Lysinuric Protein Intolerance

Autosomal recessive cationic aminoaciduria caused by a defect of the basolateral transporter y+LAT1 (SLC7A7), with postprandial hyperammonaemia, protein aversion and failure to thrive, and with multisystem complications — pulmonary alveolar proteinosis, nephropathy, secondary haemophagocytic lymphohistiocytosis and lupus-like immune dysregulation — that progress despite metabolic treatment.

Literature and regulatory information updated: 27 October 2026.

0. Initial Reference Table

Lysinuric protein intolerance (LPI) is a single entity, with no known allelic disorders of SLC7A7 and no human disease described due to variants in the partner heavy chain SLC3A2 [1–3]. The table brings together the identifiers, figures and treatments developed in this article; the values are repeated, with the same sources, in sections 3, 7, 9 and 11.

1. Introduction

1.1. Original description and the Finnish school

LPI was described in 1965 by Perheentupa and Visakorpi, in Finland, in a Lancet paper entitled «Protein intolerance with deficient transport of basic aminoacids. Another inborn error of metabolism», which brought together three Finnish patients with familial protein intolerance and abnormal transport of the basic amino acids [23, 24]. In 1971, Norio and colleagues established autosomal recessive inheritance and an incidence of about 1:60,000 in Finland, and for decades Finnish or Finnish Lapp patients accounted for almost half of the published cases [24]. The name «lysinuric protein intolerance» was proposed in this genetic study by Norio, which, together with the 1967 series of Kekomäki, confirmed autosomal recessive transmission [6]. The series of Kekomäki and colleagues comprised ten children, including several sibling pairs and one consanguineous family, with vomiting, diarrhoea, failure to thrive, hepatomegaly, diffuse cirrhosis, low urea, hyperammonaemia and leucopenia, symptoms that worsened with protein and were relieved by its restriction, and with excessive urinary excretion of ornithine, arginine and lysine but not of cystine [6]. Reports from outside Finland followed: two Japanese sisters, daughters of second cousins, with severe intellectual disability, failure to thrive and mild malabsorption (Oyanagi, 1970), and a Swedish patient of Finnish origin with intellectual disability, cerebral atrophy on imaging and marked bone fragility (Malmquist, 1971) [6]. The Finnish series of 20 patients published by Simell, Perheentupa, Rapola, Visakorpi and Eskelin in 1975 established the classic clinical picture — well-being during breastfeeding, diarrhoea and vomiting with cow's milk, spontaneous rejection of protein-rich foods, short stature, muscle wasting, osteoporosis, hepatomegaly and frequent splenomegaly, leucopenia, thrombocytopenia and constantly raised lactate dehydrogenase (LDH) — and the pathophysiological model still accepted today: plasma concentrations of lysine, arginine and ornithine were one third to one half of the normal mean, with increased renal clearances and impaired intestinal absorption on oral loading tests, and hepatic ornithine deficiency slowed the urea cycle and explained postprandial hyperammonaemia and protein aversion [25].

1.2. Localisation of the defect and the basis of treatment

Between 1980 and 1981, Rajantie, Simell and Perheentupa, and independently Desjeux and colleagues, localised the defect to the basolateral (antiluminal) membrane of the epithelial cells of the intestine and renal tubule: after oral administration of the dipeptide lysylglycine, plasma glycine rose in patients but lysine did not, because the dipeptide is absorbed across the luminal membrane and hydrolysed inside the enterocyte, but the released lysine does not leave the cell for the blood [24]. This localisation distinguishes LPI from cystinuria, whose defect is luminal [14, 24]. In 1980, a two-year trial in 19 Finnish patients showed that citrulline, a neutral amino acid absorbed by another system and converted into arginine and ornithine inside cells, corrected hyperammonaemia, increased protein intake and allowed catch-up growth, and it replaced the arginine supplementation used in the 1970s [25, 26]. In 1981, citrulline infusion reinforced the renal localisation of the defect: in patients, plasma citrulline rose as in controls, but plasma arginine and ornithine rose little, with massive argininuria, moderate ornithinuria and excessive citrulline excretion, which was interpreted as intracellular retention of arginine and ornithine for lack of basolateral efflux, with inhibition of citrulline metabolism and loss of the three amino acids into the tubular lumen [6]. In 1985, Carpenter and colleagues described a 4-year-old girl whose disease presented as infantile osteoporosis; oral citrulline increased protein tolerance, accelerated linear growth and increased bone mass, and the authors stressed that osteopenia was an almost constant complication in childhood [6].

1.3. Molecular discovery

In 1997, Lauteala and colleagues mapped the locus to the proximal long arm of chromosome 14 (14q11.2) by linkage analysis in 20 Finnish families, with strong linkage disequilibrium with markers near the TCRA locus [27]. The maximum LOD scores were 5.82 and 6.91 at two markers, and haplotype analysis delimited a 10 cM candidate interval with signs of a founder effect [6]. The following year, linkage to the same locus in 19 non-Finnish families (13 Italian and the rest from Sweden, Latvia, Morocco, Saudi Arabia and Turkey), with no linkage disequilibrium outside one Italian family cluster, indicated genetic homogeneity of LPI [6]. In 1999, two groups simultaneously published in Nature Genetics the identification of SLC7A7: Torrents and colleagues (Barcelona and Turku) found the gene mutated in 31 Finnish patients homozygous for the founder variant and in one compound heterozygous Spanish patient, and showed that a missense variant abolished transport when co-expressed with 4F2hc in Xenopus oocytes; Borsani and colleagues (Naples) identified variants in five Italian patients and the splice acceptor site alteration in four Finns [28, 29]. The Torrents abstract described the Finnish founder as a variant leading to a premature stop codon; it was later characterised as an intron 6 splice acceptor variant, now designated c.895-2A>T [1, 28].

1.4. From urea cycle disorder to multisystem disease

During the first decades LPI was treated as a «benign» urea cycle disorder, controllable with diet and citrulline; the accumulation of patient series with alveolar proteinosis, glomerulonephritis, haemophagocytic lymphohistiocytosis, autoimmunity and immunodeficiency led to its reclassification as a severe multisystem disease, in which the transport defect in non-polarised cells (macrophages and lymphocytes) causes complications that do not depend on ammonia control [30–32]. The recent publication of Chinese cohorts with monogenic lupus and of follow-up after allogeneic haematopoietic stem cell transplantation has led some authors to present it as an inborn error of metabolism and immunity [33, 34]. The Orphanet classification reflects this dual nature: LPI appears among the amino acid transport disorders and among the primary haemophagocytic lymphohistiocytoses without hypopigmentation, and is included in the classifications of inborn errors of metabolism, rare immunological diseases and rare transplant-related diseases [4].

1.5. Definition and scope

LPI is defined by the combination of increased urinary excretion and low plasma concentration of the cationic amino acids (lysine, arginine and ornithine), with postprandial hyperammonaemia and orotic aciduria, and is confirmed by biallelic pathogenic or likely pathogenic variants in SLC7A7 [1, 14]. It is one of the four «systemic» aminoacidurias in which the affected plasma amino acids are low, because the basolateral defect simultaneously impairs tubular reabsorption and intestinal absorption [14]. This article treats LPI as a single entity; hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome and cystinuria enter only the differential diagnosis, and the treatment of acute hyperammonaemia and of HLH follows the protocols for urea cycle disorders and primary haemophagocytic lymphohistiocytosis.

2. Molecular Genetics and Pathophysiology

2.1. The SLC7A7 gene and the y+LAT1/4F2hc transporter

SLC7A7 is located at 14q11.2, has 10 exons and spans 46.5 kb; the MANE Select transcript is NM_003982.4, which encodes the protein NP_003973.3 [1, 9]. The product, y+LAT1, is the light chain of a heterodimeric amino acid transporter: it binds by a disulphide bridge to the heavy chain 4F2hc (CD98, encoded by SLC3A2), which targets the complex to the plasma membrane, and the heterodimer constitutes system y+L activity at the basolateral membrane of the epithelial cells of the proximal tubule and small intestine, as well as in the lung, monocytes, macrophages and other leucocytes [1, 2, 14]. The complex functions as an antiporter: it exports the cationic amino acids lysine, arginine and ornithine from the cell in exchange for a neutral amino acid accompanied by sodium [2, 5]. System y+L can be formed by y+LAT1 (SLC7A7) or by y+LAT2 (SLC7A6) with 4F2hc; cationic transport is sodium-independent and neutral transport sodium-dependent, and cryo-electron microscopy structures of the human y+LAT1-4F2hc complex published in 2025, in inward-open and outward-open conformations, identify residue Asp243 of y+LAT1 as necessary for sodium coordination and substrate selectivity [35, 36]. No human disease due to loss of function of SLC3A2 has been described [2, 3]. According to the original complementary DNA description, y+LAT1 has 511 amino acids, about 56 kDa and 12 transmembrane domains; the heterodimer with 4F2hc is about 135 kDa and the disulphide bridge involves cysteine 109 of 4F2hc, and the 2.4 kb messenger RNA is expressed in kidney, peripheral blood leucocytes, lung, placenta, spleen and small intestine [8]. OMIM describes the gene with 11 exons in about 47 kb, on the antisense strand, with the initiation codon in exon 3, an alternative isoform lacking exon 2 (non-coding) and two functional promoters: one upstream of exon 1, active in brain, and another with a TATA box upstream of exon 2, active in kidney, small intestine and brain, which may contribute to tissue-specific regulation [8]. The difference from the 10 exons of GeneReviews results from the counting of non-coding 5' exons and explains why the same variant appears in the literature assigned to exons with different numbers [1, 8].

2.2. Epithelial transport defect

The lack of basolateral efflux produces massive urinary loss of lysine and more moderate loss of arginine and ornithine, with limited intestinal absorption of the same amino acids; the result is low plasma concentrations of cationic amino acids [14]. Tubular reabsorption is most impaired for lysine, less for arginine and minimally for ornithine [24]. The lysylglycine test, described in section 1, and in vitro studies of jejunum obtained by biopsy confirmed the defect at the antiluminal membrane [24]. Data on non-epithelial cells are contradictory: early studies in cultured fibroblasts showed no trans-stimulated efflux of lysine and of the analogue homoarginine, with heterozygotes at about 50% of control activity, but later data indicate normal cationic transport in patient fibroblasts and erythrocytes, attributed to other transporter isoforms [14, 24]. The 1988 erythrocyte study found normal effective uptake and efflux of cationic amino acids, in contrast with the same group's findings in fibroblasts [6]. In hepatocytes, cationic amino acid concentrations in biopsy samples were normal or paradoxically raised, which led to the postulate of abnormal transport between intracellular compartments [14].

2.3. Hyperammonaemia and orotic aciduria

Reduced protein tolerance and postprandial hyperammonaemia are explained by a functional deficiency of the urea cycle intermediates arginine and ornithine in hepatocytes — an intramitochondrial ornithine deficiency, as in HHH syndrome [14, 24]. Ammonia is usually normal when fasting and may rise to 500 µmol/L after protein-rich meals; plasma urea is low [24]. The substrate-limited urea cycle diverts carbamoyl phosphate to pyrimidine synthesis and raises urinary orotic acid, even on a restricted diet and markedly after a protein or alanine load [5, 24]. In the classic studies, intravenous infusion of ornithine or arginine prevented alanine load-induced hyperammonaemia; so did citrulline, with the advantage of being effective orally, because it is absorbed by a neutral amino acid system and converted into arginine and ornithine inside cells, whereas oral arginine and ornithine are poorly absorbed and cause diarrhoea [24, 25]. Protein aversion, protective against hyperammonaemia, aggravates essential amino acid deficiencies [14]. Glutamine, glycine and alanine are often raised because of cycle dysfunction [14].

2.4. Secondary nutritional deficiencies

Lysine is an essential amino acid, required for collagen formation; its chronic deficiency probably contributes to failure to thrive, osteoporosis, anaemia, hepatomegaly and immunological abnormalities [14, 24]. Arginine is the starting point of creatine synthesis and the limiting precursor of nitric oxide (NO), so extracellular arginine deficiency may lower NO production and alter vascular and immunological functions [14, 24]. Occasionally there is severe carnitine deficiency, explained by reduced intake of red meat and by endogenous biosynthesis limited by chronic lysine deficiency [14]. In the Finnish national cohort, hypocarnitinaemia was associated with female sex, renal failure and the use of ammonia scavengers [37]. Plasma metabolomics in 26 Finnish patients showed low essential and high non-essential amino acids, low phosphatidylcholines, high triacylglycerols (the long-chain ones associated with chronic kidney disease), increased plasma nitrite and a profile suggestive of hepatic steatosis or fibrosis and of oxidative stress [38].

