Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy

Abstract

Adrenomyeloneuropathy (AMN) and cerebral childhood adrenoleukodystrophy (CCALD) are the main phenotypic variants of an X-linked inherited metabolic disorder causing demyelination, X-linked adrenoleukodystrophy (X-ALD). It is caused by mutations in the ABCD1 (ALD) gene encoding a peroxisomal ABC transporter. Inactivation of the murine ALD gene does not lead to a detectable clinical phenotype in mice up to 6 months, and no cerebral pathology resembling the childhood form (CCALD) was observed. In this work, we show that older ALD-deficient mice exhibit an abnormal neurological and behavioral phenotype, starting at around 15 months. This is correlated with slower nerve conduction, and with myelin and axonal anomalies detectable in the spinal cord and sciatic nerve, but not in brain. The phenotype of ALD-deficient mice mimics features of human AMN, thus providing a model for investigating the pathogenesis of this disease.