Monogenic Recurrent and Neonatal Acute Liver Failure

Infantile liver failure syndromes (ILFS1–3), NBAS/SOPH spectrum, CALFAN (SCYL1), TRMU deficiency, cytosolic aminoacyl-tRNA synthetase deficiencies (LARS1, IARS1, MARS1, YARS1), hepatic form of DLD deficiency and related entities

Literature and regulatory information update: 26 October 2026.

0. Initial Reference Table

The following table summarises the class as a whole. The table by entity, with the identifiers of each type, is found immediately below and is taken up again, with distinguishing features and the discriminating test, in subsection 1.4.

1. Introduction

1.1. Definition of the class and scope

Paediatric acute liver failure is defined by the PALF Study Group (Pediatric Acute Liver Failure Study Group, a North American and British consortium) as biochemical evidence of acute liver injury, reflected by raised transaminases, or of hepatocellular dysfunction, reflected by raised bilirubin, associated with coagulopathy of hepatic origin not corrected by vitamin K, with an international normalised ratio (INR) ≥1.5 in the presence of encephalopathy or ≥2.0 with or without encephalopathy, in a child without known chronic liver disease [2, 19]. The European Association for the Study of the Liver (EASL) adopts an equivalent criterion, with prothrombin time above 15 seconds or INR above 1.5 with clinical encephalopathy, or prothrombin time of 20 seconds or INR of 2.0 regardless of encephalopathy, and stresses that encephalopathy is not a mandatory component in children [25]. Recurrent acute liver failure refers to the repetition of these episodes in the same patient; in the multicentre study by Lenz and colleagues, more than one episode sufficed to classify the patient as RALF [16]. These definitions were designed to identify the risk of deterioration, transplantation or death, and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) document itself recognises that the ALF phenotype may be the acute presentation of a chronic disease, a situation typical of the disorders in this class [2, 19].

This article treats as a class the monogenic forms of neonatal, infantile and recurrent ALF that lack a specific biochemical marker in blood or urine and whose diagnosis depends on molecular testing. The core of the class comprises the three OMIM infantile liver failure syndromes (ILFS1 due to LARS1, ILFS2 due to NBAS and ILFS3 due to RINT1), CALFAN syndrome (SCYL1), TRMU deficiency and the cytosolic aminoacyl-tRNA synthetase deficiencies with prominent liver disease (IARS1, MARS1, YARS1), joined by the exclusively hepatic form of dihydrolipoamide dehydrogenase (DLD) deficiency [1, 2, 8, 9]. Disorders with infantile ALF that have a biochemical marker, such as galactosaemia, tyrosinaemia type 1, urea cycle disorders, beta-oxidation defects, mitochondrial DNA (mtDNA) depletion syndromes, Wilson disease or gestational alloimmune liver disease, enter only the differential diagnosis [26, 27].

1.2. Historical overview and milestones of molecular discovery

The first entity of the class to acquire a molecular basis was TRMU deficiency. In 2009, Zeharia and colleagues described 13 unrelated infants with ALF and lactic acidaemia and normal mtDNA content, of whom 4 died during the acute episodes and the survivors had no recurrence over up to 14 years of follow-up; homozygosity mapping identified biallelic variants in TRMU, with marked reduction of 2-thiouridylation of mitochondrial tRNAs [28]. The authors proposed that the physiological limitation of sulphur in the neonatal period creates a temporal window of risk, an explanation that shaped the concept of reversible infantile respiratory chain deficiency in its hepatic form [28, 29]. OMIM records as the first clinical description that of Lev and colleagues, in 2002, of a female infant born to unrelated Yemenite Jewish parents, with fulminant lactic acidosis in the neonatal period and progressive liver failure with jaundice, ascites and coagulopathy from 9 weeks; in the Zeharia series, 7 patients of Yemenite Jewish origin shared the p.(Tyr77His) variant, suggesting a founder effect [30].

In 2008, Mégarbané and colleagues published patients with developmental delay, dysmorphism, spontaneous neonatal fractures, wrinkled skin and liver failure, who were retrospectively recognised as the first descriptions of multisystem NBAS deficiency [31, 32]. In 2010, Maksimova and colleagues defined SOPH syndrome in the Yakuts (Sakha, north-eastern Siberia), with severe postnatal growth retardation, senile face, Pelger-Huët anomaly and optic atrophy, and mapped it to 2p24.3, with 33 of 34 patients homozygous for the NBAS variant c.5741G>A p.(Arg1914His) and none of 203 Yakut controls homozygous [33]. In 2012, Casey and colleagues identified, in a consanguineous Irish Traveller family, a homozygous variant in LARS, the cytoplasmic leucyl-tRNA synthetase, in 6 individuals with ALF in the first months, anaemia, tubulopathy, seizures and hepatic deterioration with minor illnesses, and showed that the picture, though similar, was not a mitochondrial disease [18]. This entity became ILFS1 [1].

The year 2015 brought the two vesicular trafficking disorders that now dominate the class. Haack and colleagues found, by exome sequencing in 5 individuals with fever-dependent RALF and by Sanger sequencing in a further 15, biallelic NBAS variants in 6 individuals from 5 families, with reduction of NBAS and of its partner p31 in fibroblasts, and recommended NBAS analysis in infants with ALF, especially when triggered by fever [34]. Capo-Chichi and colleagues confirmed the finding in a sibship with very early onset and osteoporosis [35], and Segarra and colleagues extended the spectrum to bone, connective tissue, the immune system and the retina [36]. In the same year, Schmidt and colleagues described, in 3 individuals from 2 families, recurrent episodes of ALF in early childhood with cerebellar vermis atrophy, ataxia and peripheral neuropathy due to SCYL1 variants, an entity recorded in OMIM as autosomal recessive spinocerebellar ataxia 21 (SCAR21) [1, 37].

In 2016, Staufner and colleagues gathered 14 individuals with NBAS deficiency, defined the spectrum between isolated RALF and SOPH-like multisystem disease, demonstrated fibroblast thermosensitivity and proposed early antipyretic treatment with induction of anabolism [38]. Kopajtich and colleagues described IARS1 deficiency in the same year, with growth retardation of prenatal onset, intellectual disability, hypotonia and infantile liver disease [39]. In 2018, Lenz and colleagues described 7 patients from 5 families with SCYL1 variants and a predominantly hepatic phenotype, low-GGT cholestasis and neurodegeneration, and proposed the designation CALFAN [4]. In 2019, Cousin and colleagues identified biallelic RINT1 variants, another component of the same NBAS tethering complex, in 3 individuals with RALF of infantile onset and skeletal anomalies (ILFS3) [40]. There followed the definition of three clinical subgroups of NBAS deficiency in 110 patients [41], the description of 25 individuals with ILFS1 [15], the description of a RINT1 form with complex spastic paraplegia [42], the cohort of 62 patients with TRMU deficiency [14], the PALFES study of the genetic landscape of indeterminate paediatric ALF [16] and the cohort of 230 patients with NBAS deficiency [13].

1.3. Current classifications

Three complementary classifications coexist. OMIM numbers the infantile liver failure syndromes in order of discovery: ILFS1 (615438, LARS1), ILFS2 (616483, NBAS) and ILFS3 (618641, RINT1); the remaining entities of the class have their own OMIM titles, such as SCAR21 for SCYL1 (616719), LFIT for TRMU (613070), GRIDHH for IARS1 (617093), ILLD for MARS1 (615486) and IMNEPD2 for YARS1 (619418) [1]. The OMIM title of 616719 is recessive (SCAR21); dominant spinocerebellar ataxia 21 (SCA21) is a different entity, so the designation «SCA21» attributed to SCYL1 in a table by Saudubray and colleagues should not be used [1, 43].

The mechanism-based classification, proposed by the 2025 review by Peters and colleagues, groups the disorders predisposing to RALF triggered by fever, infection, fasting or stress into four groups: urea cycle disorders, above all ornithine transcarbamylase (OTC) deficiency and hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome; energy metabolism disorders, such as TRMU and DLD deficiencies; protein translation disorders, that is, the cytosolic aminoacyl-tRNA synthetases LARS1, IARS1 and MARS1 and, linked to translational control, Wolcott-Rallison syndrome due to EIF2AK3; and vesicular trafficking disorders, NBAS, RINT1 and SCYL1 [2]. Among the 346 intracellular trafficking genes associated with human disease, only these three cause RALF [2]. The book by Saudubray and colleagues uses an equivalent partition, separating retrograde Golgi-to-endoplasmic reticulum (ER) trafficking, cytosolic translation and mitochondrial tRNA modification [26, 43–45].

For NBAS deficiency, the 2020 subclassification by Staufner and colleagues is added, based on the location of missense variants and in-frame deletions: C-terminal region (SOPH), Sec39 domain (ILFS2) and β-propeller domain (combined phenotype) [13, 41]. Orphanet groups NBAS and RINT1 under infantile fever-associated ALF syndrome (ORPHA:464724), keeps SOPH as a separate entity (ORPHA:391677) and assigns separate entries to LARS1 (370088), TRMU (217371) and SCYL1 (466794) [5, 6, 11, 46, 47]. The generic entry ORPHA:90062 designates the clinical syndrome of ALF [48].

1.4. Table of the class

The class is heterogeneous in prognosis and treatment, but shares three features: triggering of crises by fever, infection or catabolism, the absence of a biomarker that obviates genetic testing, and the tendency for crises to attenuate with age, with exceptions [2, 16]. The distinguishing features of each type are explored in sections 2 and 3; the remaining entities appear in section 6.

2. Molecular Genetics and Pathophysiology

2.1. Common principle: a functional reserve that fails under stress

The disorders of the class share a reduced cellular function that is sufficient at rest and becomes insufficient when demand increases or when temperature destabilises the deficient protein. In vesicular trafficking disorders, fever aggravates the deficiency of the ER tethering complex, with ER stress, accumulation of reactive oxygen species (ROS) and hepatocyte apoptosis [2, 20, 38]. In aminoacyl-tRNA synthetase deficiencies, aminoacylation becomes episodically insufficient for translational demand during periods of rapid growth, illness or reduced amino acid availability due to fasting or vomiting, and some mutant enzymes lose activity with temperature [15, 21]. In TRMU deficiency, the substrate cysteine is physiologically scarce in the first months of life, which defines a transient window of vulnerability [3, 28]. ROS and the integrated stress response have been proposed as effector mechanisms common to monogenic ALF, with experimental data in NBAS and RINT1 deficiency and hypotheses in DLD deficiency, Wolcott-Rallison syndrome and transaldolase deficiency [20, 42]. This pathophysiology explains three clinical properties: fever dependence, complete or near-complete recovery between crises and attenuation with age, as metabolic demand and the frequency of infections decrease [2, 13].

2.2. NBAS and the NRZ complex

The NBAS gene (neuroblastoma amplified sequence; OMIM gene 608025) is located at 2p24.3 and was initially described as co-amplified with MYCN in neuroblastoma, a role that has not been clarified [7, 32]. The MANE Select transcript is NM_015909.4; the literature uses NM_015909.3, with the same c. and p. numbering [7, 54]. The 271 kDa protein is a peripheral membrane component of an ER tethering complex that interacts with the t-SNAREs p31 (USE1), BNIP1 and STX18 in the ER and with the v-SNARE Sec22b on vesicles, mediating fusion of Golgi-derived COPI vesicles with the ER; it links p31 to the ZW10–RINT1 pair, forming the NRZ complex (NBAS–RINT1–ZW10), part of the syntaxin 18 complex [2, 32]. The NRZ complex is also required for TANGO1 to recruit membranes from the ER–Golgi intermediate compartment (ERGIC) to COPII vesicles, so its loss also compromises anterograde transport of bulky proteins such as collagen VII [2]. NBAS deficiency was the first human disease attributed to a primary defect of retrograde Golgi-to-ER transport [32, 38].

A second function contributes to the chronic phenotype: NBAS participates in ER membrane-localised nonsense-mediated messenger RNA decay (NMD), recruiting UPF1, and regulates genes of protein trafficking and bone mineralisation, which provides a hypothesis for the temperature-independent skeletal manifestations and short stature [2, 32]. Blockade of COPII export of proinsulin, with ER stress and beta-cell apoptosis, has been proposed as the mechanism of the insulin-dependent diabetes of the SOPH subgroup [2]. Clinical overlap with other proteins of the same axis reinforces the model: homozygous intronic BNIP1 variants cause spondyloepiphyseal dysplasia with disproportionate short stature and reduced autophagic flux, and biallelic truncating TANGO1 variants cause odontochondrodysplasia type 2 (OMIM 619269), with short stature, osteopenia, insulin-dependent diabetes and deafness [2].

In patient fibroblasts, NBAS protein is reduced to 18–36% of controls and p31 also decreases; with a rise in temperature from 37 °C to 40 °C, NBAS and p31 decrease further and the cells grow less [32, 38]. Electron microscopy of hepatocytes shows enlarged and dilated ER, and ER stress response genes are overexpressed [32]. The 2026 study by Sun and colleagues, in fibroblasts from 3 patients of the ILFS2 subgroup cultured for 48 hours at 40 °C, confirmed the decrease in NBAS and p31 with unchanged RINT1, showed ER–Golgi disorganisation, dilatation of the ER lumen, increased IRE1α and decreased PERK, without ATF6 activation, increased ROS and time-dependent apoptosis, and demonstrated that NAC at 20 mM attenuated ROS and reduced early and late apoptosis [20]. This is preclinical evidence limited to the ILFS2 subgroup [20]. In NK (natural killer) cells, NBAS deficiency reduces polarisation of lytic granules and the number of cytotoxic vesicles near the Golgi, with defective degranulation, the basis of the quantitative and qualitative deficiency of NK and B cells and of the association with haemophagocytic lymphohistiocytosis (HLH) [55, 56].

No patients with complete biallelic loss of function in NBAS are known, suggesting lethality; all patients in the 2016 series had at least one missense allele or a single-amino-acid in-frame deletion [2, 32]. In the 2025 cohort, with 230 patients from 205 families and 30 countries, 158 different variants were described, 13 of them novel, distributed across the gene with greater density in the β-propeller and Sec39 domains and in the C-terminal region [13]. The distribution across subgroups was: ILFS2 (Sec39 domain) 48 patients (20.9%), SOPH (C-terminal region) 125 (54.3%), combined phenotype (β-propeller) 18 (7.8%) and 39 (17%) without a subgroup, of whom 19 had variants in two different segments, 10 in unclassified segments (N-terminal region, amino acids 1–85, and the region between the β-propeller and Sec39, amino acids 447–721) and 10 had splicing or intronic variants [13]. All 8 patients with at least one missense variant in the 447–721 region had liver involvement and 7 had ALF [13]. The numerical predominance of SOPH reflects the Yakut founder effect: 95 patients came from Russia, 91 of them living in Yakutia [13].

Genotype-phenotype correlation is strong between individuals with the same genotype, especially in the ILFS2 subgroup, and lower, although high, when only one missense allele is shared [57]. There are exceptions in all subgroups, and siblings with the same genotype may differ in the occurrence of ALF, pointing to incomplete penetrance and variable expressivity, with possible genetic, epigenetic or environmental factors [13]. Intermediate phenotypes between ALF and SOPH have been described [58]. A family with acrofrontofacionasal dysostosis and NBAS variants was published by Palagano and colleagues; OMIM lists this relationship as provisional [12, 59]. A 25-year-old woman with a previous diagnosis of cone-rod dystrophy had incomplete SOPH, without Pelger-Huët anomaly, due to a paternal splicing variant and a maternal complete deletion of NBAS, showing that one of the alleles may be a CNV [49].

2.3. RINT1

The RINT1 gene (RAD50 interactor 1; OMIM gene 610089) is located at 7q22.3, with MANE transcript NM_021930.6 [7]. The RINT1 protein is the link in the NRZ complex between ZW10 and NBAS; it also binds UVRAG to the ER, connecting retrograde transport with autophagy, and is involved in the G2/M checkpoint, telomere maintenance and centrosomes; it is essential for murine embryonic development [2, 42]. In fibroblasts from the patients of Cousin and colleagues, the splicing variant c.1333+1G>A or G>T caused exon 9 skipping, with an out-of-frame product degraded by NMD, reduced RINT1, an abnormal Golgi and impaired autophagic flux [40]. In the 3 patients of Launay and colleagues, the variant at the canonical acceptor c.1672-1 (G>A in one family and G>C in the other) generated, through use of a secondary acceptor 21 base pairs within exon 12, a single transcript with an in-frame deletion of 7 amino acids, p.(Phe558_Gln564del), a hypomorphic allele with probable residual function; the nonsense allele p.(Arg519Ter) was degraded by NMD [42]. RINT1 deficiency destabilised the NRZ complex, with reduction of ZW10 and NBAS and mislocalisation of ZW10 from the ER, and altered lipid metabolism, with abnormal lipid droplet biogenesis, decreased triglycerides and diglycerides, inhibited Lands cycle, increased ROS, reduced ATP synthesis, mitochondrial depolarisation and increased fission [42]. In Cousin's patients, without neurological symptoms, NBAS levels were normal, whereas in Launay's neurological patients they were reduced, linking loss of NRZ complex integrity to the neurological phenotype [2]. In RINT1 fibroblasts, a temperature of 40 °C fragments the Golgi, with a non-significant trend towards lower NBAS [2].