2.5. Multisystem complications: competing hypotheses

Nutritional imbalance does not explain the involvement of the lung, kidney, immune system and bone marrow [1]. y+L activity is markedly reduced in patients' monocytes and alveolar macrophages [1]. The first hypothesis, developed by Sebastio and Ogier de Baulny, was that of trapping: in immunocompetent cells, the lack of efflux would accumulate intracellular arginine, overloading the inducible NO synthase pathway and explaining PAP, kidney disease, HLH, autoimmunity and immunodeficiency; from this derived the recommendation to limit citrulline, which is converted into arginine mainly in the kidney, because doses above 100 mg/kg/day might stimulate the immune cascade in tubular, glomerular and mesangial cells, alveolar macrophages and endothelial cells [1, 14, 30]. Later data partly contradict this hypothesis: in alveolar macrophages, y+LAT1/4F2hc is responsible for arginine influx, and the defect reduces intracellular arginine and NO, with a deficient toll-like receptor 9 pathway (less type I interferon) and upregulated TLR2/1 and TLR4 receptors, with more tumour necrosis factor alpha (TNF-α) and interleukin 12 [2]. Silencing of SLC7A7 by RNA interference in THP-1 macrophages and A549 respiratory epithelial cells induced interleukin 1β and TNF-α via the NF-κB pathway independently of intracellular arginine, and conditioned medium from these macrophages activated the epithelium, which presents y+LAT1 as a brake on inflammation [39]. The cationic transporter CAT1 (SLC7A1) is upregulated in patients' epithelia but is not expressed in alveolar macrophages, which could explain the particular vulnerability of the latter [2]. Transcriptomics in 13 Finnish patients identified 926 genes with altered expression [2]. The pathogenesis of PAP remains poorly understood; increased granulocyte-macrophage colony-stimulating factor (GM-CSF) and reduced bioavailability of surfactant protein D have been proposed, in addition to the NO hypothesis [1]. In nephropathy, raised lysine in proximal tubular cells could induce reactive oxygen species, activation of NADPH oxidase and apoptosis [14].

2.6. Immunity, erythropoiesis and neural cells: recent data

In a study from Istanbul published in 2026, ten patients compared with 18 controls had fewer B cells and class-switched memory B cells, IgG deficiency, decreased lymphocyte proliferation with preserved T-cell numbers, decreased interleukins 17 and 4 with relatively preserved interferon gamma, and an altered amino acid profile after mitogenic stimulation, with correlations between amino acids and immune parameters suggesting a humoral and cellular defect linked to the metabolic alteration [40]. In inducible Slc7a7 knockout mice, erythropoiesis was impaired in the total knockout but not with deletion restricted to erythroblasts or myeloid cells; transplantation of control marrow did not correct the defect and deficient marrow did not transmit it, which links the anaemia to decreased renal erythropoietin production and to iron overload (preclinical study) [41]. In mononuclear cells from three patients, 21 intracellular metabolites were increased, and astrocytes derived from a patient's induced pluripotent stem cells had lower viability and more reactive oxygen species when exposed to ammonia, an effect attenuated by N-acetylcysteine (preclinical study) [42]. In a 6-year-old Japanese boy with digital clubbing without hypoxia, raised urinary prostaglandin E led to the hypothesis of increased prostaglandin E2 as the mechanism of clubbing [43].

2.7. Variant spectrum

By 2008, 43 different variants had been described in 130 patients from at least 98 families; by 2011, about 50 in 142 patients from 110 families; the 2020 European Clinical Utility Gene Card (CUGC) counted 69 causal variants published between 1999 and March 2020, and a 2026 Chinese series reports about 80 [15, 32, 33, 44]. Variants are distributed throughout the gene and include all types: missense and nonsense (the majority), small deletions and insertions, splice variants and large rearrangements [14, 15]. The percentage breakdown by type cited by GeneReviews from a commercial database (54.4% missense, 28.6% nonsense and 3.6% for the remaining types together) does not add up to 100% and is not reproduced as data [1]. Most variants are private; the recurrent exceptions are the Finnish founder c.895-2A>T (38 individuals), c.726G>A (13 individuals) and c.1228C>T, the most frequent in Japan and also found in a Moroccan patient [1, 15]. Large deletions arise by recombination between Alu repeats in introns 3 and 5 and the same AluY in the 3' region of the gene (the AluY is involved in 38% of rearranged chromosomes), and deletions of exons 4–11 and 6–11 have been associated with very severe phenotypes [16, 24]. Outside founder populations, deletions and large rearrangements account for 15–20% of alleles [1, 24]. Expression studies show two mechanisms of loss of function: proteins that do not reach the plasma membrane and proteins that reach it but do not transport, and most variants tested abolished y+L activity [1, 24]. In Xenopus oocytes co-expressing 4F2hc, the Finnish founder protein had no residual activity and was retained inside the cell, the p.(Leu334Arg) and p.(Gly54Val) proteins reached the membrane without transporting, and p.(Trp242Ter) was retained in the endoplasmic reticulum and Golgi apparatus [8]. The first extended screening of 20 non-Finnish patients (Mykkänen, 2000) revealed ten new variants — four deletions, two missense, two nonsense, one splice and one tandem duplication —, and the five tested functionally abolished transport [8]. The Finnish founder uses a cryptic downstream acceptor, with loss of 10 bp in the RNA, a frameshift and a stop codon 26 bp further on [8]. One case of homozygosity due to maternal uniparental isodisomy of chromosome 14 has been described: an 11-month-old Korean girl, homozygous for c.713C>T p.(Ser238Phe), with associated Temple syndrome [10, 14].

The table presents variants of population or clinical relevance, normalised on NM_003982.4 in VariantValidator (GRCh38) and, where available, with the ClinVar classification consulted on 27 October 2026 [9, 45].

The designation c.895-2A>T already corresponds to current numbering; «1181-2A>T» and «1136-2A>T» are historical counts from other points of the complementary DNA, and the equivalence is stated by GeneReviews but cannot be recalculated in VariantValidator [1, 9]. The Atlas spells the Italian insertion as «1625 ins ATAC»; the accepted notation is c.1381_1384dup, originally described as 1625insATCA in exon 9 and later as 1384insATCA in exon 10 [1, 8, 24]. The historical designations in the table are those of the original papers and the correspondences with current numbering were given by Sperandeo and colleagues in 2008; the HGVS forms were validated in VariantValidator [8, 9, 44].

2.8. Genotype-phenotype correlation, penetrance and modifiers

No genotype-phenotype correlation has been established [1, 15, 44]. Expressivity varies even among Finns homozygous for the same founder variant [14]. In a large Italian pedigree homozygous for c.1381_1384dup, one girl had severe short stature with pancreatic and renal involvement, one boy died early of PAP and another had a very mild picture, whose brother, with a similar picture, died suddenly after an influenza-like episode [1]. Five of 13 individuals homozygous for c.726G>A had a severe phenotype with PAP [1]. In the French cohort, six patients with the same genotype had different organs affected and different prognoses, and in the Japanese national survey of 35 patients there was likewise no correlation [2, 46]. Age at diagnosis ranges from the prenatal period to adulthood [1, 52, 53]. Heterozygotes are asymptomatic and are not at risk of developing the disease; biochemistry does not distinguish them from controls [1]. No genetic modifiers have been described.

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and what they measure

Knowledge of the natural history comes from national or single-centre cohorts and from literature reviews, all retrospective and with metabolic treatment already established in most patients. The Finnish cohort (39 to 43 living patients, followed centrally in Turku) describes a homogeneous population, homozygous for c.895-2A>T [11, 54]. The French cohort from Necker Hospital (16 patients from 9 families, 1977–2015) is predominantly Maghrebi and consanguineous [2]. The review by Contreras and colleagues (157 patients in 62 publications from 1990 to 2019) measures reporting frequencies, subject to publication bias [3]. The recent Chinese series come from tertiary paediatric rheumatology centres and are enriched for lupus [33, 47]. The figures from each study are not interchangeable, and the following table indicates the population to which they refer.

3.2. Infant and young child

Newborns and breastfed infants are usually asymptomatic, because human milk is low in protein [11, 14]. Symptoms appear after weaning or with higher-protein formulas and foods: feeding difficulties, vomiting and diarrhoea, with early failure to thrive in most; neurological presentation with coma is less common [1]. Episodes of postprandial hyperammonaemia manifest as food refusal, vomiting, drowsiness and stupor, which may progress to coma; they may be mistaken for food protein-induced enterocolitis syndrome (FPIES), and in that setting forced tube feeding can be fatal [14]. At around 12 months a marked aversion to protein-rich foods sets in, also observed in patients without documented hyperammonaemia [14, 24]. The liver and spleen are moderately enlarged, and muscular hypotonia and hypotrophy are present from early childhood [1, 14]. Diarrhoea may suggest malabsorption, and some patients have alopecia, reduced subcutaneous fat, lax skin folds and skin lesions similar to those of kwashiorkor, zinc deficiency or acrodermatitis enteropathica, with dry scaly dermatitis, angular cheilitis and dystrophic nails [24]. A 5-year-old boy with chronic diarrhoea, lower limb oedema and villous atrophy was diagnosed with coeliac disease and did not improve on a gluten-free diet before the diagnosis of LPI [24]. Head circumference is normal [24]. In the French cohort, birth weight and length were usually normal (mean weight 3021 g; length 49.4 cm), the mean age at diagnosis was 4.1 years and the presentations were failure to thrive (9/16), symptomatic hyperammonaemia (10/16, with hypotonia in 3 and coma in 2), thrombocytopenia (8/16), anaemia (7/16) and hepatosplenomegaly (10/16); five patients were diagnosed by family screening with minimal symptoms [2].

3.3. School-age child, adolescent and adult

At school age, the most frequent signs are failure to thrive and hepatosplenomegaly, with hypotonia, reduced muscle strength, easy bruising and fractures after minimal trauma; bone maturation and puberty are frequently delayed [14]. The classic symptoms may go unnoticed in the first two decades because the patient avoids protein without mentioning it, and the diagnosis may be made only in adulthood [1]. Adults are heterogeneous: some have moderate short stature, abundant fat on a square trunk with thin extremities, and marked hepatomegaly [14]. A 40-year-old Italian woman with chronic kidney disease, splenomegaly, thrombocytopenia, raised LDH and ferritin and hypertriglyceridaemia, with no known hyperammonaemic crises, was diagnosed only when a targeted history revealed spontaneous protein aversion and drowsiness with infections or protein excess [53]. Two brothers aged 36 and 32 years, of normal intellectual ability and in good health thanks to unconscious protein avoidance, presented in hyperammonaemic coma in adulthood (Shaw, 1989), and a 23-year-old man who had increased his protein intake in adolescence had cognitive deterioration, episodes of stupor and asterixis, and fatty liver (Kekomäki, 1968) [6]. In a French series of adults with ammonia ≥100 µmol/L (184 patients), LPI was among the inborn errors diagnosed in adulthood [58].

3.4. Central nervous system and development

Neurological development is normal when severe or prolonged hyperammonaemia is avoided, and the intellectual ability of adults ranges from normal to moderate impairment depending on the history of hyperammonaemia [1, 14]. Hyperammonaemic episodes manifest as vomiting with dizziness or headache and may reach deep coma with an isoelectric electroencephalogram, especially when large amounts of protein are given by gastric tube; there are also episodic psychiatric symptoms [24]. In the French cohort, five of 16 patients had acute hyperammonaemic encephalopathy (seizures in 4, coma in 3) and eight of 14 persistent hypotonia or developmental delay, with no significant association with raised glutamine [2]. In the Tunisian series of seven children, five had psychomotor or intellectual delay and one died of acute hyperammonaemic encephalopathy [49]. In the Chinese series with lupus, central nervous system involvement was 6/6 in patients with LPI and lupus, with seizures in three [33]. Isolated reports of encephalopathy with rare neuroimaging findings and of coexisting autism spectrum disorder, without demonstrated causality, were published in 2025–2026 [59, 60]. Non-progressive, asymptomatic lens opacities complete the neurosensory spectrum [24, 61].

3.5. Bone and growth

In the Finnish series of 29 patients followed for a mean of 18.1 years, there were 57 fractures from minor trauma, mostly in childhood, severe osteoporosis in 13, vertebral endplate impressions in 8, rachitic metaphyses in 2 and bone age delayed by 1–5 years in 23 of 24 [55]. The reference sources differ in wording: the Atlas describes two thirds of Finnish patients as having had fractures, often before age 5 years and of long bones or vertebral compressions, whereas Saudubray reports osteopenia in two thirds of adults and rare pathological fractures in adequately treated patients — the former describes early series, the latter treated disease [14, 24]. Calcium and phosphate metabolism is normal and urinary hydroxyproline is raised [24]. Osteopenia was present in 12 of 15 French patients and in 11 of 11 Chinese patients, versus 37% in an international review [2, 33]. Growth restriction results mainly from protein malnutrition, but in some cases there is growth hormone deficiency or altered secretion due to arginine depletion; mean final height in the French cohort was −2.51 standard deviations (n = 11) [1, 2].

