ESPE Abstracts

Background: Human peroxisomal fatty acyl CoA oxidase 1, encoded by the ACOX1 gene, catalyzes the first and rate limiting step in the beta oxidation of straight chain fatty acids in the peroxisomes. Biallelic mutations in ACOX1 are associated with pseudo-neonatal adrenoleukodystrophy characterized by severe hypotonia, seizures, psychomotor retardation followed by neuroregression, and death in early childhood. To date, primary adrenal insufficiency (PAI) has not been characterized in the 34

Aim: To describe characteristics of PAI in a case with pseudo neonatal adrenoleukodystrophy.

Case: A female patient was evaluated in the intensive care unit for severe respiratory distress, hypoglycemia, hyponatremia, and hyperkalemia. In her previous history, she was born to consanguineous parents at 37 weeks and 2200 grams. She was investigated for severe neonatal-onset hypotonia, seizures, severe psychomotor developmental delay, and neurological regression. A homozygous deletion of 12.9kb within the 17q25.1 chromosomal region encompassing exons 13 and 14 of the ACOX1 gene was identified by next-generation sequencing-based CNV analysis. Physical examination at sixteen months old revealed generalized hyperpigmentation and severe hypotonia. Plasma adrenocorticotropic hormone (ACTH) concentration was >1250 pg/mL (normal: 10-60 pg/mL), while plasma cortisol concentration was 1.6 μg/dL (normal: 2.5-9.1 μg/dL). Additionally, plasma renin activity was elevated at 32 ng/mL/h (normal: <2.8 ng/mL/h), Plasma sodium and potassium were 124 mmol/L (normal: 135-145 mmol/L) and 5.9 mmol/L (normal: 3.5-5.1 mmol/L), respectively. Hydrocortisone and fludrocortisone were initiated to treat PAI. Analysis of very long-chain fatty acids (VLCFA) in plasma revealed high C26/C22: 0.17 (0-0.023) and C24/C22: 1.6 (0-1.30) ratios. Cranial magnetic resonance imaging showed T2 high-intensity areas in the bilateral cerebellar white matter, pons, internal capsule, basal ganglia, and thalami. Adrenal computerized tomography demonstrated bilateral adrenal gland atrophy. A comprehensive LC-MS/MS-based plasma steroid hormone panel confirmed non-CAH PAI. 750K microarray established the ACOX1 intragenic deletion. Clinical exome sequencing excluded other possible causes of PAI.

Conclusion: Adrenal insufficiency should be considered in the phenotypic spectrum of peroxisomal disorders. Fatty acyl CoA oxidase 1 deficiency emerges as a novel peroxisomal etiology of non-CAH primary adrenal insufficiency.