Expanding the phenotype of hawkinsinuria: new insights from response to N-acetyl-L-cysteine
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.
KeywordsMetabolic Acidosis Hypophosphatemia Renal Tubular Acidosis Pyroglutamic Acid Homogentisic Acid
Compliance with ethical standards
Conflict of interest
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.
No outside funding contributed to the study.
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.
- Larsson A, Ristoff E, Anderson ME (2014) Glutathione synthetase deficiency and other disorders of the γ-Glutamyl cycle. In: Beaudet AL, Vogelstein B, Kinzler KW et al (eds) The online metabolic and molecular bases of inherited disease. The McGraw-Hill Companies, Inc., New YorkGoogle Scholar
- Thodi G, Schulpis KH, Dotsikas Y et al (2016) Hawkinsinuria in two unrelated Greek newborns: identification of a novel variant, biochemical findings and treatment. J Pediatr Endocrinol Metabol JPEM 29:15–20Google Scholar