Infantile Liver Failure Syndrome Type Research Articles

Biallelic variants in LARS1 induce steatosis in developing zebrafish liver via enhanced autophagy

BackgroundBiallelic pathogenic variants of LARS1 cause infantile liver failure syndrome type 1 (ILFS1), which is characterized by acute hepatic failure with steatosis in infants. LARS functions as a protein associated with mTORC1 and plays a crucial role in amino acid-triggered mTORC1 activation and regulation of autophagy. A previous study demonstrated that larsb-knockout zebrafish exhibit conditions resembling ILFS. However, a comprehensive analysis of larsb-knockout zebrafish has not yet been performed because of early mortality.MethodsWe generated a long-term viable zebrafish model carrying a LARS1 variant identified in an ILFS1 patient (larsb-I451F zebrafish) and analyzed the pathogenesis of the affected liver of ILFS1.ResultsHepatic dysfunction is most prominent in ILFS1 patients during infancy; correspondingly, the larsb-I451F zebrafish manifested hepatic anomalies during developmental stages. The larsb-I451F zebrafish demonstrates augmented lipid accumulation within the liver during autophagy activation. Inhibition of DGAT1, which converts fatty acids to triacylglycerols, improved lipid droplets in the liver of larsb-I451F zebrafish. Notably, treatment with an autophagy inhibitor ameliorated hepatic lipid accumulation in this model.ConclusionsOur findings suggested that enhanced autophagy caused by biallelic LARS1 variants contributes to ILFS1-associated hepatic dysfunction. Furthermore, the larsb-I451F zebrafish model, which has a prolonged survival rate compared with the larsb-knockout model, highlights its potential utility as a tool for investigating the pathophysiology of ILFS1-associated liver dysfunction.

Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease

Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity.

The Function of the <i>NBAS</i> Has Been Revealed, Will the Same Happen with Its Multisystem Pathologies?

Mutations in the NBAS gene cause two groups of diseases – SOPH-syndrome and Infantile liver failure syndrome type 2 (ILFS2, RALF), which differ in clinical manifestations, course, and prognosis. In the current review we focused on clinical and genetic aspects of these pathologies and molecular biology of the NBAS protein, its retrograde membrane traffic and nonsense-mediated RNA decay.

Pregnancy, delivery, and postpartum period in infantile liver failure syndrome type 2 due to variants in NBAS.

Biallelic pathogenic variants in the neuroblastoma amplified sequence (NBAS) gene affecting the Sec39 domain are associated with a predominant hepatic phenotype named infantile liver failure syndrome type 2 (ILFS2). Individuals are at risk of developing life-threatening acute liver failure episodes, most likely triggered by febrile infections. Pregnancy, delivery, and the postpartum period are well known triggers of decompensation in different inherited metabolic diseases and therefore entail a potential risk also for individuals with ILFS2. We studied pregnancy, birth, and postpartum period in a woman with ILFS2 (homozygous for the NBAS variant c.2708 T > G, p.(Leu903Arg)). During two pregnancies there were no complications associated with the underlying genetic condition. Two healthy boys were born by cesarean section. To reduce the risk of fever and febrile infections, we avoided prolonged labor, epidural analgesia, and breastfeeding. Maternal body temperature and liver function were closely monitored. In case of elevated body temperature, antipyretic treatment (acetaminophen, metamizole) was given without delay. Alanine and aspartate aminotransferases as well as liver function remained normal throughout the observation period. Hence, pregnancy and childbirth are feasible in women with ILFS2 under careful monitoring.

Clinical features and genetic testing of a child with hepatic failure syndrome type 2

To explore the genetic basis for a child with infantile liver failure syndrome type 2 (ILFS type 2). Clinical features of the child were analyzed. Next generation sequencing was also carried out for him. The child was found to harbor compound heterozygous variants of the NBAS gene, which included a novel nonsense c.2746A>T (p.R916X, 1456) variant in exon 24 and a missense c.3596G>A (p.C1199Y) mutation in exon 31, which has been associated with ILFS type 2. The two variants were respectively inherited from his father and mother. The compound heterozygous variants of c.3596G>A and c.2746A>T of the NBAS gene probably underlay the ILFS type 2 in this child.

