RARE DISEASE
Crigler-Najjar syndrome
Crigler-Najjar syndrome
Crigler-Najjar syndrome
Synonyms: Bilirubin uridinediphosphate glucuronosyltransferase deficiency, Bilirubin-UGT deficiency
Synonyms: Bilirubin uridinediphosphate glucuronosyltransferase deficiency, Bilirubin-UGT deficiency
Synonyms: Bilirubin uridinediphosphate glucuronosyltransferase deficiency, Bilirubin-UGT deficiency
Drug discovery
10
drugs
With orphan designations
Overview
Crigler-Najjar syndrome (CNS) is a rare autosomal recessive disorder caused by UGT1A1 mutations, impairing bilirubin conjugation and leading to severe unconjugated hyperbilirubinemia. Type 1 (CN1) features absent UDP-glucuronosyltransferase activity, requiring aggressive intervention to prevent kernicterus, while type 2 (CN2) retains partial enzyme function, managed with pharmacotherapy. Current treatments include phototherapy, phenobarbital (CN2), and liver transplantation (CN1), with emerging gene therapies under investigation [1][3][6][12].
Therapies
CN1:
Daily phototherapy (≥12 hours) to reduce bilirubin [3][9][15].
Liver transplantation as curative intervention (5-year survival: 81–95%) [3][8][13].
CN2: Phenobarbital to induce residual enzyme activity [3][5][9].
Emerging therapies: AAV-based gene therapy trials (e.g., GNT-0003) and hepatocyte transplantation [8][11][15].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
419 drug discovery papers about Crigler-Najjar syndrome, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
419 drug discovery papers about Crigler-Najjar syndrome, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2024-03-25 | Bilirubin metabolism: delving into the cellular and molecular mechanisms to predict complications
Abstract Bilirubin is a metabolic product of heme, and an increase in its level may be toxic to the body. It may be conjugated or unconjugated. Encephalopathy is caused by unconjugated bilirubin has the ability to pass through the blood-brain barrier, entering the central nervous system. Conjugated forms of bilirubin result in biliary obstruction and a change in urine colour due to a decrease in excretion. Excessive hemolysis can result from hereditary and autoimmune diseases, deficient RBC membranes, enzyme deficiency, and hemoglobin structural anomalies. In this review, we summarize all the possible mechanisms and complications regarding bilirubin. Cellular and molecular functions and mechanisms of bilirubin are explained, followed by several complications viz neurotoxicity, auditory dysfunction, and nephrotoxicity. The cause of bilirubin-induced neuronal cell damage is likely due to the elevated levels of unconjugated bilirubin in plasma, mitochondrial, and endoplasmic reticulum (ER) membranes. These disruptions in the membranes could lead to harmful effects such as neuronal excitotoxicity, energy failure in mitochondria, or an increased concentration of calcium within the cells. At the cellular level, bilirubin exerts its toxic effect by disturbing the normal functioning of neuronal cells. Bilirubin's presence can cause certain inflammatory responses, resulting in the activation of proinflammatory cytokines. Additionally, research has demonstrated that bilirubin can negatively affect auditory abilities. It disrupts the integrity of auditory pathways, resulting in auditory dysfunction and potentially causing long-term hearing impairments in infants affected by it. In conclusion, a comprehensive understanding of the complications associated with unconjugated bilirubin in neonates is essential for improving clinical management and outcomes. Understanding the cellular and molecular pathophysiology of high bilirubin may lead to a new therapeutic approach.
2019-02-28 | Improving engraftment of hepatocyte transplantation using alpha-1 antitrypsin as an immune modulator
For patients with non-cirrhotic liver-based metabolic disorders, hepatocyte transplantation can be an effective treatment. However, long-term function of transplanted hepatocytes following infusion has not been achieved due to insufficient numbers of hepatocytes reaching the liver cell plates caused by activation of the instant blood-mediated inflammatory reaction (IBMIR). Our aim was to determine if the natural immune modulator, alpha-1 antitrypsin (AAT), could improve engraftment of transplanted hepatocytes and investigate its mechanism of action. A tubing loop model was used to analyse activation of the IBMIR when human hepatocytes were in contact with ABO-matched blood and 4 mg/ml AAT. Platelet and white cell counts, complement and cytokine expression were analysed. To determine if AAT could improve short-term engraftment, female rats underwent tail vein injection of AAT (120 mg/kg) or water (control) prior to the intrasplenic transplantation of 2 × 107 male hepatocytes. At 48 h and 1 week, livers were collected for analysis. In our loop model, human hepatocytes elicited a significant drop in platelet count with thrombus formation compared to controls. Loops containing AAT and hepatocytes showed no platelet consumption and no thrombus formation. Further, AAT treatment resulted in reduced IL-1β, IL-6 and IFN-γ and increased IL-1RA compared to untreated loops. In vivo, AAT significantly improved engraftment of rat hepatocytes compared to untreated at 48 h. AAT infusion may inhibit the IBMIR, thus improving short-term engraftment of donor hepatocytes and potentially improve the outcomes for patients with liver-based metabolic disease. • Alpha-1 antitrypsin (AAT) acts as an immune modulator to improve the efficacy of hepatocyte transplantation. • Treatment with AAT decreased thrombus formation and pro-inflammatory cytokine expression in a tubing loop model. • AAT significantly improved engraftment of donor hepatocytes within the first 48 h post transplantation.
2013-05-28 | Beyond plasma bilirubin: the effects of phototherapy and albumin on brain bilirubin levels in Gunn rats.
Severe unconjugated hyperbilirubinemia, as occurs in Crigler-Najjar disease and neonatal jaundice, carries the risk of neurotoxicity. This neurotoxicity is related to the increased passage of free bilirubin (UCB(free)), the fraction of bilirubin that is not bound to plasma proteins, into the brain. We hypothesized that albumin treatment would lower the UCB(free) fraction, and thus decrease bilirubin accumulation in the brain. We treated chronic (e.g., as a model for Crigler-Najjar disease) and acute hemolytic (e.g., as a model for neonatal jaundice) moderate hyperbilirubinemic Gunn rats with phototherapy, human serum albumin (HSA) or phototherapy+HSA. In the chronic model, adjunct HSA increased the efficacy of phototherapy; it decreased plasma UCB(free) and brain bilirubin by 88% and 67%, respectively (p<0.001). In the acute model, adjunct HSA also increased the efficacy of phototherapy; it decreased plasma UCB(free) by 76% (p<0.001) and completely prevented the hemolysis-induced deposition of bilirubin in the brain. Phototherapy alone failed to prevent the deposition of bilirubin in the brain during acute hemolytic jaundice. We showed that adjunct HSA treatment decreases brain bilirubin levels in phototherapy-treated Gunn rats. We hypothesize that HSA decreases these levels by lowering UCB(free) in the plasma. Our results support the feasibility of adjunct albumin treatment in patients with Crigler-Najjar disease or neonatal jaundice.
