A case of hyperlysinemia identified by urine newborn screening

Abstract

Hyperlysinemia is a rare autosomal recessive deficiency of 2-aminoadipic semialdehyde synthase (AASS) affecting the initial step in lysine degradation. It is thought to be a benign biochemical abnormality, but reports on cases remain scarce. The description of additional cases, in particular, those identified without ascertainment bias, may help counseling of new cases in the future. It may also help to establish the risks associated with pharmacological inhibition of AASS, a potential therapeutic strategy that is under investigation for other inborn errors of lysine degradation. We describe the identification of a hyperlysinemia case identified in the Provincial Neonatal Urine Screening Program in Sherbrooke, Quebec. This case presented with a profile of cystinuria but with a very high increase in urinary lysine. A diagnosis of hyperlysinemia was confirmed through biochemical testing and the identification of biallelic variants in AASS. The p.R146W and p.T371I variants are novel and affect the folding of the lysine-2-oxoglutarate domain of AASS. The 11-month-old boy is currently doing well without any therapeutic interventions. The identification of this case through newborn urine screening further establishes that hyperlysinemia is a biochemical abnormality with limited clinical consequences and may not require any intervention.

Keywords: aminoaciduria; ascertainment bias; lysine; newborn screening; sampling bias; substrate reduction therapy.

FIGURE 1

The molecular basis of AASS deficiency in the current case. (A) Structural analysis of LOR patient variants. Left panel shows contacts to R146 with potential hydrogen bonds shown with dashed lines. Right panel shows contacts to T371. PDB code for the LOR structure is 8E8U. (B) FPLC traces of LOR variants. The UV trace for each variant on the Supderdex200 Increase column is shown overlaid along with the WT, with the variant identified in the inset. An arrow indicates where the soluble protein elutes. (C) Purification of LOR variants. The different variants were purified and analyzed by Coomassie staining of an SDS‐PAGE gel. Lanes 1–2: p.R146W nickel elution, gel filtration aggregation peak. No soluble peak was observed for this variant. Lanes 3–5: p.T371I nickel elution, aggregation peak, soluble peak of the expected size. Note that the SUMOstar tag migrates at ~15‐20 kDa. Calculated MW of the His‐SUMOstar‐LOR monomer is 62.4 kD. (D) LOR activity. LOR activity with variable concentrations for each of the three LOR substrates. The concentrations for the varied substrates are indicated in the graph. Fixed substrate concentrations are 15 mM L‐lysine, 1 mM 2‐OG, and 0.3 mM NADPH. WT protein was tested at 96 ng per 200 μL reaction, p.T371I was tested at 167 ng per 200 μL reaction.