Heterozygous X-linked adrenoleukodystrophy-associated myelopathy mimicking primary progressive multiple sclerosis

Abstract

We describe the case of a 73-year-old woman who was referred to our clinic because of a 10-year history of slowly progressive spastic paraparesis. The patient underwent a brain and spinal cord MRI that showed the presence of bihemispheral white matter hyperintensities and of a spinal cord lesion (Fig. 1). She was referred to our clinic because of suspected late-onset primary progressive multiple sclerosis. On admission, a neurologic examination showed the presence of paraparesis, increased leg tone and a spastic gait. All reflexes were brisk and a bilateral Babinski sign was elicited. Diminished sensation of vibration in both legs and bilateral hypoesthesia below the T5 level were present. Results of routine hematologic tests were normal, as were the screenings for autoimmune and infectious conditions (including testing for ANA, LAC, ACA, ANCA and antiborrelia, VDRL, and TPHA serologies). Cerebrospinal fluid isoelectric focusing showed no oligoclonal IgG bands. There was no family history of multiple sclerosis. However, the patient reported that several women (her mother, two sisters and two first-degree nieces) in her family were affected by a slowly progressive form of spastic paraparesis and that two of her brothers died when they were children after having developed motor and cognitive symptoms (Fig. 2). The differential diagnosis of primary progressive multiple sclerosis presenting as progressive spastic paraparesis includes different genetic conditions such as leucodystrophies and hereditary spastic paraplegia [1]. In particular, X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder secondary to alterations in the ABCD1 (ATP-binding cassette, sub-family D, member 1) gene that shows a wide range of phenotypic expression, from a severe cerebral progressive form in childhood to a mild adult myelopathy [2]. For this reason, the molecular analysis of the ABCD1 gene was performed on DNA extracted from peripheral blood of the patient and her relatives, and revealed a heterozygous two base pair deletion at position 1415–1416 in exon 5 (c.1415_1416delAG; p.Gln472ArgfsX83), the most common mutation in X-ALD families [3]. In females heterozygous for X-ALD, neurologic symptoms are frequent [4]. In particular, it is estimated that up to 50% of women who are heterozygous for X-ALD may develop a slowly progressive myelopathy [2]. In contrast to multiple sclerosis, spinal cord involvement in X-ALD is not characterized by an overt inflammatory component [5] and conventional spinal cord MRI usually does not show significant abnormalities other than cord atrophy late in the disease [6]. Similarly, brain MRI abnormalities attributable to ALD are seen on conventional T2-weighted images only in a small number of XALD heterozygotes [6, 7]. In our patient, a hyperintense lesion with more pronounced involvement of the dorsal M. Di Filippo (&) E. Luchetti M. Di Gregorio N. Tambasco P. Sarchielli P. Calabresi Section of Neurology, S. Maria della Misericordia Hospital, University of Perugia, Perugia, Italy e-mail: difilippo@unipg.it