2013-05-15 | Albumin administration protects against bilirubin‐induced auditory brainstem dysfunction in Gunn rat pups
Free bilirubin (Bf), the unbound fraction of unconjugated bilirubin (UCB), can induce neurotoxicity, including impairment of the auditory system, which can be assessed by brainstem auditory evoked potentials (BAEPs). We hypothesized that albumin might reduce the risk of neurotoxicity by decreasing Bf and its translocation into the brain.To determine the effects of albumin on BAEPs and brain bilirubin content in two Gunn rat pup models of acute hyperbilirubinemia.We used Gunn rat pups, which have a deficiency of the bilirubin-conjugating enzyme UGT1A1. We induced haemolysis by injection of phenylhydrazine (phz) into 14-days old pups. Subsequently, pups were treated with either i.p. human serum albumin (HSA; 2.5 g/kg; n = 8) or saline (control, n = 8). We induced acute neurotoxicity by injecting 16-days old pups with sulphadimethoxine (sulpha) and treated them with either HSA (n = 9) or saline (control, n = 10). To assess bilirubin neurotoxicity, we used the validated BAEP method and compared relevant parameters; i.e. peak latency values and interwave interval (IWI) between peak I and peak II, a marker of acute neurotoxicity.Phz and sulpha significantly increased IWI I-II by 26% and 29% (P < 0.05) in the haemolysis and the displacement model, respectively. Albumin completely prevented the increase of IWI I-II in either model. The beneficial effect of albumin in the displacement-model by means of normal BAEPs was in line with less bilirubin in the brain (NS). Interestingly, in the haemolysis model the accumulation of total bilirubin in the brain was unaltered, and BAEPs still appeared normal. This might advocate for a role of brain Bf which was calculated and showed that albumin treatment non-significantly reduces Bf concentrations in brain, compared with saline treatment.Albumin treatment is neuroprotective in acute hyperbilirubinemia in Gunn rat pups. Our present results underline the importance of functional diagnostic test of neurotoxicity above biochemical concentrations.
2009-05-28 | Normal neurological outcome in two infants treated with exchange transfusions born to mothers with Crigler-Najjar Type 1 disorder.
Patients with Crigler-Najjar Type 1 (CN-1) disorder have an unconjugated hyperbilirubinaemia due to the complete absence in activity of uridinediphosphate glucuronosyltransferase, a bilirubin-conjugating enzyme. In pregnant women with CN-1, the foetus is at high risk of being adversely affected by the bilirubin, as unconjugated bilirubin can cross the placenta and is potentially neurotoxic. We report the long-term outcomes of two infants born to women with CN-1. These infants had exchange transfusions soon after birth and have normal neurodevelopmental outcomes at 18 months and four years of age, respectively. We propose that this intervention might have improved the neurological outcome of these infants.
cell therapies
2026-05-21 | Case Report: Retransplantation for Adult-Onset Bilirubin Encephalopathy After Auxiliary Partial Liver Transplant for Crigler-Najjar Syndrome Type 1 in Childhood.
Crigler-Najjar syndrome (CNS) type 1 is a genetic disorder that leads to severe unconjugated hyperbilirubinemia. Auxiliary partial orthotopic liver transplantation (APOLT) is preferred for metabolic liver diseases as a portion of the native liver is retained. Reported here are details of a 32-year-old male who developed bilirubin encephalopathy due to graft failure 27 years after APOLT performed at 5-year-old for CNS type 1. Initially, the bilirubin level was low, which then gradually increased to 7.3 mg/dL at age 12. At the age of 31, the bilirubin level began to rise rapidly and we submitted a request for deceased donor liver transplantation (DDLT) to the Committee for the Evaluation of Indications for DDLT in Japan. However, that was deemed as not indicated, because unconjugated bilirubin-dominant hyperbilirubinemia alone is generally not considered to cause encephalopathy in adults. Despite the high bilirubin level, the patient remained neurologically asymptomatic until occurrence of acute decompensation. At 32 years old, he was admitted on an emergency basis to our hospital with severe hyperbilirubinemia and neurological symptoms. After managing his general condition with intensive care, DDLT was finally performed, resulting in a drastic resolution of various symptoms. The findings in this case show that bilirubin-induced neurotoxicity in adults may be reversible and indicate that the current liver transplantation criteria used in Japan, which limit eligibility for CNS to pediatric patients, may have contributed to delayed transplantation. Re-evaluation of the transplant eligibility criteria is necessary to allow for a more inclusive approach that encompasses adult patients.
2022-08-05 | Liver transplantation in Crigler-Najjar Syndrome Type I: A single center experience
Background and Aim: Crigler-Najjar syndrome is a rare genetic disorder of bilirubin conjugation resulting in severe and persistent unconjugated hyperbilirubinemia within the first week of life. Diagnosis is made clinically or by genetic testing. Treatment includes phototherapy beyond the neonatal period or liver transplantation. Without liver transplantation most of these kids will have neurological sequalae due to bilirubin encephalopathy or may be fatal. Here we report the profile of six cases who underwent liver transplantation for CNS I at our center. Methods: It was a retrospective study in which all children admitted to our hospital with the diagnosis of Crigler-Najjar syndrome type I and who underwent liver transplantation during the period of 1st January 2007 to 31st December 2021 were included in the study. Demographic profile, age at presentation and age at LT, family history, means of diagnosis (clinical/ genetic testing), neurological impairment, duration of phototherapy pre-LT, pre-LT LFTs, liver biopsy findings, post LT outcome and complications were all analyzed. Results: A total of six children were included in the study. There was only 1 female child. There was a wide variation in the age at presentation from the youngest being 13 months and the oldest being 13 years and 5 months. Three children had neurological impairment and all of them required exchange transfusion while in NICU. All children had pre-LT bilirubin of > 20 mg/dl and liver fibrosis in liver explant specimen. Two children developed hepatic artery thrombosis after LT. All children were discharged after LT. Conclusions: Liver transplantation is curative for CNS I with good outcome and improves the quality of life. Early liver transplantation should be considered for those patients who develop early signs of bilirubin encephalopathy, in order to prevent bilirubin induced neurological sequelae. Elevated liver transaminases and fibrosis on explant needs further evaluation to understand underlying pathophysiology.
2021-09-28 | Pediatric Liver Transplantation as Enzyme Replacement Therapy for Rare Metabolic Diseases with No Structural Liver Damage
Objective: Very rare monogenic metabolic diseases without structural liver damage can be cured by liver transplantation. This process is a surgical enzyme replacement therapy, and defective enzymes may or may not be confined to the liver. The aims of this single center study of children with metabolic diseases showing structurally normal liver parenchyma were to analyze the indications and post-operative outcomes of liver transplantation, identification of developmental and metabolic benefits of the procedure with recognition of peri-operative difficulties to improve the success rate.
Materials and Methods: Patients under the age of 19-year-old who underwent liver transplantation for metabolic disorders with no structural liver injury between January 2015 and June 2021 analyzed retrospectively. Patient and graft survivals, indications for transplantation, presence of extra-hepatic enzyme deficiency causing other organ damage, inclusion of simultaneous or sequential kidney transplantation, immunosuppressive protocols, post-transplant complications, and metabolic outcomes were identified.
Results: Eight children with primary hyperoxaluria type 1 (n = 4), Maple syrup urine disease (n = 1), Crigler-Najjar syndrome type 1 (n=1), familial hypercholesterolemia (n=1) and propionic acidemia (n = 1) received left lobe (n=6) and left lateral segment (2) allografts from living donors. The median age of 4 girls and 4 boys at time of transplantation was 6.8 years (range 2.2-12.7 years). The median follow-up time was 3.3 years (range 1.5-5.7 years). The most common post-transplant complications were biliary system complications and infections and, two patients died because of sepsis. Six patients are alive with normal functioning allografts and metabolically stable on unrestricted diet.
Conclusion: Liver transplantation is a lifesaving treatment and improves patient’s and parent’s life quality for metabolic disorders with no parenchymal injury despite strict dietary restrictions and medical therapies. Especially, living donor liver transplantation is very important for populations with very low organ donation rates.
2021-04-14 | Successful living donor liver transplantation plus domino-auxiliary partial orthotopic liver transplantation for pediatric patients with metabolic disorders.