On 14 March 2023, the ClinGen hereditary cancer panel classified the relationship between RINT1 and autosomal dominant hereditary breast carcinoma as refuted, based on the CARRIERS and BCAC case-control studies, each with more than 32,000 cases and controls, with no association for aggregated loss-of-function variants, and assigned no known relationship with familial ovarian cancer [12]. The association with early-onset breast cancer mentioned in the report by Cui and colleagues therefore does not correspond to the current assessment [12, 50].

2.4. SCYL1

The SCYL1 gene (OMIM gene 607982) is located at 11q13.1, with MANE transcript NM_020680.4; the Lenz series used NM_020680.3, with identical numbering [4, 7]. It encodes a ubiquitous cytosolic pseudokinase of 808 amino acids and about 120 kDa, with a presumably inactive N-terminal kinase-like domain and a C-terminal domain interacting with coatomer (COPB1) [2, 12]. SCYL1 forms part of the structure of COPI vesicles at the cis-Golgi, maintains Golgi morphology and participates in nuclear export of tRNAs; in deficient cells, the Golgi is markedly enlarged and disorganised [2, 37]. In liver biopsies from the CALFAN series, SCYL1 protein was absent, electron microscopy showed no intact Golgi but markedly enlarged vesicular cisternae near the bile canaliculi, and the brefeldin A assay in fibroblasts showed delayed Golgi dispersal, without alteration of BiP/Grp78 [4]. Unlike NBAS and RINT1, there are patients with biallelic loss of function of SCYL1, compatible with life, and variants are distributed across the entire gene [2]. The mdf (muscle deficient) mouse, known since 1980, is the Scyl1 loss model, with neurogenic muscular atrophy, progressive ataxia, vermis atrophy, Purkinje cell loss and thinning of the optic nerve [4, 37]. In the Lenz series, the neurological phenotype was more evident with early stop variants or early missense variants, suggesting a genotype-phenotype correlation in a small sample [4].

2.5. Cytosolic aminoacyl-tRNA synthetases

Cytoplasmic aminoacyl-tRNA synthetases (designated XARS1) attach each amino acid to its tRNA; biallelic deficiencies cause neurodegenerative or visceral phenotypes, including interstitial lung disease and liver disease, whereas the mitochondrial forms (XARS2) present mainly with combined oxidative phosphorylation deficiency [45]. Among aminoacyl-tRNA synthetase deficiencies, almost all with developmental delay, hypotonia and failure to thrive, liver disease is prominent in those due to MARS1, LARS1 and IARS1, and also in that due to YARS1 [9, 60]. LARS1 (5q32; MANE NM_020117.11) encodes leucyl-tRNA synthetase; its silencing has no mitochondrial effect, despite the clinical similarity to mitochondrial diseases [7, 18]. Aminoacylation activity of cells from patients with ILFS1 decreases significantly with elevation of temperature in vitro, in all cells studied [15]. In the study by Kok and colleagues, aminoacylation activity in fibroblasts was 23% and 21% for IARS (two patients), 27% for LARS, 28% for FARS and 45–50% for SARS; at 38.5 °C and 40 °C, the patient's LARS activity fell to 5% and FARS to 0% at 40 °C, while IARS and SARS remained stable; proliferation decreased in a dose-dependent manner with low concentrations of the respective amino acid [21]. These results support supplementation of the specific amino acid and an emergency protocol that ensures protein, unlike the «high glucose, no protein» regimen of other metabolic diseases [21]. IARS1 (9q22.31; MANE NM_002161.6), MARS1 (12q13.3; NM_004990.4) and YARS1 (1p35.1; NM_003680.4) follow the same principle [7, 9, 39, 51]. In the original ILFS1 family, all affected individuals were homozygous for two missense variants: p.(Lys82Arg), rare and considered non-pathogenic, and p.(Tyr373Cys) (OMIM designation Y373C), located in the editing domain (connective peptide 1) and predicted to destabilise the protein; the OMIM entry does not give the cDNA description [61]. In MARS1 deficiency, the 26 patients from Réunion Island, the Comoros and Madagascar were homozygous for two missense variants in cis and in strong linkage disequilibrium, p.(Ser567Leu) and p.(Ala393Thr), a regional founder effect [62]. In IARS1 deficiency, yeast studies showed that each patient in the original series had one loss-of-function allele and one hypomorphic allele [63]. In YARS1 deficiency, the p.(Tyr204Cys) variant reported in an African American infant was reclassified in OMIM as of uncertain significance [64]. Hereditary weak calf syndrome in cattle, caused by a missense variant in IARS, was the animal model that guided identification of the human deficiency [39].

2.6. TRMU

The TRMU gene (22q13.31; OMIM gene 610230; MANE NM_018006.5) encodes the mitochondrial tRNA-specific thiouridylase, which uses cysteine as a sulphur donor to thiolate the wobble position of the mt-tRNAs for lysine, glutamine and glutamate [3, 7]. 2-thiolation is required for correct and efficient synthesis of the 13 oxidative phosphorylation (OXPHOS) proteins encoded by mtDNA, and the deficiency reduces thiomodified mt-tRNAs and energy production, with combined deficiency of complexes I, III, IV and V [3, 44]. Cystathionase (cystathionine γ-lyase), the endogenous source of cysteine, has its physiological nadir in the first months of life, making cysteine a conditionally essential amino acid in that period; the coincidence between the enzymatic nadir and the severe reduction of thiolated mt-tRNAs triggers decompensation, mainly hepatic, and explains reversibility once the child passes this phase [3, 65]. Skin does not depend on TRMU for mitochondrial function, so skin biopsy has no diagnostic value [3]. TRMU deficiency belongs to the group of autosomal recessive defects of mitochondrial tRNA modification (with ERAL1, GTPBP3, MTO1, NSUN3, TRMT5, TRMT10C and others) [44].

The mechanism is loss of function [3]. The cohort of Vogel and colleagues, with 62 individuals, 47 pathogenic or likely pathogenic variants and one intragenic deletion, found a significant association between loss-of-function variants and lower survival (10 of 20 with loss-of-function variants died and 10 of 42 with other variants; p=0.022) [3, 14]. The recurrent variant c.2T>A p.(Met1?), described in several ethnic groups, is associated with early mortality despite intensive treatment, and the founder variant of Jews of Yemenite descent c.229T>C p.(Tyr77His) is associated with lower mortality, with no deaths described in homozygotes [3]. The c.28G>T p.(Ala10Ser) variant, benign for the monogenic disease, modifies expression of deafness associated with the mitochondrial variant MT-RNR1 m.1555A>G and aminoglycoside exposure in Chinese, Israeli Arab and southern European populations [3, 66, 67].

2.7. DLD

DLD (7q31.1; OMIM gene 238331; MANE NM_000108.5) encodes dihydrolipoamide dehydrogenase, the E3 component common to the pyruvate dehydrogenase, α-ketoglutarate dehydrogenase and branched-chain α-keto acid dehydrogenase complexes [7, 8]. The neurological form of pyruvate dehydrogenase complex deficiency is not developed here; the exclusively hepatic form is what matters. All individuals with an exclusively hepatic presentation in the Brassier series were homozygous for c.685G>T p.(Gly229Cys), a variant later also found in homozygotes with a neonatal neurological form [8, 53]. In the Algerian family described, DLD activity in fibroblasts was 25% and pyruvate dehydrogenase activity 70%, with no response to riboflavin [53]. ROS have been proposed as the effector mechanism in this deficiency as well [20].

2.8. Normalised recurrent and founder variants

The table gathers the variants cited in this article, normalised in VariantValidator to the MANE transcript and, when available, with the ClinVar classification accessed on 26 October 2026 [54, 67].

The variants in the TRMU GeneReviews were provided by the authors without independent verification of classification [3]. In the case of Cui and colleagues, the deletion of exons 12 to 14 of RINT1 was described without precise coordinates and could not be normalised [50].

3. Clinical Spectrum and Manifestations by System

3.1. Common pattern and differences between groups

In the PALFES study (Pediatric Acute Liver Failure Exome Study), which included 260 children from 19 countries with ALF of no cause after local investigation, patients with a diagnosis of mitochondrial disease presented in 68% of cases in the first 6 months of life (median 2.5 months), whereas vesicular trafficking and cytosolic aminoacyl-tRNA synthetase disorders began from 6 months onwards and manifested mainly as RALF [16]. RALF had higher transaminases than isolated ALF (median ALT 3900 U/L and AST 4804 U/L, versus 582 and 1395 U/L) [16]. A trigger was reported in 82 patients, an infection in 77 [16]. Vesicular trafficking disorders were rarely fatal and had significantly greater native liver survival than mitochondrial disorders [16]. The first crises of vesicular trafficking disorders occur at the age at which the proportion of indeterminate paediatric ALF is greatest [2].

The 260 PALFES patients had a median of 12 phenotypic terms in 5 systems; besides the liver, there was metabolic involvement in all, haematological in 79%, neurological in 55%, cardiovascular in 28% and immune in 25%, with hepatomegaly in 74, cholestasis in 59, ascites in 52 and jaundice in 38 patients [16]. Fifty-nine had RALF, with the second episode on average 0.9 ± 0.9 years after the first and subsequent intervals of 2.2 ± 4.8 years [16]. The median maximum INR was 3 and the median maximum total bilirubin 140 µmol/L, but 16 patients had bilirubin below 17.1 µmol/L (1 mg/dL); biopsy, performed in 104, showed steatosis in 36 and fibrosis in 34, and 30% had progressive hepatic remodelling, a sign of prior subclinical disease [16].

The table summarises table 1 of the review by Peters and colleagues, whose numbers of deaths are absolute counts in the subset with data from the supplementary tables, not percentages [2].

3.2. NBAS deficiency spectrum

3.2.1. Hepatic crises

The typical presentation is recurrent vomiting and increasing lethargy 1 to 2 days after the onset of fever, followed by very marked elevation of ALT and AST, severe coagulopathy and mild to moderate jaundice, with normal or only slightly raised alkaline phosphatase and GGT even in severe crises [32]. Transient hepatomegaly, mild hyperammonaemia and transient hepatic encephalopathy may occur; metabolic investigation shows no diagnostic abnormalities, although there may be hypoketotic hypoglycaemia with nonspecific dicarboxylic aciduria, and in vivo fatty acid oxidation is normal [32]. Some patients have hypoglycaemia during the crisis or in the period that follows it, by an unknown mechanism [32]. In the series gathered in the Atlas up to June 2016 (19 patients, excluding the Yakuts), the mean age at first ALF was 13 months, between 4 and 24 months in most, the children were highly susceptible to infections in the first years and crises could occur with each illness and even after vaccination; severity ranged from death in ALF to RALF with up to 10 episodes in childhood and intermittent elevation of transaminases without coagulopathy [32]. Biopsy showed microvesicular steatosis without fibrosis and markedly reduced or absent NBAS immunohistochemistry; complete recovery was the rule, with normal liver function between crises [32].

The 2025 international cohort of Peters and colleagues (230 patients, 30 countries, 2,681 patient-years, age at last visit from 4 months to 53 years, median 9 years; data from publications between 2008 and 2024 and from unpublished patients) refined these figures [13]. The liver was the most affected organ (63.5%), followed by the nervous system (52.2%), the skeleton (43.9%), the immune system (37%), the integument (33%) and the endocrine system (7.8%) [13]. The first hepatic crisis occurred at a median of 0.9 years (2 days to 11 years), in 88.8% in the first 3 years and in 97.2% before 5 years, earlier in SOPH than in ILFS2 [13]. The most severe crisis occurred at a median of 2.2 years, in 62.4% before 3 years [13]. Among the 27 patients without crises for at least 5 years, the last episode of ALF occurred at a median of 5 years and, by 10 years, 90% had had their last ALF; the latest episode occurred at 24 years [13]. The mean number of episodes was 3 (1 to 12) [13]. Febrile infections triggered crises in all affected patients but one; other triggers, each reported in at most 2 patients, were the postnatal catabolic period, post-vaccination fever, chemotherapy, surgery, difficult blood sampling or catheterisation, cold or heat, long journeys and the end of interferon therapy [13]. Recurrent vomiting during the crisis occurred in 43.8% and hepatic encephalopathy in 45.2% of patients with liver involvement [13].

Percentages refer to patients with data available for each parameter, and differences between subgroups were significant for all parameters in the table except age at first crisis [13]. The ILFS2 subgroup had higher transaminases, bilirubin, INR and ammonia and lower albumin than SOPH, with encephalopathy of median grade III [13]. The authors warn of publication bias: cases with very high transaminases are more often published, so the medians may be overestimated [13]. The 2025 review gives, for ILFS2, a mean maximum AST of 13,359 U/L and an ALT of 9146 U/L (n=32) [2]. The founding series of Haack and colleagues, summarised in OMIM, included 11 patients from 10 families, mostly of European descent, aged 3 to 37 years, with RALF onset in the first 2 years in almost all and at 6 years in one; none died, but 2 had older siblings who had died of ALF in early childhood, and 4 had isolated comorbidities such as cardiomyopathy, autoimmune gastrointestinal disease or epilepsy [69]. Rius and colleagues described a girl with fulminant crises from 13 months, triggered by viral illnesses, with lactic acidosis and sometimes hypoketotic hypoglycaemia and hyperammonaemia, recovery with dextrose-containing fluids, a normal liver between crises, microvesicular steatosis on biopsy during a crisis and normal development at 9 years, 3 years after the last ALF [69]. Compared with other causes of ALF, NBAS crises have particularly high transaminases and INR, which points to the diagnosis without establishing it [13, 16].

Histology, available in 64 patients (median age at biopsy 1.9 years), showed fibrosis in 41.7%, with no difference between subgroups or between patients with and without normalisation of transaminases between crises, steatosis in 85% and necrosis in 54%, with no cirrhosis on biopsy [13]. In the SOPH subgroup, more than half of the patients with liver involvement had persistently raised transaminases and 11 of 15 permanent hepatomegaly, whereas in the other subgroups hepatomegaly was restricted to crises [13]. A single SOPH patient with chronic progressive disease has been described, with fibrosis, portal hypertension and oesophageal varices at 20 years and hepatic hydrothorax at 33 [13]. In a Turkish series of 5 patients, those not transplanted had fibrosis on biopsy or elastography, and one presented as acute-on-chronic liver failure with predominant cholestasis: normal function between crises does not guarantee an uninjured liver [70].

3.2.2. Extrahepatic manifestations

Short stature is among the most frequent findings: in the Yakuts, the mean height standard deviation score was −4.44 in females and −3.16 in males; in the 2016 Staufner cohort the mean was −2.64; in the most severe case described in the Atlas, a girl aged 4 years and 9 months measured 83.5 cm (−6.10 standard deviations, with a genetic target height of +0.89) [32]. The severity of short stature is associated with thin bones, epiphyseal dysplasia with multiple phalangeal pseudoepiphyses, large late-closing fontanelles, short neck, abnormal thorax and frequent or spontaneous fractures, sometimes from the neonatal period [32]. Two patients had small C1 and C2 cervical vertebrae, with cervical instability [32]. In SOPH, reduced bone mineral density may reach an osteogenesis imperfecta phenotype, with delayed bone age and vertebral body anomalies [2].

Facial dysmorphism, present in most, includes a long face, flat malar regions, hypotelorism, prominent eyebrows, pointed chin, thin upper lip and reduced periorbital fat with a proptotic appearance; lax and wrinkled skin and reduced subcutaneous fat give a progeroid appearance, but many patients look normal [32]. In SOPH, the face is triangular, with a broad forehead and marked progeroid appearance, and the cutis laxa GeneReviews includes SOPH in the differential diagnosis of lax skin [2, 71]. Acrofrontofacionasal dysostosis type 3, also associated with NBAS, enters the differential. Most patients have normal intelligence; some have developmental delay and hypotonia and two had epilepsy [32]. Magnetic resonance imaging (MRI) showed mild nonspecific cerebral atrophy, with mild supratentorial white matter deficit or superior vermis atrophy, in 6 of 8 patients of the 2016 series; in the Yakuts it was normal in 18 of 24 [32].