3.6. Lung: interstitial disease and alveolar proteinosis

Interstitial changes often progress without symptoms from childhood; progression to severe PAP is the most feared potentially fatal complication, and fibrosis may develop independently of PAP [1]. In a Finnish radiological study of 31 patients (225 radiographs), four children died of respiratory failure (PAP at three autopsies; pulmonary haemorrhage and cholesterol granulomas in the fourth), one adult had reversible respiratory failure due to bronchiolitis obliterans and, among 25 asymptomatic patients, there were signs of fibrosis on 8 of 25 radiographs and on 8 of 14 HRCT scans, with mild perfusion abnormalities in 9 of 12 and lung function abnormalities in 8 of 12 [56]. At Necker Hospital, between 1980 and 2012, pulmonary involvement affected 10 of 14 children (71%): acute onset in 5, progressive in 3 and asymptomatic in 2, with histological PAP in 10 of 10, fibrosis in 5, and six deaths from respiratory failure [62]. In the extended French cohort (16 patients), respiratory symptoms were never the initial presentation; the six patients with early lung disease (mean age 2.24 years) died at a mean age of 4.0 years, whereas the four with initially imaging-only involvement (pulmonary diagnosis at a mean age of 5.5 years) were alive at a mean age of 29.6 years; acute respiratory failure was always associated with viral or bacterial infection, and PAP was associated with death (p = 0.034) [2]. Clinically, PAP manifests as progressive exertional dyspnoea, tachypnoea and cough, aggravated by respiratory infections, with reduced breath sounds, inspiratory crackles, recession, cyanosis and, more rarely, digital clubbing; haemoptysis and intermittent fever may occur [1, 24]. HRCT shows ground-glass opacities with smooth thickening of the interlobular and intralobular septa (crazy-paving pattern), frequent cysts and, in some, fibrosis [2, 51]. An Italian child died of PAP recurring in the graft after heart-lung transplantation [63]. LPI is listed among the monogenic causes of interstitial lung disease and PAP in the European Respiratory Society pictorial review [64].

3.7. Kidney

Renal involvement is glomerular and tubular. Isolated mild proteinuria is the initial sign and progresses to proximal tubular dysfunction and nephrocalcinosis [1]. In the Finnish cohort of 39 patients, proteinuria was present in 74%, haematuria in 38%, arterial hypertension in 36%, creatinine was raised in 38% and cystatin C in 59%; four were on dialysis, with severe anaemia poorly responsive to erythropoietin and iron [54]. In a later evaluation of 41 Finnish patients, urinary β2-microglobulin was raised in 90%, cystatin C in 62%, creatinine in 48%, and 17% progressed to end-stage kidney disease (5 transplanted); citrulline doses and fasting plasma citrulline were similar in patients with decreased and normal glomerular filtration rate (GFR) [57]. In the French cohort, proximal tubulopathy (glycosuria with normoglycaemia and/or β2-microglobulinuria) was present in 11 of 11 tested; six had chronic kidney disease (CKD) at a mean age of 18.6 years and half of the cohort had a GFR below 90 mL/min at age 20 years [2]. Tubular acidosis, decreased phosphate reabsorption and generalised aminoaciduria form a Fanconi syndrome, sometimes complete and with rickets, which may mask the diagnostic pattern [1, 24]. Six French children with nephropathy in childhood included four with CKD (one end-stage) and one with membranoproliferative glomerulonephritis with polyclonal deposits which, on relapse of the nephrotic syndrome, changed to monoclonal IgG1 kappa deposits [65]. In five renal biopsies from Paris, there was proximal tubulopathy in four, nephrotic proteinuria in three, non-specific tubulointerstitial lesions and nephrocalcinosis in three, one membranoproliferative glomerulonephritis with a lupus-like «full house» pattern that evolved to monotypic IgG1κ responsive to immunomodulators, and one non-AA, non-AL glomerular amyloidosis [66]. Membranoproliferative glomerulonephritis has also been reported in a Turkish child [67]. At the autopsies of four children with LPI (Parto, 1994), three had clinical renal failure but all four had histological signs of immune-complex glomerulonephritis, in addition to PAP in three, liver failure, cytopenias with a severe bleeding tendency, amyloid in lymph nodes and spleen, and osteoporosis; in a 21-year-old woman who died in hyperammonaemic coma after years of poor adherence to diet and supplements, autopsy showed micronodular cirrhosis with steatosis, PAP and glomerulonephritis with predominantly IgA deposits (McManus, 1996) [6]. In the Chinese series, tubulopathy (urinary alpha-1-microglobulin and/or N-acetyl-β-D-glucosaminidase) was present in all, without progressive renal dysfunction during follow-up [33].

3.8. Haematology, HLH and coagulation

Mild normochromic or hypochromic anaemia, leucopenia and thrombocytopenia are frequent, with slightly raised reticulocytes; serum ferritin, zinc and LDH are constantly raised, with iron and transferrin usually normal [14]. In the 1975 Simell series, leucocytes were below 4000/mm³ in 15 of 20 patients and platelets below 150,000/mm³ in 17 [25]. Most, if not all, patients show biological features of HLH — hypertriglyceridaemia, hypofibrinogenaemia, hyperferritinaemia, hypoalbuminaemia, raised transaminases and LDH —, but few develop the clinical syndrome with fever, hepatosplenomegaly and haemophagocytosis in the bone marrow, spleen or lymph nodes [14]. In 1999, Duval and colleagues described four patients, all meeting HLH criteria, with bone marrow haemophagocytosis by mature histiocytes, hypercytokinaemia and soluble interleukin 2 receptor up to 18.6 times normal, and concluded that intermittent HLH is a regular feature of the disease [68]. In a group from southern Italy, five of six bone marrows examined showed large cells resembling sea-blue histiocytes, suggesting Niemann-Pick disease (with normal sphingomyelinase), and prominent erythrophagocytosis [24]. In the French cohort, five patients met the HLH-2004 criteria; ferritin was above 500 µg/L in 11 of 12 and triglycerides above 3.0 mmol/L in 10 of 12 [2]. About 10% of HLH cases are due to rare diseases, and among the inborn errors of metabolism LPI and lysosomal acid lipase deficiency are those that most frequently develop HLH [69]. In 15 Finnish adults, all with mild to moderate renal failure, there was a moderate bleeding tendency (score of 4 on the International Society on Thrombosis and Haemostasis bleeding assessment tool, ISTH-BAT) without spontaneous haemorrhage, normal classical clotting times, abnormal FIBTEM on rotational thromboelastometry (ROTEM) and PFA-100, low fibrinogen and factor XIII, very high D-dimers and plasmin-α2-antiplasmin complexes and shortened clot lysis — a hyperfibrinolysis profile linked to the metabolic and renal defect [70]. Plasma calprotectin is extremely raised (median 622,338 µg/L versus 608 µg/L in controls, in 10 Finnish patients), by an unknown mechanism [71]. Fatal haemorrhages have been described [11].

3.9. Immunity, infections and autoimmunity

Serum IgG is high, with abnormalities of lymphocyte subsets and of the humoral response; varicella is usually severe and there are potentially fatal bacterial infections [1, 14]. LE cells, antinuclear and anti-DNA antibodies, hypergammaglobulinaemia or low immunoglobulins and hypocomplementaemia are found [1]. SLE and a lupus-like immune dysregulation have gained weight in recent series. At the Children's Hospital of Fudan University (Shanghai), among 420 children with SLE, 171 underwent genetic testing, 19 had monogenic lupus and six of these (31.6%) had biallelic SLC7A7 variants, the most frequent monogenic lupus gene at that centre [33]. Compared with 136 children with SLE without a variant, the six with LPI were diagnosed earlier (6.6 versus 10.5 years), all had protein intolerance and short stature, bone mineral density with a Z-score of −3.1, less mucocutaneous involvement (16.7% versus 71.3%), more pulmonary involvement (83.3% versus 9.6%), central nervous system involvement (83.3% versus 12.5%) and hepatosplenomegaly (83.3% versus 13.2%), higher ferritin and LDH and absent anti-Sm antibodies, with similar disease activity [33]. The review by Tan and colleagues (20 paediatric patients with LPI and SLE or lupus-like dysregulation, including two sisters from Beijing) showed antinuclear antibodies in 18, hypocomplementaemia in 17, anti-double-stranded DNA in 9, renal involvement in 13, respiratory in 12 and haematological in 14 [47]. The frequency of SLE depends on the series: 34.8% of published Chinese cases, 6.3% in France, 3.4% in Finland and 3% in the 2021 review, with tertiary-centre bias in the Chinese series [3, 33]. In 1996, immune-complex disease compatible with SLE was described in a 3-year-old boy of Norwegian ancestry, and the authors proposed that immune-complex disease underlay the respiratory involvement (Parsons, 1996) [6]. The Finnish cohort also describes rheumatoid arthritis [11]; the 2021 review describes vitiligo, immune thrombocytopenic purpura and anti-NMDA receptor encephalitis [3].

3.10. Lipids, pancreas, liver and heart

Most adults have combined hyperlipidaemia [14]. In 39 Finnish patients (3–64 years), mean total cholesterol was 7.16 mmol/L, high-density lipoprotein (HDL) cholesterol 1.21 mmol/L and triglycerides 4.0 mmol/L, with higher triglycerides in renal dysfunction and hyperlipidaemia progressive with age, not explained by fat intake [72]. A high-carbohydrate diet may contribute to triglycerides, but does not explain hypercholesterolaemia or severe hypertriglyceridaemia (>11 mmol/L, >1000 mg/dL) [1]. Acute pancreatitis is a potentially fatal complication whose relationship with hypertriglyceridaemia is not defined; in the French cohort there was recurrent acute pancreatitis in two patients, with triglycerides up to 10.3 mmol/L, not prevented by a statin in one case or by a fibrate at maximum dose in another [1, 2]. Some children and adults progressed to end-stage liver failure, with extensive fatty degeneration and micronodular cirrhosis; in others, liver biopsy is normal or shows lipid droplets [24]. In the French cohort there was an acute myocardial infarction in a 34-year-old non-smoking man with mild CKD and hypertension, and a sinus arrest requiring a pacemaker at age 22 years; hepatic and renal amyloidosis have also been described [2]. The Finnish cohort reports myocardial infarction and exercise-induced myocardial ischaemia [11].

3.11. Pregnancy in women with LPI

In the Finnish cohort of 18 pregnancies in 9 mothers with LPI (19 children), there was an increased risk of anaemia, pre-eclampsia and intrauterine growth restriction during pregnancy and of haemorrhagic complications at delivery; the pregnancies were successful with surveillance and the children generally had normal development [73]. GeneReviews reports that most of the children were born preterm, between 31 and 39 weeks [1]. The 2021 review includes three pregnant women with anaemia, thrombocytopenia and, in one, proteinuria [3]. The reports from Spain and the United Kingdom, developed in sections 7 and 10, describe anaemia requiring transfusion, severe thrombocytopenia, hyperammonaemia precipitated by corticosteroids and postpartum vertebral fractures [50, 74].

3.12. Treated and untreated disease

Citrulline, diet and nitrogen scavengers significantly improve the metabolic symptoms — hyperammonaemia and the associated intellectual impairment are preventable —, but the renal, pulmonary, haematological and immunological complications, which are the main causes of morbidity and mortality, develop and progress under current therapy [1, 14, 31]. The 1975 Simell series and the Finnish pulmonary and bone series of the 1970s–1990s describe patients with less uniform treatment; the cohorts after 2000 describe patients on citrulline and diet [2, 25, 55, 56]. Some patients, children and adults, died after progressive multiorgan failure, often initiated by interstitial involvement and PAP, with glomerulonephritis and renal failure and a severe bleeding diathesis [14].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age and setting

Phenotypic variability has led to many misdiagnoses, and LPI should enter the reasoning of different specialties depending on age and the dominant organ [1, 2]. The table summarises the settings in which the sources recommend requesting biochemical and molecular investigation.

4.2. Clues from the history and examination

The most useful question concerns diet: spontaneous refusal of meat, fish, eggs and dairy products since the first year of life, often not mentioned by the patient or family, and drowsiness, nausea or headache after protein meals or during infections [24, 53]. A normal fasting ammonia does not exclude the disease; ammonia should be sampled after a protein-containing meal [1, 5]. Examination looks for short stature, hepatosplenomegaly, hypotonia, signs of osteoporosis, skin and hair changes, digital clubbing and pulmonary crackles [1, 24]. The metabolic triad of protein intolerance, short stature and osteopenia was present in all Chinese patients with LPI and lupus [33].

