Lysinuric Protein Intolerance:
Pearls to Detect this Otherwise Easily Missed Diagnosis
Firas Alqarajeh ,
Deanship of Medicine
Introduction
Lysinuric Protein Intolerance (LPI; OMIM
#222700):
• Autosomal recessive disorder.
• Characterized by deficient membrane transport of
cationic amino acids lysine, ornithine and arginine.
• Caused mainly (92-95%) by pathogenic variants in
SLC7A7 on chromosome 14 at locus 14q11.2.
- SLC7A7 gene encodes a y+L amino acid transporter-
1 (y+LAT-1) (Figure 1):
- Responsible for the transport of dibasic amino acids
at the basolateral membrane of epithelial cells in the
intestines and kidneys.
- Results in impairment of intestinal transport and
renal proximal tubule loss of the affected amino
acids.
- Concentration of dibasic amino acids is low in
plasma and high in urine.
- Patients may be present with the following:
• Elevated neutral amino acids; citrulline, alanine,
glycine, proline and glutamine.
• Gastrointestinal symptoms (vomiting and diarrhea).
• Failure to thrive after weaning breast milk.
• Protein aversion, leading to malnutrition, osteopenia,
and anemia.
• Symptoms linked to a secondary urea cycle
derangement (episodic postprandial hyperammonemia
with resultant seizures or coma.
• Neurological manifestations (hypotonia, lethargy and
abnormal behavior).
Figure 1: Pathophysiology of lysinuric protein
intolerance
(Ogier de Baulny, Schiff, & Dionisi-Vici, 2012)
1
Nahla Samman1
1 Faculty
2 George Washington University, School of Medicine and Health Sciences, Washington, DC, USA
3 Rare Disease Institute, Children’s National Health System, Washington, DC, USA
Case: 4-year-old African-American boy.
Patient’s history:
• Born full-term via vaginal delivery,
following an uneventful pregnancy.
• birth weight of 2722 grams (9th
percentile).
• He required two weeks in the
Neonatal Intensive Care Unit for
neonatal abstinence syndrome and
poor feeding.
• He was only breastfed a handful of
times, and various formulas were tried
without success.
• His difficulties with feeding persisted
following discharge.
• Soon after birth, he developed chronic
diarrhea.
• During 1st year of life:
• He suffered from multiple respiratory
tract infections. • Readmitted after 2 weeks with fever, decreased oral intake, weight loss,
• Motor development: up to his age.
• Social and language development:
advanced; he was very talkative and • The 60 most common CFTR mutations tested negative.
interactive. • Plasma and urine amino acids were collected and the patient was started
• Age 2-3 years:
• First presented with rectal prolapse. • SLC7A7
• Cystic fibrosis was considered but
sweat chloride testing was negative.
• He went on to develop recurrent rectal
prolapse,
• At three years old he required surgical
reduction.
• The cause of the rectal prolapse was
likely diarrhea and malnutrition,
secondary to his underlying diagnosis.
• He was again admitted for emesis and
weight loss in the setting of chronic
diarrhea and worsening abdominal
distention.
• It was reported that despite his
persistent weight loss, he typically
had a good appetite.
• His family denied both generalized
protein aversion and episodes of
severe illness following protein-rich
meals.
, Jacklyn 2
Omorodion , Kerri 3
Bosfield , Natasha 3
Shur , Carlos R. Ferreira 3
of Medicine, Al-Quds University, Jerusalem, Palestine
Case Presentation Discussion
At the time of presentation: Several diagnostic pearls can be learned from our patient:
• Weight: 13.2 kg (3.2th percentile). 1. The initial urine amino acid profile showed only a modest elevation of dibasic
• Height: 93 cm (1.6 percentile). amino acids. Close to normal concentration of urine amino acids have been
occasionally described at presentation. Interestingly, our patient showed a
• Significant hepatomegaly with a liver span of 18 cm.
typical urine amino acid profile once his nutritional status had improved.
• Laboratory examinations:
2. Initial plasma amino acid profile revealed that the dibasic amino acid
- Mild anemia
concentrations were within the normal range, although in all cases close to the
- Hypokalemia
lower limit of normal; interestingly, previous publications have shown a
- Hypoalbuminemia in the setting of transaminitis borderline significant association between lysine levels close to the lower limit
- Normal ammonia
of normal and a poor prognosis .