To investigate the efficacy of living donor liver transplantation (LDLT) plus domino-auxiliary partial orthotopic liver transplantation (D-APOLT) in pediatric patients with metabolic disorders. From May 2017 to October 2018, two patients with ornithine aminotransferase deficiency (OTCD) and one patient with type I Crigler-Najjar syndrome (CNS1) received LDLT, their livers were prepared as donors for D-APOLT. Two patients with CNS1 received domino liver grafts from OTCD patients; one OTCD patient received a domino liver graft from a CNS1 patient. The mean follow-up was 26.6 months. The liver function and ammonia remained in the normal range at the end of the follow-up in all recipients. One D-APOLT patient experienced portal vein thrombosis 2 days after transplantation and required reoperation, this patient presented an imbalance of portal blood perfusion between the native and the domino liver at 8 months after liver transplant. The imbalance was improved by interventional radiology treatment. Two LDLT patients experienced early mild acute rejection. The non-cirrhotic livers from pediatric patients with metabolic liver disease can be used as domino donor grafts for selected pediatric patients with different metabolic liver disease. D-APOLT achieves ideal recipient outcomes and provides a strategy to expand donor source for children.
2021-02-22 | Outcome of liver transplantation and prevalence of liver fibrosis in Crigler‐Najjar syndrome
Crigler-Najjar syndrome (CNS) is a rare inherited disorder that is characterized by high levels of non-hemolytic, unconjugated hyperbilirubinemia leading to brain damage and even death. Liver transplantation (LT) can correct the metabolic defect, but there are little data regarding LT in this patient cohort. The liver parenchyma has been considered to be structurally normal in CNS, but there is growing evidence of clinically silent but histologically significant fibrosis in CNS patients.We included 13 patients in our retrospective study who underwent LT at our center. Patient survival, graft function, and long-term complications were evaluated over a median follow-up period of 10 years (range: 1-16 years). In addition, the prevalence of histologically relevant fibrosis was characterized.The overall survival among our LT patients was 100%. The graft survival was only 61.5%. During the follow-up period, 5 LT patients had to undergo retransplantation. More than 45% of our patients showed histological signs of fibrosis.LT remains the only definite therapeutic option for severe CNS but needs to be considered thoroughly regarding the clinical risk-benefit-ratio and impact on quality of life. Furthermore, hepatic parenchymal injury needs to be considered while evaluating future therapeutic options for CNS.
gene therapies
2026-05-29 | Rewriting hepatic fate: emerging gene therapy strategies for liver disease
Several anatomical and physiological features make the liver particularly suitable for gene-based therapeutic strategies, including its extensive vascularization, fenestrated sinusoidal endothelium, and high metabolic capacity. In the past decade, liver-directed gene therapies have evolved from experimental concepts to clinical applications for various inherited and systemic disorders. Adeno-associated viral vectors, lentiviral systems, and lipid nanoparticles are currently the main platforms for delivering therapeutic genes and genome-editing tools to hepatocytes. Genome editing technologies such as CRISPR-Cas nucleases, base editors, and prime editors have enabled more precise modification of endogenous loci. Early clinical studies in disorders like hemophilia, transthyretin amyloidosis, ornithine transcarbamylase deficiency, and Crigler-Najjar syndrome show that partial correction of hepatic gene function can lead to meaningful clinical benefits. However, several challenges hinder broader clinical implementation, including immune responses to viral capsids and nanoparticle components, dose-dependent toxicity, limited packaging capacity of some vectors, and uncertainties about long-term safety and durability, especially in pediatric populations. Efficient and cell-type-specific delivery beyond hepatocytes remains a major challenge, particularly for diseases driven by non-parenchymal cells or malignant transformation. This article discusses recent advancements in delivery technologies and genome editing approaches for liver disease, as well as current translational barriers and emerging strategies aimed at enhancing specificity, durability, and safety. Collectively, these advances suggest that increasingly precise and programmable gene-based interventions may play a central role in future therapies for a broad spectrum of liver diseases.
2026-01-09 | Engineering Liver-Specific Promoters: A Comprehensive Review of Design, Mechanisms, and Clinical Applications in Gene Therapy.
The liver is a primary metabolic hub and a pivotal target for gene therapy, owing to its capacity for protein secretion, role in metabolic homeostasis and immune tolerance. Liver-directed gene therapies are used to treat numerous inherited metabolic disorders and coagulation factor deficiencies including hemophilia (A and B), Crigler-Najjar syndrome, mucopolysaccharidoses, phenylketonuria, Fabry, Gaucher, Wilson and Pompe diseases. The efficacy and safety of liver-directed gene therapy rely on the use of strong tissue-specific promoters. To date, there are many different liver-specific promoters used in preclinical and clinical studies, including novel completely synthetic promoters. This review provides a comprehensive analysis of the design, engineering and application of liver-specific promoters. Furthermore, we discuss fundamental principles of gene expression regulation in the liver and the physiological and immunological characteristics that make it a suitable target organ for gene therapy delivery.
2025-12-01 | From Childhood Icterus to Adolescent Gallstones: Clinically Diagnosed Crigler-Najjar Syndrome Type II
From Childhood Icterus to Adolescent Gallstones: Clinically Diagnosed Crigler-Najjar Syndrome Type IIDanish Kumar GoswamiEmail: daniahgoswami34@gmail.com Institute/Affiliation: Department of Internal Medicine, Liaquat University of Medical and Health
2025-10-01 | Cholestasis in Crigler–Najjar Syndrome Type I: An Uncommon Histopathological Finding in a Rare Disorder
Abstract Crigler–Najjar syndrome is a rare autosomal recessive disorder characterized by severe unconjugated hyperbilirubinemia. Liver histopathology in Crigler–Najjar Syndrome typically reveals fibrosis, while features of cholestasis are rarely reported. We describe an 8-month-old male infant with persistent unconjugated hyperbilirubinemia, global developmental delay, and spasticity. Liver biopsy demonstrated canalicular bile plugs and focal bile duct proliferation, suggestive of cholestasis – a rare finding in Crigler–Najjar Syndrome. Despite initial diagnostic uncertainty due to this atypical presentation, genetic testing confirmed a homozygous mutation in the uridine diphosphate-glucuronosyltransferase 1A1 gene consistent with Crigler–Najjar Syndrome Type I.
2024-12-01 | Approaches to therapy of Crigler–Najjar syndrome type 1 in children
The review is focused on exploring the etiology, pathogenesis, clinical manifestations, and primarily the contemporary treatment methods for Crigler–Najjar syndrome type 1. It considers relevant data regarding the efficacy and safety of the currently existing therapeutic strategies. Effective management of this condition relies on early diagnosis and prompt initiation of treatment, which are crucial for preventing disabling neurological complications associated with bilirubin encephalopathy in patients with Crigler–Najjar syndrome type 1. Prolonged phototherapy is the key treatment method, while liver transplantation represents a radical approach. Recent advances in gene therapy and the use of mesenchymal multipotent stromal cells present novel opportunities for developing alternative, less invasive treatment modalities aimed at improving the quality of life in such patients and reducing their dependence on long-term phototherapy, along with post-transplantation risk.