4.3. Emergency signs

Emergencies are hyperammonaemic encephalopathy (intractable vomiting, lethargy, seizures, coma), especially after a protein load, forced tube feeding or parenteral nutrition with amino acids — a patient with failure to thrive went into hyperammonaemic coma after starting parenteral feeding [14, 24]; acute respiratory failure in a patient with PAP or interstitial disease, usually triggered by viral or bacterial infection [2]; clinical HLH with fever, progressive cytopenias and coagulopathy [14]; haemorrhage, particularly at delivery or during invasive procedures, owing to hyperfibrinolysis and thrombocytopenia [70, 73]; varicella in a non-immunised patient [14]; and acute pancreatitis [1]. Corticosteroids, used in several of these complications, can precipitate hyperammonaemia: in a pregnant woman, hyperammonaemia appeared within 24 hours of an intravenous corticosteroid given for fetal lung maturation [50, 79].

4.4. Newborn screening

LPI is not a target of the European or North American newborn screening programmes described in the sources. In northern Japan (Iwate), between 1999 and 2002, a population-based molecular screening programme for the founder variant R410X covered 4568 newborns (about 100% of births in the area), identified 40 heterozygotes (0.88%) and estimated an incidence of 1:51,984, at a cost of 30 US cents per person, comparable to the screening programmes in place in Japan [13]. Citrulline may be raised from birth and detected incidentally on tandem mass spectrometry screening; in an Italian series of 10 newborns with mild citrulline elevation (<100 µmol/L), molecular investigation identified LPI, among other diagnoses [15, 75]. A negative screen does not exclude the disease, because mildly raised citrulline is neither a constant nor a targeted marker.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

There are no validated formal clinical criteria. The diagnosis rests on the combination of increased urinary excretion and low plasma concentration of the cationic amino acids, especially lysine, with postprandial hyperammonaemia and orotic aciduria, and is established by identifying biallelic pathogenic or likely pathogenic variants in SLC7A7 [1, 14]. Two variants of uncertain significance (VUS) or one pathogenic variant with one VUS neither establish nor exclude the diagnosis [1]. Molecular analysis is indicated whenever the biochemical data are unclear and when the presentation is isolated HLH or PAP that could be attributed to other causes [14].

5.2. Biochemistry: ammonia, orotic acid and amino acids

Ammonia is usually normal when fasting and rises after protein-rich meals [1]. Urinary orotic acid is increased and practically constant in the postprandial period in untreated patients, but there are two pitfalls: some patients have orotic aciduria without hyperammonaemia, and orotic acid may be normal after prolonged fasting or when the untreated patient has excluded protein-rich foods [1, 14]. Among plasma amino acids, lysine, arginine and ornithine are usually below normal for age — typically lysine <80 µmol/L, arginine <40 µmol/L and ornithine <30 µmol/L —, but may be normal; serine, glycine, citrulline, proline, alanine and glutamine are increased [1, 14]. Plasma glutamine is generally above 1000 µmol/L in urea cycle disorders and in LPI, unlike in the organic acidaemias [61]. In most hyperammonaemias plasma lysine rises; low lysine, with low ornithine and arginine, contrasting with high urinary excretion of these dibasic amino acids, is diagnostic of LPI [61]. In 24-hour urine, excretion of cationic amino acids is increased, especially that of lysine; when the loss is not evident, the renal clearances of lysine, arginine and ornithine are calculated with the creatinine clearance formula, replacing creatinine with the 24-hour urinary excretion of the amino acid and its fasting plasma concentration [1]. Serine, glycine, citrulline, proline, alanine and glutamine appear in excess in the urine but with normal clearance [1, 24]. A urinary result without simultaneous plasma values is almost uninterpretable [5].

The Atlas prints these plasma values in «mmol/L»; the order of magnitude corresponds to µmol/L [24]. The mean plasma citrulline of 232 µmol/L in the Simell series contrasts with Saudubray's description of citrulline as «±↑» and GeneReviews' «increased» without magnitude, and may reflect patients already supplemented, because the series does not specify the treatment [1, 24, 80].

5.3. Biochemical pitfalls

Urinary excretion may be within the reference range with very limited protein intake [14]. In two French patients aged 16.2 and 12.6 years, the first analysis showed almost normal excretion of dibasic amino acids (urinary lysine 32–33 µmol/mmol creatinine) and only repeat testing, prompted by clinical suspicion, revealed the loss [2]. In a 4-year-old African American boy with chronic diarrhoea, weight loss, rectal prolapses and hypoalbuminaemia, the initial urinary amino acids showed no major elevation of lysine or ornithine because of malnutrition, and the typical profile appeared only after parenteral nutrition [76]. Fanconi syndrome, complete in some patients, produces generalised aminoaciduria that may obscure the cationic pattern, and in that situation calculation of clearances or an oral lysine or arginine load clarifies the loss and intestinal absorption [24]. LPI can mimic N-acetylglutamate synthase deficiency [81] and, in an Iranian exome sequencing study in children with hyperammonaemia, a patient with an SLC7A7 variant had an organic aciduria profile [82]. The combination of orotic aciduria with hyperexcretion of cationic amino acids distinguishes LPI from the other hyperammonaemias: an enzymatic urea cycle defect does not lose lysine, arginine and ornithine in the urine, and a primary aminoaciduria does not raise orotic acid [5, 15]. The urea cycle disorders guideline notes that LPI, like ASS and arginase deficiencies and HHH syndrome, may give a positive result on the allopurinol test (orotic acid and orotidine in four fractionated 6-hour urine samples after oral allopurinol), designed to identify carriers of OTC deficiency and of limited sensitivity and specificity; a positive result therefore requires the full biochemical differential diagnosis [83].

5.4. Supporting laboratory findings

Serum LDH, ferritin and zinc are usually raised, triglycerides and cholesterol often increased, and there is non-specific anaemia, leucopenia and thrombocytopenia; subclinical HLH is a diagnostic clue [1, 15]. Urinary β2-microglobulin is a sensitive early marker of tubular involvement [57].

5.5. Genetic testing: strategy

GeneReviews proposes two routes: when there is clinical-biochemical suspicion, sequencing of SLC7A7 followed, if zero or one variant is found, by targeted deletion and duplication analysis; alternatively, a multigene panel that includes deletion and duplication analysis; when the diagnosis has not been considered (atypical phenotype), exome or genome sequencing [1]. In Finland, confirmation is by testing for the founder variant c.895-2A>T, and in Japanese patients testing can begin with c.1228C>T [1, 14]. In the French cohort, sequencing covered the nine coding exons [2].

These figures are proportions of alleles detectable by each method, not clinical sensitivity. According to the CUGC, Sanger sequencing detects more than 99% of variants in the regions analysed; the authors give analytical sensitivity and specificity «close to 95%» for sequencing, a clinical sensitivity probably very high when the clinical-biochemical phenotype is present, lower in forms with an incomplete biochemical phenotype or diagnosed in adulthood, and a clinical specificity close to 100% [15]. The negative predictive value approaches 100% when the index case variant is known [15].

5.6. Limitations of testing

About 5% of patients with the clinical and biochemical features of LPI have no variant detectable by Sanger, and deep intronic variants or intragenic deletions and duplications should be suspected [15]. Large deletions and duplications may not be excluded by next-generation sequencing and require MLPA or chromosomal microarray [14]. A negative molecular result does not exclude LPI when the biochemistry is typical. Apparent homozygosity should be confirmed by parental testing, because it may result from uniparental isodisomy (with implications for recurrence risk) or from an undetected deletion in trans [10]. Biochemistry distinguishes neither carriers from controls nor affected fetuses [1].

5.7. Molecular report

The report should state the gene, the transcript with version (NM_003982.4, MANE Select), the HGVS nomenclature at complementary DNA and protein level, zygosity, the class according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria, the method and its limitations (including whether copy number analysis was performed) and, when there is homozygosity or a VUS, the recommendation for segregation analysis [1, 9]. As part of the literature uses another transcript (NM_001126106) and the historical nomenclature differs from the current one, the variant should be converted to NM_003982.4 before comparison with databases [2, 9].

5.8. Practical algorithm

5.9. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, molecular prenatal diagnosis and preimplantation genetic testing (PGT) are possible, the latter according to the legislation of each country [1, 15]. The feasibility of prenatal diagnosis was demonstrated in 1999 by linkage analysis, before the gene was identified [6]; the first prenatal diagnosis by direct variant testing was performed in a Tunisian family, on amniotic fluid, for c.1185_1188del [48]. Fetal colonic hyperechogenicity should prompt referral to a genetics clinic and, where appropriate, amniocentesis for molecular diagnosis, because it is associated with LPI, cystinuria-lysinuria and hypotonia-cystinuria syndrome [52].

6. Differential Diagnosis

6.1. Comparative table

6.2. Other hyperammonaemias

Among the intoxication-type hyperammonaemias without ketoacidosis, LPI sits alongside the urea cycle disorders, carbonic anhydrase VA deficiency, HHH syndrome and glutamine synthetase deficiency; with ammonia above 100 µmol/L, respiratory alkalosis and normal glucose, the first three hypotheses are the urea cycle disorders, HHH syndrome and LPI [61]. Except in argininaemia, citrin deficiency and LPI, the most severe manifestation of the urea cycle disorders is neonatal hyperammonaemic encephalopathy; in LPI, the major expression is failure to thrive [84]. What distinguishes LPI from an enzymatic urea cycle defect is the urinary loss of lysine, arginine and ornithine with low plasma levels, and what distinguishes it from a primary aminoaciduria is orotic aciduria [5, 15]. Simell stressed in 1975 that the hepatic defect, with ornithine deficiency and postprandial hyperammonaemia, distinguishes LPI from the other hyperdibasic aminoacidurias [25]. HHH syndrome shares the intramitochondrial ornithine deficiency, but has high plasma ornithine and homocitrullinuria [24, 80]. LPI enters the differential diagnosis of the urea cycle disorders with the same biochemical signature.

6.3. Cystinuria

Cystinuria is the other dibasic aminoaciduria and the closest biochemical differential. It results from a defect of the apical b0,+ transporter (rBAT/b0,+AT, encoded by SLC3A1 and SLC7A9) and raises urinary cystine in addition to lysine, arginine and ornithine; plasma amino acids are normal, there is no orotic aciduria or hyperammonaemia, and the clinical picture is lithiasis [5, 14]. In LPI, urinary cystine is normal [2]. Prenatal colonic hyperechogenicity is common to both: in a French series of 33 cases with follow-up, 63% had cystinuria-lysinuria, 8% LPI and 4% hypotonia-cystinuria syndrome [52].

Dibasic aminoaciduria type I is a rare entity, with no known gene, whose description rests on two families. In the first, French-Canadian (Whelan and Scriver, 1968), 13 members of an extended family lost lysine, ornithine and arginine in the urine with normal plasma concentrations, in a vertical transmission pattern compatible with autosomal dominant inheritance; only the proband had symptoms, a mild intestinal malabsorption. In the second, of Italian origin and with first-cousin parents (Kihara, 1973), a patient interpreted as homozygous had severe intellectual disability and adverse reactions to three phenothiazines, and eleven relatives over four generations had excretions compatible with heterozygosity [7]. Bergeron and Scriver (1985) then proposed two autosomal recessive dibasic aminoacidurias, probably due to different genes: in type I, the homozygote has profound intellectual disability without hyperammonaemia or protein intolerance and the heterozygote has modest dibasic aminoaciduria; in type II, which is LPI, the homozygote has protein intolerance, hyperammonaemia and failure to thrive and the heterozygote does not lose cationic amino acids in the urine [7]. The two readings of the mode of transmission (dominant in the original family, recessive with partial expression in heterozygotes in the 1985 proposal) coexist in the entry and have not been resolved by molecular studies. For the differential diagnosis, a cationic aminoaciduria with normal plasma, without orotic aciduria or hyperammonaemia and also present in the parents argues against LPI and points to this entity or to cystinuria [7, 14].

6.4. Secondary HLH and familial HLH

HLH associated with LPI may meet the HLH-2004 criteria and is often intermittent; LPI should be considered in any patient with HLH, particularly when the familial HLH panel is negative or when there is failure to thrive, protein aversion or hyperammonaemia [24, 68, 69]. The haematological picture with raised ferritin and LDH, cytopenias and haemophagocytosis also appears in propionic acidaemia, carnitine palmitoyltransferase I deficiency and neonatal haemochromatosis [24]. The primary forms, the diagnostic criteria and induction treatment follow those of primary haemophagocytic lymphohistiocytosis.

6.5. PAP and paediatric interstitial lung disease

Autoimmune PAP, caused by anti-GM-CSF antibodies, accounts for about 90% of PAP and mainly affects adults; in LPI, the GM-CSF pathway is intact [51]. In children, the differential includes hereditary PAP due to variants in the GM-CSF receptor genes (CSF2RA, CSF2RB) and the surfactant genes, and the aminoacyl-tRNA synthetase lung diseases (MARS1) [51, 61, 64]. The coexistence of hepatosplenomegaly, failure to thrive, cytopenias and raised ferritin points towards LPI.