All Yakuts had optic nerve atrophy, with a mean visual acuity of 0.23 ± 0.21 and complete achromatopsia due to non-progressive cone dysfunction in all but one, with mean onset of visual loss at 4.3 years; non-Yakut patients mostly have normal vision or a mild phenotype, with myopia, strabismus or hypermetropia [32]. Pelger-Huët anomaly, hypolobulation of granulocytes, is present in all Yakuts and in only some of the others, and may be absent even in SOPH [32, 49]. Hypogammaglobulinaemia and reduced NK cells are associated with frequent infections; coeliac disease and Crohn disease have been described, one case of each in 14 patients [32, 56]. In a series of 224 children with HLH, NBAS was the second most frequently mutated gene (2.11%), after PRF1 [55]. Insulin-dependent diabetes occurs in SOPH [2]. Outside the Yakuts, Balasubramanian and colleagues described two boys with SOPH, compound heterozygous for p.(Arg1914His) and a truncating variant, with recurrent infections, hypogammaglobulinaemia, lymphopenia, low-impact fractures or a femoral fracture at 3 months, osteopenia with thin tubular bones and wormian bones, optic atrophy with nystagmus and worsening liver function during intercurrent illnesses; one of them had ketotic hypoglycaemia and the other moderate intellectual disability and autism [68]. Silverstein and colleagues described in 2025 a 21-year-old woman with SOPH, initially diagnosed as Wiedemann-Rautenstrauch syndrome, with relative macrocephaly and enlarged lateral ventricles, cutis laxa, osteopenia with wormian bones, primary ovarian insufficiency at 10 years, peripapillary atrophy without optic nerve atrophy and intermittent elevations of transaminases [68].

3.3. ILFS3 (RINT1)

Up to 2023, 6 patients had been described: 3 of Cousin and colleagues, from Europe and East Asia, with the same splicing variant in combination with a missense variant or in-frame deletion, and 3 Europeans of Launay and colleagues [2]. Five of the 6 had at least one ALF precipitated by fever, with onset between 8 months and 10 years; two died of ALF at 14 months and 3 years; recovery between episodes was total or partial, one patient normalised transaminases for the first time at 8 years and another had the first documented crisis at 10 years [2]. The mean maximum AST was 6753 U/L and ALT 5481 U/L (n=5) [2]. Biopsies show nonspecific injury, with fibrosis, steatosis and a mild increase in Kupffer cells [40]. The skeleton shows vertebral body anomalies with anterior beaking and hypoplasia, similar to those of the mucopolysaccharidoses, kyphosis, wormian bones and short stature in 3 of 6, and changes in the pelvis and femoral heads have been described [2, 40]. Psychomotor development was normal in Cousin's 3 patients, whereas Launay's 3 had motor delay, progressive complex spastic paraplegia with onset between 18 months and 3 years, ataxia, nystagmus, optic nerve hypoplasia and dysmorphism with anteverted nose, high-arched palate, broad forehead and low-set ears [2, 42]. One of these patients died at 14 months of ALF, probably before the neurological phenotype became manifest, and autopsy showed hepatic steatosis and vacuolisation of the renal proximal tubules [42]. A consanguineous Chuvash family had neutropenia without skeletal or neurological changes [12]. In Cousin's description, summarised in OMIM, onset was at 8 months, 10 months and 3 years, each patient had 4 to 8 episodes with raised transaminases, hepatomegaly, cholestasis and coagulopathy, sometimes with encephalopathy; one patient, born at 34 weeks, died of respiratory failure at 3 years, another was transplanted, and all had normal development and cognition; the Peters review attributes the death at 3 years to ALF, a discrepancy the sources do not resolve [2, 72]. The 2025 case of Cui and colleagues added growth restriction, global delay, cranial dysmorphism and delayed bone age, and is described in section 10 [50]. The authors stress that the vertebral and acetabular dysplasia and irregular femoral epiphyses of ILFS3 differ from the atypical osteogenesis imperfecta phenotype of NBAS deficiency [50].

3.4. CALFAN (SCYL1)

The liver and the nervous system are affected in sequence. Liver disease usually appears in the first year, as recurrent low-GGT cholestatic dysfunction and episodes of ALF triggered by fever, with a median onset of 12 months (4 to 48 months, n=20) [2, 12]. Unlike NBAS and RINT1, the course is cholestatic and progressive, with fibrosis, cytolysis is less fulminant and frank ALF is less frequent; there were no deaths among 23 compiled patients [2]. In the series of Lenz and colleagues, 3 of 7 patients had neonatal jaundice; all had a severe cholestatic crisis triggered by a common febrile illness in the first 18 months, except one, with onset at 4 years, with AST higher than ALT, raised direct bilirubin, impaired coagulation, normal or slightly raised GGT, hepatomegaly in all and splenomegaly in 4 [4]. Laboratory recovery occurred within weeks, but all 7 patients had fibrosis; each patient had 3 to 5 crises, not always meeting ALF criteria, and the families with early onset stopped having episodes at 21–30 months [4]. Laboratory values during crises ranged from maximum ALT of 59 to 2453 U/L, maximum AST of 61 to 4804 U/L, maximum total bilirubin of 3 to 438 µmol/L, maximum GGT of 13 to 105 U/L (normal <60 U/L), alkaline phosphatase up to 2533 U/L and maximum INR of 0.9 to 5.0 [4].

Neurological manifestations are progressive and later: in the hepatic series there was secondary microcephaly in 6 of 7, mild speech delay in 5, speech regression in 1, mild cognitive impairment in 3 and severe intellectual disability in 1, with ataxia in none, and mild cerebral atrophy at 10 and 7 years in the two sisters with an early stop variant [4]. Schmidt's two young adult siblings, of European descent, had episodes of liver failure associated mainly with fever from about 9 months, which ended later in childhood, with chronic fibrotic liver disease and marked hepatosplenomegaly; they had early-onset ataxia with intention tremor, sensorimotor neuropathy with foot drop, neurogenic stuttering, selective non-progressive vermis atrophy and subclinical optic atrophy with preserved acuity [73]. Spagnoli and colleagues described an Italian girl with episodic fever-triggered tremor at 2 years, ataxia, upgaze palsy, oculomotor apraxia, distal chorea and axonal motor polyneuropathy, with neurological symptoms worsening during febrile illnesses [73]. The original description by Schmidt and colleagues, with a predominantly neurological phenotype, included vermis atrophy, ataxia, tremor, peripheral neuropathy and optic atrophy [2, 37]. Short stature, hip and femoral dysplasia, scoliosis, lumbar hyperlordosis and vertebral anomalies are common; nephrotic syndrome, ureteropelvic junction obstruction, palmoplantar hyperkeratosis, precocious puberty and, in one patient, recurrent episodes of acute respiratory failure have also been described [2, 4]. The GeneReviews on paediatric genetic cholestatic disorders adds chronic anaemia to the picture [10].

3.5. ILFS1 (LARS1)

In the original Irish Traveller family, the 6 individuals had ALF in the first months, anaemia, renal tubulopathy, developmental delay, seizures, failure to thrive and deterioration of liver function with minor illnesses [18]. The 2015 series of 10 patients, with the first non-Irish patient, of Ashkenazi origin, showed early failure to thrive, recurrent liver dysfunction, anaemia, hypoalbuminaemia and seizures in all, developmental delay in 90% and encephalopathic episodes triggered by febrile illness in 80%, fatal in 2; two patients over 28 years of age were clinically well [17]. Low birth weight, failure to thrive, anaemia and hypoalbuminaemia are among the first signs, liver dysfunction appears before 1 year and episodes become less severe with age [17]. The 2020 series of 25 individuals from 15 families described recurrent elevation of transaminases up to ALF and encephalopathic episodes, both triggered by febrile illness, with MRI compatible with metabolic stroke, and highlighted that encephalopathic episodes with seizures may occur independently of hepatic crises; growth retardation, microcytic anaemia, neurodevelopmental delay, hypotonia and infection-associated seizures were prevalent [15]. The oldest patient in the Irish family was 33 years old [19]. In the 4-generation family, the earliest presentation was at 2 months, patients improved intermittently and only had acute symptoms under physiological stress, liver biopsy in 3 showed steatosis and fibrosis, and raised lactate, abnormal MRI and seizures suggested mitochondrial disease, which was excluded by biochemical and genetic investigation [61].

3.6. IARS1, MARS1 and YARS1 deficiencies

IARS1 deficiency is characterised by severe growth retardation of prenatal onset, intellectual disability and hypotonia; of the 3 initial patients, 2 had infantile liver disease with fibrosis and steatosis, one of them with ALF during infections, and all had zinc deficiency [39]. Neonatal cholestasis and recurrent hepatic crises are among its presentations [26]. Kopajtich's 3 patients had microcephaly of −3 to −5 standard deviations and were 18, 19 and 3 years old at last examination, and Orenstein and colleagues described a boy of Arab parents with neonatal liver failure and cholestasis, round face, soft, translucent and hyperelastic skin and joint laxity [63]. MARS1 deficiency manifests as early-onset pulmonary alveolar proteinosis, with death before 2 years in one third of patients, liver disease, growth retardation and systemic inflammation [51]. The first patient, described by van Meel and colleagues in 2013, had severe failure to thrive, vomiting and hypotonia in the first month and, between 3 and 9 months, liver failure, intermittent lactic acidosis, aminoaciduria, hypothyroidism, interstitial lung disease and transfusion-dependent anaemia, with canalicular cholestasis, steatosis and iron deposition on liver biopsy [62]. Hadchouel and colleagues gathered in 2015 26 patients from Réunion Island, the Comoros and Madagascar with severe respiratory distress in early childhood, alveolar proteinosis and frequent death from pulmonary fibrosis, all with liver disease (raised enzymes, steatosis, fibrosis and sometimes cirrhosis); three patients from Tunisia and France, with later respiratory onset, had no liver involvement [62]. A 2026 cohort study described the neurodevelopmental profile of children with MARS1-related alveolar proteinosis [74].

YARS1 deficiency, described in more than 30 individuals (17 from 7 families with diverse variants and 14 from 7 families homozygous for p.(Arg367Trp)), combines developmental delay, pre- and postnatal failure to thrive, gastrointestinal involvement (feeding difficulties, recurrent vomiting, bleeding, chronic diarrhoea, pancreatic insufficiency), chronic hypochromic microcytic anaemia, hypothyroidism, hypoglycaemia, cystic lung disease or interstitial fibrosis, retinitis pigmentosa, sensorineural deafness, frequent infections and sparse hair [9]. Liver disease usually appears by 12 months, ranging from stable hepatomegaly with mild steatosis or fibrosis to severe chronic cholestatic liver failure and cirrhosis, more severe in genotypes other than p.(Arg367Trp) homozygosity; in survivors, liver function usually stabilises after 2–3 years [9]. In the Amish family of Williams and colleagues, about half of the 7 patients were born prematurely, many with intrauterine growth restriction, and 4 died between 10 and 25 months from end-stage liver disease or infection; they had intellectual disability, microcephaly, sensorineural deafness, chronic cholestatic liver disease with progressive fibrosis and cirrhosis, pancreatic insufficiency and frequent bloodstream infections [64]. Hyperinsulinaemic hypoglycaemia has also been described in one infant [64]. Seven children with severe liver disease died between 10 and 25 months from liver disease and multiorgan failure, mainly in the context of systemic infections [9].

3.7. TRMU deficiency

Without targeted treatment, infants become symptomatic between 2 and 4 months with transient acute liver dysfunction, severe persistent lactic acidosis, hypoglycaemia, hyperammonaemia and poor weight gain [3]. With adequate support, hepatic changes, including coagulopathy, and metabolic changes improve or normalise; lactic acidaemia improves but typically does not normalise, and neurological dysfunction, cardiomyopathy and respiratory failure may persist or appear later [3]. To date, 62 individuals from 56 families have been described, 60 probands and 2 at-risk siblings [3]. TRMU deficiency and reversible infantile respiratory chain deficiency due to MT-TE are transient forms of mitochondrial disease.

The GeneReviews data come from series published between 2009 and 2023 [3]. Liver disease generally begins with isolated elevation of transaminases and may progress to ALF with coagulopathy and hyperammonaemia at 2–4 months; 23% have recurrent episodes in the first year, mainly in the first 5 months, up to a maximum of 5 episodes per child [3]. ALF occurred only in the first year of life, in 43 of 62 [14]. Hepatomegaly does not correlate with ALF; there may be variceal bleeding and progression to fibrosis, cirrhosis, macro- and microvesicular steatosis and cholestasis [3]. Lactic acidosis probably begins before the other manifestations; hyperalaninaemia and lactic aciduria help distinguish chronic lactic acidosis from lactic acidaemia secondary to ALF [3]. Vomiting is often the first manifestation, growth restriction may precede ALF, and some patients needed a feeding tube or gastrostomy to maintain glucose infusion after hepatic recovery [3]. Acute respiratory failure due to insufficient effort and, according to emerging evidence, central apnoea may occur [3]. Two patients with Leigh syndrome and 5 with dilated cardiomyopathy have been described; one infant had nephromegaly and proteinuria that resolved within months, and dysphagia may appear before decompensation [3]. Leigh syndrome enters the differential.

3.8. DLD deficiency, hepatic form

The hepatic form may appear from the neonatal period to the third decade, with liver injury or failure preceded by nausea and vomiting, frequently with encephalopathy or coagulopathy; deaths from liver failure have been described, including in late presentations [8]. Crises recur throughout life and decrease with age, precipitated by catabolism, intercurrent illness, fever and dietary extremes, with increased susceptibility to hepatotropic viruses, such as Epstein-Barr virus, and to drugs such as paracetamol; outside crises intellect is normal, but there are cramps, behavioural changes and visual loss [8]. Biopsy shows increased glycogen and mild fibrosis, or steatosis with Reye-like acute necrosis [8]. In Brassier's Algerian family, 2 children died at birth from liver failure and 3 adult siblings had recurrent episodes of cytolysis with liver failure or Reye-like syndrome since childhood, with normal lactate, pyruvate, plasma amino acids and urinary organic acids [53].

3.9. Wolcott-Rallison syndrome and other closely related entities

Wolcott-Rallison syndrome, due to biallelic variants of EIF2AK3, which encodes PERK, the ER sensor of misfolded proteins, combines neonatal or early infantile diabetes, growth retardation, multiple epiphyseal dysplasia and infection-associated ALF, with marked clinical overlap with NBAS deficiency [2, 20]. Patients with neonatal diabetes and episodes of febrile ALF should be tested for this syndrome. Transaldolase deficiency (TALDO1), with oxidative stress due to NADPH and glutathione depletion, causes progressive fibrosis or cirrhosis, anaemia, pancytopenia and renal and cardiac manifestations, which are rare in NBAS deficiency [20].

4. Clinical Recognition and Warning Signs

4.1. Epidemiological context of suspicion

An estimated 500 to 600 cases of paediatric ALF occur per year in the United States, about half before 4 years of age [19]. Metabolic diseases account for 28–36% of paediatric ALF in the PALF Study Group registry, and the cause remained indeterminate in 43% of the 1144 participants, a percentage that fell from 48% to 30.8% with the introduction of standardised diagnostic recommendations [19]. In Europe and North America the aetiology remains indeterminate in about half of cases [16, 25]. It is in this indeterminate group, and above all in children with repeated crises, that the disorders of this class are concentrated: exome yield was 41% in infants and 64% in RALF [16]. NASPGHAN lists as clues to metabolic disease consanguinity, recurrent miscarriages, sibling deaths, diarrhoea, vomiting, failure to thrive and developmental delay [19].

4.2. When to suspect, by age

In the neonatal period, liver failure with jaundice, coagulopathy, hepatocellular necrosis, hypoglycaemia, ascites and oedema, accompanied by vomiting and failure to thrive, requires first considering treatable disorders with a marker (galactosaemia, tyrosinaemia type 1, hereditary fructose intolerance) and gestational alloimmune liver disease, and then respiratory chain disorders, above all mtDNA depletion disorders [25, 26]. Small-for-gestational-age infants with neonatal ALF suggest hepatocerebral mtDNA depletion syndrome, IARS1 deficiency or, as in the case described by Cui, RINT1 deficiency [39, 50, 75].

Between 2 and 4 months, the combination of acute liver dysfunction with raised GGT and transaminases, hyperammonaemia, conjugated hyperbilirubinaemia, severe persistent lactic acidosis, persistent hypoglycaemia, poor feeding and failure to gain weight suggests TRMU deficiency [3]. Murali and colleagues recommend suspecting TRMU deficiency in all children with persistent lactic acidosis and hypoglycaemia [76]. After 4 months, if ALF has resolved with symptomatic care, the picture may evolve into Leigh-like syndrome, cardiomyopathy, hepatomegaly, poor weight gain and lactic acidosis [3].