small molecules
2025-11-30 | Treatment of Severe Unconjugated Hyperbilirubinemia with Phenobarbitone in Two First-Degree Siblings with Crigler-Najjar Syndrome (CNS) Type 2: A Success Story
Background: Crigler–Najjar syndrome (CNS) type 2 is a rare autosomal recessive disorder of bilirubin conjugation caused by mutations in the UGT1A1 gene. It presents in infancy with unconjugated hyperbilirubinemia that does not respond to phototherapy but improves with phenobarbitone, which enhances residual enzyme activity. Although phenobarbitone remains the cornerstone of treatment, familial recurrence of CNS type 2 is rarely reported in pediatric literature. Case: We report two siblings born to consanguineous parents who presented with progressive jaundice during early infancy. The first child, a 2-month-old boy, had multiple hospitalisations for phototherapy without benefit. Laboratory evaluation revealed total bilirubin of 31 mg/dL with normal liver function and no evidence of hemolysis. Genetic testing confirmed a homozygous UGT1A1 (c.1456T>G; p.Tyr486Asp) mutation. He was treated with phenobarbitone (5–8 mg/kg/day) and calcium phosphate, achieving a bilirubin level <10 mg/dL within 4 weeks. Three years later, his younger sister developed similar unconjugated jaundice from day 4 of life and harboured the same mutation; she responded well to phenobarbitone alone. Both siblings remain well on long-term follow-up. Discussion: This case highlights the genetic basis and favorable response of CNS type 2 to phenobarbitone, which induces hepatic UGT1A1 expression. Familial clustering of CNS 2, though reported in few global studies, is seldom documented from India. Conclusion: Early genetic diagnosis, timely institution of phenobarbitone, and family counselling are critical for successful management of CNS type 2. These cases reaffirm the long-term safety and efficacy of phenobarbitone in familial presentations of this rare disorder.
2025-11-07 | Yellow-eyed man and dromomania: A case of adult-onset psychiatric symptoms in Crigler–Najjar syndrome type II
A 30-year-old man presented with long-standing, treatment-resistant psychiatric symptoms including compulsive wandering, hallucinations, and obsessive behaviors. Physical examination revealed deep yellow sclera present since childhood. Genetic testing identified compound heterozygous mutations in the UGT1A1 gene, confirming Crigler–Najjar syndrome type II. Initiation of phenobarbitone and adjunctive therapy led to a marked reduction in serum bilirubin and clinical symptoms. This case highlights the possibility of bilirubin-induced neurological dysfunction presenting in adulthood as a chronic psychiatric condition.
2025-08-08 | Tapentadol withdrawal, a newer trend in opioid overuse in Nepal: A case report.
Crigler-Najjar Syndrome Type 2 (CNS2) is a rare autosomal recessive disorder characterized by unconjugated hyperbilirubinemia due to partial deficiency of the enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We present a case of a 13-month-old male admitted to Kanti Children's Hospital with persistent jaundice since birth. Diagnostic evaluation accompanied by gene sequencing confirmed CNS2 and the patient was effectively managed with orally administered phenobarbitone. CNS2 can be distinguished from other potential causes of unconjugated hyperbilirubinemia based on bilirubin concentration and the affected patient's response to phenobarbitone. Genetic counselling is essential for the recognition and prevention of severe hyperbilirubinemia which, in the absence of timely medical intervention, may lead to neurotoxicity. Keywords: Case report; crigler-Najjar syndrome; genetic counseling; phenobarbitone; unconjugated hyperbilirubinemia.
2025-06-29 | A Rare Case of Crigler-Najjar Syndrome Type 2
Crigler–Najjar Syndrome Type 2 (CNS2) is a rare autosomal recessive disorder characterized by unconjugated hyperbilirubinemia due to partial deficiency of the enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We present a case of a 13-month-old male admitted to Kanti Children’s Hospital with persistent jaundice since birth. Diagnostic evaluation accompanied by gene sequencing confirmed CNS2 and the patient was effectively managed with orally administered phenobarbitone. CNS2 can be distinguished from other potential causes of unconjugated hyperbilirubinemia based on bilirubin concentration and the affected patient’s response to phenobarbitone. Genetic counselling is essential for the recognition and prevention of severe hyperbilirubinemia which, in the absence of timely medical intervention, may lead to neurotoxicity. Keywords: Case report; crigler-Najjar syndrome; genetic counseling; phenobarbitone; unconjugated hyperbilirubinemia.
2024-04-26 | A Case of Crigler-Najjar Syndrome Type II During Pregnancy and Its Management
Crigler-Najjar syndrome (CNS) is a genetic syndrome that results in increased levels of unconjugated bilirubin due to less or completely nonfunctional enzyme, uridine diphosphoglucoronyltransferase (UDPGT) in hepatocytes. When bilirubin metabolism is compromised, hyperbilirubinemia is caused, which results in increased levels of unconjugated and conjugated bilirubin in the bloodstream. CNS is an autosomal recessive disorder, usually noticeable as people get older. This disorder is divided into two types: CNS type I and CNS type II, which are caused by homozygous or compound heterozygous mutations in the UDP glucuronosyltransferase family 1 member A1 (UGT1A1) gene. The disorder affects all races and genders equally, with a prevalence of one per million births. CNS type I is more severe and has almost undetectable UDPGT expression activity, and affected individuals die before one year of age. Consanguineous marriages are a major risk factor as CNS is inherited in an autosomal recessive manner. Being rare, maternal CNS type II is yet to be completely understood in terms of its impact on the mother, her pregnancy, and the infant. We aim to present a case of a pregnant female with CNS type II and its clinical course. She was monitored closely during her pregnancy. The treatment protocol was followed as per previously reported cases and was managed on low, non-teratogenic doses of phenobarbitone. A successful outcome with the birth of a healthy infant having normal neurological development till six months follow-up was observed.
other
2024-01-31 | Development of a minimal PBPK-QSP modeling platform for LNP-mRNA based therapeutics to study tissue disposition and protein expression dynamics
Physiologically based pharmacokinetic models have gained significant recognition as effective mathematical models that enable deeper mechanistic investigation of drug delivery and tissue disposition. Here we describe the development of a platform PBPK-quantitative systems pharmacology (QSP) model to study tissue delivery of lipid nanoparticle (LNP) based mRNA therapeutics. The model is calibrated to published data in the context of Crigler-Najjar syndrome. Sensitivity analyses were performed to explore factors that influence protein expression and pharmacodynamic response following LNP-mRNA liver disposition. The most sensitive determinants of protein exposures were mRNA stability, translation, and cellular uptake rate, while the liver influx rate of lipid nanoparticle did not appreciably impact protein expression. Indeed, protein expression level may be tuned by modulation of mRNA degradation rate. However, simulations predicted that when the intrinsic half-life of the translated protein falls below a certain threshold, lowering mRNA degradation rate may not rescue protein exposure, a design feature that should be considered in optimal design of mRNA therapeutics. Additionally, interplay of LNP degradation rate and mRNA escape rate from endosomes was found to be crucial in modulation of protein expression. Simulations predicted that at a given LNP degradation rate, protein exposure varied linearly with mRNA escape rate. We further extended the model by incorporating LNP recycling to identify conditions necessary for observing a second peak in mRNA pharmacokinetics (PK). Simulations predict that with a fast recycling and slow tissue re-uptake rates, a robust second peak is observed in the plasma mRNA concentration curve. The amplitude and timing of the second peak could be tuned with recycling and re-uptake rates. Modeling results indicate that within the context of non-secreted mRNA mediated enzyme replacement therapy, recycling may depress or improve protein exposure depending on the re-uptake rate of the recycled LNP. The model is subsequently used to generate virtual animal cohorts to investigate optimal dosing and schedule of the compound. Virtual instances of the model were then employed to identify design principles that potentially reduce dosing frequency while maintaining efficacy. This study demonstrates the potential applications of coupled PBPK-QSP model for LNP based mRNA therapeutics as a translational platform.
