Lysinuric protein intolerance

Lysinuric protein intolerance (LPI) is a multisystem inborn error of cationic amino acid transport. Affected infants typically present after weaning from breast milk or formula with feeding difficulties, vomiting, diarrhoea and failure to thrive; episodes of postprandial hyperammonaemic coma may occur but are less common. Moderate hepatosplenomegaly, muscular hypotonia and hypotrophy are observed from early infancy, and poor growth with delayed skeletal maturation becomes apparent after the first year, with osteoporosis predisposing to pathologic fractures. Progressive interstitial lung changes are frequently detected early without overt respiratory symptoms; progression to pulmonary alveolar proteinosis is a well-recognised, life-threatening complication that may occur in childhood. Glomerular and tubular involvement is common, manifesting initially as mild proteinuria and evolving to proximal tubular dysfunction and nephrocalcinosis. A presentation resembling haemophagocytic lymphohistiocytosis/macrophage activation syndrome has been repeatedly observed. Clinical expressivity is highly variable, and diagnosis is occasionally established in adulthood.

The estimated incidence in Finland and Japan is approx. 1/60,000 live births, reflecting founder variant populations. The incidence is substantially lower or unknown elsewhere, and affected individuals have been reported from at least 25 countries, with over 200 cases published.

LPI is caused by biallelic pathogenic germline loss-of-function variants in SLC7A7 (14q11.2).

SLC7A7 encodes y(+)L amino acid transporter 1 (y(+)LAT-1), the light chain of the heterodimeric system y(+)L cationic amino acid transporter involved in the cellular uptake and exchange of the cationic amino acids lysine, arginine, and ornithine. The protein is mainly expressed in the intestine and kidneys, where it facilitates amino acid absorption and reabsorption. Loss of transporter activity impairs intestinal absorption and renal reabsorption of lysine, arginine and ornithine, produces intracellular ornithine deficiency in the liver, and results in functional urea-cycle impairment with postprandial hyperammonaemia and multisystemic metabolic disease.

LPI is inherited in an autosomal recessive manner. At conception, each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier screening is possible once the familial pathogenic variants have been identified.

The diagnosis is based on the characteristic biochemical fingerprint: elevated plasma ammonia after a protein-rich meal, increased urinary orotic acid excretion, decreased plasma concentrations of lysine, arginine and ornithine, and markedly increased 24-hour urinary excretion of cationic amino acids – particularly lysine. Confirmation requires identification of biallelic pathogenic germline variants in SLC7A7.

Main differential diagnoses include:

• : recurrent hyperammonaemia without the LPI biochemical fingerprint of cationic aminoaciduria and low plasma lysine/arginine/ornithine; orotic aciduria can overlap with ornithine transcarbamylase deficiency, but the plasma amino acid pattern differs; ARG1, ASL ASS1, CPS1, NAGS, OTC, SLC25A13, SLC25A15.
• Familial haemophagocytic lymphohistiocytosis: failure to thrive, hepatosplenomegaly, fever, hypertriglyceridaemia, elevated ferritin and cytopenias overlap with the haemophagocytic/macrophage-activation presentation of LPI; absence of postprandial hyperammonaemia and cationic aminoaciduria favours primary HLH; PRF1, UNC13D and others.
• Lysosomal storage disorders: hepatosplenomegaly, interstitial lung disease and haematologic abnormalities can mimic LPI; absence of cationic aminoaciduria and presence of characteristic enzymatic or storage-material findings distinguish these disorders; e.g., GBA, NPC1 and others.

• Establishing the diagnosis at the molecular level confirms the clinical suspicion and ends the diagnostic odyssey.
• The molecular diagnosis is the prerequisite for specific and individualised surveillance of the multiorgan complications  including lung disease, renal disease and osteoporosis – which is planned and adjusted by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variants are known, predictive and carrier testing of at-risk relatives is technically possible.

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• Stroup BM, Li X, Ho S, Zhouyao H, Chen Y, Ani S, et al. Delayed skeletal development and IGF-1 deficiency in a mouse model of lysinuric protein intolerance. Disease models & mechanisms. 2023;16(8). doi: 10.1242/dmm.050118. PMID: . PMCID: PMC10445726.