• Congenital disorders of glycosylation were considered:
3. Upon institution of total parenteral nutrition, his plasma amino acid analysis
- Carbohydrate deficient transferrin levels were only slightly elevated:
showed increased concentrations of arginine and ornithine, as opposed to the
inconsistent with congenital disorders of glycosylation, though possible in expected decreased plasma concentration of those amino acids. It has been
cases of hereditary fructose intolerance. previously shown that patients with LPI who undergo continuous infusion of
- Urine amino acids were significant for elevated lysine and ornithine, arginine and ornithine show a higher plasma concentration of both amino acids
though not to the extent expected in lysinuric protein intolerance. when compared to control individuals undergoing the same infusion regimen,
• Discharged with a working diagnosis of hereditary fructose intolerance, indicating decreased metabolic clearance for dibasic amino acids.
instructed to follow a fructose-free diet. 4. The continuous infusion of amino acids in the form of total parenteral nutrition
- Initially: improved on the fructose-free diet thus alters the typical plasma amino acid profile expected in LPI, as the
- After three days: he developed food aversion and began spiking decreased metabolic clearance trumps the increased urinary excretion of dibasic
intermittent fevers. amino acids.
5. The main goals of LPI management are to provide adequate nutrition to the
worsening abdominal distension and pain following an additional patient while also preventing hyperammonemia:
- It is recommended that dietary protein be restricted to 0.7-1.2 g/kg/day and
episode of rectal prolapse.
supplemental citrulline be given, limited to 100 mg/kg/day.
- Ammonia scavengers can also be used if needed, based on plasma ammonia and
glutamine levels.
on empiric citrulline while awaiting results. - Carnitine supplementation is also required as individuals with LPI tend to be carnitine
gene testing came back negative for any pathogenic mutations. deficient.
- Deletion\duplication of the SLC7A7 gene: pending results (15-20% of - Due to the low plasma lysine levels in this population, lysine supplementation also
patients). can be given with L-lysine hydrochloride, dosed at 0.05-0.55 mmol/kg although there
• Following protein restriction and initiation of citrulline to correct for the is limited lysine absorption given the transport defect.
- Hyperammonemic crises are managed similar to those of urea cycle disorders, and
intracellular defects of arginine and ornithine, carnitine was also started
include protein intake cessation, initiation of intravenous fluids and ammonia
as levels were found to be low.
scavengers, citrulline supplementation, and plasma and urine collection for diagnostic
- Patient’s condition improved. purposes.
- Discharged home on NG feeds.
- His family reports he has had significantly more energy.
- His hair has begun to darken. References
Table 1: Results of plasma amino acids analyses before and after TPN
• Awrich, A. E., Stackhouse, W., Cantrell, J., Patterson, J., & Rudman, D. (1975).
Amino acid Level before TPN* Level after TPN* Reference range Hyperdibasicaminoaciduria, hyperammonemia, and growth retardation: Treatment with arginine,
Arginine 15 121 10-111 lysine, and citrulline. The Journal of Pediatrics, 87(5):731-8.
Ornithine 24 146 22-120 • Borsani, G., Bassi, M., Sperandeo, M., Grandi, A. D., Anna, B., Riboni, M., . . . Sebastio, G. (1999).
SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein
Lysine 65 139 42-284
* μmol/L
intolerance. Nature Genetics volume, 297–301.
• Carpentieri, D., Barnhart, M. F., Aleck, K., Miloh, T., & deMelloa, D. (2015). Lysinuric protein
Table 2: Results of urine amino acids analyses before and after TPN intolerance in a family of Mexican ancestry with a novel SLC7A7 gene deletion. Case report and
Amino acid Level before TPN* Level after TPN* Reference range review of the literature. Molecular genetics and metabolism reports, 2: 47–50.
Arginine 60 1027 16-67 • Esposito, V., Lettiero, T., Fecarotta, S., Sebastio, G., Parenti, G., & Salerno, M. (2006). Growth
hormone deficiency in a patient with lysinuric protein intolerance. Eur J Pediatr, 165(11):763-6.
Ornithine 147 866 0-82 • Ogier de Baulny, Hélène, Schiff, Manuel, & Dionisi-Vici, Carlo. (2012). Lysinuric protein intolerance
Lysine 2620 8696 19-539 (LPI): A multi organ disease by far more complex than a classic urea cycle disorder. Molecular
* mmol/mol of creatinine Genetics and Metabolism, 106(1), 12-17. doi: https://doi.org/10.1016/j.ymgme.2012.02.010.