NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism

Abstract

Aminoacylase 1 deficiency is a novel inborn error of metabolism. The clinical significance of the deficiency is under discussion, as well as the possible consequences of the defect for brain metabolism and function. This study includes the five originally published cases as well as three novel ones. NMR spectroscopy of urine, serum and cerebrospinal fluid has been used to study these patients. A typical profile with 11 accumulating N-acetylated amino acids was observed in urine from the patients. The concentration of most of the accumulating metabolites is typically 100-500 micromol/mmol creatinine. Two additional minor N-acetylated metabolites remain unidentified. The concentrations of the accumulating metabolites are <20 micromol/L in serum from the patients. Interestingly we found no evidence of an increased concentration of N-acetylated amino acids in the cerebrospinal fluid from one patient. Our data define aminoacylase 1 deficiency at the metabolite level providing a specific urinary profile of accumulating N-acetylated amino acids.

NMR-Based Screening for Inborn Errors of Metabolism: Initial Results from a Study on Turkish Neonates

“…Moreover, prenatal diagnosis may then be possible in subsequent pregnancies (Lehotay et al 2011). Screening for metabolic disorders may be based on tandem MS (Lehotay et al 2011;Chace and Kalas 2005) or NMR (Engelke et al 2008;Wevers et al 1999). Although tandem-MS is more frequently used, NMR possesses several advantages.…”

“…1 H-NMR spectroscopy of body fluids constitutes a complementary technique in the diagnosis of numerous congenital metabolic diseases (Engelke et al 2008;Moolenaar et al 2003;Wevers et al 1994Wevers et al , 1999Holmes et al 1997). It shows the majority of proton-containing compounds and therefore provides an overall view of metabolism, giving a characteristic 'fingerprint' of almost all hydrogen nuclei in a metabolite.…”

“…Some neonates with congenital metabolic diseases have already been investigated qualitatively by NMR spectroscopy (Engelke et al 2008;Moolenaar et al 2003). Nevertheless, there is no systematic, automated, and standardized NMR-based analytical technique.…”

Genetic determinants of metabolism in health and disease: from biochemical genetics to genome-wide associations

“…Uniform newborn screening for multiple inborn errors of metabolism, including urea-cycle disorders and amino- and organic-acidurias, using heel-prick testing with GC-MS-MS exemplifies the power of targeted metabolomic analysis to diagnose these diseases and enable the interruption of pathological processes resulting from genetic mutations [44]. More recently, untargeted NMR spectroscopy and MS have been used to diagnose known inborn errors [45-48], identify novel inborn errors using biofluid profiling [49,50] and identify complex downstream metabolic consequences [51-53] and biomarkers of organ pathology resulting from genetic mutations [54-56]. …”

“…As a result, diagnosis of suspected inborn errors has been reported for many Mendelian diseases [45-50], especially using NMR spectroscopy. In some cases, metabolic profiling of biofluids from patients with suspected inborn errors has led to the discovery of previously undescribed diseases, with the identification of causal genes following the description of metabolic perturbations, as occurred with aminoacylase 1 deficiency and beta-ureidopropionase deficiency [49,50]. …”