Hyperexcretion of homocitrulline in a Malaysian patient with lysinuric protein intolerance

Habib, Anasufiza; Yunus, Zabedah Md; Azize, Nor Azimah Abdul; Ch’ng, Gaik-Siew; Ong, Winnie Peitee; Chen, Bee-Chin; Hsu, Ho-Torng; Wong, Ke-Juin; Pitt, James; Ngu, Lock Hock

doi:10.1007/s00431-013-1947-1

Cited by 7 publications

(4 citation statements)

References 7 publications

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“…We show here that loss of Slc7a7 in mice causes hyperferritinemia and reduced erythrocyte size, similar to what is seen in LPI (Habib et al 2013;Ko et al 2012). The tissue iron redistribution evident in Slc7a7-deficient mice has also been reported in some patients with LPI (Ceruti et al 2007;Parto et al 1994).…”

Section: )supporting

confidence: 86%

DefectiveSlc7a7transport reduces erythropoietin compromising erythropoiesis and iron homeostasis

Sotillo

Giroud-Gerbetant

Couso

et al. 2021

Preprint

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Slc7a7 encodes for y+LAT1, a transporter of cationic amino acid across the basolateral membrane of epithelial cells. Mutations in SLC7A7 gene give rise to Lysinuric Protein Intolerance (LPI), a rare autosomal recessive disease with wide variability of complications. Intriguingly, y+LAT1 is also involved in arginine transport in non polarized cells such as macrophages. Here we report that complete inducible Slc7a7 ablation in mouse compromises systemic arginine availability that alters proper erythropoiesis and that dysfunctional RBC generation leads to increased erythrophagocytosis, iron overload and an altered iron metabolism by macrophages. Herein, uncovering a novel mechanism that links amino acid metabolism to erythropoiesis and iron metabolism. Mechanistically, the iron exporter ferroportin-1 expression was compromised by increased plasma hepcidin causing macrophage iron accumulation. Strikingly, lysozyme M-cell-specific knockout mice failed to reproduce the total knockout alterations, while bone marrow transplantation experiments resulted in the resolution of macrophage iron overload but could not overcome erythropoietic defect. This study establishes a new crucial link between systemic arginine availability in erythropoiesis and iron homeostasis.

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Section: )supporting

confidence: 86%

DefectiveSlc7a7transport reduces erythropoietin compromising erythropoiesis and iron homeostasis

Sotillo

Giroud-Gerbetant

Couso

et al. 2021

Preprint

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“…We identified a homozygous nonsense variant of SLC7A7 (NM_001126105.3:c.1417C > T,p.R473*). This variant was previously reported to cause LPI, 11,12 and was confirmed by Sanger sequencing. No other pathogenic variants, including those causing RTA, Fanconi syndrome, or rickets, were detected.…”

Section: Case Reportsupporting

confidence: 69%

Lysinuric protein intolerance exhibiting renal tubular acidosis/Fanconi syndrome in a Japanese woman

Hanafusa,

Nakamura,

Kamijo

et al. 2023

JIMD Reports

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Lysinuric protein intolerance (LPI), caused by pathogenic variants of SLC7A7, is characterized by protein aversion, failure to thrive, hyperammonemia, and hepatomegaly. Recent studies have reported that LPI can cause multiple organ dysfunctions, including kidney disease, autoimmune deficiency, pulmonary alveolar proteinosis, and osteoporosis. We report the case of a 47‐year‐old Japanese woman who was initially diagnosed with renal tubular acidosis (RTA), Fanconi syndrome, and rickets. At the age of 3 years, she demonstrated a failure to thrive. Urinary amino acid analysis revealed elevated lysine and arginine levels, which were masked by pan‐amino aciduria. She was subsequently diagnosed with rickets at 5 years of age and RTA/Fanconi syndrome at 15 years of age. She was continuously treated with supplementation of vitamin D3, phosphate, and bicarbonate. A renal biopsy at 18 years of age demonstrated diffuse proximal and distal tubular damage with endocytosis‐lysosome pathway abnormalities. Distinctive symptoms of LPI, such as protein aversion and postprandial hyperammonemia were not observed throughout the patient's clinical course. The patient underwent a panel‐based comprehensive genetic testing and was diagnosed with LPI. As the complications of LPI involve many organs, patients lacking distinctive symptoms may develop various diseases, including RTA/Fanconi syndrome. Our case indicates that proximal and distal tubular damages are notable findings in patients with LPI. The possibility of LPI should be carefully considered in the management of RTA/Fanconi syndrome and/or incomprehensible pathological tubular damage, even in the absence of distinctive symptoms; furthermore, a comprehensive genetic analysis is useful for diagnosing LPI.

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“…High levels of citrulline on NBS have not been previously associated with LPI. However, some patients of Malaysian origin have been reported to have slightly elevated plasma citrulline levels on biochemical studies [ 22 , 23 ]. The persistence of citrulline elevation in our patient, together with these previously reported cases, lead us to think that increased citrulline values could be associated with LPI, rather than being a coincidental finding.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Serendipities of Expanded Newborn Screening

Yahyaoui

Blasco‐Alonso

Gonzalo-Marín

et al. 2020

Genes

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Incidental findings on newborn screening (NBS) are results that are not the target of screening within a given NBS program, but rather are found as a result of the screening and resulting diagnostic workup for that target. These findings may not have an immediate clinical impact on the newborn, but are sometimes an additional benefit of NBS programs and may be considered secondary targets of NBS programs. This work describes four case reports that had incidental findings on the NBS, which eventually led to the diagnosis of another metabolic disease instead of the one that was initially suspected. The first case was a new defect in the cationic amino acid transporter-2 (CAT-2), which was oriented as an arginase-1 deficiency in the newborn. The second case was a maternal glutaric aciduria type 1 (GA-1) that mimicked a carnitine transporter deficiency in the newborn. The third report was a case of lysinuric protein intolerance (LPI), which appeared as high levels of citrulline on the NBS. The fourth case was a mother with homocystinuria that was diagnosed during the biochemical study of vitamin B12 status. All cases provide new or interesting data that will help guide differential diagnosis in the future.

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Hyperexcretion of homocitrulline in a Malaysian patient with lysinuric protein intolerance

Abstract: The diagnosis of LPI is usually not suspected by clinical findings alone, and specific laboratory investigations and molecular analysis are important to get a definitive diagnosis.

Cited by 7 publications

References 7 publications

DefectiveSlc7a7transport reduces erythropoietin compromising erythropoiesis and iron homeostasis

DefectiveSlc7a7transport reduces erythropoietin compromising erythropoiesis and iron homeostasis

Lysinuric protein intolerance exhibiting renal tubular acidosis/Fanconi syndrome in a Japanese woman

Metabolic Serendipities of Expanded Newborn Screening

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