proteins
2024-03-25 | Bilirubin metabolism: delving into the cellular and molecular mechanisms to predict complications
Abstract Bilirubin is a metabolic product of heme, and an increase in its level may be toxic to the body. It may be conjugated or unconjugated. Encephalopathy is caused by unconjugated bilirubin has the ability to pass through the blood-brain barrier, entering the central nervous system. Conjugated forms of bilirubin result in biliary obstruction and a change in urine colour due to a decrease in excretion. Excessive hemolysis can result from hereditary and autoimmune diseases, deficient RBC membranes, enzyme deficiency, and hemoglobin structural anomalies. In this review, we summarize all the possible mechanisms and complications regarding bilirubin. Cellular and molecular functions and mechanisms of bilirubin are explained, followed by several complications viz neurotoxicity, auditory dysfunction, and nephrotoxicity. The cause of bilirubin-induced neuronal cell damage is likely due to the elevated levels of unconjugated bilirubin in plasma, mitochondrial, and endoplasmic reticulum (ER) membranes. These disruptions in the membranes could lead to harmful effects such as neuronal excitotoxicity, energy failure in mitochondria, or an increased concentration of calcium within the cells. At the cellular level, bilirubin exerts its toxic effect by disturbing the normal functioning of neuronal cells. Bilirubin's presence can cause certain inflammatory responses, resulting in the activation of proinflammatory cytokines. Additionally, research has demonstrated that bilirubin can negatively affect auditory abilities. It disrupts the integrity of auditory pathways, resulting in auditory dysfunction and potentially causing long-term hearing impairments in infants affected by it. In conclusion, a comprehensive understanding of the complications associated with unconjugated bilirubin in neonates is essential for improving clinical management and outcomes. Understanding the cellular and molecular pathophysiology of high bilirubin may lead to a new therapeutic approach.
2019-02-28 | Improving engraftment of hepatocyte transplantation using alpha-1 antitrypsin as an immune modulator
For patients with non-cirrhotic liver-based metabolic disorders, hepatocyte transplantation can be an effective treatment. However, long-term function of transplanted hepatocytes following infusion has not been achieved due to insufficient numbers of hepatocytes reaching the liver cell plates caused by activation of the instant blood-mediated inflammatory reaction (IBMIR). Our aim was to determine if the natural immune modulator, alpha-1 antitrypsin (AAT), could improve engraftment of transplanted hepatocytes and investigate its mechanism of action. A tubing loop model was used to analyse activation of the IBMIR when human hepatocytes were in contact with ABO-matched blood and 4 mg/ml AAT. Platelet and white cell counts, complement and cytokine expression were analysed. To determine if AAT could improve short-term engraftment, female rats underwent tail vein injection of AAT (120 mg/kg) or water (control) prior to the intrasplenic transplantation of 2 × 107 male hepatocytes. At 48 h and 1 week, livers were collected for analysis. In our loop model, human hepatocytes elicited a significant drop in platelet count with thrombus formation compared to controls. Loops containing AAT and hepatocytes showed no platelet consumption and no thrombus formation. Further, AAT treatment resulted in reduced IL-1β, IL-6 and IFN-γ and increased IL-1RA compared to untreated loops. In vivo, AAT significantly improved engraftment of rat hepatocytes compared to untreated at 48 h. AAT infusion may inhibit the IBMIR, thus improving short-term engraftment of donor hepatocytes and potentially improve the outcomes for patients with liver-based metabolic disease. • Alpha-1 antitrypsin (AAT) acts as an immune modulator to improve the efficacy of hepatocyte transplantation. • Treatment with AAT decreased thrombus formation and pro-inflammatory cytokine expression in a tubing loop model. • AAT significantly improved engraftment of donor hepatocytes within the first 48 h post transplantation.
2013-05-28 | Beyond plasma bilirubin: the effects of phototherapy and albumin on brain bilirubin levels in Gunn rats.
Severe unconjugated hyperbilirubinemia, as occurs in Crigler-Najjar disease and neonatal jaundice, carries the risk of neurotoxicity. This neurotoxicity is related to the increased passage of free bilirubin (UCB(free)), the fraction of bilirubin that is not bound to plasma proteins, into the brain. We hypothesized that albumin treatment would lower the UCB(free) fraction, and thus decrease bilirubin accumulation in the brain. We treated chronic (e.g., as a model for Crigler-Najjar disease) and acute hemolytic (e.g., as a model for neonatal jaundice) moderate hyperbilirubinemic Gunn rats with phototherapy, human serum albumin (HSA) or phototherapy+HSA. In the chronic model, adjunct HSA increased the efficacy of phototherapy; it decreased plasma UCB(free) and brain bilirubin by 88% and 67%, respectively (p<0.001). In the acute model, adjunct HSA also increased the efficacy of phototherapy; it decreased plasma UCB(free) by 76% (p<0.001) and completely prevented the hemolysis-induced deposition of bilirubin in the brain. Phototherapy alone failed to prevent the deposition of bilirubin in the brain during acute hemolytic jaundice. We showed that adjunct HSA treatment decreases brain bilirubin levels in phototherapy-treated Gunn rats. We hypothesize that HSA decreases these levels by lowering UCB(free) in the plasma. Our results support the feasibility of adjunct albumin treatment in patients with Crigler-Najjar disease or neonatal jaundice.
2013-05-15 | Albumin administration protects against bilirubin‐induced auditory brainstem dysfunction in Gunn rat pups
Free bilirubin (Bf), the unbound fraction of unconjugated bilirubin (UCB), can induce neurotoxicity, including impairment of the auditory system, which can be assessed by brainstem auditory evoked potentials (BAEPs). We hypothesized that albumin might reduce the risk of neurotoxicity by decreasing Bf and its translocation into the brain.To determine the effects of albumin on BAEPs and brain bilirubin content in two Gunn rat pup models of acute hyperbilirubinemia.We used Gunn rat pups, which have a deficiency of the bilirubin-conjugating enzyme UGT1A1. We induced haemolysis by injection of phenylhydrazine (phz) into 14-days old pups. Subsequently, pups were treated with either i.p. human serum albumin (HSA; 2.5 g/kg; n = 8) or saline (control, n = 8). We induced acute neurotoxicity by injecting 16-days old pups with sulphadimethoxine (sulpha) and treated them with either HSA (n = 9) or saline (control, n = 10). To assess bilirubin neurotoxicity, we used the validated BAEP method and compared relevant parameters; i.e. peak latency values and interwave interval (IWI) between peak I and peak II, a marker of acute neurotoxicity.Phz and sulpha significantly increased IWI I-II by 26% and 29% (P < 0.05) in the haemolysis and the displacement model, respectively. Albumin completely prevented the increase of IWI I-II in either model. The beneficial effect of albumin in the displacement-model by means of normal BAEPs was in line with less bilirubin in the brain (NS). Interestingly, in the haemolysis model the accumulation of total bilirubin in the brain was unaltered, and BAEPs still appeared normal. This might advocate for a role of brain Bf which was calculated and showed that albumin treatment non-significantly reduces Bf concentrations in brain, compared with saline treatment.Albumin treatment is neuroprotective in acute hyperbilirubinemia in Gunn rat pups. Our present results underline the importance of functional diagnostic test of neurotoxicity above biochemical concentrations.
2009-05-28 | Normal neurological outcome in two infants treated with exchange transfusions born to mothers with Crigler-Najjar Type 1 disorder.
