O-10 ABCD1 GENE MUTATION IN AN IRANIAN FAMILY WITH X-LINKED ADRENOLEUKODYSTROPHY AND DIVERSE CLINICAL MANIFESTATIONS

Abstract Introduction A hereditary condition known as X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene, which is found at the Xq28 locus. This gene produces a transporter protein that imports very long-chain fatty acids into peroxisomes. ALDP dysfunction causes high amounts of very-long-chain saturated fatty acids (VLCFAs) in the blood and tissues, resulting in the development of ALD. Given the wide range of symptom severity seen in X-ALD, this study aims to understand the clinical manifestations associated with different mutations in the ABCD1 gene among Iranian family with several patients. Clinical Case A 42-year-old male proband, diagnosed with Addison’s disease 15 years ago following a psychotic episode, and has since been managed with glucocorticoid and mineralocorticoid replacement therapy. In 2020, approximately 15 years after the initial diagnosis, the patient developed progressive neurologic symptoms, including paresthesia, gait and balance disturbances, dysphagia, spastic paraparesis, accompanied by brainstem changes observed on neuroimaging. Taking family history and examination revealed a younger brother’s unknown death (suspected adrenal crisis) and another male sibling with motor disorders. A nephew was diagnosed with Addison’s disease and later developed limb spasms and occasional nocturia, he went under the care of a neurologist and occupational therapist. Given the clinical presentation and suspicion of adrenoleukodystrophy, plasma levels of very-long-chain fatty acids (VLCFA) were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the proband. Then the pedigree was drawn, and genomic DNA was isolated from peripheral blood samples. The ten coding exons of the ABCD1 gene were analyzed through conventional Sanger sequencing in the proband. The identified mutation in the proband was then assessed in other family members using the same sequencing method. In addition to VLCFAs imbalance, pathogenic mutation was identified in the exon 5 of the ABCD1 gene, with del AG at nucleotide 1415-1416, corresponding to the frameshift at the residue 472 (c.1415-1416delAG, p. Gln472fs). Segregation confirmed in affected males and carrier females. Conclusion Given the X-linked inheritance pattern, genetic counseling and prenatal diagnosis (PND) are essential for pregnancies in carrier females within this family, in order to prevent the recurrence of the disorder in future offspring.