Isolated Mild Intellectual Disability Expands the Aminoacylase 1 Phenotype Spectrum

Abstract

Aminoacylase 1 (ACY1) deficiency is a rare inborn error of metabolism presenting with heterogeneous neurological symptoms such as psychomotor delay, seizures, intellectual disability and it is characterized by increased urinary excretion of N-acetylated amino acids. We report on a new patient who presented ACY1 deficiency in association with isolated mild intellectual disability, but neither neurological symptoms nor autistic features. The child showed a compound heterozygous mutation (p.Glu233Asp) and a novel p.Ser192Arg fs*64, predicting an unstable transcript and resulting in very low protein levels.This new ACY1 deficient child was identified through regular screening for inborn error of metabolism adopted in our department in all cases of intellectual disability. This report supports a recommendation to perform metabolic investigations in patients with isolated mild intellectual disability.

The mercapturic acid pathway

“…Aminoacylase-1 deficiency is an autosomal-recessive inborn error of metabolism (entry 609924; https://www.omim.org/; accessed 31 October 2019) characterized by the increased excretion of N-acetyl-L-amino acids and by several developmental disabilities, including muscular hypotonia, seizures, delayed psychomotor development, and autistic behavior (van Coster et al 2005;Sass et al 2007;Engelke et al 2008;Tylki-Szymanska et al 2010;Sommer et al 2011;Alessandri et al 2014;Ferri et al 2014). Mutational analysis shows lossof-function mutations associated with abnormal splicing (Sass et al 2006;Sommer et al 2011;Ferri et al 2014).…”

“…Aminoacylases may serve to salvage N-acyl amino acids formed by protein degradation (Endo 1980;Giardina et al 1997;Pittelkow et al 1998;Perrier et al 2005;Lindner et al 2008b). The spectrum of N-acetyl amino acids found in the urine of human subjects with aminoacylase 1 deficiency (https://www.omim.org/entry/609924; accessed 31 October 2019) affords insight into the role of the aminoacylases in the processing of N-acetyl amino acids derived from N-acetylated peptides (Engelke et al 2008;Alessandri et al 2014Alessandri et al , 2018.…”

Biochemical and Histological Study of Aminoacylase-1 Purified from Amniotic Fluid in Rats with Oxidative Stress Induced by Lead Acetate

“…Besides, N-acetylcysteine is an important antioxidant that can work to remove OS, and may serve as an L-cysteine produced as an important amino acid. It becomes an antioxidant through its entry into the production of various antioxidants like glutathione which is involved in the removal of toxic chemical compounds resulting from various oxidative processes or from various environmental pollutants (7). Oxidative stress can lead to different effects on cell components including mitochondria dysfunction, as well as loss of maintenance of the electrical and chemical membrane of the inner membrane of mitochondria, and changes in the electron transport chain function, these changes lead to a decrease on the production of energy in cell as ATP, as well as the cause of some diseases for example, heart failure, albuminuria, atherosclerosis and diabetes (8).…”