Patients with Crigler-Najjar Type 1 (CN-1) disorder have an unconjugated hyperbilirubinaemia due to the complete absence in activity of uridinediphosphate glucuronosyltransferase, a bilirubin-conjugating enzyme. In pregnant women with CN-1, the foetus is at high risk of being adversely affected by the bilirubin, as unconjugated bilirubin can cross the placenta and is potentially neurotoxic. We report the long-term outcomes of two infants born to women with CN-1. These infants had exchange transfusions soon after birth and have normal neurodevelopmental outcomes at 18 months and four years of age, respectively. We propose that this intervention might have improved the neurological outcome of these infants.
cell therapies
2026-05-21 | Case Report: Retransplantation for Adult-Onset Bilirubin Encephalopathy After Auxiliary Partial Liver Transplant for Crigler-Najjar Syndrome Type 1 in Childhood.
Crigler-Najjar syndrome (CNS) type 1 is a genetic disorder that leads to severe unconjugated hyperbilirubinemia. Auxiliary partial orthotopic liver transplantation (APOLT) is preferred for metabolic liver diseases as a portion of the native liver is retained. Reported here are details of a 32-year-old male who developed bilirubin encephalopathy due to graft failure 27 years after APOLT performed at 5-year-old for CNS type 1. Initially, the bilirubin level was low, which then gradually increased to 7.3 mg/dL at age 12. At the age of 31, the bilirubin level began to rise rapidly and we submitted a request for deceased donor liver transplantation (DDLT) to the Committee for the Evaluation of Indications for DDLT in Japan. However, that was deemed as not indicated, because unconjugated bilirubin-dominant hyperbilirubinemia alone is generally not considered to cause encephalopathy in adults. Despite the high bilirubin level, the patient remained neurologically asymptomatic until occurrence of acute decompensation. At 32 years old, he was admitted on an emergency basis to our hospital with severe hyperbilirubinemia and neurological symptoms. After managing his general condition with intensive care, DDLT was finally performed, resulting in a drastic resolution of various symptoms. The findings in this case show that bilirubin-induced neurotoxicity in adults may be reversible and indicate that the current liver transplantation criteria used in Japan, which limit eligibility for CNS to pediatric patients, may have contributed to delayed transplantation. Re-evaluation of the transplant eligibility criteria is necessary to allow for a more inclusive approach that encompasses adult patients.
2022-08-05 | Liver transplantation in Crigler-Najjar Syndrome Type I: A single center experience
Background and Aim: Crigler-Najjar syndrome is a rare genetic disorder of bilirubin conjugation resulting in severe and persistent unconjugated hyperbilirubinemia within the first week of life. Diagnosis is made clinically or by genetic testing. Treatment includes phototherapy beyond the neonatal period or liver transplantation. Without liver transplantation most of these kids will have neurological sequalae due to bilirubin encephalopathy or may be fatal. Here we report the profile of six cases who underwent liver transplantation for CNS I at our center. Methods: It was a retrospective study in which all children admitted to our hospital with the diagnosis of Crigler-Najjar syndrome type I and who underwent liver transplantation during the period of 1st January 2007 to 31st December 2021 were included in the study. Demographic profile, age at presentation and age at LT, family history, means of diagnosis (clinical/ genetic testing), neurological impairment, duration of phototherapy pre-LT, pre-LT LFTs, liver biopsy findings, post LT outcome and complications were all analyzed. Results: A total of six children were included in the study. There was only 1 female child. There was a wide variation in the age at presentation from the youngest being 13 months and the oldest being 13 years and 5 months. Three children had neurological impairment and all of them required exchange transfusion while in NICU. All children had pre-LT bilirubin of > 20 mg/dl and liver fibrosis in liver explant specimen. Two children developed hepatic artery thrombosis after LT. All children were discharged after LT. Conclusions: Liver transplantation is curative for CNS I with good outcome and improves the quality of life. Early liver transplantation should be considered for those patients who develop early signs of bilirubin encephalopathy, in order to prevent bilirubin induced neurological sequelae. Elevated liver transaminases and fibrosis on explant needs further evaluation to understand underlying pathophysiology.
2021-09-28 | Pediatric Liver Transplantation as Enzyme Replacement Therapy for Rare Metabolic Diseases with No Structural Liver Damage
Objective: Very rare monogenic metabolic diseases without structural liver damage can be cured by liver transplantation. This process is a surgical enzyme replacement therapy, and defective enzymes may or may not be confined to the liver. The aims of this single center study of children with metabolic diseases showing structurally normal liver parenchyma were to analyze the indications and post-operative outcomes of liver transplantation, identification of developmental and metabolic benefits of the procedure with recognition of peri-operative difficulties to improve the success rate.
Materials and Methods: Patients under the age of 19-year-old who underwent liver transplantation for metabolic disorders with no structural liver injury between January 2015 and June 2021 analyzed retrospectively. Patient and graft survivals, indications for transplantation, presence of extra-hepatic enzyme deficiency causing other organ damage, inclusion of simultaneous or sequential kidney transplantation, immunosuppressive protocols, post-transplant complications, and metabolic outcomes were identified.
Results: Eight children with primary hyperoxaluria type 1 (n = 4), Maple syrup urine disease (n = 1), Crigler-Najjar syndrome type 1 (n=1), familial hypercholesterolemia (n=1) and propionic acidemia (n = 1) received left lobe (n=6) and left lateral segment (2) allografts from living donors. The median age of 4 girls and 4 boys at time of transplantation was 6.8 years (range 2.2-12.7 years). The median follow-up time was 3.3 years (range 1.5-5.7 years). The most common post-transplant complications were biliary system complications and infections and, two patients died because of sepsis. Six patients are alive with normal functioning allografts and metabolically stable on unrestricted diet.
Conclusion: Liver transplantation is a lifesaving treatment and improves patient’s and parent’s life quality for metabolic disorders with no parenchymal injury despite strict dietary restrictions and medical therapies. Especially, living donor liver transplantation is very important for populations with very low organ donation rates.
2021-04-14 | Successful living donor liver transplantation plus domino-auxiliary partial orthotopic liver transplantation for pediatric patients with metabolic disorders.
To investigate the efficacy of living donor liver transplantation (LDLT) plus domino-auxiliary partial orthotopic liver transplantation (D-APOLT) in pediatric patients with metabolic disorders. From May 2017 to October 2018, two patients with ornithine aminotransferase deficiency (OTCD) and one patient with type I Crigler-Najjar syndrome (CNS1) received LDLT, their livers were prepared as donors for D-APOLT. Two patients with CNS1 received domino liver grafts from OTCD patients; one OTCD patient received a domino liver graft from a CNS1 patient. The mean follow-up was 26.6 months. The liver function and ammonia remained in the normal range at the end of the follow-up in all recipients. One D-APOLT patient experienced portal vein thrombosis 2 days after transplantation and required reoperation, this patient presented an imbalance of portal blood perfusion between the native and the domino liver at 8 months after liver transplant. The imbalance was improved by interventional radiology treatment. Two LDLT patients experienced early mild acute rejection. The non-cirrhotic livers from pediatric patients with metabolic liver disease can be used as domino donor grafts for selected pediatric patients with different metabolic liver disease. D-APOLT achieves ideal recipient outcomes and provides a strategy to expand donor source for children.