Between 6 months and 5 years, the pattern of repeated hepatic crises 1 to 2 days after the onset of fever, with transaminases in the thousands, raised INR, normal GGT and alkaline phosphatase and complete recovery between episodes, should prompt joint testing of NBAS, RINT1 and SCYL1 [2, 12, 32]. The features pointing to each gene are short stature, fractures, lax skin, optic atrophy and Pelger-Huët anomaly for NBAS; beaked vertebrae and, in some families, spastic paraplegia for RINT1; and low-GGT cholestasis, fibrosis and secondary microcephaly for SCYL1 [2, 4]. The combination of ALF in the first months with anaemia, hypoalbuminaemia, tubulopathy, seizures and failure to thrive suggests ILFS1 [17, 18]. Neonatal cholestasis with prenatal growth restriction suggests IARS1 deficiency, lung disease with liver disease suggests MARS1 or YARS1 deficiency, and neonatal diabetes with febrile ALF suggests Wolcott-Rallison syndrome [2, 9, 39, 51]. At any age, and especially in patients of Ashkenazi Jewish or Arab and Maghrebi descent, Reye-like hepatic crises with vomiting, precipitated by catabolism, suggest the hepatic form of DLD deficiency [8, 53].

RALF crises due to NBAS and LARS1 were in the past mistaken for Reye syndrome [26]. The distinguishing criterion is that in Reye-like coma bilirubin is normal and transaminases only slightly raised, as in beta-oxidation and urea cycle defects, whereas in NBAS deficiency transaminases are markedly raised and coagulopathy is severe [26].

4.3. Warning and emergency signs

Early recognition of the crisis allows the emergency protocol to be started before ALF sets in. In patients with a known diagnosis of a vesicular trafficking disorder, the Heidelberg protocol defines as activation criteria fever above 38 °C, recurrent vomiting or drowsiness [20]. There is no temperature threshold validated in comparative studies, and the 2025 cohort recommends immediate medical attention for all febrile infections and at all ages, because the latest crisis occurred at 24 years [12, 13]. Influenza infection had an ALF incidence of 75% in NBAS crises, higher than other viral illnesses [20]. Signs of severity, valid for all paediatric ALF, are encephalopathy of any grade, hypoglycaemia, metabolic acidosis (pH <7.30 or bicarbonate <18 mmol/L), INR >1.8, oliguria or serum sodium <130 mmol/L, bilirubin >300 µmol/L and reduction in liver size, criteria suggested by EASL for referral to a specialised centre [25]. Ammonia above 200 µmol/L is a risk factor for death from cerebral oedema [19]. NASPGHAN recommends early contact with a paediatric liver transplant centre and monitoring in a paediatric intensive care unit [19].

4.4. Newborn screening

The sources consulted describe no newborn screening programmes for any of the disorders of the class, which have no biochemical marker measurable in dried blood spots. In DLD deficiency, newborn screening by citrulline or leucine did not identify asymptomatic individuals, although citrulline was raised in 3 symptomatic individuals [8]. Galactosaemia, which belongs to the neonatal differential, should be checked in the newborn screening result [26].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no consensus clinical criteria for any of the entities of the class; diagnosis rests on the combination of a suggestive picture with the identification of biallelic pathogenic or likely pathogenic variants in the respective gene [2, 3]. The PALF Study Group entry criteria, described in section 1, identify ALF but are not intended to be a diagnostic definition; in RALF, the definition is challenged by the presence of an underlying chronic disease, usually genetic [2, 19]. In the PALFES study, 201 of 260 patients met strict ALF criteria, including RALF, and the results in the subcohort meeting the PALF Study Group criteria were comparable [16].

5.2. Initial laboratory assessment and its limits

NASPGHAN proposes an aetiological investigation ordered by age and notes that about half of paediatric ALF occurs before 4 years of age, an age at which the available blood volume requires tests to be prioritised [19]. The parameters that define severity and that, in NBAS deficiency, have prognostic value are INR, bilirubin, albumin, ammonia, blood glucose and lactate [12, 13]. In the newborn, EASL adds ferritin and transferrin saturation for gestational alloimmune liver disease, and high-dose aciclovir until herpes simplex virus is excluded [25]. Suspicion of galactosaemia, tyrosinaemia type 1 or hereditary fructose intolerance requires specific tests and immediate dietary measures [27]. In advanced ALF, nonspecific changes secondary to hepatocellular injury appear, such as melituria (galactosuria, glycosuria, fructosuria), hyperammonaemia, hyperlactataemia, hypoglycaemia after a short fast, hypertyrosinaemia above 200 µmol/L and hypermethioninaemia sometimes above 500 µmol/L, which should not be mistaken for a primary inborn error [26].

Lactate does not discriminate mitochondrial disease: in the Birmingham audit it was abnormal in all infants with mitochondrial disease and also in 25 of 34 without it, and hepatic mtDNA copy number was low in 8 of 15 infants without mitochondrial disease [77]. NASPGHAN agrees that lactate ≥2.5 mmol/L and a lactate/pyruvate ratio >25 are neither specific nor predictive [19]. The Birmingham authors conclude that transplant decisions should not be based on hepatic mtDNA copy number without proven variants and that testing for variants in DGUOK, POLG, MPV17, TWNK and TRMU should begin at presentation, with results ideally within days and certainly within 15 days [77]. In TRMU deficiency, hyperalaninaemia and lactic aciduria distinguish chronic lactic acidosis from that secondary to critical illness [3].

In vesicular trafficking disorders there is no biomarker in blood or urine [2, 12]. Exceptionally high transaminases and INR are associated with NBAS deficiency but do not establish the diagnosis [16]. Low or normal GGT during a cholestatic crisis points to SCYL1 [4]. In one patient with CALFAN, isoelectric focusing of transferrin and apolipoprotein CIII showed a CDG type II pattern only during a crisis, normal afterwards, so transient abnormal glycosylation during a crisis does not exclude SCYL1 [4]. A peripheral blood smear with Pelger-Huët anomaly is an inexpensive clue in the SOPH subgroup, but is neither sensitive nor specific [12, 49]. In the hepatic form of DLD deficiency, biochemical markers (lactate, pyruvate, branched-chain amino acids, urinary α-ketoglutarate) may be normal, especially outside crises [8, 53].

5.3. First-line genetic test

The PALFES study established a genetic diagnosis in 97 of 260 children (37%), with a VUS in 19 and no prioritised variant in 144 (55%) [16]. Thirty-six genes were identified, 21 of them in single cases; the most frequent were NBAS (n=20, 21% of diagnoses), MPV17 (n=8) and DGUOK (n=7); 92 of the 97 diagnoses were autosomal recessive, 53 homozygous, and consanguinity was associated with a diagnosis in 61% [16]. By functional group, mitochondrial diseases accounted for 45% of diagnoses, vesicular trafficking 28% and cytosolic aminoacyl-tRNA synthetases 10% [16]. Yield was 40% below 5 years, 14% from 6 years, 41% in infants and 64% in RALF [16]. Figure 4 of the paper groups the 36 genes into four classes: vesicular trafficking (NBAS, SCYL1, RINT1); mitochondrial diseases (MPV17, DGUOK, TRMU, DLD, SERAC1, BOLA3, MICOS13, UQCRC2, BCS1L, TWNK, LRPPRC, MRPS23, POLG, SLC25A13, SUCLG1 and a second mitochondrial ribosomal protein gene whose name cannot be read reliably in the figure); cytosolic aminoacyl-tRNA synthetases (YARS1, LARS1, IARS1, MARS1, QRSL1); and others (ZNFX1, CFTR, AP4M1, ATP7B, CACNA1E, ITCH, NSD1, PCK1, PRF1, SLC37A4, SPTB, STAT3) [16]. Yield was about 30% in isolated ALF and 64% in RALF, and native liver survival was significantly greater in vesicular trafficking (n=21) than in mitochondrial diseases (n=28) [16]. Figure 5 places these genes within a broader set of known paediatric ALF genes, which includes, among vesicular trafficking disorders, STX11, STXBP2 and UNC13D (familial HLH) and, among the cytosolic synthetases, AARS1, and, among the mitochondrial genes, beta-oxidation defects, respiratory chain subunits and assembly factors, cofactors and mtDNA replication and translation genes such as GFM1, TFAM and TSFM [16]. The authors acknowledge biases that may have overestimated the yield: preferential inclusion of mitochondrial and RALF cases and low representation of POLG, previously tested in a targeted manner [16].

On the basis of these data, Lenz and colleagues recommend exome or genome sequencing in parallel with metabolic analyses and as first line in every child with ALF, and point to rapid genome sequencing, with a 24-hour turnaround, as an option [16]. NASPGHAN considers urgent exome sequencing the most accurate diagnostic tool in mitochondrial liver disease [19]. The review by Peters and colleagues recommends exome sequencing in RALF of unknown aetiology and testing of close relatives, especially siblings [2]. For TRMU deficiency, the GeneReviews proposes a mitochondrial disease, cholestasis or infantile ALF panel including TRMU, or exome or genome sequencing, the latter increasingly used [3]. In Yakuts, targeted testing for the NBAS founder allele c.5741G>A is the fastest route, and in Ashkenazi Jews targeted testing for DLD c.685G>T may be the first step [8, 12]. A negative genetic test does not exclude the disease, and the Haack study, which gave rise to ILFS2, was performed precisely in patients without a diagnosis after conventional investigation [16, 34].

5.4. Limits of molecular tests

The proportion of pathogenic variants detected by each method is not equivalent to the clinical sensitivity of the test. In TRMU deficiency, according to HGMD data gathered in the GeneReviews, sequencing detected 26 of 28 pathogenic variants and targeted deletion/duplication analysis 2 of 28 [3]. In NBAS deficiency, one of the alleles may be a complete gene deletion, so analysis must include CNV [12, 49]. In RINT1 deficiency, Cui's case had a deletion of exons 12 to 14 in trans with a splicing variant [50]. Intronic and splicing variants accounted for 10 of the 39 NBAS patients without an assigned subgroup, and variants at the RINT1 c.1672-1 acceptor were only interpreted with RNA studies [13, 42]. Apparent homozygosity should prompt consideration of a deletion of one or more exons not detected by sequencing or uniparental isodisomy, and absence of the variant in one parent, with confirmed parentage, should prompt consideration of a de novo variant or parental mosaicism [3]. In the PALFES study, mtDNA variants were assessed from exome data, whose coverage of the mitochondrial genome is limited [16]. In patients with mitochondrial disease, the biochemical phenotype may be present in the liver and absent in muscle, and the clinically affected tissue should be reinvestigated if genetic testing in blood is negative [44].

5.5. Functional and tissue tests

NBAS immunohistochemistry on liver biopsy and Western blot in fibroblasts can help validate variants of uncertain significance; functional confirmation of thermosensitivity in fibroblasts is a research assay [12, 32, 38]. Loss of SCYL1 in tissue confirmed the missense variants of the CALFAN series [4]. In aminoacyl-tRNA synthetase deficiencies, aminoacylation assays may facilitate diagnosis, but in most cases the path is rapid progression to a broad molecular test [21, 45].

In TRMU deficiency, biopsies are not necessary for diagnosis [3]. If liver biopsy is performed in ALF, the tissue should be snap-frozen for biochemistry and fixed in glutaraldehyde for electron microscopy; histology may show bridging, portal and perisinusoidal fibrosis, micronodular cirrhosis, necrosis, mitochondrial proliferation, micro- and macrovesicular steatosis, canalicular cholestasis, ductular proliferation, ballooning degeneration, increased hepatic iron and oncocytic hepatocytes [3]. Respiratory chain complex activity in the liver is variable, but complex IV is uniformly decreased, and blue native gel electrophoresis (BN-PAGE) shows abnormal assembly mainly of complexes I and IV; in muscle there may be ragged red fibres and deficiency of complexes I, III and IV [3]. Abdominal ultrasound may show an enlarged and hyperechoic liver, diffuse steatosis and persistent nodules, and brain MRI lesions of the thalamus and putamen, basal ganglia, brainstem and superior cerebellar peduncles, with possible normalisation after recovery and a lactate peak on spectroscopy in the acute phase [3]. For mitochondrial investigation, fresh tissue is used for mitochondrial respiration and tissue frozen on dry ice for enzymology, histochemistry, Western blot and BN-PAGE [44].

5.6. Report content and variant classification

The report should identify the gene, the reference transcript with version (for example NM_015909.4 for NBAS, NM_021930.6 for RINT1, NM_020680.4 for SCYL1, NM_018006.5 for TRMU), the HGVS description at cDNA and protein level, zygosity, the phase of the variants when known and the classification according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria [7, 13]. In TRMU deficiency, two biallelic VUS, or one pathogenic variant with one VUS, neither establish nor exclude the diagnosis [3]. Parental segregation analysis confirms the in trans configuration, and the functional assays described above may reclassify VUS in research laboratories [3, 38]. In the PALFES study, only 52% of pathogenic or likely pathogenic variants were already recorded in ClinVar [16]. The NBAS c.5741G>A variant is classified as pathogenic in ClinVar without conflicts, whereas YARS1 c.1099C>T p.(Arg367Trp) has conflicting classifications, and the TRMU c.28G>T p.(Ala10Ser) variant should not be reported as a cause of ALF [67].

5.7. Practical algorithm

5.8. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis by amniocentesis or chorionic villus sampling and preimplantation genetic testing are possible for all entities of the class [3]. In TRMU deficiency, prenatal diagnosis also has therapeutic value, because it allows maternal L-cysteine supplementation in the third trimester and initiation of supplementation in the newborn [3]. Counselling aspects are developed in section 8.

6. Differential Diagnosis

6.1. Comparative table

6.2. Differential within the class

The first axis is age at onset. Mitochondrial diseases, including TRMU deficiency, present mainly in the first 6 months, whereas vesicular trafficking and aminoacyl-tRNA synthetase disorders usually begin after 6 months [16]. The second axis is the biochemical pattern of the crisis: transaminases in the thousands and very high INR in NBAS and RINT1, low-GGT cholestasis in SCYL1, severe persistent lactic acidosis and hypoglycaemia in TRMU, and anaemia with hypoalbuminaemia in LARS1 [2, 3, 13, 17]. The third axis is the course between crises: normalisation in ILFS2, partial recovery in ILFS3, progressive fibrosis in CALFAN and in SOPH with persistent transaminase elevation [2, 4, 13]. The fourth axis is the extrahepatic phenotype, summarised in the table in section 1.4. As the three vesicular trafficking genes share the pattern of febrile RALF with recovery, they should be tested together [12].

TRMU deficiency is distinguished from DGUOK and MPV17 deficiencies because ALF is transient and reversible and neurological involvement is less; DGUOK deficiency has similar manifestations, onset, metabolic profile and progression, and MPV17 deficiency often begins later and has more neurological findings [3, 14]. POLG-related disorders are the most common mitochondrial cause of liver failure in childhood and valproate can precipitate it [3, 44]. In the Birmingham audit, the 5 infants with genetic mitochondrial liver disease among 39 with ALF all had mtDNA depletion syndrome (DGUOK 2, POLG 2, MPV17 1) and 4 died within 3 weeks, whereas TRMU cases are important because spontaneous recovery with support is likely [77]. The TRMU GeneReviews adds, with hypoglycaemia and metabolic acidosis, the organic acidaemias and beta-oxidation defects (MCAD, SCAD, VLCAD), in which presentation often occurs in the first weeks [3].

The hepatic form of DLD deficiency resembles NBAS deficiency in its fever-triggered crises with recovery, but is accompanied by vomiting in all patients, raised lactate in three quarters and encephalopathy in half, persists into adulthood and has a founder allele amenable to targeted testing [8, 53]. The DLD GeneReviews stresses that isolated liver involvement has a broad differential, with the cause unidentified in up to 50% of cases, and includes NBAS deficiency, beta-oxidation and carnitine cycle defects and mitochondrial diseases [8].

