A new study in six Chinese men with adrenomyeloneuropathy (AMN) revealed a novel ABCD1 gene mutation, alterations such as skin hyperpigmentation, spasticity, and sexual dysfunction, as well as brain lesions in two of the patients.
The research, “Clinical, neuroimaging, biochemical, and genetic features in six Chinese patients with Adrenomyeloneuropathy,” was published in the journal BMC Neurology.
AMN, the adult-onset form of adrenoleukodystrophy (ALD), is characterized by nerve fiber degeneration, progressive paraparesis (partial paralysis of both legs), and sensory disturbances, with a subset of these patients also experiencing loss of myelin — the protective coating that surrounds nerve fibers — in the brain.
In the study, a team with the Chinese PLA General Hospital characterized the clinical, biochemical, neuroimaging, and genetic features of six men with AMN (median age at symptom onset was 29.8 years, and age range was between 21 and 38 years) from August 2012 to January 2018.
All patients underwent magnetic resonance imaging (MRI) scans of the brain and spinal cord. Five underwent nerve conduction and genetic studies.
Three men had a suspected positive family history of AMN. The one family member who agreed to undergo a genetic test was later shown to also have the condition.
Results revealed that five out of the six patients experienced stiffness or weakness of the legs, while the other man had pain in his back.
Also, five patients had sexual dysfunction, yet had normal testosterone levels. All patients experienced spasticity, paresis (partial paralysis or weakness), and increased tendon reflexes, which are consistent with Addison’s disease. Five had urinary disturbance, and one experienced personality change, memory impairment, and dysarthria (slurred or slow speech).
Five had hyperpigmentation in the lips, around the nipples, and in the gums, which was associated with marked increases in the plasma levels of adrenocorticotropic hormone (ACTH). Following treatment with hydrocortisone, ACTH levels normalized in two of these men, with further reductions in skin pigmentation and fatigue.
Four patients showed abnormal nerve conduction, and all six had evidence of spinal atrophy (shrinkage) on MRI. One patient exhibited no mood or memory disturbances until the last visit. These disturbances occurred in parallel with progressive lesions in the corpus callosum (a band of nerve fibers connecting the two sides of the brain).
All five patients who underwent biochemical tests had plasma levels of very long-chain fatty acids (VLCFA) above the normal range, as were their levels of lignoceric/behenic and cerotic/behenic acids ratios — in line with an AMN diagnosis.
Five mutations were found in the ABCD1 gene, four of which (reported previously) are missense mutations — changes in the building blocks of DNA, called nucleotides, leading to a different amino acid — and also associated with cerebral ALD. The remaining patient had a previously unreported frameshift mutation — a variant that alters the way the gene sequence is read — which generates a shorter protein.
“In conclusion, this study aims at illuminating basic features from the clinical, neuroimaging, biochemical, and genetic aspects of some Chinese AMN patients,” the researchers wrote.
They suggested that “plasma VLCFA and ABCD1 gene analysis should be tested for the patients who present with Addison disease and spastic paraparesis…. It is also critical to diagnose AMN rapidly, owing to the insistent demands of genetic counseling, and applications of targeted and specific treatment options.”