2021-02-22 | Outcome of liver transplantation and prevalence of liver fibrosis in Crigler‐Najjar syndrome
Crigler-Najjar syndrome (CNS) is a rare inherited disorder that is characterized by high levels of non-hemolytic, unconjugated hyperbilirubinemia leading to brain damage and even death. Liver transplantation (LT) can correct the metabolic defect, but there are little data regarding LT in this patient cohort. The liver parenchyma has been considered to be structurally normal in CNS, but there is growing evidence of clinically silent but histologically significant fibrosis in CNS patients.We included 13 patients in our retrospective study who underwent LT at our center. Patient survival, graft function, and long-term complications were evaluated over a median follow-up period of 10 years (range: 1-16 years). In addition, the prevalence of histologically relevant fibrosis was characterized.The overall survival among our LT patients was 100%. The graft survival was only 61.5%. During the follow-up period, 5 LT patients had to undergo retransplantation. More than 45% of our patients showed histological signs of fibrosis.LT remains the only definite therapeutic option for severe CNS but needs to be considered thoroughly regarding the clinical risk-benefit-ratio and impact on quality of life. Furthermore, hepatic parenchymal injury needs to be considered while evaluating future therapeutic options for CNS.
gene therapies
2026-05-29 | Rewriting hepatic fate: emerging gene therapy strategies for liver disease
Several anatomical and physiological features make the liver particularly suitable for gene-based therapeutic strategies, including its extensive vascularization, fenestrated sinusoidal endothelium, and high metabolic capacity. In the past decade, liver-directed gene therapies have evolved from experimental concepts to clinical applications for various inherited and systemic disorders. Adeno-associated viral vectors, lentiviral systems, and lipid nanoparticles are currently the main platforms for delivering therapeutic genes and genome-editing tools to hepatocytes. Genome editing technologies such as CRISPR-Cas nucleases, base editors, and prime editors have enabled more precise modification of endogenous loci. Early clinical studies in disorders like hemophilia, transthyretin amyloidosis, ornithine transcarbamylase deficiency, and Crigler-Najjar syndrome show that partial correction of hepatic gene function can lead to meaningful clinical benefits. However, several challenges hinder broader clinical implementation, including immune responses to viral capsids and nanoparticle components, dose-dependent toxicity, limited packaging capacity of some vectors, and uncertainties about long-term safety and durability, especially in pediatric populations. Efficient and cell-type-specific delivery beyond hepatocytes remains a major challenge, particularly for diseases driven by non-parenchymal cells or malignant transformation. This article discusses recent advancements in delivery technologies and genome editing approaches for liver disease, as well as current translational barriers and emerging strategies aimed at enhancing specificity, durability, and safety. Collectively, these advances suggest that increasingly precise and programmable gene-based interventions may play a central role in future therapies for a broad spectrum of liver diseases.
2026-01-09 | Engineering Liver-Specific Promoters: A Comprehensive Review of Design, Mechanisms, and Clinical Applications in Gene Therapy.
The liver is a primary metabolic hub and a pivotal target for gene therapy, owing to its capacity for protein secretion, role in metabolic homeostasis and immune tolerance. Liver-directed gene therapies are used to treat numerous inherited metabolic disorders and coagulation factor deficiencies including hemophilia (A and B), Crigler-Najjar syndrome, mucopolysaccharidoses, phenylketonuria, Fabry, Gaucher, Wilson and Pompe diseases. The efficacy and safety of liver-directed gene therapy rely on the use of strong tissue-specific promoters. To date, there are many different liver-specific promoters used in preclinical and clinical studies, including novel completely synthetic promoters. This review provides a comprehensive analysis of the design, engineering and application of liver-specific promoters. Furthermore, we discuss fundamental principles of gene expression regulation in the liver and the physiological and immunological characteristics that make it a suitable target organ for gene therapy delivery.
2025-12-01 | From Childhood Icterus to Adolescent Gallstones: Clinically Diagnosed Crigler-Najjar Syndrome Type II
From Childhood Icterus to Adolescent Gallstones: Clinically Diagnosed Crigler-Najjar Syndrome Type IIDanish Kumar GoswamiEmail: daniahgoswami34@gmail.com Institute/Affiliation: Department of Internal Medicine, Liaquat University of Medical and Health
2025-10-01 | Cholestasis in Crigler–Najjar Syndrome Type I: An Uncommon Histopathological Finding in a Rare Disorder
Abstract Crigler–Najjar syndrome is a rare autosomal recessive disorder characterized by severe unconjugated hyperbilirubinemia. Liver histopathology in Crigler–Najjar Syndrome typically reveals fibrosis, while features of cholestasis are rarely reported. We describe an 8-month-old male infant with persistent unconjugated hyperbilirubinemia, global developmental delay, and spasticity. Liver biopsy demonstrated canalicular bile plugs and focal bile duct proliferation, suggestive of cholestasis – a rare finding in Crigler–Najjar Syndrome. Despite initial diagnostic uncertainty due to this atypical presentation, genetic testing confirmed a homozygous mutation in the uridine diphosphate-glucuronosyltransferase 1A1 gene consistent with Crigler–Najjar Syndrome Type I.
2024-12-01 | Approaches to therapy of Crigler–Najjar syndrome type 1 in children
The review is focused on exploring the etiology, pathogenesis, clinical manifestations, and primarily the contemporary treatment methods for Crigler–Najjar syndrome type 1. It considers relevant data regarding the efficacy and safety of the currently existing therapeutic strategies. Effective management of this condition relies on early diagnosis and prompt initiation of treatment, which are crucial for preventing disabling neurological complications associated with bilirubin encephalopathy in patients with Crigler–Najjar syndrome type 1. Prolonged phototherapy is the key treatment method, while liver transplantation represents a radical approach. Recent advances in gene therapy and the use of mesenchymal multipotent stromal cells present novel opportunities for developing alternative, less invasive treatment modalities aimed at improving the quality of life in such patients and reducing their dependence on long-term phototherapy, along with post-transplantation risk.
small molecules
2025-11-30 | Treatment of Severe Unconjugated Hyperbilirubinemia with Phenobarbitone in Two First-Degree Siblings with Crigler-Najjar Syndrome (CNS) Type 2: A Success Story
Background: Crigler–Najjar syndrome (CNS) type 2 is a rare autosomal recessive disorder of bilirubin conjugation caused by mutations in the UGT1A1 gene. It presents in infancy with unconjugated hyperbilirubinemia that does not respond to phototherapy but improves with phenobarbitone, which enhances residual enzyme activity. Although phenobarbitone remains the cornerstone of treatment, familial recurrence of CNS type 2 is rarely reported in pediatric literature. Case: We report two siblings born to consanguineous parents who presented with progressive jaundice during early infancy. The first child, a 2-month-old boy, had multiple hospitalisations for phototherapy without benefit. Laboratory evaluation revealed total bilirubin of 31 mg/dL with normal liver function and no evidence of hemolysis. Genetic testing confirmed a homozygous UGT1A1 (c.1456T>G; p.Tyr486Asp) mutation. He was treated with phenobarbitone (5–8 mg/kg/day) and calcium phosphate, achieving a bilirubin level <10 mg/dL within 4 weeks. Three years later, his younger sister developed similar unconjugated jaundice from day 4 of life and harboured the same mutation; she responded well to phenobarbitone alone. Both siblings remain well on long-term follow-up. Discussion: This case highlights the genetic basis and favorable response of CNS type 2 to phenobarbitone, which induces hepatic UGT1A1 expression. Familial clustering of CNS 2, though reported in few global studies, is seldom documented from India. Conclusion: Early genetic diagnosis, timely institution of phenobarbitone, and family counselling are critical for successful management of CNS type 2. These cases reaffirm the long-term safety and efficacy of phenobarbitone in familial presentations of this rare disorder.