Other cellular trafficking disorders enter the differential, especially of chronic liver disease: ARC syndrome (VPS33B, VIPAS39), type II CDG (COG2, COG4, COG5, COG6, COG7, COG8, RFT1, TMEM165, TMEM199), MEDNIK syndrome (AP1S1) and trichohepatoenteric syndrome (SKIV2L, TTC37); and, among those causing ALF or hepatitis-like episodes, BCAP31, HYOU1, COG4, STX11 and STXBP2, in addition to Wilson disease (ATP7B) [43]. TANGO2 deficiency may combine episodes of rhabdomyolysis with manifestations mimicking fatty acid oxidation defects [43]. In paediatric hepatic steatosis, Saudubray includes cellular trafficking disorders (NBAS, RINT1, SCYL1), beta-oxidation defects, hereditary fructose intolerance, fructose-1,6-bisphosphatase deficiency, glycogen storage diseases VI and IX, CDG and bile acid synthesis defects [26]. Orphanet assigns separate entries to Navajo neurohepatopathy (MPV17, ORPHA:255229), GRACILE syndrome (BCS1L, ORPHA:53693), hepatoencephalopathy due to combined oxidative phosphorylation deficiency type 1 (GFM1, ORPHA:137681), combined deficiency type 4 (TUFM, ORPHA:254925) and MEGDEL syndrome (SERAC1, ORPHA:352328) [86].

6.3. Differential with haemophagocytosis and non-genetic causes

HLH is a common cause of paediatric ALF and presents with high fever, hepatosplenomegaly, raised alkaline phosphatase and lactate dehydrogenase and smear abnormalities, with diagnosis by bone marrow or biopsy [25]. The fever, cytolysis and high ferritin of the NBAS crisis may overlap with this picture, and NBAS deficiency is itself a genetic cause of HLH; the HLH panel should include NBAS [12, 55]. Saudubray also includes TRMU deficiency among the metabolic diseases with macrophage activation syndrome [26]. EASL notes that about 10% of indeterminate paediatric ALF develop bone marrow failure simultaneously or weeks to months later, and that ALF without jaundice should prompt investigation for metabolic disease [25]. Paracetamol poisoning, which in the United States accounts for 13% of paediatric ALF, and viral infections, which account for 8%, always enter the initial differential [16].

7. Treatments and Risk Management Strategies

7.1. Principles and level of evidence

None of the disorders of the class has a curative treatment or a specific graded guideline; there are no randomised trials for any entity, and recommendations come from retrospective cohorts, case series, the experience of reference centres and pathophysiological extrapolation [2, 3, 13, 21]. The GeneReviews states that there are no published clinical practice guidelines for TRMU deficiency [3]. The NASPGHAN paediatric ALF guidelines (2022) and the EASL ALF guidelines (2017) apply to the supportive treatment of any crisis [19, 25]. In each group, treatment is defined by the pathophysiological target: in vesicular trafficking disorders, preventing temperature and catabolism from aggravating NRZ complex deficiency; in TRMU deficiency, providing cysteine during the window of vulnerability; in aminoacyl-tRNA synthetase deficiencies, ensuring protein and the relevant amino acid; in DLD deficiency, avoiding catabolism and treating acidosis [2, 3, 8, 21]. All drugs used for a specific purpose in this class are off-label.

7.2. Vesicular trafficking disorders (NBAS, RINT1, SCYL1): emergency protocol for fever

7.2.1. Rationale and organisation

Staufner and colleagues observed, in 6 patients with NBAS deficiency, that early and consistent antipyretic treatment and induction of anabolism with intravenous glucose and parenteral lipids attenuated and shortened crises, especially when started early, and that effective antipyresis could even prevent them [32, 38]. The 2025 review recommends, for all three disorders, a written emergency plan, education of family members and the primary care team and an emergency card with clear instructions to treat fever early, and considers that early and consistent implementation determines outcome [2]. The basis for this recommendation is limited: the study by Hammann and colleagues showed that presymptomatic diagnosis with an emergency protocol did not prevent ALF, with a non-significant trend towards milder crises (ALT, AST, INR and mortality) [13, 57]. The effect in RINT1 and SCYL1 is extrapolated from NBAS [2]. In the cohort of 230 patients, only 63 had a recorded individual emergency protocol; 75 received antipyretics, 77 anabolic glucose infusions, 40 lipids, 39 vitamin K, 20 fresh frozen plasma and 13 NAC, and the lack of per-crisis data prevented assessment of the effect of each measure [13]. The Atlas advises that the patient carry an emergency card, letter or bracelet with instructions and contacts [32].

The local Heidelberg protocol, published in 2026, is activated by fever above 38 °C, recurrent vomiting or drowsiness, and comprises an antipyretic, intravenous glucose by age with insulin if needed, intravenous lipids at 1–2 g/kg/day and oral NAC, the first dose of which may be given at home; if there is liver failure, NAC is switched to the paracetamol poisoning regimen [20]. In the methods of the same study, patients with frequent or severe crises received, at the first signs of liver involvement, oral NAC at home (150 mg/kg/day in 3 doses) and were sent to the emergency department, where they received intravenous glucose, intravenous lipids at 1 g/kg/day and NAC at paracetamol poisoning doses [20].

7.2.2. Antipyretic: metamizole and the controversy over paracetamol and ibuprofen

The 2025 cohort and the review by the same group recommend, in addition to physical measures, metamizole (dipyrone) as a single dose of 8–16 mg/kg orally or parenterally, with a minimum interval of 6 hours and a maximum single dose of 1000 mg [2, 13]. They advise against ibuprofen because of the bleeding risk when liver function is impaired and against paracetamol because its toxicity induces the integrated stress response and ROS, processes suspected in the pathogenesis [2, 13]. The Infobox of the 2026 Heidelberg protocol, published by the same group, accepts paracetamol and ibuprofen «if necessary» as alternatives to metamizole, which shows that the choice is not absolute; NASPGHAN notes that non-steroidal anti-inflammatory drugs are nephrotoxic in ALF [19, 20]. In TRMU deficiency, the GeneReviews advises considering avoidance of paracetamol during episodes of liver dysfunction, because of a theoretical concern about oxidative stress, and in DLD deficiency there is increased susceptibility to paracetamol injury [3, 8]. The metamizole recommendation is an expert position, not a regulatory indication, and the reference dose is that of Peters: 8–16 mg/kg as a single dose, minimum interval of 6 hours, up to 1000 mg per dose [2]. The SmPC, cited for comparison, gives the same single dose up to 14 years of age and adds the interval of 6–8 hours, up to 4 times a day, and the weight-based daily maxima in the following table, which complete the Peters recommendation, which has no explicit maximum daily dose; the approved indication is limited to high fever that does not respond to other therapies, so use as an early first-line antipyretic falls outside the labelled conditions [2, 87, 88].

Metamizole is a pyrazolone analgesic and antipyretic. In the European Union, medicinal products containing it are authorised through national procedures, and the Article 31 referral (opinion of the Committee for Medicinal Products for Human Use of 13 December 2018; European Commission decision of 20 March 2019) harmonised the posology: severe pain and fever not responding to other treatments, with a single dose of 8–16 mg/kg in children and adolescents up to 14 years of age, a dose of 10 mg/kg generally being sufficient for fever in children, and, from 15 years and 53 kg, up to 1000 mg per dose, up to 4 times a day, at intervals of 6–8 hours, up to 4000 mg/day; the injectable route allows up to 5000 mg/day [87]. The effect appears within 30–60 minutes orally and within 30 minutes parenterally; intravenous injection must be very slow because of the risk of a hypotensive reaction [87]. Oral and injectable forms are contraindicated below 3 months or 5 kg, and the intravenous route below 1 year, an age at which only the intramuscular route is used [87]. In hepatic or renal impairment, elimination is reduced, so multiple high doses should be avoided; no reduction is needed for short-term use [87].

The table reproduces Annex III of the 2019 European referral [87]. In Portugal, metamizole is marketed as Nolotil® (metamizole magnesium), as a solution for injection of 2000 mg/5 ml and as 575 mg capsules [88, 89]. The SmPC of the injection reproduces the weight-based paediatric posology of the table, with a single dose of 8–16 mg/kg up to 14 years and up to 4 doses a day at intervals of 6–8 hours, and adds that it is administered only intravenously or by deep intramuscular injection, with the solution warmed to body temperature, intravenously slowly, not more than 1 ml per minute, with the patient lying down and with monitoring of blood pressure, heart rate and respiration, and with equipment to treat shock [88]. The 575 mg capsules are not recommended or indicated below 15 years, because of the fixed dose, and in adults allow up to 6 doses a day at intervals of 4–6 hours, up to 3450 mg/day [89]. Both SmPCs state as indication severe acute pain and high fever not responding to other antipyretic therapies, and add to the contraindications congenital glucose-6-phosphate dehydrogenase deficiency, acute intermittent hepatic porphyria, analgesic-induced asthma and the third trimester of pregnancy [88, 89]. In Brazil, dipyrone has an active registration as Novalgina® (dipyrone monohydrate) and as numerous generics; the professional package insert could not be consulted [90]. The second referral, under Article 107i (position of the coordination group of 18 September 2024; European Commission decision of 22 November 2024), addressed agranulocytosis, which is not dose-dependent and may occur at any time during treatment or shortly afterwards, even after previous uneventful use [91]. Patients should stop the drug and seek immediate help if they have fever, chills, sore throat or painful mucosal lesions, should have a full blood count with differential and maintain discontinuation until the result; when metamizole is used for fever, the first symptoms of agranulocytosis may go unnoticed [91]. Metamizole is contraindicated in patients with previous agranulocytosis due to pyrazolones or pyrazolidines, with bone marrow disease or with diseases affecting the production or function of blood cells [91]. This last contraindication deserves individual consideration in NBAS deficiency, which features Pelger-Huët anomaly, NK cell deficiency and hypogammaglobulinaemia, and in the family with RINT1 and neutropenia; the sources consulted do not discuss this conflict, and the decision should include a baseline blood count and monitoring [12, 32, 91]. It is contraindicated in the third trimester of pregnancy and during breastfeeding and is not recommended in the first and second trimesters, single doses being acceptable if there is no alternative [87]. A search of Drugs@FDA and the openFDA label database found no Food and Drug Administration (FDA) authorisation or label for human use of metamizole in the United States [92].

7.2.3. Anabolic infusion of glucose and lipids

Induction of anabolism with intravenous glucose and parenteral lipids had a beneficial effect in individual NBAS cases, without systematic analysis, and is also proposed for SCYL1 and RINT1 [2, 38]. The Heidelberg protocol doses glucose by age and uses lipids at 1–2 g/kg/day, with insulin if needed to maintain glucose intake [20].

The Portuguese SmPC of SMOFlipid® 200 mg/ml indicates, in newborns, an initial dose of 0.5–1.0 g lipids/kg/day, with successive increases of 0.5–1.0 g/kg/day up to 3.0 g/kg/day, a maximum rate of 0.125 g/kg/hour and continuous infusion over more than 24 hours in preterm infants, and in children a maximum of 3 g/kg/day at a maximum of 0.15 g/kg/hour; in children under 2 years, the solution must be protected from light [93]. SMOFlipid® 20% has an active registration in Brazil [90]. The lipid dose of 1–2 g/kg/day is within the ranges of the FDA label of a lipid emulsion (SMOFlipid®, soybean oil, medium-chain triglycerides, olive oil and fish oil), which indicates, in parenteral nutrition, 0.5–1 g/kg/day as the initial dose from 0 to 2 years with a maximum of 3 g/kg/day, 1–2 g/kg/day from 2 to 11 years with a maximum of 3, 1 g/kg/day from 12 to 17 years with a maximum of 2.5, and 1–2 g/kg/day in adults with a maximum of 2.5 [20, 94]. Use as an anabolic agent during a crisis is off-label. NASPGHAN advises using lipids in ALF unless a beta-oxidation or mitochondrial disorder is suspected, and in beta-oxidation defects recommends continuous glucose at 10 mg/kg/min, with no maximum dose defined in the source, and avoidance of intravenous lipids [19]. It follows that, in a first crisis without a molecular diagnosis, the decision to infuse lipids depends on reasonable exclusion of a beta-oxidation defect; in TRMU deficiency, high dextrose concentrations may worsen lactic acidosis [3, 19].

7.2.4. N-acetylcysteine in crises

NAC is the antidote for paracetamol poisoning and a glutathione precursor with antioxidant action [2, 95]. The 2025 review considers that its use in NBAS, RINT1 and SCYL1 crises «may be considered», because of the suspected mechanism, favourable unpublished experience in individual patients and its low adverse effect profile, and it is practice at the Heidelberg centre [2]. The retrospective study by Sun and colleagues compared 49 crises in 12 individuals with NAC and 37 crises in 12 individuals without NAC, a total of 86 crises in 16 patients [20]. Maximum INR was lower with NAC in descriptive statistics, but in generalised linear mixed models INR decreased with age and increased in the ILFS2 subgroup, with no significant effect of NAC; the same occurred with ALT; with NAC there was a trend towards longer hospital stay and more intensive care admissions, and there was one death in each group [20]. In the 5 patients with both treated and untreated crises, the highest transaminases of each individual always occurred in crises without NAC, and the frequency of ALF was lower with NAC in 3 [20]. Patients were older in crises with NAC, initiation was sometimes late and there was no stratification by time to treatment; the authors conclude that no definitive conclusions can be drawn, that NAC would have to start at the onset of the febrile episode and that prospective studies are needed [20]. NAC was well tolerated, with no reported adverse effects [20].

This position diverges from the paediatric guidelines. In the double-blind, placebo-controlled PALF Study Group trial in 184 children with ALF not caused by paracetamol, intravenous NAC did not improve 1-year survival and reduced transplant-free survival (section 7.12) [96]. NASPGHAN reserves NAC for confirmed or highly probable paracetamol toxicity [19]. EASL notes the lack of benefit in the paediatric study, which included numerous cases of metabolic cause, and advises limiting NAC to 5 days because of the risk of functional immunoparesis and nosocomial sepsis [25]. In adults, the American College of Gastroenterology (ACG) suggests intravenous NAC in ALF not caused by paracetamol (strong recommendation, moderate quality), based on the transplant-free survival benefit with grade I–II coma [97]. NAC in crises of vesicular trafficking disorders is therefore a specialised-centre, off-label option contrary to the NASPGHAN position, which should be discussed with the family.

The regimens used by the Heidelberg group are: prophylactic, 50 mg/kg orally 3 times a day (150 mg/kg/day); in liver failure, orally, 140 mg/kg followed by 70 mg/kg every 4 hours for 72 hours, or intravenously, 150 mg/kg over 60 minutes, 50 mg/kg over 4 hours and 100 mg/kg over 16 hours, a total of 300 mg/kg over 21 hours [20]. These regimens, with the 5-day limit proposed by EASL, are the reference doses when NAC is used in a specialised centre [20, 25]. The labels, cited for comparison (that of Acetadote® in the USA and the SmPC of Fluimucil® in Portugal), approve only the intravenous regimen of 300 mg/kg over 21 hours in paracetamol poisoning, and the US label also provides for continuing beyond 300 mg/kg if paracetamol remains detectable or if transaminases or INR rise [95, 98]. The Heidelberg intravenous regimen matches the labels in dose, with an off-label indication; the oral prophylactic regimen of 150 mg/kg/day, the 72-hour oral regimen, whose label was not consulted, the doses of 70–150 mg/kg/day in TRMU deficiency and the continuous infusion of 150 mg/kg/day for up to 7 days in the Squires trial fall outside the labelled conditions, which also do not provide for the 5-day limit [3, 20, 25, 96]. The intravenous regimen matches the FDA label of Acetadote® (acetylcysteine 200 mg/mL, 6000 mg/30 mL vial, hyperosmolar at 2600 mOsmol/L, diluted in sterile water, 0.45% sodium chloride or 5% dextrose), approved in 2004 and revised on 30 April 2025, whose indication is to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of paracetamol in adults and children weighing at least 5 kg [95]. The label requires the 3-bag regimen up to 40 kg and adjusts the volume to weight: from 5 to 20 kg, 150 mg/kg in 3 mL/kg over 1 hour, 50 mg/kg in 7 mL/kg over 4 hours and 100 mg/kg in 14 mL/kg over 16 hours; from 21 to 40 kg, the same doses in 100, 250 and 500 mL [95]. Adverse reactions include hypersensitivity reactions in 8% of adults and 10% of children (urticaria or facial flushing 7.6%, pruritus 4.1%, respiratory symptoms 2.2%, oedema 1.2%, anaphylaxis 0.2% and hypotension 0.1% in children), bronchospasm, which requires monitoring of asthmatic patients, flushing 30–60 minutes after initiation, and fluid overload with hyponatraemia, seizures and death, so the volume is reduced below 40 kg [95]. Paediatric safety and efficacy have not been established in controlled studies, and use from 5 kg is based on clinical practice [95]. During breastfeeding, milk may be pumped and discarded for 30 hours [95]. In Portugal, intravenous acetylcysteine is marketed as Fluimucil® 200 mg/ml concentrate for solution for infusion (25 ml vial containing 5000 mg), whose SmPC, approved on 18 January 2024, provides the same regimen of 3 consecutive infusions (150 mg/kg over 60 minutes, 50 mg/kg over 4 hours, 100 mg/kg over 16 hours; 300 mg/kg over 21 hours), preferably in 5% glucose, with a ceiling of 110 kg for dose calculation [98]. Below 40 kg the dose is the same, but the volume is adapted to weight because of the risk of pulmonary vascular congestion: the first infusion uses a 50 mg/ml solution at 3 ml/kg/h and the next two a 6.25 mg/ml solution at 2 and 1 ml/kg/h; in a 12 kg child, for example, this is 38 ml over 1 hour, 100 ml over 4 hours and 208 ml over 16 hours [98]. The SmPC describes anaphylactoid reactions, very rarely fatal, mostly manageable by temporary interruption of the infusion, and recommends weighing breastfeeding, because the risk to the breastfed child cannot be excluded [98]. In Brazil, Fluimucil® and acetylcysteine generics have active registrations, but the open data do not identify the injectable form [90].

