Hyperammonemia in a Child Presenting with Growth Delay, Short Stature, and Diarrhea Naif A.M. Almontashiri, 1,2,3 Didem Demirbas, 3 Gerard T. Berry, 3 and Roy W.A. Peake 1* CLINICAL HISTORY AND BACKGROUND A 5-year-old male child was referred to the metabolism clinic with a history of failure to thrive, chronic intermit- tent emesis, diarrhea, seizures, hypotonia, and growth hormone deficiency. He was also noted to experience frequent falling episodes. Routine biochemistry testing revealed increased plasma ammonia concentration at 184 mol/L (reference interval, 16 – 47) and lactate dehydro- genase concentration at 445 U/L (reference interval, 110 –295). Plasma free and total carnitine concentrations were decreased at 5 mol/L (reference interval, 26 – 60) and 17.1 mol/L (reference interval, 32– 84), respec- tively. Orotic acid excretion in urine was also markedly increased at 80 mmol/mol creatinine (reference in- terval, 0.2–1.5). Plasma insulin-like growth factor-I (IGF-I) 4 concentration was also decreased at 25 ng/mL (reference interval, 50 –286). Paired plasma and urine spec- imens were collected for amino acid analysis using ultraper- formance liquid chromatography. The results are shown in Table 1. DIAGNOSIS AND SUMMARY This patient has lysinuric protein intolerance (LPI), an autosomal recessive disorder of amino acid transport, caused by mutations in the solute carrier family 7, mem- ber 7 (SLC7A7) gene (1, 2, 3 ). Although the worldwide incidence is not known, LPI is estimated to occur in approximately 1 in 60000 newborns in Finland and Ja- pan (2). The SLC7A7 gene product is the y+L amino acid transporter 1 (y + LAT1), required for the transport of dibasic amino acids (lysine, arginine, and ornithine) across the basilateral or antiluminal membrane of epithe- lial cells within the small intestine and kidney into the interstitium (Fig. 1). Individuals with pathogenic muta- tions in SLC7A7 have defective transport, resulting in amino acid malabsorption and renal loss of the dibasic amino acids, largely explaining the biochemical features of the disorder (4, 5 ). The transport defect in LPI is evident from the dis- tinctive amino acid patterns exhibited in paired plasma and urine specimens (Table 1). Plasma concentrations of lysine, ornithine, and arginine are typically decreased or low/normal, with reciprocal increases in polar neutral amino acids such as serine and asparagine. The increased plasma glutamine concentration reflects the impaired ni- trogen metabolism and hyperammonemia observed with this disorder. Although decreased concentrations of orni- thine in hepatocytes has been hypothesized to be key, the precise mechanism of the hyperammonemia in LPI is poorly understood. The deficiency of urea cycle interme- diates arginine and ornithine in the liver likely results in the accumulation of carbamyl phosphate, causing exces- sive urinary excretion of orotic acid, as observed in this patient. Urine amino acids typically exhibit dibasic ami- noaciduria, with lysine excretion proportionally greater (6, 7 ). Renal tubular reabsorption of lysine is much more severely affected than that of arginine and ornithine. However, the urinary amino acid profile in LPI is not always obvious, particularly in the context of variable protein intake and plasma concentrations of basic amino acids; the extent of lysinuria is more obvious when intake is invariably increased. Additional abnormalities may in- clude increased plasma lactate dehydrogenase and carni- tine deficiency, the latter of which is likely caused by the 1 Department of Laboratory Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA; 2 Center for Genetics and Inherited Diseases, Taibah University, Almadinah Al- munwarah, Saudi Arabia; 3 Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Center for Life Science Building, Boston, MA. * Address correspondence to this author at: Department of Laboratory Medicine, Bos- ton Children’s Hospital, Harvard Medical School, Boston, MA 02115. E-mail: roy.peake@childrens.harvard.edu. Received April 19, 2018; accepted May 14, 2018. DOI: 10.1373/clinchem.2018.291146 © 2018 American Association for Clinical Chemistry 4 Nonstandard abbreviations: IGF-I, insulin-like growth factor-I; LPI, lysinuric protein intol- erance; y+LAT-1, y+L amino acid transporter 1. Clinical Chemistry 64:8 1260–1269 (2018) Genetic Metabolic Series 1260 Downloaded from https://academic.oup.com/clinchem/article/64/8/1260/5608898 by guest on 05 June 2023