AMINOACYLASE I DEFICIENCY: A NEW INBORN ERROR OF METABOLISM LOCATED IN THE PROTEIN DEGRADATION PATHWAY OF N-ACETYLATED PROTEINS

Objectives: A hitherto unreported inborn error of metabolism is presented in a neonate with an encephalopathy expressed in the first weeks of life as generalized convulsions, hypotonia and feeding difficulties and associated with sensorineural hearing loss.

Methods: Cerebral MRI, GC-MS and MR spectroscopy of urine, enzymatic analysis in lymphoblasts, western blotting, gene analysis and protein expression studies were used to investigate the patient.

Results: Abnormal cortico-subcortical signals were visualized on cerebral MRI in the fronto-parietal and temporo-occipital regions. In the urine excessive amounts N-acetyl amino acids were detected by GC-MS and NMR spectroscopy (N-acetylserine, N-acetylglutamine, N-acetylglutamate, N-acetylalanine, Nacetylmethionine, N-acetylglycine and smaller amounts of N-acetylthreonine, Nacetylleucine, N-acetylvaline and N-acetylisoleucine). In EBV transformed lymphoblasts aminoacylase I was found to be deficient and cross-reacting-material of this enzyme severely decreased as shown by SDS-PAGE and immunoblotting. DNA sequencing of the encoding ACY1 gene showed the homozygous c 1057 C>T transition, predicting the p Arg353Cys substitution. Both parents were heterozygous for the mutation. Protein expression studies showed that the R353C mutant protein left no activity.

Conclusion: Although the metabolic derangement and the hearing loss persisted, the convulsions and feeding problems gradually ceased during subsequent weeks. At six months of age, neuromotor development was within normal limits but slight cortical atrophy was demonstrated by cerebral MRI. Adequate description of the clinical phenotype and estimates about the incidence of this defect must await the report of more observations.