6.6. Early-onset lupus

LPI may present as paediatric-onset SLE and is, at one Chinese centre, the most frequent monogenic lupus gene [33]. The immune dysregulation associated with LPI is distinguished from classic SLE by earlier diagnosis, the metabolic triad (protein intolerance, short stature, osteopenia), more frequent pulmonary and central nervous system involvement, hepatosplenomegaly, higher ferritin and LDH and the absence of anti-Sm antibodies [33, 47]. In a Chilean boy with early-onset SLE, nephritis, thrombotic microangiopathy and death, LPI was suspected only after death, by trio exome sequencing, and ammonia and amino acids had never been measured [3].

6.7. Malabsorption, skin and lysosomal diseases

Vomiting, diarrhoea, hypoproteinaemia and failure to thrive suggest coeliac disease, and villous atrophy may be present in LPI; lack of response to a gluten-free diet should prompt amino acid testing [1, 24]. The cutaneous picture of acrodermatitis enteropathica is distinguished by zinc: in acrodermatitis and zinc deficiency it is low, in LPI it is high [14, 24]. Lysosomal diseases share hepatosplenomegaly, interstitial disease and cytopenias, and in the Italian series sea-blue histiocytes suggested Niemann-Pick disease until normal sphingomyelinase ruled it out [1, 24].

7. Treatments and Risk Management Strategies

7.1. Sources of recommendations and level of evidence

There is no LPI-specific guideline or formal consensus; there are no randomised trials, and the evidence comes from cohorts, case series and expert opinion [1, 5]. The management references are the 2020 European CUGC (Martinelli and colleagues, EuroGentest and the European Society of Human Genetics), the 2018 GeneReviews, the 2022 Saudubray chapter and the empirical consensus described by the 2017 French cohort [1, 2, 14, 15]. For acute hyperammonaemia and for nitrogen scavenger doses, the LPI sources refer to the European urea cycle disorders guidelines: the 2012 version and the first revision of 2019, which reassessed all recommendations with the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology and remains focused on the classic enzymatic deficiencies of the cycle and on NAGS and ORNT1 deficiencies; LPI appears in it only in the differential diagnosis, alongside citrin deficiency and ornithine aminotransferase deficiency, for lack of specific evidence on management [17, 83]. The crisis and maintenance doses that follow are therefore extrapolated from the urea cycle disorders; the 2019 dose tables retain the 2012 values for arginine, benzoate, phenylbutyrate and citrulline [83]. The goals of treatment are to prevent hyperammonaemia, ensure sufficient intake of protein and essential amino acids for metabolism and growth, and detect and treat organ complications early; follow-up requires an experienced dietitian and a metabolic disease team [1, 14, 15].

7.2. Initial evaluation after diagnosis

After diagnosis, GeneReviews recommends a history of hyperammonaemic crises and respiratory symptoms, neurological assessment, respiratory assessment (chest radiograph, HRCT and pulmonary function tests), growth assessment, liver and spleen ultrasound, haematological assessment (bone marrow aspirate may be necessary), immunological assessment (immunoglobulins and, if indicated, autoantibodies and immune complexes), renal function, bone densitometry, and referral to biochemical genetics and genetic counselling [1]. The French cohort adds direct measurement of GFR (not only estimation) when renal dysfunction is suspected and testing for carnitine and selenium deficiencies (hypocarnitinaemia in 3 of 4 and low selenium in 4 of 5 tested) [2]. The lupus series justify a baseline immunological panel with antinuclear antibodies, complement, anti-double-stranded DNA and anti-SSA, ferritin and full blood count [33, 47]. Haemostasis assessment (fibrinogen, factor XIII, ROTEM/FIBTEM, D-dimers) is useful before procedures and deliveries [70].

7.3. Acute hyperammonaemic crisis

Crises in LPI rarely require dialysis or haemofiltration, and management follows that of the urea cycle disorders: stop protein, halt catabolism with energy in the form of glucose and lipids, give intravenous arginine and nitrogen scavengers, and reintroduce protein early [1, 14, 15]. Complete protein restriction should not exceed 24 to 48 hours, because it causes catabolism of essential amino acids; the enteral route should be resumed as soon as possible, by nasogastric tube if necessary, with ondansetron for vomiting [1, 17]. Phenylacetate may deplete branched-chain amino acids, which should be measured and supplemented if necessary [1]. The action thresholds of the urea cycle disorders guideline are: ammonia above the upper limit, stop protein (24 hours, up to 48 hours in the 2012 version; at most 24 hours in the 2019 revision), intravenous glucose (10 mg/kg/min in the newborn, 8 mg/kg/min in the infant and 6 mg/kg/min at later ages) with insulin if necessary and ammonia every 3 hours; 100–250 µmol/L (150–250 in the newborn), start L-arginine and intravenous scavengers; 250–500 µmol/L, everything intravenously and prepare haemo(dia)filtration if there is significant encephalopathy, starting it if ammonia does not fall rapidly within 3 to 6 hours; 500–1000 µmol/L, immediate haemo(dia)filtration; above 1000 µmol/L, consider palliative care [17, 83]. The 2019 revision adds general precautions: avoid hypotonic solutions and exchange transfusion (a source of catabolism), do not repeat scavenger boluses, reduce the glucose infusion rate rather than increase insulin if hyperglycaemia with lactate above 3 mmol/L appears, monitor blood glucose at 30 minutes and then hourly when insulin is used, account for the sodium in the scavengers (1 g of sodium benzoate contains 7 mmol of sodium and 1 g of sodium phenylbutyrate 5.4 mmol) and monitor and supplement phosphate early, especially during haemodialysis [83]. Ammonia should be measured in venous blood, because capillary samples give falsely high values; point-of-care devices serve only as an approximation in hospital, because some have an upper detection limit of about 280 µmol/L [83]. The prognosis is very poor with coma lasting more than three days, overt intracranial hypertension or peak ammonia above 1000 µmol/L, although very high ammonia is not an absolute criterion and patients with normal outcome despite initial ammonia above 1000 µmol/L have been described [17, 83].

Classic studies in five Finnish patients with hyperammonaemia induced by intravenous L-alanine (6.6 mmol/kg over 90 minutes) showed that benzoate or phenylacetate (2.0 mmol/kg) reduced peak ammonia without statistical significance (107 µmol/L with alanine alone versus 60 with benzoate and 79 with phenylacetate), with transient toxicity (dizziness, nausea, vomiting) in four patients at the end of the combined infusions; the authors suggested therapeutic plasma limits of 4.5 mmol/L for benzoate and 3.5 mmol/L for phenylacetate [88]. The 2012 guideline states that, when citrulline is given, concomitant arginine is usually unnecessary; in LPI, infusion of arginine, ornithine or citrulline is effective, and intravenous arginine is the option described by GeneReviews [1, 17, 24]. In a 10-year-old boy in Cleveland with ammonia of 250 to 374 µmol/L, acute treatment with 10% dextrose, intravenous lipids, intravenous sodium phenylacetate/benzoate and L-arginine resolved the hyperammonaemia [89]. The 2019 Japanese review describes practice in Japan: collect plasma and urinary amino acids and urinary orotic acid before drugs, because raised LDH and ferritin already point to LPI; 10% or higher-concentration glucose via a central venous catheter, with 60–100 kcal/kg/day and insulin if there is hyperglycaemia; intravenous L-arginine (Argi U®) 100–250 mg/kg/day as first line, adding, if insufficient, sodium phenylbutyrate at label doses (450–600 mg/kg/day below 20 kg; 9.9–13.0 g/m²/day above) and/or sodium benzoate 100–250 mg/kg/day intravenously or orally; continuous haemodialysis if ammonia does not respond; and, if necessary, non-absorbable oral antibiotics (kanamycin, neomycin), lactulose or probiotics to reduce intestinal ammonia production [31]. These arginine and scavenger doses are below the 250 mg/kg boluses of the European urea cycle disorders guideline, which remains the reference; the same review notes that interstitial pneumonia and haemophagocytic syndrome may have an acute course as severe as hyperammonaemia [31, 83].

7.4. Diet and protein restriction

The recommended protein intake is 1–1.5 g/kg/day in children and 0.5–0.8 g/kg/day in adults, adjusted to individual tolerance, which varies widely between patients and changes with infections, pregnancy and lactation [14, 15]. The sources differ slightly at the extremes: GeneReviews gives 0.8–1.5 g/kg/day in children and the Atlas 0.5–0.7 g/kg/day in adults; the French cohort describes an empirical target of 1 g/kg/day, and Finnish renal transplant recipients ate about 1 g/kg/day [1, 2, 11, 24]. Most patients already restrict protein spontaneously, and the aim is to guarantee the minimum intake of essential amino acids without triggering hyperammonaemia [14, 24]. Food records from 28 Finnish patients (1.5–61 years) showed diets very deficient in calcium, vitamin D, iron and zinc, with a risk of energy and essential amino acid deficiency; all patients need regular supplementation with calcium, vitamins and trace elements [14, 90]. Raised triglycerides raised the question of a diet low in long-chain fatty acids with medium-chain triglycerides, still without evidence [2]. Urinary orotic acid is the most sensitive tool for adjusting diet and citrulline [1, 14].

7.5. L-citrulline

Citrulline is the mainstay of chronic treatment: normally absorbed by a neutral amino acid system, it is converted into arginine and ornithine inside cells and replenishes the urea cycle intermediates [24, 26]. It is not an authorised medicinal product; it is prescribed as a compounded preparation or a food for special medical purposes. The sources differ on the dose, and the divergence is resolved by the highest-ranking LPI-specific source, the European CUGC, which agrees with GeneReviews. The 2019 Japanese review follows the same limit of about 100 mg/kg/day, to avoid excessive NO production, and describes with citrulline a fall in ammonia, increased food intake and daily activity and reduced hepatomegaly; it considers oral L-arginine (Argi U® 120–380 mg/kg/day) effective but limited by the osmotic diarrhoea of malabsorption and controversial because of intracellular excess of arginine and NO, and indicates L-carnitine 20–50 mg/kg/day in secondary hypocarnitinaemia and L-lysine 20–50 mg/kg/day [31].

The reference dose is therefore up to 100 mg/kg/day, usually 50–100 mg/kg/day divided into 3 to 5 doses with protein meals, adjusted by urinary orotic acid, postprandial ammonia and plasma citrulline at the upper limit of normal [1, 14, 15]. The 100 mg/kg/day limit derives from the hypothesis that excess intracellular arginine would stimulate NO production and the inflammatory cascade in macrophages, kidney and lung [14, 30]. The hypothesis has been challenged by data showing decreased arginine and NO in alveolar macrophages and by the association of low arginine with cardiovascular disease, and the French authors propose reassessing the dose [2]. In practice, the cohorts use doses close to the limit: a mean of 90 mg/kg/day in Finnish renal transplant recipients, about 80 mg/kg/day in Finnish patients evaluated for nephropathy — with no difference between patients with decreased and normal GFR — and 94 mg/kg/day in the British pregnant woman in section 10 [11, 50, 57]. The urea cycle disorders guideline limits citrulline to 6 g/day; in a Spanish pregnant woman 3 to 9 g/day were used, adjusted to ammonia and orotic acid [17, 74]. In the two-year trial in 19 Finnish patients, citrulline increased protein intake, haemoglobin, albumin and valine, normalised orotic acid excretion and allowed catch-up growth in 7 of 9 children with short stature, but did not change hepatosplenomegaly or several biochemical abnormalities [26]. The sources describe no specific adverse effects of citrulline at these doses.

7.6. Oral nitrogen scavengers

Sodium benzoate or sodium phenylbutyrate is added to diet and citrulline when glutamine and glycine remain persistently very high, or to allow the lowest effective dose of citrulline [1, 14]. In the French cohort, seven patients received scavengers (sodium phenylbutyrate in six and/or sodium benzoate in three) for ammonia above 80 µmol/L [2].

