Accurate discrimination of Hartnup disorder from other aminoacidurias using a diagnostic ratio

H A Haijes; Hubertus C M T Prinsen; Monique G M de Sain-van der Velden; Nanda M Verhoeven-Duif; Peter M van Hasselt; Judith J M Jans

doi:10.1016/j.ymgmr.2019.100551

Accurate discrimination of Hartnup disorder from other aminoacidurias using a diagnostic ratio

Mol Genet Metab Rep. 2019 Dec 27:22:100551. doi: 10.1016/j.ymgmr.2019.100551. eCollection 2020 Mar.

Authors

H A Haijes^{1

2}, Hubertus C M T Prinsen¹, Monique G M de Sain-van der Velden¹, Nanda M Verhoeven-Duif¹, Peter M van Hasselt², Judith J M Jans¹

Affiliations

¹ Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
² Department of Pediatrics, Section Metabolic Disorders, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Abstract

Introduction: Hartnup disorder is caused by a deficiency of the sodium dependent B⁰ AT1 neutral amino acid transporter in the proximal kidney tubules and jejunum. Biochemically, Hartnup disorder is diagnosed via amino acid excretion patterns. However, these patterns can closely resemble amino acid excretion patterns of generalized aminoaciduria, which may induce a risk for misdiagnosis and preclusion from treatment. Here we explore whether calculating a diagnostic ratio could facilitate correct discrimination of Hartnup disorder from other aminoacidurias.

Methods: 27 amino acid excretion patterns from 11 patients with genetically confirmed Hartnup disorder were compared to 68 samples of 16 patients with other aminoacidurias. Amino acid fold changes were calculated by dividing the quantified excretion values over the upper limit of the age-adjusted reference value.

Results: Increased excretion of amino acids is not restricted to amino acids classically related to Hartnup disorder ("Hartnup amino acids", HAA), but also includes many other amino acids, not classically related to Hartnup disorder ("other amino acids", OAA). The fold change ratio of HAA over OAA was 6.1 (range: 2.4-9.6) in the Hartnup cohort, versus 0.2 (range: 0.0-1.6) in the aminoaciduria cohort (p < .0001), without any overlap observed between the cohorts.

Discussion: Excretion values of amino acids not classically related to Hartnup disorder are frequently elevated in patients with Hartnup disorder, which may cause misdiagnosis as generalized aminoaciduria and preclusion from vitamin B3 treatment. Calculation of the HAA/OAA ratio improves diagnostic differentiation of Hartnup disorder from other aminoacidurias.

Keywords: Amino-aciduria; Diagnostic ratio; Diagnostics; Hartnup disorder; Inborn error of metabolism; LPI, lysinuric protein intolerance; MIM, Mendelian inheritance in man; Urinary amino acid analysis.