Abstract
Hawkinsinuria is a rare disorder of tyrosine metabolism that can manifest with metabolic acidosis and growth arrest around the time of weaning off breast milk, typically followed by spontaneous resolution of symptoms around 1 year of age. The urinary metabolites hawkinsin, quinolacetic acid, and pyroglutamic acid can aid in identifying this condition, although their relationship to the clinical manifestations is not known. Herein we describe clinical and laboratory findings in two fraternal twins with hawkinsinuria who presented with failure to thrive and metabolic acidosis. Close clinical follow-up and laboratory testing revealed previously unrecognized hypoglycemia, hypophosphatemia, combined hyperlipidemia, and anemia, along with the characteristic urinary metabolites, including massive pyroglutamic aciduria. Treatment with N-acetyl-L-cysteine (NAC) restored normal growth and normalized or improved most biochemical parameters. The dramatic response to NAC therapy supports the idea that glutathione depletion plays a key role in the pathogenesis of hawkinsinuria.
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Natalia Gomez-Ospina, Anna I. Scott, Gia Oh, Donald Potter, Veena V. Goel, Lauren Destino, Nancy Baugh, Gregory M. Enns, Anna-Kaisa Niemi, Tina M. Cowan declare that they have no conflict of interest.
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No outside funding contributed to the study.
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This study was approved by the Stanford University Institutional Review Board (IRB). All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki, 1975, as revised in 2000. Informed consent was obtained from the parents of the patients involved in this study.
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Communicated by: Ron A Wevers
Natalia Gomez-Ospina and Anna I. Scott Co-first authors
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Supplemental Table 1
Additional routine laboratory findings in two individuals with hawkinsinuria. (XLSX 12 kb)
Supplemental Table 2
Nutritional assessment. (XLSX 11 kb)
Supplemental Fig. 1
Serum amino acid levels during the observed clinical course. Patient 1 is shown in dashed lines (data points as circles); patient 2 is shown in solid lines (data points as triangles). The solid, grey, horizontal lines mark the upper and lower limits of normal values for patients at 1–24 months of age. a Tyrosine. b Phenylalanine. c Cysteine. d Glutamine. e Alanine. f Valine. g Leucine. h Isoleucine. Line breaks and asterisk indicate start of N-acetyl-L-cysteine (NAC) treatment. (JPG 168 kb)
Supplemental Fig. 2
Amino acid chromatograms. Representative chromatograms of plasma and urine amino acid analysis are shown. a Chromatogram of patient 2’s plasma amino acids. b Chromatogram of patient 1’s urine amino acids. (PPTX 89 kb)
Supplemental Fig. 3
Urine organic acid chromatograms. Panel A shows the urine organic acid metabolites for patient 1 at clinical presentation and after treatment with N-acetyl-L-cysteine (NAC). Panel B shows urine organic acids for patient 2 at the same time points. For all organic acid analyses, urine volume was normalized to 10 mg of creatinine. Compounds of interest are numbered: 1 lactic acid, 2 3-hydroxyisobutyric acid, 3 internal standard (p-chlorobenzoic acid), 4 pyroglutamic acid, 5 4-hydroxycyclohexylacetic acid, 6 4-hydroxyphenylacetic acid, 7 quinolacetic acid, 8 homogentisic acid, 9 hippuric acid, 10 4-hydroxyphenyllactic acid, 11 4-hydroxyphenylpyruvic acid, and 12 external standard (tetracosane). The inset shows the full-scale chromatograms before treatment. (JPG 131 kb)
(JPG 122 kb)
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Gomez-Ospina, N., Scott, A.I., Oh, G.J. et al. Expanding the phenotype of hawkinsinuria: new insights from response to N-acetyl-L-cysteine. J Inherit Metab Dis 39, 821–829 (2016). https://doi.org/10.1007/s10545-016-9963-8
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DOI: https://doi.org/10.1007/s10545-016-9963-8