LAUSR

Dear Sirs Adrenoleukodystrophy (ALD) is an X-linked disease caused by ABCD1 pathogenic variants. In males, ALD is clinically characterized by a wide phenotypic spectrum ranging from the most severe childhood cerebral form to Addison-only phenotype. In adult males, adrenomyeloneuropathy (AMN) is the most common phenotype. AMN usually presents in young adults with a varying degree of spastic–ataxic gait, sensory disturbances, bladder dysfunction, impotence and adrenal failure. Virtually all males carrying ABCD1 pathogenic variants who reach adulthood are expected to develop AMN [1]. We report two males with different ABCD1 pathogenic variants who are still asymptomatic (i.e., without any subjective abnormalities [2]) in their seventh decade of life, and who were identified by reviewing the clinical and laboratory information of our cohort of 53 adult ALD subjects followed in our Institute from January 2004 to December 2019. Subject 1 was an asymptomatic 62-year-old man assessed because the son of his sister suffered from AMN due to the p.R389C (c.1165C > T) ABCD1 pathological variant, his sister was an asymptomatic carrier, and his daughter, who wanted to be tested because she had two male children, was found to be a carrier (Fig. 1a). Neurological examination showed only diffuse deep tendon hyperreflexia, without any clinical evidence of adrenal failure, but the dosage of very long-chain fatty acids (VLCFAs) revealed a mild increase of C26:0 [1.70 μmol/L, normal value (n.v.): < 1.5] and genetic testing confirmed the presence of the known familial mutation. Brain MRI, nerve conduction studies, serum cortisol and ACTH were normal, whereas lower limb central motor conduction times (CMCTs) and central somatosensory conduction times (CSCTs) were prolonged [CMCTs = 19.2 ms (right), 20.0 ms (left), n.v. < 16.7; CSCTs = 20.1 ms (right), 21.3 ms (left), n.v. < 17.3]. At age 70, the subject complained only of erectile dysfunction, and neurological examination remained unchanged. Subject 2 was an asymptomatic 56-year-old man assessed because his first-degree cousin suffered from AMN due to the p.W339G (c.1015 T > G) ABCD1 pathogenic variant (Fig. 1b). Neurological examination was normal and there was no clinical evidence of adrenal failure, but the dosage of VLCFAs revealed a marked increase of C26:0 (3.40 μmol/L, n.v. < 1.5), and genetic testing confirmed the presence of the known familial mutation. He refused further laboratory investigations. At the age of 63, before a surgery to remove a tumour, neurological examination (performed elsewhere), and serum cortisol were normal, whereas ACTH was 71,73 pg/mL (n.v. 4.70–48.40). At the last telephone followup when he was 65, he remained asymptomatic, i.e., without any psychopathological, motor, sensory or autonomic symptoms, and without adrenal hormone-replacement therapy. In males, ALD is considered invariably symptomatic, with typical onset before the age of 40 [3], and very rarely in the early fifties [3, 4]. Elderly asymptomatic hemizygous males were exceptionally mentioned in large case series [5–7], but they were not well documented (Table 1). Our subjects are worth reporting because they provide evidence that ALD males may remain free of obvious ALDrelated symptoms even very late in life, and support the thesis that ALD is an X-linked disease with incomplete penetrance in males [8], or at least that some hemizygous males have such mild manifestations that they don’t even notice. We cannot predict when these asymptomatic subjects will develop clinical manifestations, if ever, but their existence should be kept in mind first for genetic counseling to not miss the investigation of relatives of ALD index cases. This is important also because children carrying ABCD1 * Ettore Salsano [email protected]