For sodium phenylbutyrate, the reference dose in LPI (up to 250 mg/kg/day) is below the usual range of the European and US labels (450–600 mg/kg/day below 20 kg), and use in LPI is outside the approved indications, which are limited to CPS, OTC and ASS deficiencies [14, 17, 79, 92]. In the EU, glycerol phenylbutyrate has an indication extended to ASL and arginase deficiencies and HHH syndrome, but not to LPI [94]. The adverse effects of sodium phenylbutyrate in the European SmPC are mainly reproductive and gastrointestinal: very common amenorrhoea and irregular menstruation; common anaemia, thrombocytopenia, leucopenia, metabolic acidosis, decreased appetite, depression, headache, syncope, oedema, abdominal pain, vomiting, dysgeusia, abnormal body odour, renal tubular acidosis and hypokalaemia; uncommon pancreatitis and peptic ulcer [92]. Serum potassium should be monitored, because renal excretion of phenylacetylglutamine may cause urinary potassium loss, and plasma glutamine should be kept below 1000 µmol/L, and ammonia, arginine, essential amino acids (especially the branched-chain ones), carnitine and serum proteins within normal limits [92, 93]. The sodium load requires caution in heart failure, severe renal impairment and states with sodium retention and oedema — a relevant situation in LPI with chronic kidney disease [79, 93]. Signs of neurotoxicity (vomiting, nausea, headache, somnolence or confusion without hyperammonaemia) should prompt measurement of phenylacetate [94, 96].

7.7. L-lysine

Lysine supplementation is controversial [15]. L-lysine HCl at a carefully titrated dose, 20–30 mg/kg/day in 3 to 4 doses with meals, raises plasma lysine to the low-normal range without adverse effects [1, 14, 91]. In a 12-month trial in 27 Finnish patients, individualised low doses with meals improved fasting plasma lysine without hyperammonaemia or other adverse effects, and the authors considered that supplementation can be started early [97]. In six patients, doses of 0.55 and 1.1 mmol/kg per dose caused profuse diarrhoea, whereas 0.05 mmol/kg per dose three times a day for three days kept plasma lysine normal before and after meals in 2 of 3, with no effect on the urea cycle [98]. The Atlas cites the historical range of 0.05–0.5 mmol/kg three times a day, limited by malabsorption and intestinal tolerance [24]. In the 1980 trial, lysine added to citrulline brought no additional benefit and caused colic and diarrhoea in some patients [26]. Among Finnish renal transplant recipients, four of eight received lysine, a mean of 21 mg/kg/day [11]. ε-N-acetyl-lysine and intravenous lysine also raise plasma lysine [24].

7.8. L-carnitine

Hypocarnitinaemia was found in 8 of 37 Finnish patients (8–52 years), associated with female sex, renal failure and ammonia scavengers; three of eight had muscle weakness that disappeared with carnitine, oral lysine did not correct the deficiency and oral L-carnitine raised total carnitine, but the free/total ratio remained subnormal in all but one [37]. The reference dose in LPI, when deficiency is documented, is 25–50 mg/kg/day [1, 17, 37]; the French cohort cites 20–50 mg/kg/day [2]. The US label of levocarnitine (Carnitor®) indicates, in secondary carnitine deficiency due to inborn errors of metabolism, 50–100 mg/kg/day in divided doses in infants and children, starting at 50 mg/kg/day, with a maximum of 3 g/day, and 1–3 g/day in adults (990 mg tablets two to three times a day) — above the dose used in LPI [99]. The Portuguese SmPC of levocarnitine could not be consulted (section 7.15).

7.9. Lung disease and alveolar proteinosis

There is no established therapy for the late complications [1, 15]. Whole-lung lavage is the best approach to PAP in LPI; relapses may require serial lavages [1, 15]. In an Italian boy with PAP diagnosed at age 16 years, one whole-lung lavage kept him free of clinical, radiological or functional recurrence two years later [77]. Results are not consistent: in the Necker series, two whole-lung lavages were not effective, and all French patients with PAP underwent total bronchoalveolar lavage [2, 62]. In unstable infants, lavage may require venovenous extracorporeal membrane oxygenation (ECMO); in PAP in general, whole-lung lavage has been the reference treatment since the 1960s, with positive responses in 60–84%, but it is difficult, expensive and poorly tolerated in children [51]. High-dose corticosteroids were effective in a few patients when started early and without response in others [1, 14, 24]; in the French cohort, three patients in respiratory failure with HLH received corticosteroids without respiratory improvement, and the authors consider that corticosteroids in PAP have no clear rationale or benefit and increase infectious risk [2]. GM-CSF has contradictory results: it proved ineffective or even worsened the course in an Italian case [1, 63], whereas experimental inhaled sargramostim produced an excellent response in a Finnish patient with PAP refractory to corticosteroids and lavages, without adverse effects, and a slight improvement in lung function in another patient, an effect that could not be evaluated [100]. In a Hungarian infant girl, subcutaneous GM-CSF at 10 µg/kg/day from 11 months was associated with episodes of fever and leucocytosis without infection, and the switch at 22 months to inhaled sargramostim at 125 µg/day was accompanied by disappearance of the fever and weaning from daytime respiratory support [51]. The rationale for GM-CSF is established in autoimmune PAP, in which anti-GM-CSF antibodies neutralise the cytokine; in LPI the GM-CSF pathway is intact, and any use is off-label [51, 101]. The French authors consider GM-CSF ineffective or dangerous in HLH associated with LPI [2]. Heart-lung transplantation is contraindicated: a 13-year-old boy died 26 months after transplantation from recurrence of PAP in the graft [2, 15, 63]. Bone marrow transplantation has been proposed to correct the alveolar macrophage defect [1, 15]. In a Japanese man in his fourth decade with fibrosing interstitial disease, off-label nintedanib was followed by acute exacerbation two years later and death [102]. General measures include early targeted antibiotic therapy, vaccination and respiratory physiotherapy [2].

7.10. HLH, immune dysregulation and lupus

The treatment of the immunological and bone marrow complications, including clinical HLH, is still experimental and should be guided by specialists according to standardised protocols, such as the HLH induction protocols [14, 15]. There have been good individual responses to immunosuppressants and high-dose intravenous immunoglobulin (IVIG), including ciclosporin A with corticosteroids in a boy with HLH and PAP [14, 15, 103]. In the French cohort, two patients received HLH-directed treatment (corticosteroids and ciclosporin), effective in one [2]. In the Chinese series of six patients with LPI and SLE, all received hydroxychloroquine, four pulsed methylprednisolone (secondary HLH, neuropsychiatric lupus, severe nephritis), most additional immunosuppressants and one belimumab, in addition to metabolic treatment; five of six reached lupus low disease activity state within 0.5 to 2.5 years, three stopped corticosteroids after 3 to 5 years and one died of severe COVID-19 [33]. In the two sisters from Beijing, prednisone (2 and 1 mg/kg/day) with tofacitinib 2.5 mg/day, used exploratorily and off-label, was followed by improvement in one and a fatal outcome in the other, after poor adherence and unsupervised corticosteroid reduction [47]. There is no established immunosuppressive regimen for the pulmonary or lupus disease of LPI [47]. Corticosteroids cause protein catabolism and may raise ammonia: the scavenger SmPCs recommend more frequent ammonia monitoring when they are needed [50, 79, 92].

7.11. Haematopoietic stem cell transplantation

A child from Beijing with SLE and severe relapsing HLH, refractory to methylprednisolone, mycophenolate and IVIG, went into remission after allogeneic haematopoietic stem cell transplantation (HSCT) [47, 104]. In 2026, the 21-year follow-up of a second patient who underwent allogeneic peripheral blood stem cell transplantation for HLH was published, presented as treatment of an inborn error of metabolism and immunity; the abstract does not describe the metabolic, renal or pulmonary outcome [34]. HSCT is, so far, a case-report option for refractory HLH and a hypothesis for PAP.

7.12. Kidney

No treatment — strict adherence to diet, citrulline or high-dose corticosteroids — has been shown to influence the course of kidney disease, and there is no preventive regimen for renal injury beyond antiproteinuric, antihypertensive and lipid-lowering agents [1, 11]. The French cohort recommends measuring GFR (not merely estimating it), starting an angiotensin-converting enzyme (ACE) inhibitor early in proteinuria or hypertension, and treating autoimmune nephropathies with classic immunosuppression [2]. Renal biopsy is relevant when there are glomerular signs, because it identifies lesions with specific treatment [66]. A 13.8-year-old boy with immune-complex membranoproliferative glomerulonephritis was treated as lupus nephritis with corticosteroids, mycophenolate mofetil and an ACE inhibitor, leaving residual proteinuria of about 1 g/day [2]. Dialysis and renal transplantation are possible [54]. In the Finnish national renal transplant cohort (2005–2023), eight patients (mean age 41.9 years) received ten grafts; there was acute rejection in 4 of 10 grafts (versus 10–15% in transplant recipients without LPI), delayed graft function in 3 of 10, infections in all, coagulation dysfunction in 5 of 8 without unusual surgical bleeding, and four grafts lost; graft survival was 80%, 68.6% and 51.4% at 1, 5 and 10 years, and patient survival 88%, 86% and 50%, with three deaths from LPI-related metabolic dysfunction and one from PAP six months after transplantation [11]. After transplantation, plasma citrulline fell from 120 to 49 µmol/L and lysine rose from 125 to 162 µmol/L, with protein tolerance unchanged or subjectively better; in a Dutch patient, renal transplantation substantially improved protein tolerance and ornithine, lysine and arginine levels [11, 105]. The immunosuppression used in Helsinki since 2004 is mycophenolate, corticosteroid and ciclosporin or tacrolimus, with basiliximab or antithymocyte globulin induction only in the presence of anti-HLA antibodies, poor matching or retransplantation; plasmapheresis for humoral rejection was feasible with reduced flow, after acute haemolysis at the first session [11]. The anaemia of end-stage kidney disease responds poorly to erythropoietin and iron [54].

7.13. Dyslipidaemia, bone and growth

Hyperlipidaemia is treated first with dietary modification and fish oil and then with drugs [1]. In 22 Finnish patients who started atorvastatin or simvastatin, cholesterol and triglycerides fell by 32% at six months and HDL cholesterol rose by 13%, with good tolerance, and the authors recommend atorvastatin and early initiation [24, 72]. The LPI sources give no doses; the US label of atorvastatin (Lipitor®) indicates in adults 10–20 mg once daily to start, within a range of 10–80 mg/day, and in patients aged 10 years and over with heterozygous familial hypercholesterolaemia 10–20 mg/day — doses extrapolated to LPI [106]. In the French cohort, a statin and a fibrate at maximum dose did not prevent relapses of pancreatitis [2]. Osteoporosis is treated with calcium, vitamin D and treatment of protein deficiency; oral alendronate improved bone mineral density in a patient with severe osteoporosis [14, 107]. The article does not give the dose; the US label of alendronate with colecalciferol (Fosamax Plus D®) indicates in adults with osteoporosis 70 mg once weekly, fasting, with water and 30 minutes before any food or medicine, without lying down in that interval — an extrapolated dose, with no paediatric data in the sources [108]. Growth hormone has been used in several children with good response and without adverse effects: four Finnish children aged 7–16 years, with low insulin-like growth factor 1 (IGF-1) and delayed bone age, received 0.035–0.050 mg/kg/day for 3–4.5 years and gained 0.7–1.8 standard deviations in height, without catch-up of bone age and without episodes of hyperammonaemia [1, 14, 109]. In the French cohort, growth hormone improved height in two of two patients with concomitant deficiency, and in the Chinese series it was started in three patients after disease control [2, 33].

7.14. Infections and vaccination

Immunisation against pneumococcus and varicella-zoster virus and annual influenza vaccination are recommended [1, 14]. The response to polysaccharide vaccines may be poor, and patients with non-protective titres should be revaccinated [1]. A patient with no history of varicella should be vaccinated or, if exposed, managed as immunocompromised, and non-immunised patients with varicella should receive aciclovir immediately [1, 14]. The LPI sources give no aciclovir doses; the US label of intravenous aciclovir indicates, for varicella-zoster infection in the immunocompromised, 10 mg/kg as a one-hour infusion every 8 hours for 7 days from age 12 years and 20 mg/kg every 8 hours below age 12 years, with a maximum of 20 mg/kg every 8 hours, rapid injection prohibited and adjustment to renal function (12-hour interval with creatinine clearance 25–50 mL/min/1.73 m², 24-hour interval with 10–25 and half the dose every 24 hours with 0–10) — an indication approved for zoster and applied to varicella by analogy [110]. Respiratory infections should be minimised, because they trigger acute respiratory failure in PAP [1, 2].

7.15. Regulatory status

No medicinal product has an approved indication for LPI. Nitrogen scavengers are authorised for urea cycle disorders and are used off-label in LPI; citrulline, lysine and oral sodium benzoate are not authorised medicinal products [17, 79, 92].

In Portugal, the centralised authorisations (Ammonaps®, Pheburane®, Ravicti®) are valid; the applicable SmPC is that of the EMA, consulted in the agency's product information version, and marketing and reimbursement could not be confirmed because Infomed was unavailable (503 and 404 responses) on 27 October 2026 [92–94]. In Brazil, the open data of the National Health Surveillance Agency (ANVISA) contain no registration of sodium phenylbutyrate, glycerol phenylbutyrate or injectable phenylacetate/benzoate, and the registrations of molgramostim and levocarnitine are listed as inactive; access will depend on importation or compounding [114].