7.2.5. Immunoglobulin and prevention of infections

In NBAS deficiency with hypogammaglobulinaemia, immunoglobulin replacement should be considered to reduce the infections that trigger crises [32, 36]. The sources consulted give no dose for this condition; the extrapolated dose is that of the FDA label of a 10% intravenous normal human immunoglobulin (Privigen®, May 2026 label) in primary humoral immunodeficiency, 200–800 mg/kg every 3–4 weeks, adjusted by pre-infusion IgG level and clinical response [99]. The label includes a boxed warning for thrombosis and for renal dysfunction and acute renal failure in predisposed patients [99]. Influenza infection had an ALF incidence of 75% in NBAS crises, significantly higher than other viral illnesses, and the authors strongly recommend seasonal influenza vaccination for all individuals with NBAS deficiency [20]. Vaccinations may trigger crises, but the 2025 cohort recorded post-vaccination fever as an isolated trigger, in at most 2 patients [13, 32]. The sources consulted do not discuss the general vaccination schedule; the fever protocol applies to any febrile episode, including post-vaccination fever [2, 38]. Febrile infections require immediate medical attention at all ages [12].

7.3. TRMU deficiency: cysteine supplementation

As endogenous cysteine supply is physiologically low in the first months and TRMU needs cysteine to thiolate mt-tRNAs, the initial manifestations, above all liver disease, may be attenuated by exogenous oral supplementation; the GeneReviews recommends starting L-cysteine and NAC as soon as the diagnosis is suspected, while awaiting confirmation [3]. Murali and colleagues consider combined supplementation before molecular diagnosis a low-risk approach that may increase survival and attenuate severity [76]. There is no consensus on the best method; NAC also improves redox potential and is recommended with cysteine, and limited evidence suggests that NAC works best in combination with L-cysteine, especially in the first year [3]. The doses used in the Murali series were 85 to 300 mg/kg/day of L-cysteine, with a target of 300 mg/kg/day in total, and 70 to 150 mg/kg/day of NAC; infant formulas enriched in L-cysteine help reach the target, and supplementation should be maintained for at least the first year [3]. Taurine, a direct substrate of thiouridylation, could theoretically be useful, but there are no published data on its use [3].

In the Vogel cohort, survival beyond the acute decompensation phase was 84% with L-cysteine or NAC, versus 61% without supplementation, and supplementation with at least one source of cysteine, typically NAC, significantly improved survival [3, 14]. Supplementation alone did not change native liver survival, because hepatic necrosis does not appear to improve once it has begun [3]. In at-risk siblings treated before symptoms, hepatic and metabolic dysfunction was easier to manage than in older siblings, but one was listed for transplantation for severe hyperammonaemia before stabilising, and the evidence does not allow the conclusion that supplementation fully prevents liver disease [3, 76]. Soler-Alfonso and colleagues described a sibling with a prenatal diagnosis who started L-cysteine early, recovered liver function and avoided transplantation, whereas the older sibling died [65].

Oral L-cysteine is used as a food supplement, with no label for this indication. The only form of cysteine with an FDA label is injectable cysteine hydrochloride Elcys® (50 mg/mL, equivalent to 34.5 mg/mL of cysteine; 2500 mg/50 mL pharmacy bulk vial), approved on 16 April 2019 and revised on 9 April 2026, indicated only as an additive to amino acid solutions to meet the nutritional requirements of newborns on total parenteral nutrition and of adult and paediatric patients with severe liver disease on parenteral nutrition; it is not intended for direct intravenous infusion [100]. The labelled dose, from 0 to 11 years, is 22 mg per gram of amino acids (15 mg of cysteine per gram), with amino acid intake of 3–4 g/kg/day below 1 month, 2–3 g/kg/day up to 1 year and 1–2 g/kg/day from 1 to 11 years, and 7 mg/g of amino acids from 12 years; risks include metabolic acidosis, especially in preterm infants, and hyperammonaemia, of particular relevance between 0 and 2 years [100]. The doses for TRMU deficiency, 85–300 mg/kg/day orally, are far above those resulting from this nutritional indication [3, 100]. None of the agents has FDA approval for TRMU deficiency [12].

Supportive treatment follows the GeneReviews: standard symptomatic treatment of hypoglycaemia, lactic acidosis, coagulopathy and hyperammonaemia; feeding therapy and gastrostomy if problems persist, with a low threshold for videofluoroscopic swallowing assessment; support until recovery of cardiac function in cardiomyopathy; antiseizure medication for seizures and brain imaging for Leigh syndrome; ventilatory support in respiratory failure and tracheostomy if there is central apnoea; physiotherapy, occupational therapy and positioning devices; social services, care coordination and palliative care or home nursing [3]. In mitochondrial disease, levetiracetam and clobazam appear to be the most effective antiseizure medications, and sodium valproate should be avoided, especially with POLG variants, because it can precipitate ALF [44].

7.4. Aminoacyl-tRNA synthetase deficiencies: protein and specific amino acid

In ILFS1, Casey and colleagues observed that leucine supplementation had no appreciable impact on patients' well-being, but concluded that the traditional management of reducing or withholding protein in metabolic liver disease may not be appropriate and recommended ensuring sufficient natural protein intake during illness [17]. Saudubray's book reports that high-dose leucine or total protein infusion improved acute liver dysfunction in LARS1 deficiency [45]. Kok and colleagues treated 4 patients for 5 to 32 months, in a case series without a control group, with L-isoleucine 35–70 mg/kg/day in 3 doses (IARS1), L-leucine 35–100 mg/kg/day (LARS1), L-phenylalanine 40–100 mg/kg/day (FARSB) and L-serine 85.7–97.5 mg/kg/day (SARS1), with natural protein fortification of 2.5 g/kg/day, increased to 3.5 g/kg/day during illness, and with intensified treatment during infections, strict antipyresis and an emergency protocol for fasting, fever and infection [21]. In the patient with LARS1, the switch from isoleucine, given in error for 9 months, to leucine was followed by increased oral intake, discontinuation of tube feeding at 6 months, improvement in height from −3.1 to −2.7 standard deviations and in head circumference from −2.3 to −1.6, and normalisation of transaminases, bilirubin, immunoglobulins and liver ultrasound; in the patient with IARS1 there was improvement in lung function, no admissions for infection versus 5 in the previous 2 years, and worsening during a 2-week interruption [21]. The patient with FARSB and severe liver disease initially improved, but died from bleeding of pre-existing oesophageal varices [21]. Safety parameters remained stable over 6 months to 2 years and 8 months [21]. Parenteral nutrition improved liver function in one patient with MARS1 [21].

In MARS1 deficiency, daily oral methionine in 4 patients, compared with historical controls, improved respiratory function, cleared the lipoproteinaceous material and allowed whole-lung lavages to be stopped in all; the 3 dependent on oxygen or non-invasive ventilation were weaned within 60 days, and liver dysfunction, inflammation and growth retardation improved or resolved [51]. The methionine dose is not given in the abstract consulted. In IARS1 deficiency, zinc supplementation benefited growth in one patient, with no dose given in the abstract [39]. In YARS1 deficiency, tyrosine at 100 and then 200 mg/kg/day brought no clear improvement in an infant with steatohepatitis, and compassionate use continues [9]. All these amino acids are supplements without marketing authorisation as medicinal products for these indications. Protein fortification diverges from NASPGHAN, which allows restriction to 1 g/kg/day in hyperammonaemia, and agrees with EASL, which advises against restricting protein below 1 g/kg except in urea cycle defects and organic acidaemias [19, 25].

7.5. DLD deficiency, hepatic form

The acute treatment proposed by the GeneReviews consists of treating or removing precipitating factors (infection, fasting, drugs), avoiding hepatotoxins, giving intravenous fluids with dextrose at 6–8 mg/kg/min with appropriate electrolytes or frequent meals, considering correction of metabolic acidosis with sodium bicarbonate, considering dichloroacetate if lactate falls on its introduction, considering dialysis if lactic acidosis persists with encephalopathy and using fresh frozen plasma for coagulopathy [8]. Intravenous sodium benzoate and sodium phenylacetate are of doubtful use, because hyperammonaemia accompanies or results from the liver dysfunction that metabolises these scavengers [8]. Episodes of catabolic stress, such as intercurrent illness, surgery or pregnancy, require follow-up by a metabolic disease specialist [8]. In a crisis of the neurological form, 10% dextrose, bicarbonate, withholding of protein for at most 24 hours, isoleucine and valine and levocarnitine at 50–100 mg/kg/day are used; in chronic treatment, protein close to the recommended daily allowance, a ketogenic or high-fat diet and dichloroacetate at 50–75 mg/kg/day, with a risk of peripheral neuropathy; one patient with myopathy responded to riboflavin at 220 mg/day [12]. In the Brassier family there was no response to riboflavin [53]. NAC has been proposed in DLD deficiency on the basis of the oxidative mechanism, without clinical data [20].

7.6. Supportive treatment common to all crises

The coagulopathy of ALF marks hepatocellular dysfunction and is not equivalent to bleeding risk, because procoagulants and anticoagulants are both reduced [19]. The reference dose and route for vitamin K are those of NASPGHAN: in paediatric ALF, 1 mg in the infant to 10 mg in the older adolescent subcutaneously, not orally, bearing in mind that the intramuscular and intravenous routes carry a boxed warning in the USA [19]. The labels, cited for comparison, are those in the following paragraph: the US label of injectable phytomenadione agrees on the preferred subcutaneous route, whereas the Portuguese SmPC of Kanakion® MM (oral or slow intravenous route) and of Kanakion® MM Paediatric does not provide for the subcutaneous route and allows the oral route; in Portugal, the subcutaneous route recommended by NASPGHAN falls outside the SmPC conditions [19, 101–103]. Injectable phytomenadione (FDA generic labels, for example that of 17 April 2025) carries a warning of severe reactions, including fatal ones, of the anaphylactic type with intravenous and intramuscular administration, even on the first dose, should be given subcutaneously whenever possible and, intravenously, very slowly, at a maximum of 1 mg/min; in the newborn, the treatment dose for haemorrhagic disease is 1 mg, and failure of the prothrombin time to respond within 2–4 hours indicates another diagnosis; in neonates, especially preterm infants, doses above those recommended are associated with haemolysis and hyperbilirubinaemia [101]. In Portugal, phytomenadione is marketed as Kanakion® MM 10 mg/1 ml, for oral use or slow intravenous injection and which must not be given intramuscularly, and as Kanakion® MM Paediatric 2 mg/0.2 ml, preferred in the newborn and below 1 year, with oral, intramuscular or intravenous administration; in the treatment of haemorrhagic disease of the newborn, the SmPC recommends 1 mg intravenously initially, with subsequent doses guided by clinical status and coagulation [102, 103]. In Portugal, where the subcutaneous presentation is not in the SmPC, the approved alternative is the slow intravenous or oral route of the SmPC [19, 102]. In Brazil, Kavit®, Vikatron®, Hyvit K® and Eskavit® have active registrations [90]. By definition, the coagulopathy of ALF does not correct with vitamin K [2]. Fresh frozen plasma is not used prophylactically, but before invasive procedures or in severe bleeding [19].

Fever contributes to cerebral hyperaemia, and NASPGHAN recommends a cooling blanket to maintain normothermia [19]. Ammonia above 200 µmol/L is a risk factor for death from cerebral oedema; an electroencephalogram is indicated if there are myoclonus or seizures; non-steroidal anti-inflammatory drugs are nephrotoxic; blood cultures should be taken and antibiotics started at the slightest suspicion of sepsis, because fever may be absent; and relative adrenal insufficiency should be considered in refractory hypotension [19]. EASL recommends, in children, broad-spectrum prophylactic antibiotics and antifungals in intensive care, mechanical ventilation in grade 3 encephalopathy or grade 1–2 encephalopathy requiring sedation, and intracranial pressure monitoring only above 2 years with signs of intracranial hypertension awaiting transplantation [25]. Extracorporeal liver support systems are not recommended routinely, and plasmapheresis may serve as a bridge to transplantation [19]. Enteral feeding is preferable to parenteral nutrition [19].

In neonatal ALF, EASL recommends high-dose intravenous aciclovir until herpes simplex virus is excluded [25]. The FDA label of aciclovir sodium for injection (July 2025) indicates, in neonatal herpes simplex infection, from birth to 3 months, 10 mg/kg as a 1-hour infusion every 8 hours for 10 days, mentions the use of 15 or 20 mg/kg every 8 hours with safety and efficacy not established, and sets a maximum of 20 mg/kg every 8 hours; rapid bolus injection and the intramuscular and subcutaneous routes should be avoided [104]. The reference recommendation is that of EASL, high-dose aciclovir, without specifying the dose [25]. For comparison, the label indicates 10 mg/kg every 8 hours in neonatal infection and describes the use of 15–20 mg/kg every 8 hours, with safety and efficacy not established, up to a maximum of 20 mg/kg every 8 hours [104].

7.7. Specific measures in initial management before diagnosis

As soon as a metabolic disease with liver failure is considered, Saudubray recommends excluding galactose, fructose and protein from the diet, while maintaining the remaining nutrients, until confirmation; once galactosaemia or hereditary fructose intolerance is confirmed, protein is reintroduced, and when tyrosinaemia type 1 is suspected nitisinone is started with a diet low in phenylalanine and tyrosine [27]. Withholding protein is not appropriate in ILFS1 nor, according to EASL, below 1 g/kg outside urea cycle defects and organic acidaemias, and in vesicular trafficking defects the priority is anabolism with glucose and lipids [2, 17, 25]. In an infant aged 2–4 months with persistent lactic acidosis and hypoglycaemia, L-cysteine and NAC may be started before diagnosis [3, 76].

7.8. Liver transplantation

EASL considers transplantation the only proven treatment in children meeting poor-prognosis criteria and accepts, as non-validated paediatric listing criteria, INR >4 and total bilirubin >300 µmol/L (17.6 mg/dL) regardless of encephalopathy; contraindications are fixed dilated pupils, uncontrolled sepsis and severe acute respiratory distress syndrome, and relative contraindications are progressive or severe neurological disease with an unacceptable neurological outcome and systemic diseases in which transplantation is not curative, such as HLH [25]. In valproate-associated ALF, which may reveal an unsuspected mitochondrial disease, NASPGHAN considers transplantation contraindicated [19]. The underlying genetic disease does not affect the transplanted liver in the predominantly hepatic disorders of this class [3].

In NBAS deficiency, the 16 transplanted patients of the cohort of 230 (10 ILFS2, 3 combined, 1 SOPH, 2 without subgroup) were all transplanted for ALF, at a median age of 2.15 years and with a median follow-up of 5 years; 5-year survival was 70%, there was no recurrence of ALF, and 7 of the 16 had normalisation of liver function and normal development [13]. There were complications in 9: mild elevations of transaminases during febrile illness (2), repeated acute kidney injury due to tacrolimus overdose (1), rejection or drug-induced injury (2), retransplantation (2), early death from multiorgan failure (1) and severe infection (1), the latter two with hypogammaglobulinaemia [13]. Mortality among transplanted patients (18.8%) was almost double that of the cohort, possibly owing to selection of severe cases [13]. The 2025 review records transplantation in 6 NBAS, 2 RINT1 and 4 CALFAN patients, none with new crises, and considers transplantation in NBAS and RINT1 a last resort, to be discussed, for example, when there are deceased siblings; in SCYL1, the progressive neurological phenotype is a potential contraindication, and difficult neurological deterioration after transplantation has been described [2, 105]. CALFAN patient F3:II.4, transplanted at 23 months after the fourth crisis with stage 3–4 fibrosis, was well 8 years later, with no new decompensations [4]. In the Turkish series, transplanted patients had normal function and histology without hepatic or extrahepatic recurrence [70]. One Atlas patient, transplanted at 3 years, had no further crises [32].