Deep phenotyping of MARS1 (interstitial lung and liver disease) and LARS1 (infantile liver failure syndrome 1) recessive multisystemic disease using Human Phenotype Ontology annotation: Overlap and differences. Case report and review of literature

IntroductionAminoacyl transfer RNA (tRNA) synthetases are associated with diseases when mutations occur in their encoding genes. Pulmonary alveolar proteinosis can be caused by mutation in the methionyl-tRNA synthetase (MARS) gene while mutations in the leucine-tRNA synthetase (LARS) gene lead to infantile liver failure syndrome type 1.We report the case of a patient with LARS1 pathogenics variants and two patients with MARS1 pathogenics variants. The aim of this study was to analyze the phenotypes of our three patients in detail and classify cases in the literature using Human Phenotype Ontology (HPO) terms. ResultsThe first patient has two previously undescribed heterozygous variants in LARS1 (c.1818dup and c.463A>G). The other two patients' MARS1 variants (c.1177G>A and c.1700C>T) have already been described in the literature.All three patients had anemia, hepatomegaly, feeding difficulties, failure to thrive and hypoalbuminemia.Including ours, 65 patients are described in total, for whom 117 phenotypic abnormalities have been described at least once, 41.9% of which both in patients with LARS1 and MARS1 mutations. ConclusionPatients with LARS1 and MARS1 mutations seem to share a common phenotype but further deep phenotyping studies are required to clarify the details of these complex pathologies.

Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish

Leucyl-tRNA synthetase (LARS) is an enzyme that catalyses the ligation of leucine with leucine tRNA. LARS is also essential to sensitize the intracellular leucine concentration to the mammalian target of rapamycin complex 1 (mTORC1) activation. Biallelic mutation in the LARS gene causes infantile liver failure syndrome type 1 (ILFS1), which is characterized by acute liver failure, anaemia, and neurological disorders, including microcephaly and seizures. However, the molecular mechanism underlying ILFS1 under LARS deficiency has been elusive. Here, we generated Lars deficient (larsb−/−) zebrafish that showed progressive liver failure and anaemia, resulting in early lethality within 12 days post fertilization. The atg5-morpholino knockdown and bafilomycin treatment partially improved the size of the liver and survival rate in larsb−/− zebrafish. These findings indicate the involvement of autophagy in the pathogenesis of larsb−/− zebrafish. Indeed, excessive autophagy activation was observed in larsb−/− zebrafish. Therefore, our data clarify a mechanistic link between LARS and autophagy in vivo. Furthermore, autophagy regulation by LARS could lead to development of new therapeutics for IFLS1.

Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants in LARS1

PurposeBiallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. MethodsIndividuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. ResultsTwenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. ConclusionILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.

NBAS disease: 14 new patients, a recurrent mutation, and genotype-phenotype correlation among 24 Chinese patients.

Neuroblastoma amplified sequence (NBAS)-associated disease has a wide phenotypic spectrum, including infantile liver failure syndrome type 2 (ILFS2, OMIM #616483), short stature with optic nerve atrophy and Pelger-Huët anomaly (SOPH) syndrome (OMIM #614800), and a combined phenotype overlapping ILFS2 and SOPH syndrome. The mutation spectra of NBAS and its genotype-phenotype correlation among Chinese were not clear. Clinical and genetic data were retrospectively collected from the medical charts of patients with biallelic NBAS mutations, as well as from Chinese patients in previously published reports. Fourteen new patients were identified, including 10 novel mutations: c.648-1G>A, c.2563_c.2577+5del/p.His855_Gln859del, c.3115C>T/p.Gln1039Ter, c.3284G>A/p.Trp1095Ter, c.2570C>T/p.Ala857Val, c.6859G>T/p.Asp2287Tyr, c.1028G>A/p.Ser343Asn, c.1177_1182delinsAGATAGA/p.Val393ArgfsTer2, c.3432_3435dupCAGT/p.Ala1146GlnfsTer14, and c.680_690dupACTGTTTCAGC/p.Phe231ThrfsTer35. All 14 patients presented as fever-triggered liver injury, including nine patients that satisfied the criteria of acute liver failure (ALF) in whom c.3596G>A/p.Cys1199Tyr occurred five times. Nine patients had extrahepatic manifestations including short stature, skeletal abnormalities, intellectual disability, ophthalmic abnormalities, low levels of serum immunoglobulins, facial dysmorphism, and cardiac abnormalities. Ten other Chinese patients were collected through a review of published works. Genotype-phenotype analysis in 24 Chinese patients revealed that the percentage of ALF patients with variants in the Sec39 domain was significantly higher than that in the C-terminal (100% vs. 12.5%, P = 0.000), and the percentage of multi-organ/system involvement in patients with variants in the Sec39 domain was significantly lower than that in the C-terminal (40% vs. 100%, P = 0.0128). We reported 14 new patients, 10 novel mutations, and a unique recurrent mutation. Correlation analysis indicated that the domain of missense and non-frameshift insertion/deletion mutations in NBAS protein is related to phenotype among Chinese patients.

Defining clinical subgroups and genotype–phenotype correlations in NBAS-associated disease across 110 patients

PurposePathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. MethodsIndividuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. ResultsOne hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger–Huët anomaly/SOPH). ConclusionWe define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.