7.16. Trials and interventional studies

Studies in LPI are small, open-label, without a concurrent control group and without confidence intervals in the available abstracts; they do not allow comparison between them or estimation of effects on the outcomes that weigh most on prognosis (PAP, kidney disease, HLH). The IMPALA-2 trial is randomised and controlled, but in a different disease — autoimmune PAP, mediated by anti-GM-CSF antibodies —, and its result does not transfer to the PAP of LPI, in which the GM-CSF pathway is intact [51, 85]. On 27 October 2026, ClinicalTrials.gov listed no interventional trials in LPI, only two observational studies (NCT05706714, T helper cell phenotype in urea cycle disorders, Istanbul, completed in 2023 with 65 participants; NCT04983069, prenatal colonic hyperechogenicity, Montpellier, status unknown, 400 participants planned) [115]. No negative, suspended or withdrawn trials were found; a negative search does not prove their non-existence.

7.17. Developments in the last twelve months

Between October 2025 and October 2026, the LPI literature consisted of observational studies, case reports and preclinical studies, without interventional trials. At the observational level, the Shanghai series identified SLC7A7 as the most frequent paediatric monogenic lupus gene at a referral centre, and the Beijing review brought together 20 paediatric patients with LPI and lupus-like dysregulation [33, 47]. An immunological study of ten patients described a humoral and cellular defect correlated with the amino acid profile [40]. At the case report level, the following were published: the 21-year follow-up after allogeneic HSCT for HLH, a pregnancy complicated by immune dysregulation and severe thrombocytopenia, a North American case with a novel variant and intolerance to glycerol phenylbutyrate, an Indian case of encephalopathy with an ultra-rare variant, an Indian case with macrocephaly, hepatosplenomegaly and myelosuppression, HLH revealed by atypical bone marrow haemophagocytosis in Tunisia, and coexistence with autism spectrum disorder [34, 50, 59, 60, 89, 116, 117]. At the preclinical level in 2025, slightly before the window, are the structures of the y+LAT1-4F2hc complex, the link between anaemia and renal erythropoietin in the mouse and the injury of stem cell-derived astrocytes [35, 36, 41, 42]. On the regulatory front, the only active process identified is that of inhaled molgramostim in autoimmune PAP, which does not include LPI (section 7.15) [111, 112].

7.18. Agents and circumstances to avoid

Large boluses of protein or amino acids and forced tube feeding, which can be fatal, should be avoided; parenteral nutrition with amino acids to correct failure to thrive triggered hyperammonaemic coma [1, 14, 24]. The sources differ on prolonged fasting: the Atlas includes it, with infections and high protein intake, among the causes of persistent hyperammonaemia, and GeneReviews considers it uncertain whether it triggers crises; in practice, catabolism is avoided with energy intake during intercurrent illness and perioperatively [1, 17, 24]. Corticosteroids increase protein catabolism and ammonia, and valproate and haloperidol have been associated with hyperammonaemia in urea cycle disorders; when they are needed, ammonia should be monitored more frequently [79, 92]. Heart-lung transplantation is contraindicated [15]. Sodium-containing scavengers require caution in chronic kidney disease with sodium retention [93]. Glycerol phenylbutyrate loses efficacy in pancreatic insufficiency or malabsorption, both possible in LPI [94].

7.19. Pregnancy and lactation

Pregnancy in a woman with LPI is high-risk and should be followed at a metabolic disease centre with high-risk obstetrics, with frequent plasma amino acids and ammonia and preparation for pre-eclampsia and haemorrhage during and after delivery; delivery should be centralised in units with capacity for haemorrhage and rare metabolic diseases [1, 73]. Preconception counselling allows drugs to be reviewed: sodium phenylbutyrate (Ammonaps®, Pheburane®) is contraindicated in pregnancy and breastfeeding in the European SmPC, with an obligation of effective contraception, and glycerol phenylbutyrate should not be used in pregnancy unless the clinical situation requires it [92–94]. Sodium benzoate was continued in the published pregnancies because of wider experience; it conjugates glycine, which takes part in haemoglobin synthesis and should be monitored [74]. In the published Spanish pregnancy, L-citrulline (3–9 g/day) and sodium benzoate (4–6 g/day) were adjusted to ammonia and urinary orotic acid, protein and energy were increased with essential amino acid supplements, and during active labour 10% glucose at 62 mL/h with oral citrulline and benzoate, ammonia every 8 hours (always <80 µmol/L) and intravenous tranexamic acid 900 mg were given [74]. Thrombocytopenia in a pregnant woman with LPI requires exclusion of pre-eclampsia, HELLP syndrome and thrombotic microangiopathy and monitoring for HLH postpartum with validated scores such as the HScore [50]. The sFlt-1/PlGF ratio (soluble fms-like tyrosine kinase 1 to placental growth factor) helps to exclude pre-eclampsia, but the thrombocytopenia and transaminase abnormalities inherent to LPI confound the picture [74]. Corticosteroids for fetal lung maturation may precipitate hyperammonaemia within the next 24 hours, and metabolic support (intravenous glucose, scavenger) should be anticipated [50]. Lactation is possible with caloric support and ammonia monitoring, taking into account calcium loss in a woman with low bone density; in the Spanish pregnancy, exclusive breastfeeding lasted six months with maternal intake ≥2000 kcal/day [50, 74]. The European SmPCs contraindicate breastfeeding on sodium phenylbutyrate [92, 93].

7.20. Perioperative care, procedures and transition

Before surgery, biopsy or delivery, haemostasis should be assessed, because hyperfibrinolysis and thrombocytopenia increase the bleeding risk even with normal classical clotting times [70]. Preoperative fasting should be accompanied by intravenous glucose to avoid catabolism, with early reintroduction of protein and citrulline, according to the principles of acute management [1, 17]. Plasmapheresis in a patient with coagulopathy requires flow control [11]. Respiratory deterioration before or after renal transplantation should raise suspicion of PAP [11]. LPI requires regular lifelong surveillance, to avoid the adverse effects of treatment (malnutrition and insufficient intake of essential amino acids) and to diagnose organ complications [15]. In Finland, all patients, regardless of age, are followed at the Department of Paediatrics of Turku University Hospital; in other countries, transition to adult metabolic disease teams should ensure continuity of renal, pulmonary, haematological and cardiovascular surveillance [2, 11].

7.21. Recommendations and divergences between sources

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risks

LPI is inherited in an autosomal recessive manner [1]. The parents of a patient are obligate heterozygotes, asymptomatic and not at risk of developing the disease [1]. Each sibling of a patient has, at conception, a 25% chance of being affected, 50% of being an asymptomatic carrier and 25% of being neither affected nor a carrier [1]. All children of a patient are obligate heterozygotes; the risk of their having affected children depends on the status of the other parent, who is more likely to be a carrier in consanguineous couples and in populations with a founder effect [1, 2]. The parents' siblings have a 50% chance of being carriers [1].

Apparent homozygosity in a patient whose father is not a carrier should prompt investigation of uniparental isodisomy: in the Korean girl with maternal isodisomy of chromosome 14, only the mother was a carrier and the recurrence risk is not 25% [10].

8.2. Carrier testing and cascade testing

Carrier testing requires prior identification of the familial variants; biochemistry (plasma amino acids, orotic acid) does not distinguish carriers from controls [1]. After molecular confirmation in the index case, cascade testing of relatives is recommended [15]. At-risk siblings of a patient should be evaluated: by molecular testing when the variants are known, with plasma and urinary amino acids and orotic acid while awaiting the result, and by clinical and biochemical assessment when they are not [1]. In the French cohort, five patients were diagnosed by family screening with minimal symptoms, and in Tunisia screening of healthy siblings identified heterozygotes and normal homozygotes [2, 48]. Early identification of affected siblings allows diet and citrulline to be started before the first hyperammonaemic crisis, but the course of late complications differs even between siblings with the same initial presentation [2, 15]. In northern Japan, population screening of newborns for R410X carriers showed a carrier frequency of 0.88% [13].

8.3. Prenatal diagnosis and preimplantation genetic testing

Prenatal diagnosis and PGT are possible once the familial variants have been identified; biochemistry does not distinguish affected fetuses [1]. The CUGC accepts PGT according to national legislation [15]. In the Tunisian family in which the first molecular prenatal diagnosis was made, amniotic fluid testing identified one fetus homozygous and another heterozygous for c.1185_1188del [48]. Colonic hyperechogenicity detected on fetal ultrasound may be the first sign of the disease in a family without a history, and should lead to referral to a genetics clinic and, where appropriate, amniocentesis [52]. When the molecular diagnosis has not been confirmed in a patient, DNA banking should be considered [1].

8.4. Counselling before and during pregnancy in an affected woman

The optimal time for counselling is before pregnancy, and it should be offered to young adults who are affected, carriers or at risk [1]. For a woman with LPI, preconception counselling includes review of drugs (sodium phenylbutyrate is contraindicated in pregnancy in the EU), nutritional and metabolic optimisation, renal, haematological, immunological and bone assessment, and information on the risks of anaemia, pre-eclampsia, fetal growth restriction, haemorrhage at delivery and postpartum hyperammonaemia [50, 73, 92]. The pregnancy of the British woman in section 10 was unplanned and reached the clinic at 13 weeks, without prior counselling [50]. A consanguineous partner increases the risk of an affected child; in that case, the newborn's ammonia and amino acids were normal [50].

8.5. Counselling of minors

GeneReviews places the optimal time for carrier testing before pregnancy and recommends offering it to young adults who are affected, carriers or at risk; in at-risk minor siblings, diagnostic testing is indicated, because early diagnosis allows diet and citrulline to be started before the first hyperammonaemic crisis [1, 15].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

LPI is rare: Saudubray reports a few hundred published patients worldwide, GeneReviews more than 200, and the 2025 Finnish cohort more than 200 cases in at least 25 countries, one third of them Finnish [1, 11, 14]. The existing incidence estimates come from founder populations and cannot be transposed to the general population: they correspond to the upper limit of what a founder effect produces [5].

9.2. Founder populations and geographical distribution

In Finland, all patients except one are homozygous for c.895-2A>T, with a common haplotype compatible with a single founder [11, 14, 24]. In northern Japan, R410X (c.1228C>T) occurs exclusively on one intron 8 haplotype (31 chromosomes), a founder effect estimated at at least 130 generations (about 2600 years) [12]. In Italy there are family clusters, mainly in the south, and the largest known pedigree is homozygous for c.1381_1384dup; c.726G>A occurs in Italy, Morocco and North Africa [1, 44]. By 2008, only Finland showed a genuine founder effect with widespread homozygosity [44]. In Tunisia and the Maghreb, c.1185_1188del (1471delTTCT) is recurrent in consanguineous families: of seven Tunisian children followed between 1992 and 2022, five had this variant, none with pulmonary involvement [48, 49]. In the French cohort, the families were from the Maghreb (4), France (2), Turkey, Lebanon and Guinea (1 each), with consanguinity in 12 of 16 patients [2]. In China, c.625+1G>A predominates, with 65.2% of Chinese alleles in exon 4 [33]. Clusters have also been described in Norway, and sporadic cases on all continents, including Spain, Turkey, Israel, the United Kingdom and Northern Ireland, Lithuania, Hungary, Korea, Iran and India [1, 10, 14, 24, 51, 59, 82].

9.3. United States, Portugal and Brazil

In the United States, the sources describe isolated cases — the first reports in the 1970s and 1980s, a family of Mexican ancestry with a novel deletion, a 4-year-old African American boy and a 10-year-old boy in Cleveland — without a prevalence estimate [1, 24, 76, 89]. The sources consulted contain no data from Portugal or Brazil; no targeted geographical searches were performed, and absence from these sources does not demonstrate absence of patients in those countries.

9.4. Phenotypic differences between populations

The frequencies of complications vary between series, but part of the variation reflects the mode of recruitment. Progressive renal dysfunction affected 25 of 41 Finns (61.0%) and 6 of 16 French patients (37.5%), versus 0 of 15 Chinese cases with tubulopathy, and SLE 34.8% of published Chinese cases, versus 6.3% in France and 3.4% in Finland; the Chinese series comes from a paediatric rheumatology centre, which enriches the sample for lupus [33]. Pulmonary involvement was frequent and severe in the French cohort and absent in Tunisian children with c.1185_1188del [2, 49]. The absence of genotype-phenotype correlation in all series precludes attributing these differences to the variant [44, 46].

9.5. Special populations

The pregnant woman (sections 7.19 and 10), the patient with chronic kidney disease or a renal transplant (section 7.12) and the adult diagnosed late (section 3.3) have specific needs. Patients from consanguineous families and founder populations benefit from cascade testing and couple counselling [2, 13].

