI showed mild to moderate confluent hyperintense lesions on T2 weighted and fluid attenuated inversion recovery images (FLAIR) in the posterior periventricular white matter (not shown).
After six months of oral prednisone, 20 mg twice daily, the patient had significant improvement in his leg stiffness and gait. Reflexes became normal, but the sensory deficits were unchanged. ACTH levels declined from 3122 to 26 pg/ml. On visual evoked response testing, P100 latencies became normal (OS/OD, P100 = 106.6/110.0 ms; fig 1). Brain stem auditory evoked responses showed improvement by the appearance of wave II and III in the left side, but no change in the right side. The left peroneal somatosensory evoked response became nearly normal, with a P27 latency of 35.5 ms; the right P27 peak appeared at a latency of 44.8 ms. Median somatosensory evoked response and peripheral nerve conduction velocities were unchanged. The visual evoked response and brain stem auditory evoked response findings were sustained at the 15 month follow up studies (not shown). Following six and 15 months of prednisone treatment, interval MRI showed that the lesions were stable compared with the pretreatment scan. There was no clear progression of MRI involvement (not shown).
The neurological findings and history in this patient are typical of adrenomyeloneuropathy, and this diagnosis was confirmed by the abnormally high plasma levels of very long chain fatty acids. In addition, brain MRI studies showed the presence of moderately severe cerebral inflammatory involvement, as occurs in approximately 30% of patients with adrenomyeloneuropathy.1 The demyelinating or inflammatory lesions affecting the spinal cord and brain stem long tracts that are characteristic of this disorder are the likely causes of the gait disturbance, the prolonged interpeak latencies of the peroneal somatosensory evoked response, and the abnormalities of brain stem auditory evoked response before prednisone treatment. The posterior periventricular lesion noted on MRI indicates that the patient had inflammation or demyelination in the visual radiations, which probably correlates with the initially abnormal visual evoked response. Adrenocorticosteroid replacement therapy restored the plasma ACTH level to normal, improved the gait disturbance, and completely corrected the visual evoked response latencies.
Prolonged interpeak latencies of the somatosensory evoked response and the brain stem auditory evoked response, with nearly normal or normal amplitudes, reflect demyelination. The reduced interpeak latencies from the brain stem auditory evoked response and the peroneal somatosensory evoked response after treatment indicate remyelination.3 No patients with X-linked adrenoleucodystrophy appear to have spontaneous remissions.1 Therefore the clinical and evoked response improvement is likely to be attributable to prednisone treatment. Although two male patients with adrenomyeloneuropathy showed neurological improvement after starting on prednisone, neither patient had simultaneous improvement in their evoked responses and MRI.4,5 Our findings are thus consistent with the hypothesis that steroid replacement therapy ameliorated the inflammation or demyelination in our patient. His improvement with prednisone replacement suggests that a more systematic analysis of the neurological effects of corticosteroid treatment in X-linked adrenoleucodystrophy is warranted.
We thank Dr Gerald Raymond from the Kennedy–Krieger Institute for his comments and Diane Petryk from Buffalo VA Medical Center for her excellent technical support. The investiators were supported in part by grant RR00052 from the United States Public Health Service (HWM), National Institutes of Health (NIH-NINDS) 1 K23 NS42379-01 (RB), and local funds from the Department of Veteran Affairs, Medical Center, Buffalo, New York (EF).