Infantile liver failure syndrome type 2

Infantile liver failure syndrome type 2

Loss of Leucyl-tRNA synthetase b leads to ILFS1-like symptoms in zebrafish

Leucyl-tRNA synthetase (LARS) is a kind of aminoacyl-tRNA synthetases (aaRSs), which is important for protein synthesis. Following the discovery of three clinical cases which carry LARS mutations, it has been designated as the infantile liver failure syndrome type 1 (ILFS1) gene. ILFS1 is a kind of infantile hepatopathy, which is difficult to diagnose and manage. As the mechanism underlying this disease is poorly understood and LARS is conserved among vertebrates, we obtained zebrafish larsbcq68 mutant via CRISPR/Cas9 technology to investigate the role of larsb in vivo. In mutant, the proliferation ability of liver was drastically decreased at later stages accompanied with severe DNA damage. Further studies demonstrated that the mTORC1 signaling was hyperactivated in larsbcq68 mutant. Inhibition of mTORC1 signaling pathway by Rapamycin or mTORC1 morpholino can partially rescue the liver failure of the mutants. These data revealed that larsb mutation caused ILFS1-like phenotype in zebrafish, and indicated this mutant may serve as a potential model for ILFS1. Furthermore, we demonstrated that rapamycin treatment can partially rescue the liver defect in mutants, thus providing a practicable therapeutic plan for ILFS1.

Severe Neonatal Manifestations of Infantile Liver Failure Syndrome Type 1 Caused by Cytosolic Leucine-tRNA Synthetase Deficiency.

Deleterious mutations in cytosolic leucine-tRNA synthetase (LARS) cause infantile liver failure syndrome, type 1 (ILFS1), a recently recognized, rare autosomal recessive disorder (OMIM151350). Only six families with ILFS1 have been reported in the literature. Patients with ILFS1 are typically diagnosed between 5 and 24months of age with failure to thrive, developmental delays, encephalopathy, microcytic anemia, and chronic liver dysfunction with recurrent exacerbations following childhood illnesses. Neonatal manifestations of this disorder have not been well documented. We report a premature female newborn with intrauterine growth restriction, failure to thrive, congenital anemia, anasarca, and fulminant liver failure leading to lethal multiple organ failure. Liver failure in this infant was characterized by a disproportionate impairment of liver synthetic function, including severe coagulopathy and hypoalbuminemia without significant defects in liver detoxification or evidence of hepatocellular injury during early phase of the disease. Whole-exome sequencing of child-parent trio identified two inherited missense mutations in LARS in this patient. One, c.1292T>A; p.Val431Asp, has been reported in patients with ILFS1, while the other, c.725C>T; p.Pro242Leu, is novel. Both mutations involve amino acid residues in the highly conserved editing domain of LARS, are predicted to be functionally deleterious, and presumably contribute to the clinical manifestations in this patient. This is the first case documenting neonatal manifestation of ILFS1, highlighting early, severe, and disproportionate defects in liver synthetic function. Timely diagnosis of ILFS1 is crucial to guide critical clinical management and improve outcomes of this rare and potentially life-threatening disorder.

Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS.

Recessive LARS mutations were recently reported to cause a novel syndrome, infantile liver failure syndrome type 1 (ILFS1), in six Irish Travellers. We have since identified four additional patients, including one of Ashkenazi origin, representing the largest ILFS1 cohort to date. Our study aims to define the ILFS1 clinical phenotype to help guide diagnosis and patient management. We clinically evaluated and reviewed the medical records of ten ILFS1 patients. Clinical features, histopathology and natural histories were compared and patient management strategies reviewed. Early failure to thrive, recurrent liver dysfunction, anemia, hypoalbuminemia and seizures were present in all patients. Most patients (90 %) had developmental delay. Encephalopathic episodes triggered by febrile illness have occurred in 80 % and were fatal in two children. Two patients are currently >28 years old and clinically well. Leucine supplementation had no appreciable impact on patient well-being. However, we suggest that the traditional management of reducing/stopping protein intake in patients with metabolic hepatopathies may not be appropriate for ILFS1. We currently recommend ensuring sufficient natural protein intake when unwell. We report the first non-Irish ILFS1 patient, suggesting ILFS1 may be more extensive than anticipated. Low birth weight, early failure to thrive, anemia and hypoalbuminemia are amongst the first presenting features, with liver dysfunction before age 1. Episodic hepatic dysfunction is typically triggered by febrile illness, and becomes less severe with increasing age. While difficult to anticipate, two patients are currently >28 years old, suggesting that survival beyond childhood may be associated with a favourable long-term prognosis.