Even a series of progress have been accomplished on the AMN, a comprehensive exploration with perspective of clinical, neuroimaging, biochemical, and genetic analysis in Chinese AMN patients is still lack.
AMN was proposed due to the involvement of a slowly progressive paraparesis, adrenal insufficiency, hypogonadism combined with peripheral nerves neuropathy and sphincter disturbances4. With the discovery and application of VLCFA, AMN was soon found to be a form of phenotypic X-ALD17,18. Nevertheless, neuropathologic study has revealed a more indolent degenerative process, different from the inflammatory cerebral phenotypes5,19. Moreover, reports elucidated that the genotype–phenotype correlation in ALD patients is not evident20-23. In our cohort，although they each had the same genotype, the various clinical manifestations of patients 1, 2, 4, and 5 were consistent with the AMN phenotype, which is inconsistent with previously reported results 12-15. These data mean that in addition to primary defect in ABCD1, environmental factors and/or other genes show a strong connection with the development of the disease. This study further confirms that genotype and phenotype may not correlate.
In our cohort, median onset age of neurological symptoms was 29.8 years and ranged 21–38 years, consisted with previous reports24,25. Five of these patients developed skin pigmentation when they were young. Interestingly, patient 5 had no apparent skin color changes or abnormal plasma ACTH up to the date of follow-up. Moser et al have suggested that there were 33% of AMN patients with normal adrenal function at all points (normal cortisol response to ACTH and normal baseline ACTH levels). Nevertheless, it’s likely that this percentage was underestimated, which may be attributed to part of neurologists who didn’t have sufficient knowledge to interpret the result as adrenal function is normal24. Therefore, we think that “myeloneuropathy-only” is an important phenotype of ALD. There were two of six patients (patient 1 and 6,) with cerebral involvement (33%), higher than that (about 19%) reported by van Geel et al, but lower than that (about 63%) from de Beer et al10,26. It is noteworthy that the patient's mental state, walking ability and verbal ability showed significant deterioration about half a year after the divorce. According to previous reports, head trauma may be a possible environmental trigger27-29 but other modifiers (both genetic and environmental) have not yet been identified. We boldly guess that emotional trauma (such as divorce) may be an enviromental factor, which intiates or aggravates cerebral disease.
MRI is an important tool for diagnosis and detecting the evolution of the disease. As displayed in FIG.4, patient 1’s head MRI evolution indicated that intracranial lesions originate from the splenium of the corpus callosum and then increasingly extend to the periventricular and occipital-parietal white matter. Interestingly, patient 1 didn’t show any obvious mood, memory disturbance or other psychiatric symptoms, which implies that white matter lesions on MRI may preact symptoms. It is consistent with the findings of van der Knaap et al30,31. Therefore, regular head MRI evaluation is very important for patients with AMN or ALD32,33. The brain MRI of patient 6 showed extensive lesions, including splenium of corpus callosum, bilateral symmetrical temporo-parietal-occipital white matter, bilateral corticospinal tract, and bilateral dentate nuclei of cerebellar, some lesions confluent. The lesions were compatible with previous results of Loes et al34,35. Although no enhancement of demyelinating lesions of patient 6’s head MRI were observed, diffusion-weighted images showed slightly increased signal intensity with the splenium of the corpus callosum as well as parieto-occipital white matter. Meanwhile, the patient experienced a considerable decline in cognitive function. It demonstrates that he develops into the rapidly progressive neuroinflammatory stage and his condition will deteriorate progressively.
Although patient 1 received Lorenzo’s oil treatment regularly, plasma C26:0 levels were nearly normal, intracranial lesions are still developing. It is compatible with previous studies 36,37.
In our cohort, we found a novel frameshift mutations in patient 6 (FIG. 6). The Sanger sequencing results of ABCD1 gene in the family demonstrated a nucleotide insertion mutation A at cDNA nucleotide 1843(c.1843dup) which was observed in the patient's mother. In addition, this frameshift mutation was not reported in previous studies. Combining with the clinical, imaging and biochemical characteristics of the patient, we recommend to define the mutation as Pathogenic.