ACOX1-Deficiency Causing a Severe Developmental Delay and Epilepsy

Background: The 4 year old patient is the first child of consanguine parents of Kurdish origin (Irak). At approximately 34 weeks of gestation ascites and a small bladder volume was noted on prenatal ultrasound. He was born per Caesarean-section at 37+6 weeks of gestation with a birth weight of 2300g. He presented as a floppy infant with a weak suck and developed neonatal jaundice. During the first months of life myoclonic and grand mal seizures were noted. He had a sensory hearing deficit and an ophthalmologic white dot dystrophy. He learned to grasp, rolling to the side and to creep at age 2. Since the age of 2.5 years developmental regression was noted. He successively lost all motoric functions, followed by inability to swallow and spasticity of the legs.

Methods: Cranial MRI showed a reduced volume in the frontotemporal region; EEG showed multifocal spike-waves. Elevated dicarbon-aciduria was repeatedly noted on examination of organic acids. For possible peroxisomal disorder very long chain fatty acids (VLCFA), phytanic acid in blood and metabolites of bile acids in urine were examined. Peroxisomal function in fibroblasts was examined at the Genetic Metabolic Disease Laboratory in Amsterdam.

Results: Very long chain fatty acid (C26:0) were increased as well as the ratio of 26:0/22:0. Plasmalogens and bile acids were normal. Fibroblast culture revealed no activity of acyl-CoA oxidase 1 (ACOX1), and a mildly reduced function of DHAPAT, normal function of D-bifunctional protein, an abnormal VLCFA profile with increased C26:0 level in the phospholipid fraction. D3/C22 loading test showed a reduced beta-oxidation and chain-elongation of D3/C22. Mutation analysis (Genetic Metabolic Disease laboratory, Amsterdam ) of ACOX1 on chromosome 17q25 revealed a homozygous variant: c.904C>T (p.ARG302X; class 5-variant).

Conclusion: The variant c.904C>T in ACOX1 had already been described in the literature and confirmed the diagnosis of ACOX1-deficiency. ACOX1 is involved in degradation of VLCFA, especially during peroxisomal beta-oxidation. VLCFA cannot be degraded and accumulation impairs function in the nervous system leading to a leucodystrophy. To date only few patients with ACOX1 deficiency have been described. Most patient learn to walk, speak a few words and regression is noted at an age of 28 months. Our patient was symptomatic after birth, showed a primary psychomotor delay followed by regression and the clinical picture of a rapidly progressive leucodystrophy.