2025-11-07 | Yellow-eyed man and dromomania: A case of adult-onset psychiatric symptoms in Crigler–Najjar syndrome type II
A 30-year-old man presented with long-standing, treatment-resistant psychiatric symptoms including compulsive wandering, hallucinations, and obsessive behaviors. Physical examination revealed deep yellow sclera present since childhood. Genetic testing identified compound heterozygous mutations in the UGT1A1 gene, confirming Crigler–Najjar syndrome type II. Initiation of phenobarbitone and adjunctive therapy led to a marked reduction in serum bilirubin and clinical symptoms. This case highlights the possibility of bilirubin-induced neurological dysfunction presenting in adulthood as a chronic psychiatric condition.
2025-08-08 | Tapentadol withdrawal, a newer trend in opioid overuse in Nepal: A case report.
Crigler-Najjar Syndrome Type 2 (CNS2) is a rare autosomal recessive disorder characterized by unconjugated hyperbilirubinemia due to partial deficiency of the enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We present a case of a 13-month-old male admitted to Kanti Children's Hospital with persistent jaundice since birth. Diagnostic evaluation accompanied by gene sequencing confirmed CNS2 and the patient was effectively managed with orally administered phenobarbitone. CNS2 can be distinguished from other potential causes of unconjugated hyperbilirubinemia based on bilirubin concentration and the affected patient's response to phenobarbitone. Genetic counselling is essential for the recognition and prevention of severe hyperbilirubinemia which, in the absence of timely medical intervention, may lead to neurotoxicity. Keywords: Case report; crigler-Najjar syndrome; genetic counseling; phenobarbitone; unconjugated hyperbilirubinemia.
2025-06-29 | A Rare Case of Crigler-Najjar Syndrome Type 2
Crigler–Najjar Syndrome Type 2 (CNS2) is a rare autosomal recessive disorder characterized by unconjugated hyperbilirubinemia due to partial deficiency of the enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We present a case of a 13-month-old male admitted to Kanti Children’s Hospital with persistent jaundice since birth. Diagnostic evaluation accompanied by gene sequencing confirmed CNS2 and the patient was effectively managed with orally administered phenobarbitone. CNS2 can be distinguished from other potential causes of unconjugated hyperbilirubinemia based on bilirubin concentration and the affected patient’s response to phenobarbitone. Genetic counselling is essential for the recognition and prevention of severe hyperbilirubinemia which, in the absence of timely medical intervention, may lead to neurotoxicity. Keywords: Case report; crigler-Najjar syndrome; genetic counseling; phenobarbitone; unconjugated hyperbilirubinemia.
2024-04-26 | A Case of Crigler-Najjar Syndrome Type II During Pregnancy and Its Management
Crigler-Najjar syndrome (CNS) is a genetic syndrome that results in increased levels of unconjugated bilirubin due to less or completely nonfunctional enzyme, uridine diphosphoglucoronyltransferase (UDPGT) in hepatocytes. When bilirubin metabolism is compromised, hyperbilirubinemia is caused, which results in increased levels of unconjugated and conjugated bilirubin in the bloodstream. CNS is an autosomal recessive disorder, usually noticeable as people get older. This disorder is divided into two types: CNS type I and CNS type II, which are caused by homozygous or compound heterozygous mutations in the UDP glucuronosyltransferase family 1 member A1 (UGT1A1) gene. The disorder affects all races and genders equally, with a prevalence of one per million births. CNS type I is more severe and has almost undetectable UDPGT expression activity, and affected individuals die before one year of age. Consanguineous marriages are a major risk factor as CNS is inherited in an autosomal recessive manner. Being rare, maternal CNS type II is yet to be completely understood in terms of its impact on the mother, her pregnancy, and the infant. We aim to present a case of a pregnant female with CNS type II and its clinical course. She was monitored closely during her pregnancy. The treatment protocol was followed as per previously reported cases and was managed on low, non-teratogenic doses of phenobarbitone. A successful outcome with the birth of a healthy infant having normal neurological development till six months follow-up was observed.
other
2024-01-31 | Development of a minimal PBPK-QSP modeling platform for LNP-mRNA based therapeutics to study tissue disposition and protein expression dynamics
Physiologically based pharmacokinetic models have gained significant recognition as effective mathematical models that enable deeper mechanistic investigation of drug delivery and tissue disposition. Here we describe the development of a platform PBPK-quantitative systems pharmacology (QSP) model to study tissue delivery of lipid nanoparticle (LNP) based mRNA therapeutics. The model is calibrated to published data in the context of Crigler-Najjar syndrome. Sensitivity analyses were performed to explore factors that influence protein expression and pharmacodynamic response following LNP-mRNA liver disposition. The most sensitive determinants of protein exposures were mRNA stability, translation, and cellular uptake rate, while the liver influx rate of lipid nanoparticle did not appreciably impact protein expression. Indeed, protein expression level may be tuned by modulation of mRNA degradation rate. However, simulations predicted that when the intrinsic half-life of the translated protein falls below a certain threshold, lowering mRNA degradation rate may not rescue protein exposure, a design feature that should be considered in optimal design of mRNA therapeutics. Additionally, interplay of LNP degradation rate and mRNA escape rate from endosomes was found to be crucial in modulation of protein expression. Simulations predicted that at a given LNP degradation rate, protein exposure varied linearly with mRNA escape rate. We further extended the model by incorporating LNP recycling to identify conditions necessary for observing a second peak in mRNA pharmacokinetics (PK). Simulations predict that with a fast recycling and slow tissue re-uptake rates, a robust second peak is observed in the plasma mRNA concentration curve. The amplitude and timing of the second peak could be tuned with recycling and re-uptake rates. Modeling results indicate that within the context of non-secreted mRNA mediated enzyme replacement therapy, recycling may depress or improve protein exposure depending on the re-uptake rate of the recycled LNP. The model is subsequently used to generate virtual animal cohorts to investigate optimal dosing and schedule of the compound. Virtual instances of the model were then employed to identify design principles that potentially reduce dosing frequency while maintaining efficacy. This study demonstrates the potential applications of coupled PBPK-QSP model for LNP based mRNA therapeutics as a translational platform.
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Drug Discovery Landscape
10 orphan drug designations for Crigler-Najjar syndrome.
10 orphan drug designations for Crigler-Najjar syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
rAAV8-hUGT1A1 | gene therapies | FDA | 2024-10-29 | — | Genethon |
Volrubigene ralaparvovec | gene therapies | EMA | 2016-11-18 | — | Audentes Therapeutics UK Limited |
modified mRNA encoding UGT1A1 protein, formulated in lipid nanoparticles | RNAs | FDA | 2016-07-05 | — | Moderna Therapeutics, Inc. |
Modified mRNA encoding the UGT1A1 protein | RNAs | EMA | 2016-06-27 | — | Moderna Biotech Spain S.L. |
non-replicating recombinant adeno-associated viral vector, serotype 8, expressing the 1A1 isoform of the bilirubin-uridine diphosphate glucuronosyltransferase gene | gene therapies | FDA | 2016-05-24 | — | Audentes Therapeutics, Inc. |
Adeno-associated viral vector serotype 8 containing the human UGT1A1 gene | gene therapies | EMA | 2014-10-15 | — | Généthon |
Volrubigene ralaparvovec | gene therapies | EMA | 2014-08-22 | — | Fondazione Telethon Ets |
heterologous human liver derived progenitor cells | cell therapies | FDA | 2012-03-09 | — | Promethera Biosciences |
Heterologous human adult liver derived stem cells | cell therapies | EMA | 2007-11-29 | — | Cellaion |
Flumecinol | small molecules | FDA | 1985-01-15 | — | Farmacon, Inc. |
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