Novel <b><i>ABCD1</i></b> Gene Mutation in Adrenomyeloneuropathy with Hypoplasia and Agenesis of the Corpus Callosum

Abstract

Background: Adult adrenomyeloneuropathy (AMN) is caused by mutations in the ABCD1 gene. Some pure AMN patients develop cerebral demyelination late in life. However, hypoplasia and agenesis of the corpus callosum (CC) has never been reported in AMN patients. Objective: To describe a new clinical variant of AMN that is possibly caused by a novel ABCD1 gene mutation. Methods: A total of 10 members in an X-linked inherited family were examined. The age at onset, progression of disability, and clinical manifestations were collected. Blood tests of the index case were conducted in an academic hospital. Cerebral and spinal MRI was performed in 4 affected members using a Siemens 3.0-T or Hitachi 1.0-T MR scanner. Whole-exome sequencing was conducted in the index case, which was subsequently validated by Sanger sequencing in the family. Results: The patients displayed typical degenerative spastic paraparesis and peripheral sensorimotor neuropathy with some intrafamilial variations. In addition to neurological deficits, all male patients displayed alopecia since adolescence. Furthermore, an increase in plasma long-chain fatty acids was observed. Based on these presentations, adult AMN was diagnosed for the patients. Intriguingly, cerebral MRI showed multiple types of hypoplasia and agenesis of the CC including anterior remnant CC agenesis, truncated corpus and splenium, anterior remnant CC agenesis along with thin corpus and splenium. Whole-exome sequencing revealed a nonsense mutation (c.231G>A) which results in a truncated protein product (p.W77X) that might be nonfunctional. No other mutations associated with alopecia or hypoplasia and agenesis of the CC were identified in the exome-sequencing database. Conclusion: In addition to the typical symptoms such as spastic myelopathy, cognitive impairment, mixed neuropathy, and alopecia, AMN patients can also display hypoplasia and agenesis of the CC, which was not described in the other AMN patients reported before.

Diverse clinical manifestations of X-linked adrenoleukodystrophy in a Chinese family with identical multisite variants of ABCD1 gene

“…The mother and the elder brother of the proband had similar symptoms, late onset and slow progress. The relatively mild and slow progression of the disease in the proband’s elder brother followed the pattern of adult-onset AMN (Qiu et al ., 2018). AMN is more common in adult males, usually onset after the age of 30 (Turk et al ., 2020), progressing slowly.…”

“…In the present study, the proband’s mother was heterozygous for the three variants. The relatively mild and slow progression of the disease in the proband’s mother followed the pattern of adult-onset AMN (Qiu et al ., 2018). In addition, although no prospective studies have systematically assessed this, progress is considered to be slower (Engelen et al ., 2014a).…”

Burden of illness and mortality in men with Adrenomyeloneuropathy: a retrospective cohort study

“…Additional research is needed in several areas, including on healthcare costs, HRU and clinical burdens for women with ALD; and male ALD with cerebral inflammatory brain disease, which affects up to 30% of adult AMN men [ 20 ]. It is also unclear whether the increased morbidities and mortality are an indirect effect of AMN complications, for example, decreased mobility; or whether they reflect hitherto unrecognized disease complications of ALD.…”

A novel ABCD1 G1202A mutation in a Chinese patient with pure adrenomyeloneuropathy and literature review

“…We reviewed 18 papers including 32 cases with AMN: the clinical features of these patients were summarized in Table 1 . 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 …”