In TRMU deficiency, transplantation has been described in 11 children, at a median age of 4 months, 4 at the first ALF episode, 6 after recurrent episodes and 1 at 11 years for hepatoblastoma, the only described case of this neoplasm in the disease [3]. Transplantation did not change overall survival, and 2 patients died after transplantation, from variceal bleeding and from multiorgan failure; the decision is individual, and transplantation may be considered before targeted therapy in carriers of p.(Met1?), who apparently respond less to cysteine [3]. Lenz and colleagues point out that transplantation in mitochondrial diseases is controversial because of neurological, cardiac or neuromuscular involvement, but that TRMU deficiency and the hepatic form of DLD deficiency have scant extrahepatic involvement and a good neurological prognosis [16]. NASPGHAN adds that mitochondrial diseases, with the exception of POLG-related disorders, tolerate solid organ transplantation with similar survival, although multisystem involvement may not be apparent at the time of transplantation [19]. Saudubray accepts occasional organ transplantation for isolated involvement of a single organ in an otherwise healthy child [44].

7.9. Other interventions

In patients with NBAS deficiency and hypoplastic cervical vertebrae, fixation surgery for cervical instability may be needed [32]. Osteopenia and fractures warrant skeletal assessment, and ophthalmological, immunological and growth follow-up is described in section 11 [12]. In aminoacyl-tRNA synthetase deficiencies, tube or gastrostomy feeding was often needed before specific supplementation [21]. In TRMU deficiency, physiotherapy, occupational therapy and speech therapy form part of the plan [3].

7.10. Dosing table

7.11. Comparative regulatory status

The ANVISA package inserts could not be read (package insert database with a server error); the Brazilian registrations come from ANVISA open data, which do not indicate the pharmaceutical form or posology [90]. The sources consulted identified no orphan designations, applications or authorisations for any disorder of the class, but the FDA and European Medicines Agency orphan designation databases were not searched.

7.12. Treatment trials and studies

The trials and studies in the table do not allow indirect comparisons: only the Squires trial is randomised, and it included paediatric ALF of all causes unrelated to paracetamol, without separate results for the disorders of this class [96]. The survival differences in the TRMU deficiency cohorts are observational, subject to selection and era bias, and those of Kok and Hadchouel refer to 4 patients each [14, 21, 51]. The negative Squires trial is the highest-level evidence available on NAC in children and takes precedence over Sun's observational data when NAC is discussed outside TRMU deficiency [20, 96]. In adults, the US Acute Liver Failure Study Group trial showed better transplant-free survival with NAC in ALF not caused by paracetamol with grade I–II coma (52% versus 30%), a result that cannot be transposed to children [97]. On ClinicalTrials.gov, the search of 26 October 2026 found no registered trials for NBAS, SCYL1, RINT1, TRMU or LARS1; there is a Chinese observational study of the aetiology and prognosis of paediatric ALF (NCT06778941, 400 patients, planned for 2025–2029) and two trials of NAC in ALF not caused by paracetamol limited to adults (NCT06872372 and NCT07765823); a negative search does not demonstrate the absence of studies in other registries [108].

7.13. Developments in the last 12 months

Between 26 October 2025 and 26 October 2026 the following were published: the study by Sun and colleagues (August 2026), with preclinical evidence in fibroblasts that fever induces ER stress, ROS and apoptosis in NBAS deficiency and that NAC attenuates them, and a retrospective clinical study with no significant effect of NAC, accompanied by publication of the Heidelberg emergency protocol and the recommendation of influenza vaccination [20]; the report by Jung and colleagues of SOPH without Pelger-Huët anomaly, with complete deletion of NBAS, and the review of 110 SOPH cases (case study) [49]; the fatal ILFS3 case of Cui and colleagues, with cranial dysmorphism and delayed bone age (case study) [50]; and the cohort study by Grosmaitre and colleagues on neurodevelopment in MARS1-related alveolar proteinosis (only the title was consulted) [74]. On the regulatory side, the Elcys® label was revised on 9 April 2026 without a new indication, and no authorisations, opinions or designations were identified for the class [100, 108]. The 2025 review is not aware of any ongoing gene therapy approaches for NBAS deficiency, whose large gene size is an obstacle [2].

7.14. Agents and circumstances to avoid

In TRMU deficiency, drugs that increase metabolic demand, such as corticosteroids, or inhibit mitochondrial activity, such as valproic acid and prolonged propofol infusion, should be avoided, as should fasting; if corticosteroids are indicated, they are used under the guidance of a metabolic disease specialist, with lactate monitoring; high dextrose concentrations may worsen lactic acidosis, and avoidance of paracetamol during liver dysfunction should be considered [3]. In vesicular trafficking disorders, the 2025 review advises against ibuprofen and paracetamol during crises [2]. In DLD deficiency, fasting, hepatotoxic drugs and extreme diets should be avoided [8]. In aminoacyl-tRNA synthetase deficiencies, protein restriction and fasting should be avoided [17, 21]. Valproate is contraindicated when mitochondrial disease is suspected, particularly with POLG variants [25, 44]. Nucleoside analogues cause acquired mtDNA depletion, as shown by the suspension of the fialuridine trials in 1994 after 6 deaths from ALF [75]. In the beta-oxidation defects of the differential, intravenous lipids, valproate, non-steroidal anti-inflammatory drugs and salicylates are avoided [19].

7.15. Pregnancy, lactation, perioperative care and transition

In TRMU deficiency, the only published experience in pregnancy with an affected fetus is that of a mother who took L-cysteine 500 mg twice a day in the third trimester; the child had a milder course than the affected sister [3]. Metamizole is contraindicated in the third trimester and during breastfeeding [87]. Acetylcysteine crosses the placenta, data in pregnancy are insufficient, and during breastfeeding milk may be pumped and discarded for 30 hours [95]. In DLD deficiency, pregnancy and surgery are episodes of catabolic stress requiring specialised follow-up [8]. The sources consulted do not describe pregnancies in women with NBAS, RINT1 or SCYL1 deficiency, nor reproduction in patients with TRMU deficiency [3]. In the perioperative period, the 2025 cohort recorded surgery, chemotherapy and difficult blood sampling as isolated triggers of NBAS crises, which justifies maintaining the anabolic protocol and temperature control around procedures [13]. In TRMU deficiency, prolonged propofol infusion should be avoided [3]. As NBAS crises decrease with age but have occurred up to 24 years, and as DLD deficiency and ILFS1 persist into adulthood, transition to adult care should hand over the emergency plan [8, 13, 17]. ALF may occur in adults with urea cycle disorders, another reason to keep these disorders in the differential beyond the paediatric age [27].

7.16. Guideline recommendations and divergences

The ESPGHAN position, published as proceedings of a 2020 monothematic conference, states that it does not represent the society's policy and was not used as a guideline [109]. The main divergence concerns NAC: the paediatric societies rely on the negative Squires trial, and the Heidelberg group on a pathophysiological rationale and non-significant observational data [20, 96]. The divergence over the antipyretic results from the unavailability of metamizole in some countries and from the conflict between the theoretical hepatotoxicity of paracetamol and the bleeding and renal risk of ibuprofen [2, 19].

8. Reproductive Options and Family Counselling

8.1. Inheritance pattern and recurrence risks

All entities of the class are autosomal recessive [2, 3, 8]. The parents of an affected child are presumed heterozygous, and both should be tested for the identified variants [3]. In each pregnancy of the same couple, the risk is 25% of an affected child, 50% of an asymptomatic carrier and 25% of a non-carrier; heterozygotes are asymptomatic and are not at risk of disease [3]. The proband's aunts and uncles have a 50% probability of being carriers [3]. All children of a patient are obligate heterozygotes, unless the partner is a carrier or affected [3]. If the variant is found in only one parent, with confirmed parentage, a de novo variant in the proband or parental post-zygotic mosaicism should be considered; apparent homozygosity requires exclusion of an undetected deletion on the other allele or uniparental isodisomy [3]. In NBAS deficiency, complete deletion of the gene on one allele has been documented, which makes CNV analysis part of parental testing [49].

Intrafamilial variability limits prediction: in NBAS deficiency, siblings with the same genotype may differ in the occurrence of ALF, although the correlation between individuals with the same genotype is strong, especially in the ILFS2 subgroup [13, 57]. The useful information for the family is that the subgroup predicted by genotype and the proband's history give the best estimate of severity in an affected sibling, without individual certainty [13, 57]. Lenz and colleagues stress that only a genetic diagnosis allows the recurrence risk in another child to be predicted [16]. Cui's case shows the consequence of the lack of a diagnosis: the older sister died at 19 months of fulminant ALF without genetic testing, which the parents declined, and a new pregnancy without counselling resulted in a second affected child [50].

8.2. Cascade testing and presymptomatic diagnosis

Testing of siblings is recommended in vesicular trafficking disorders, so that the emergency plan is ready before the first crisis [2, 12]. The 2025 review mentions reports of milder or prevented crises in NBAS patients diagnosed before symptoms through family history and treated early [2]. In the cohort of 230 patients, one patient diagnosed through family screening and treated with early antipyresis had only Pelger-Huët anomaly up to 5 years of age [13]. The study by Hammann and colleagues, however, did not show that presymptomatic diagnosis prevents ALF [57]. In TRMU deficiency, the newborn sibling of a patient should receive L-cysteine, and possibly NAC, from birth until the result of testing for the familial variants, if there is no prenatal diagnosis [3]. Earlier supplementation was associated with a better course in 2 at-risk siblings [3, 76]. Carrier testing requires that the familial variants be identified, and should be offered to the partner of a known carrier, especially in populations with founder variants: Jews of Yemenite descent for TRMU c.229T>C, Yakuts for NBAS c.5741G>A, Ashkenazi Jews and Arab populations for DLD c.685G>T, the Amish for YARS1 c.499C>A and Irish Travellers for LARS1 [3, 8, 9, 17, 33, 53].

In RINT1 deficiency, heterozygotes, including the parents of a proband with ILFS3, should not be considered at oncological risk or placed on enhanced breast surveillance, because the relationship with hereditary breast carcinoma has been refuted by ClinGen [12]. In TRMU deficiency, carriers of the c.28G>T p.(Ala10Ser) variant, which does not cause the liver disease, may have an increased risk of aminoglycoside-induced deafness if they also carry MT-RNR1 m.1555A>G [3].

8.3. Prenatal diagnosis and preimplantation genetic testing

Once the familial pathogenic variants have been identified, prenatal diagnosis by amniocentesis or chorionic villus sampling and preimplantation genetic testing are possible; counselling should ideally take place before pregnancy [3]. In TRMU deficiency, prenatal diagnosis guides maternal L-cysteine supplementation in the third trimester and immediate supplementation of the newborn; the child whose mother received 500 mg of L-cysteine twice a day had a milder course than the affected sister [3]. For entities without prenatal treatment, prenatal diagnosis informs the couple's reproductive decision and the preparation of the emergency plan for the newborn [2]. The differential of neonatal ALF includes gestational alloimmune liver disease, with a recurrence risk of up to 90% in a subsequent pregnancy, preventable with intravenous immunoglobulin during pregnancy; its counselling differs completely, because it is not genetic [25, 78].

8.4. Counselling of minors and content of the consultation

Testing of asymptomatic minor siblings is justified in the disorders of this class because the result has immediate clinical consequences, that is, the emergency plan for fever or cysteine supplementation in the newborn [2, 3]. The consultation should address recurrence risk, variability of severity, the written emergency plan, the emergency card, information to be given to the nursery, school and primary care, influenza vaccination in NBAS deficiency and, in TRMU deficiency, supplementation in the next newborn [2, 3, 20, 32]. Parents should know that crises tend to attenuate with age, but that susceptibility diminishes without disappearing [13].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What the available figures measure

There is no validated population estimate of prevalence or incidence for any entity of the class [12]. Orphanet classifies SOPH, infantile fever-associated ALF syndrome (NBAS and RINT1), CALFAN and ILFS1 as <1/1,000,000, but the case counts it associates with these entries (39 for SOPH and 11 for the fever-associated syndrome) are far below the number of published patients, 230 with biallelic NBAS variants in 2025 and 110 SOPH cases reviewed in 2026 [12, 13, 49]. Numbers of published patients measure the literature, not frequency: 230 with NBAS deficiency [13], 62 with TRMU deficiency [14], 25 with ILFS1 [15], about 23 with CALFAN [2], 6 with ILFS3 up to 2023, plus Cui's case and the sister without genetic testing [2, 50], 3 with IARS1 deficiency in the original description and 1 in 2017 [39, 63] and more than 30 with YARS1 deficiency [9].

Casey and colleagues estimated the prevalence of infantile liver failure at less than 1 per 1,000,000, an estimate cited by OMIM without a description of the method [61]. The best measure of the relative importance of the class is the proportion of diagnoses in a reference population of indeterminate paediatric ALF: in the PALFES study, 37% of 260 children from 19 countries had a genetic diagnosis, NBAS accounted for 21% of diagnoses and vesicular trafficking disorders for 28% [16]. This proportion refers to children without a diagnosis after local investigation, recruited mainly in Germany, Japan and the United Kingdom (70%), with possible overrepresentation of mitochondrial disease and RALF; it is not a population rate [16]. A single-centre retrospective series of 148 paediatric ALF cases (2001–2011), studied with a next-generation sequencing panel before the exome era, found a genetic cause in 27% of indeterminate cases [16]. In the Birmingham audit (39 consecutive infants with ALF, 2009–2011; 30 white, 5 Asian and 4 black), there was genetic mitochondrial liver disease in 5 (12.8%; the article's abstract gives 17% and the results 13%, an internal discrepancy) and one case of RALF due to NBAS [77]. The introduction of the same article cites about 20% of infantile ALF as due to genetic mitochondrial liver disease [77].

9.2. United States and Europe

In the United States, an estimated 500 to 600 paediatric ALF cases occur per year, without regional variation and stable over the last decade; the main causes are paracetamol poisoning (13%), metabolic diseases (10%) and viral infections (8%) [16, 19]. The PALF Study Group registry, with 1144 children from 19 centres in the United States, Canada and the United Kingdom (1999–2014), attributed 28–36% of paediatric ALF to metabolic diseases and left 43% indeterminate [19]. Paediatric ALF accounts for about 8% of annual paediatric liver transplants in the United States, and up to 10.3% according to NASPGHAN [2, 19]. In Europe there is no systematic data collection; single-centre series attribute 14–28% to inherited metabolic diseases and 12–16% to viral infections, and the most common causes are infectious and metabolic [2, 16]. Incidence is probably higher in developing countries, owing to infectious hepatitis; in Argentina, vaccination against hepatitis A virus reduced transplant listings for this virus from 60% to 0% [19]. The sources consulted contain no data from Portugal or Brazil for any entity of the class, nor for paediatric ALF in general; this absence in the sources does not demonstrate that no published data exist.

9.3. Founder populations

The NBAS variant c.5741G>A p.(Arg1914His) has a carrier frequency of 1.3% (13 per 1000) in healthy Yakuts of the Sakha Republic, an estimated age of 804 ± 140 years and homozygosity in 33 of 34 patients with SOPH from that population [33, 110]. As this is an isolate with non-random mating, birth prevalence cannot be reliably derived from the Hardy-Weinberg law [12]. In the 2025 cohort, 91 of the 230 patients lived in isolation in Yakutia, which explains the predominance of the SOPH subgroup and the rarity of liver disease in that subgroup (liver abnormality in 11% of Yakuts) [13]. China contributed 29 patients [13]. In TRMU deficiency, the c.229T>C p.(Tyr77His) variant is a founder variant in Jews of Yemenite descent, among whom the disease is particularly common [3]. In DLD deficiency, the carrier frequency of c.685G>T p.(Gly229Cys) in Ashkenazi Jews is 1:94 to 1:110 and the estimated disease frequency 1:35,000 to 1:48,000, probably underestimated; the variant is also frequent in Arab, Middle Eastern and Maghrebi patients [8, 53, 111]. ILFS1 was described as a founder disease of Irish Travellers, and the first non-Irish patient was of Ashkenazi origin [17, 18]. In YARS1 deficiency, p.(Pro167Thr) is a founder variant in the Amish population [9]. In MARS1 deficiency, the cis variants p.(Ser567Leu) and p.(Ala393Thr) were found in homozygosity in 26 patients from Réunion Island, the Comoros and Madagascar [62]. Consanguinity was associated with a diagnostic yield of 61% in the PALFES study, with homozygosity in 20 of 22 diagnoses [16].