9.6. Reference networks and patient organisations

In Europe, the relevant reference network is MetabERN, in the subnetwork for disorders of intermediary metabolism (amino acid transport disorders); the complications justify coordination with ERN-LUNG (PAP and interstitial disease), ERN RITA (HLH and immune dysregulation) and ERKNet (kidney disease) [18–21]. GeneReviews lists the European registry E-IMD (European Registry and Network for Intoxication Type Metabolic Diseases), the Urea Cycle Disorders Consortium and its registry, the international patient registry of the National Urea Cycle Disorders Foundation and the contact registry of the Rare Diseases Clinical Research Network [1]. Patient organisations include the National Urea Cycle Disorders Foundation, which has a page dedicated to LPI, and Metabolic Support UK [1, 22].

10. Illustrative Clinical Case

10.1. Pregnancy in a woman with LPI, immune dysregulation and severe thrombocytopenia

McCarron and colleagues published in 2026, in the United Kingdom, the case of a 25-year-old woman, daughter of consanguineous parents, the second of two affected siblings (the brother with a milder course), with LPI confirmed by the homozygous frameshift variant c.1262del p.(Pro421ArgfsTer98) in SLC7A7 (transcript not stated in the paper; the notation matches normalisation on NM_003982.4) and a previous first-trimester miscarriage [9, 50]. She had had two infection-triggered episodes of HLH at ages 14 and 16 years and SLE with arthritis and lupus nephritis at age 15 years, and remained on hydroxychloroquine 200 mg/day; estimated GFR was above 90 mL/min/1.73 m², with persistent proteinuria (urinary protein/creatinine ratio of 100 mg/mmol) and no hypertension [50]. She had hypothyroidism on levothyroxine and very low bone mineral density (Z-score of −5.0 at the lumbar spine and −3.4 at the hip) with an osteomalacia profile (25-hydroxyvitamin D <10 nmol/L, phosphate 0.56 mmol/L, calcium 2.06 mmol/L, alkaline phosphatase 282 U/L), treated with intramuscular ergocalciferol 300,000 IU every three months, and selenium and folate deficiencies; she had no lung disease on radiograph and no splenomegaly on ultrasound [50]. Baseline therapy was L-citrulline 94 mg/kg/day and sodium benzoate 75 mg/kg/day in four doses, with poor adherence, and protein intake was about 30 g/day (0.56 g/kg/day) owing to aversion, with a weight of 47.1 kg [50].

The pregnancy was unplanned and reached the clinic at 13 weeks, without preconception counselling; glutamine was 899 µmol/L, urinary orotic acid 27.4 µmol/mmol creatinine (reference 0.0–3.4) and ammonia transiently reached 91 µmol/L, values that normalised with an increase in sodium benzoate to 100 mg/kg/day in two doses (to improve adherence) and a change of citrulline, at the same total dose, to two doses [50]. A thyrotropin of 20 mIU/L required an increase in levothyroxine, and platelets fell from 221 to 105 ×10⁹/L [50]. The team estimated the protein requirement at 40 g/day, which the patient tolerated up to 50 g/day; owing to intolerance of glucose polymers she received a lipid emulsion, and the targets were, by trimester, 41, 50 and 70 g/day of protein and 1950, 2237 and 2416 kcal/day, with 25 g/day of protein in the first five days postpartum and gradual increase to 50 g [50]. Throughout pregnancy, plasma lysine fell from 99 to 47–53 µmol/L, arginine from 77 to 7–13 µmol/L and ornithine from 53 to values below 5–7 µmol/L, and glutamine remained between 695 and 899 µmol/L [50].

In the second and third trimesters, under joint follow-up by inherited metabolic diseases, maternal-fetal medicine, haematology and rheumatology, thrombocytopenia worsened to 36 ×10⁹/L and haemoglobin ranged between 87 and 105 g/L, with a nadir of 70 g/L and transfusion; haptoglobin was 0.17 g/L without schistocytes, coagulation and fibrinogen were normal, C4 was low (0.09 g/L) and anti-double-stranded DNA negative [50]. At 27 weeks, ferritin was 1319 µg/L after intravenous iron, triglycerides 1.4 mmol/L, fibrinogen 2.0 g/L and the HScore 72, a low probability of HLH; the thrombocytopenia was treated as immune thrombocytopenic purpura with prednisolone (10 and then 20 mg/day) and two doses of IVIG 1 g/kg two weeks apart, with partial response and corticosteroid-induced diabetes, and prophylactic low-molecular-weight heparin was stopped with platelets below 60 ×10⁹/L [50]. Within 24 hours of an intravenous corticosteroid for fetal lung maturation, ammonia rose to 171 µmol/L and was treated with intravenous dextrose at 2 mL/kg/h and intravenous sodium phenylbutyrate 250 mg/kg/day [50]. Figure 1 of the paper shows the course of haemoglobin and platelets during pregnancy and postpartum (https://pmc.ncbi.nlm.nih.gov/articles/PMC13331876/figure/jmd270109-fig-0001/) [50].

Caesarean section was performed at 35 weeks, with a loss of about 800 mL and haemoglobin of 70 g/L, requiring transfusion; intravenous dextrose at 2 mL/kg/h was maintained during delivery and for the following 72 hours [50]. The newborn, weighing about 2 kg, had a brief special care admission and, although the partner was consanguineous, had normal ammonia and amino acids [50]. Mixed feeding was stopped in the third week; at four weeks postpartum, the patient sustained vertebral fragility fractures at T10 and L1 after a fall [50]. Platelets normalised, prednisolone was stopped and the urinary protein/creatinine ratio fell to 60 mg/mmol; gestational weight gain was 7.6 kg, below the recommended 11.5–16 kg [50].

10.2. What the case illustrates and what should not be generalised

The case brings together the immune dysregulation of adult LPI (previous HLH, SLE with nephritis), severe thrombocytopenia of multifactorial cause, protein malnutrition with essential amino acid deficiencies aggravated by pregnancy, osteoporosis with fragility fractures and corticosteroid-precipitated hyperammonaemia [50]. Some measures belong to the report and are not routine: intravenous sodium phenylbutyrate is not an authorised preparation and oral sodium phenylbutyrate is contraindicated in pregnancy in the European SmPC, so the choice of scavenger in a crisis during pregnancy requires individual consideration; sodium benzoate was the chronic scavenger in this and the other published pregnancy [17, 74, 92]. The absence of preconception counselling and poor adherence to baseline therapy weighed on the outcome.

10.3. Complementary case: PAP in an infant

Vojcek and colleagues described in 2024, in Hungary, an 8-month-old girl, the first child of a non-consanguineous couple, previously healthy, who presented with severe respiratory failure (peripheral oxygen saturation of 70%), requiring intubation, with a weight of 6600 g (below the 3rd centile), hepatosplenomegaly, cytomegalovirus in the bronchoalveolar lavage, LDH of 807 U/L, ferritin of 707 µg/L and low IgA; computed tomography showed a crazy-paving pattern (figure 1 of the paper: https://pmc.ncbi.nlm.nih.gov/articles/PMC11149197/figure/Fig1/) [51]. Corticosteroids (5 mg/kg/day), azithromycin and hydroxychloroquine had no effect; exome sequencing revealed compound heterozygosity in SLC7A7 for c.1429+2T>C (maternal) and c.821A>G p.(Tyr274Cys) (paternal) [51]. The first whole-lung lavage was interrupted by desaturation and repeated on venovenous ECMO (3100 mL over 210 minutes), with a small subacute ischaemic cerebellar lesion on magnetic resonance imaging; relapse one month later was treated with a second lavage using a selective bronchial blocker, without ECMO [51]. On subcutaneous GM-CSF and then inhaled sargramostim (section 7.9), the child came off daytime respiratory support and, at age 2 years, had normal cognition and language with a one-year motor delay [51]. The use of GM-CSF is off-label and does not replace lavage as first-line treatment [15, 51].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

With diet and citrulline, hyperammonaemia and the resulting intellectual impairment are preventable, and intellectual development is normal in the absence of prolonged coma; the prognosis depends on the late complications, which progress under current treatment and are the main causes of morbidity and mortality [1, 14, 15]. The natural history in older age is not characterised, because few patients have reached the age of 50 years [14]. In the French cohort, six of 16 patients died at a mean age of 4.0 years, all from respiratory failure associated with PAP, and PAP was associated with death (p = 0.034); patients with initially imaging-only pulmonary involvement were alive at a mean age of 29.6 years [2]. Age-adjusted plasma lysine at diagnosis was higher in those who died, and diagnosis before 1.5 years was a borderline predictor of shorter survival, without statistical significance (p = 0.08 and p = 0.16), which probably reflects more severe and earlier forms [2]. In the Tunisian series, six of seven children were alive after a median of 11 years [49]. Chronic kidney disease appears at a mean age of 18.6 years in the French cohort, with half of the patients having a GFR below 90 mL/min at age 20 years; in Finland, 10% to 17% progress to end-stage kidney disease, and the mean time between the first sign of kidney disease and transplantation was 10 years (3–18) [2, 11, 57]. After renal transplantation, patient survival was 50% at 10 years [11]. Hyperlipidaemia progresses with age and there are coronary events in young adults [2, 72]. These figures come from small, treated cohorts and are not equivalent to lifetime risks.

11.2. Principles of surveillance

GeneReviews states that no specific surveillance guidelines have been proposed and that the frequency of visits is determined by age and severity; no source consulted defines validated intervals for LPI [1]. Surveillance should be lifelong, directed at the adverse effects of treatment (malnutrition, insufficient intake of essential amino acids) and at early diagnosis of organ complications [15]. The early signs of hyperammonaemia to teach the family are lethargy, nausea, vomiting and poor feeding in the young child, and headache and mood changes in older children [1].

The table brings together what the sources recommend and the practice described in the cohorts; where no interval has been published, the frequency is individualised, as GeneReviews specifies [1].

11.3. Organised follow-up

The Finnish model centralises all patients in a single department, with annual plasma amino acids and follow-up regardless of age [11]. The complications require a team with metabolic diseases, nutrition, respiratory medicine, nephrology, haematology, immunology or rheumatology and, in women, high-risk obstetrics, coordinated with the European reference networks described in section 9.6 [15, 18].

12. Summary and Final Considerations

Lysinuric protein intolerance is an autosomal recessive cationic aminoaciduria caused by biallelic variants in SLC7A7, the gene for the y+LAT1 light chain of the basolateral y+L transporter, described in Finland in 1965 and identified molecularly in 1999 [23, 28, 29]. The loss of lysine, arginine and ornithine in the urine and their poor intestinal absorption produce a functional deficiency of urea cycle intermediates, with postprandial hyperammonaemia, orotic aciduria, protein aversion and failure to thrive after weaning, and a chronic lysine deficiency that contributes to osteoporosis and immunological abnormalities [1, 14]. The defect in macrophages and other immune cells underlies the complications that dominate the prognosis — PAP and interstitial disease, tubular and glomerular nephropathy, secondary HLH, lupus-like autoimmunity, hyperfibrinolysis and dyslipidaemia —, and these complications progress under metabolic treatment [2, 30, 31].

The diagnosis rests on paired plasma and urinary amino acids, urinary orotic acid and postprandial ammonia, and is confirmed by sequencing of SLC7A7 with deletion and duplication analysis, which account for 15–20% of alleles outside Finland [1, 15, 16]. Malnutrition and protein restriction can normalise urinary excretion, and isolated presentations such as HLH, PAP, early-onset SLE or adult chronic kidney disease justify direct molecular testing [2, 14, 33, 53, 76]. The measured incidence comes from founder populations — 1:60,000 in Finland and 1:57,000 in northern Japan — and does not apply to other populations; the sources consulted have no data from Portugal or Brazil [1, 12].

Chronic treatment combines protein restriction (1–1.5 g/kg/day in children, 0.5–0.8 g/kg/day in adults), L-citrulline up to 100 mg/kg/day in 3 to 5 doses with meals, nitrogen scavengers when glutamine remains high, low-dose lysine and carnitine when deficient, with calcium, vitamin and trace element supplements; acute hyperammonaemia is managed with the doses of the urea cycle disorders guidelines, by extrapolation [1, 14, 15, 17]. No medicinal product has an approved indication for LPI, and the scavengers authorised for urea cycle disorders are used off-label, with sodium phenylbutyrate contraindicated in pregnancy in the EU [92, 93]. Whole-lung lavage is the first-line treatment of PAP, GM-CSF has contradictory results and heart-lung transplantation is contraindicated; HSCT appears in reports of refractory HLH [15, 34, 63, 100, 104]. There are no ongoing interventional trials in LPI [115]. Surveillance is lifelong, multidisciplinary and without validated intervals, focused on nutritional status, kidney, lung, haematology, immunity, bone and cardiovascular risk, and pregnancy requires follow-up at a referral centre [1, 15, 50, 73].

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