9.4. Special populations

In newborns, gestational alloimmune liver disease is the most common cause of ALF, and the class has little strictly neonatal expression, because crises due to IARS1, LARS1, SCYL1 and NBAS often begin after the neonatal period [25, 26]. In the PALFES study, 5 of 50 newborns had ALT <100 U/L, 2 of them with DGUOK deficiency, and gestational alloimmune disease was not included [16]. Adults may have crises due to NBAS (up to 24 years), DLD and urea cycle defects [8, 13, 27]. Patients with NBAS deficiency and hypogammaglobulinaemia or NK deficiency form a specific infectious risk group [32, 56].

9.5. European Reference Networks and patient associations

ERN RARE-LIVER, the European Reference Network for rare hepatological diseases, includes a paediatric group and a section for patient organisations [22]. MetabERN covers inherited metabolic diseases, including TRMU deficiency, DLD deficiency and aminoacyl-tRNA synthetase deficiencies [23]. ERN-RND covers the neurological phenotype of SCYL1 and RINT1 [24]. The TRMU GeneReviews lists the American Liver Foundation, the Childhood Liver Disease Research Network (ChiLDReN), Liver Canada, Liver UK, the United Mitochondrial Disease Foundation and the patient contact registry of the North American Mitochondrial Disease Consortium [3, 112]. The Children's Liver Disease Foundation operates in the United Kingdom [113]. No patient association specific to NBAS, RINT1 or SCYL1 deficiency was identified in the search performed.

10. Illustrative Clinical Case

10.1. Case 1: CALFAN due to a homozygous SCYL1 variant

Lenz and colleagues described, as the exemplary case of the CALFAN series, a boy born to healthy non-consanguineous German parents, born at term with normal weight, who had neonatal hyperbilirubinaemia that resolved without phototherapy [4]. At 11 months, one week after a febrile illness with diarrhoea and fatigue, scleral jaundice appeared, with a cholestatic pattern, direct hyperbilirubinaemia, raised AST, mildly impaired liver function and only marginally raised GGT; tests normalised within a month, with AST persisting at about 60 U/L [4]. By 23 months he had had 3 further similar episodes, always with febrile infections, and hepatomegaly only during crises [4]. Across the episodes, ALT ranged from 79 to 880 U/L (median 183), AST from 230 to 1964 U/L (median 732), total bilirubin from 17 to 118 µmol/L, direct bilirubin from 12 to 102 µmol/L, GGT from 13 to 77 U/L (median 69; normal <60), alkaline phosphatase from 403 to 1197 U/L, INR from 1.08 to 1.56 and albumin from 33.9 to 39 g/L [4].

In the crisis at 23 months, glycosylation of transferrin and apolipoprotein CIII showed a CDG type II pattern, which subsequently normalised; urinary bile acids and infectious and immunological investigations were negative, ultrasound scans were normal and abdominal MRI showed heterogeneous perfusion suggestive of fibrosis [4]. Liver biopsy at 15 months showed lipid inclusions and portal and periportal fibrosis with a ductular reaction [4]. After 23 months there were no new crises, despite febrile infections [4]. At 21 months the only neurological finding was secondary microcephaly, with slightly delayed speech and transient stuttering; at 3 years and 1 month frequent falls appeared, attributed to mild truncal and proximal weakness, with a normal electroencephalogram, MRI with subcortical T2 hyperintensity due to incomplete myelination and foci of gliosis on FLAIR, without atrophy of the cerebellum or optic nerves, and normal spinal MRI; at 3 years and 7 months he was asymptomatic; the clinical table of the series records secondary microcephaly of −2.94 standard deviations [4]. Exome sequencing identified the homozygous SCYL1 variant NM_020680.4:c.1882C>T p.(Gln628Ter), and loss of the protein was confirmed in tissue [4, 54]. Figure 2 of the paper shows the hepatic histology and ultrastructure of the patients in the series, with microvesicular steatosis, fibrosis, CK7-positive ductular proliferation and a disorganised Golgi on electron microscopy (https://pmc.ncbi.nlm.nih.gov/articles/PMC5989927/figure/Fig2/) [4].

The case brings together the elements that distinguish CALFAN: cholestatic crises with low or normal GGT triggered by fever, laboratory recovery with underlying fibrosis, cessation of crises at around 2 years and a neurological phenotype that becomes apparent later [2, 4]. It also shows that transient abnormal glycosylation during a crisis may lead to a mistaken diagnosis of CDG if it is not repeated outside the crisis [4]. The reported management was supportive; the fever protocol with early antipyresis, recommended in 2025 for SCYL1 by extrapolation from NBAS, was not part of the case [2, 4].

10.2. Case 2: fatal ILFS3 due to compound heterozygous RINT1 variants

Cui and colleagues described a boy, the second child of non-consanguineous parents, followed at the Children's Hospital of the Xinjiang Uygur Autonomous Region, China, born at 38 weeks weighing 2.0 kg and measuring 45 cm, below the 3rd centile, and admitted for 8 days to neonatal care for low weight and suspected intrauterine infection [50]. He had weak sucking and progressive cognitive, motor, language and growth delay: head control at 4 months, not sitting or walking at 2 years and 6 months and language limited to single words [50]. He had short stature, severe wasting, a broad forehead and cranial dysmorphism with a short anteroposterior and elongated laterolateral diameter, without craniosynostosis on MRI, without hepatosplenomegaly; lumbar radiography showed localised kyphosis and beak-like deformities of the anterior margins of L3 to L5, and bone age was delayed by about 6 months at 9 months [50].

He had febrile acute liver injury at 9 and 19 months, with maximum AST/ALT of 2461/1902 U/L and 4161/7156 U/L and INR of 1.4, and febrile ALF with vitamin K-refractory coagulopathy at 29 and 30 months, with AST/ALT of 4867/1426 and 4438/17,367 U/L, INR of 7.3 and 8.6, prothrombin time of 60.5 and 98.9 seconds, total bilirubin of 70.9 and 91.08 µmol/L and blood glucose of 3.72 and 2.76 mmol/L [50]. Episodes began with fever of 38–40 °C after infection, lethargy and vomiting, and transaminases never normalised between crises (AST/ALT minima of 286/47 to 825/178 U/L) [50]. He received antipyretics, hepatoprotectors, antivirals and anti-infectives and fresh frozen plasma, with only partial improvement; in the fourth episode, severe ALF progressed to hepatorenal syndrome with oedema and oliguria, and he died during continuous venovenous haemodiafiltration [50]. Liver transplantation was not performed because of financial constraints [50]. The exome identified a deletion of exons 12 to 14 and the splicing variant NM_021930.6:c.1672-1G>T p.? of RINT1 in compound heterozygosity, without functional studies or metabolic screening [50]. The older sister, also small for gestational age and with global delay, had died at 19 months, one day after admission, of fulminant ALF with encephalopathy and hyperammonaemia (AST/ALT 12,688/21,035 U/L, INR 7, blood glucose 2.36 mmol/L), without genetic testing because the parents declined [50]. Figure 1 of the paper shows the photographs and cranial MRI (https://pmc.ncbi.nlm.nih.gov/articles/PMC12554618/figure/F1/) and figure 2 the lumbar radiograph with the beaked vertebrae and the bone age (https://pmc.ncbi.nlm.nih.gov/articles/PMC12554618/figure/F2/) [50].

The case documents the recurrent RINT1 c.1672-1 splice acceptor, also affected in the two Launay families, the progression to increasingly severe ALF without intercrisis normalisation and the importance of counselling after the death of the first child [42, 50]. The reported «hepatoprotectors» have no basis in the guidelines consulted, and the authors attribute to RINT1 an association with breast cancer that ClinGen refuted in 2023 [12, 50]. The emergency protocol with early antipyresis and anabolic infusion and assessment for transplantation, discussed in section 7, were not part of the management described [2].

10.3. Siblings with TRMU deficiency treated before symptoms

In the series of Murali and colleagues, summarised in the GeneReviews, patient 2 had a prenatal diagnosis; the mother received L-cysteine 500 mg twice a day in the third trimester, and after birth the child received NAC at 150 mg/kg/day and L-cysteine at 140 mg/kg/day, later reduced to 110 and 85 mg/kg/day for maintenance, and bicarbonate at 1.2 mEq/kg/day, which was not needed in the long term [3, 76]. He had lactic acidosis, hypoglycaemia and hyperammonaemia from 2 months and raised transaminases, but not ALF; at 12 months he was asymptomatic and developing normally, despite persistently raised lactate, transaminases and conjugated bilirubin, and at 3 years he remained asymptomatic with raised lactate [3]. The affected sister, diagnosed after symptoms, had had a more severe course [3]. Patient 6, previously described by Soler-Alfonso, received cysteine from birth, but was admitted at 6 months with vomiting, transaminitis, raised lactate and hyperammonaemia, and during a month in hospital liver function worsened without liver failure; he received blood products for coagulopathy, intravenous bicarbonate and lactulose, was listed for transplantation and was discharged on oral sodium citrate and citric acid, NAC and L-cysteine [3, 65]. At 26 months he had stage 4 micronodular cirrhosis, hepatomegaly and short stature, walked unaided, had normal fine motor skills and said few words [3]. The two cases show that early supplementation attenuates the course but does not guarantee prevention of liver disease, and the doses used are those of a series, not an established posology [3].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis by entity

In the PALFES study, at the time of analysis, 181 of the 260 children were alive (134 with native liver and 47 transplanted) and 79 had died, 9 after transplantation; 72% of deaths from ALF occurred in the first year of life, and native liver survival was greater in RALF than in isolated ALF, greater in vesicular trafficking disorders than in mitochondrial disorders and lower the earlier the onset [16]. These figures refer to a cohort of indeterminate ALF treated in specialised centres, not to the natural history of each disease.

In NBAS deficiency, the cohort of 230 patients recorded 24 deaths (10.4%), with a median age at death of 2.2 years (4 months to 24 years), and ALF was the main cause (66.7%); in the combined and ILFS2 subgroups it was the only cause, except for one death during transplantation, and in SOPH 2 of 6 deaths were due to ALF [13]. Mortality was 22.2% in the combined subgroup and 4.8% in SOPH [13]. Native liver survival was 83.9% overall, 95.2% in SOPH, 66.7% in ILFS2 and 61.1% in the combined subgroup [13]. Among the 95 patients with at least one ALF, mortality was 18.9% and survival with non-native liver 32.6%, values that compare favourably with the 30–47% mortality and 48–76% survival with non-native liver described in paediatric ALF of all causes, indicating a higher rate of spontaneous recovery [13]. The factors associated with an unfavourable outcome (transplantation or death) were subgroup (ILFS2 and combined versus SOPH), the presence of ALF, maximum INR (mean 10.25 versus 4.84), maximum total bilirubin (128.4 versus 78.87 µmol/L), minimum albumin (29.35 versus 35.21 g/L), maximum ammonia (256.9 versus 154.3 µmol/L) and maximum PELD score (Pediatric End-Stage Liver Disease; 172.5 versus 67.09); maximum transaminases did not differ significantly [13]. The association between skeletal involvement or short stature and a better outcome reflects the SOPH subgroup and not a protective effect [13]. Susceptibility decreases with age, with 90% of patients having had their last ALF by 10 years, but does not disappear [13]. Fibrosis may progress silently between crises [13, 70].

In TRMU deficiency, 20 of 60 infants symptomatic at initial assessment died: 8 from complications of liver failure (one from variceal bleeding), 8 from multiorgan failure, 3 from cardiorespiratory failure and 1 from sepsis, with a median age at death of 3 months [3]. In the Vogel cohort, 42 of 62 were alive at a median age of 6.8 years (0.6 to 22) after a median follow-up of 3.6 years, and ALF was generally transient and reversible [14]. Neurodevelopmental delay occurred in 11 and persisted in 4 survivors, and it is not known whether it is primary or secondary to ALF; in a retrospective study of 25 individuals, 9 resolved the delay months after hepatic recovery, 5 retained it and 11 were lost to follow-up or died [3, 14]. In the Zeharia series, survivors had no recurrence over up to 14 years of follow-up [28]. The risk of childhood liver neoplasia, theoretical as in other mitochondrial liver diseases, materialised in a hepatoblastoma at 11 years [3].

In CALFAN there were no deaths among 23 compiled patients, but fibrosis is constant in the original series and the neurological phenotype progresses with age [2, 4]. In ILFS3, the 2025 review records 3 deaths in 6 patients in its table and 2 deaths from ALF in the text, at 14 months and 3 years; Cui's case adds one death and that of the sister [2, 50]. In ILFS1, encephalopathic episodes were fatal in 2 of 10 patients, and 2 patients over 28 years of age were clinically well [17]. In YARS1 deficiency, 7 children with severe liver disease died between 10 and 25 months and one p.(Arg367Trp) homozygote died at 15 years of an unknown cause; in survivors, liver function stabilises after 2–3 years [9]. In MARS1 deficiency, one third die before 2 years without treatment [51]. In the hepatic form of DLD deficiency, crises recur throughout life, decrease with age and may be fatal even in late presentations [8].

11.2. Surveillance

The sources do not establish surveillance intervals for NBAS, RINT1 or SCYL1 deficiency, so frequency is clinical; the annual intervals indicated derive from the TRMU GeneReviews [3, 12].

11.3. Prognosis with treatment and gaps

The effect of treatment is documented only in TRMU deficiency, in which cysteine supplementation was associated with survival of 84% versus 61% [3, 14]. In NBAS deficiency, the data do not allow the effect of each measure of the emergency protocol to be assessed, and presymptomatic diagnosis with a protocol did not prevent ALF [13, 57]. In aminoacyl-tRNA synthetase deficiencies, improvement with the specific amino acid has been described in series of 4 patients [21, 51]. Transplantation eliminates recurrence of ALF in NBAS deficiency and CALFAN, but does not change extrahepatic disease and, in TRMU deficiency, did not improve overall survival [2, 3, 13].

12. Summary and Final Considerations

The monogenic forms of infantile and recurrent ALF without a biochemical marker bring together disorders of vesicular trafficking between the Golgi and the ER (NBAS, RINT1, SCYL1), cytosolic aminoacyl-tRNA synthetase deficiencies (LARS1, IARS1, MARS1, YARS1), TRMU deficiency and the hepatic form of DLD deficiency, all autosomal recessive [1, 2]. They share a functional reserve that fails with fever, infection or catabolism, crises that tend to attenuate with age and a diagnosis that depends on genetic testing [2, 16]. In paediatric ALF of indeterminate cause, exome sequencing establishes the diagnosis in 37% of children and in 64% of those with recurrent crises, and NBAS is the most frequent gene; therefore, rapid exome or genome sequencing, with CNV analysis, should run in parallel with metabolic investigation from the first crisis [16].

Clinical recognition relies on age and the pattern of the crisis. An infant aged 2 to 4 months with persistent lactic acidosis and hypoglycaemia and ALF suggests TRMU deficiency, and L-cysteine with NAC may begin before the molecular result [3, 76]. Crises 1 to 2 days after the onset of fever, with transaminases in the thousands, high INR and recovery between episodes, suggest NBAS or RINT1, and low-GGT cholestasis with fibrosis suggests SCYL1 [2, 4, 32]. Anaemia, hypoalbuminaemia and tubulopathy point to LARS1, lung disease to MARS1 or YARS1 and neonatal diabetes to Wolcott-Rallison syndrome [2, 9, 17, 51].

Treatment is supportive, with specific elements of limited evidence: the fever protocol with early antipyresis and anabolism in vesicular trafficking disorders, cysteine in TRMU deficiency and sufficient protein with the missing amino acid in aminoacyl-tRNA synthetase deficiencies [2, 3, 21]. The choice of antipyretic and the use of NAC outside TRMU deficiency divide the sources: the Heidelberg group recommends metamizole, absent from the US market and subject to haematological contraindications in the EU, and considers NAC, which the PALF Study Group paediatric trial and NASPGHAN do not support [2, 19, 91, 96]. Liver transplantation eliminates recurrence of ALF, but is reserved for selected cases, because of the natural attenuation of crises and, in SCYL1, neurological progression [2, 13].

Prognosis differs between entities: native liver survival is 95.2% in SOPH and 61.1% in the combined NBAS phenotype, there were no deaths among 23 patients with CALFAN, and one third of symptomatic infants with TRMU deficiency died, at a median age of 3 months [2, 3, 13]. Follow-up covers the liver between crises, where fibrosis may progress silently, and the extrahepatic manifestations of each type [12, 70]. Genetic counselling and testing of siblings allow the emergency plan to be prepared before the first crisis and, in TRMU deficiency, supplementation of the next newborn from birth [2, 3]. Data from Portugal and Brazil are lacking in the sources consulted, as are prospective studies of the emergency protocol and trials of specific treatment.

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