Crigler-Najjar syndrome

The syndrome, first described by the two doctors Dr. John Crigler and Dr. Victor Najjar in 1952, is characterized by a congenital disorder in the metabolism of bilirubin. Existing treatment options aim to reduce the amount of unconjugated bilirubin in the blood. However, this sometimes requires relatively complex procedures. Alternatives include liver transplantation or possibly a hepatocyte transplant. But there is light on the horizon: a gene therapy has achieved promising results in a clinical trial.

Bilirubin is a degradation product of the red blood pigment haemoglobin and is formed when red blood cells break down. Normally, the enzyme UGT1A1 (UDP-glucuronosyltransferase 1 polypeptide A1) catalyzes the formation of the water-soluble bilirubin diglukuronide in the smooth endoplasmic reticulum of the liver, which is then excreted into the intestine via the bile ducts [1–3]. However, people affected by Crigler-Najjar syndrome lack this enzyme, so that bilirubin accumulates in the body and, without treatment, leads to significant neurological damage or even death [1]. In Crigler-Najjar syndrome type 1, the UGT enzyme is completely inactive and in type 2 it is greatly reduced [4]. Both forms are caused by genetic defects in the UGT1A1 gene on chromosome 2. Due to the genetic nature of the disease, both parents must be carriers of the mutation for their child to be affected [2]. It is estimated that less than 1 in 1 million newborns worldwide are affected by Crigler-Najjar syndrome.

Clinical appearance

Crigler-Najjar syndrome type 1 usually manifests itself immediately after birth as excessive hyperbilirubinemia, which, if left untreated, usually leads to kernicterus with severe neurological damage. As a result, affected patients often die in early childhood if untreated. Newborns are particularly susceptible to neurological damage caused by hyperbilirubinemia, as the still developing liver is heavily stressed by the breakdown of fetal hemoglobin in the first days of life and the blood-brain barrier is not yet very well developed [11]. Slightly elevated serum bilirubin levels and jaundice are not uncommon in newborns, but bilirubin levels should be carefully monitored if there is any sign of an increase.

Crigler-Najjar syndrome type 2 is less severe than type 1, where kernicterus is rare, but the disturbing symptoms with yellowing of the skin and extensive pruritus can severely impair quality of life [4]. In some people, the diagnosis is not made until adulthood, such as in the case report summarized in the box [5]. Kernicterus is rare in type 2, but can occur especially when the affected person is ill, not eating or under anesthesia [2]. Whether severe jaundice within a few days of birth could be Crigler-Najjar syndrome can be confirmed by clinical assessment, family history, genetic and laboratory tests. A classic finding would be, for example, a high level of unconjugated bilirubin in the blood or a lack of conjugated bilirubin in the bile. Genetic tests to identify mutations in the UGT1A1 gene can confirm the diagnosis [2].

Case report: CNS type 2 diagnosis in adulthood
A 21-year-old man had been plagued by recurrent episodes of jaundice since early childhood. For the past 6 months, he had been particularly troubled by persistent jaundice accompanied by occasional vomiting.

History: His birth was without complications at the time, there was no neonatal jaundice and no need for blood transfusions. He reached the developmental milestones expected for his age and there was no cause for concern. At the age of 5 years, his parents first noticed a strange yellowish discoloration of his eyes, which was not accompanied by fever, itching, abdominal pain or clay-colored stools, but the urine was strongly discolored. The patient then underwent various alternative and complementary treatments. Unfortunately, none of these measures led to a complete cure of his condition. According to the recollection of the patient’s parents, the highest serum bilirubin level ever measured was 12 mg/dL.

Current diagnostic investigations: The current examination revealed jaundice without organomegaly. Other clinical investigations also showed normal results and offered no immediate explanation for his persistent jaundice. However, routine investigations revealed indirect hyperbilirubinemia with normal liver enzymes. Ultrasound examination of the abdomen was unremarkable. A comprehensive hemolytic examination was then performed, but all of the tests were negative. Based on the onset, course and presence of unconjugated hyperbilirubinemia, a provisional diagnosis of non-hemolytic unconjugated hyperbilirubinemia was made. With the suspicion of a congenital indirect bilirubinemia syndrome, an analysis for UGT1A1 mutations was started, which was positive and indicated the presence of a partial enzyme deficiency. This led to the definitive diagnosis of Crigler-Najjar syndrome type 2.

Therapy: To manage the patient’s symptoms and improve his quality of life, he was given oral phenobarbital at a dose of 5 mg/kg. Remarkably, a significant reduction in the patient’s serum bilirubin levels was observed within just two weeks of starting treatment. Thus, the therapy proved to be effective.

according to [5]

Currently available therapy options

The primary goal of treating patients with Crigler-Najjar syndrome is to reduce the amount of unconjugated bilirubin in the blood as quickly and consistently as possible. This is recommended for Crigler-Najjar syndrome type 1 (CNS I) and type 2 (CNS II) in different ways [2].

Conservative treatment of CNS I is based on three pillars [4]:

Consistent daily blue light phototherapy (this makes bilirubin water-soluble)
Administration of tinprotoporphyrin, an inhibitor of heme oxygenase (attenuates bilirubin elevations)
Administration of calcium carbonate and calcium phosphate (increases the secretion of unconjugated bilirubin in the intestine)

This therapy can extend life expectancy and delay the onset of neurological complications. Another treatment option, liver transplantation, should be attempted as early as possible. Allogeneic transplantation of hepatocytes is currently in the experimental phase.

CNS II is treated by administering phenobarbital once daily [4]. Alternatively, rifampicin is also possible. By inducing enzymatic activity, the bilirubin concentration in the plasma can be reduced to safe levels.

Gene therapy study: opportunities and risks
D’Antiga et al. investigated the safety and efficacy of a single intravenous infusion of an AAV vector encoding UGT1A1 in 5 patients with Crigler-Najjar syndrome [6,7].

In three of those treated with a higher dose, bilirubin levels fell below 30 µmol per liter (17.5 mg/dl), so that phototherapy could be discontinued for the next 18 months of follow-up [7]. However, a complete normalization of the bilirubin level was not achieved in any case.

According to Di Dato et al. the duration of efficacy of a single infusion of the AAV vector is currently still unclear [6,8]. In addition, it has been reported that in patients with haemophilia, gene therapy can lead to the development of persistent, high-titer, cross-reactive neutralizing AAV antibodies, which could rule out the possibility of further vector administrations [9]. Multiple infusions with AAV vectors may also pose a risk of genotoxicity [10].

Gene therapy as a potential alternative treatment method

The use of AAV (Adeno-Associated Virus) vectors, for example, has been approved by the US Food and Drug Administration (FDA) for gene replacement therapy for patients with spinal muscular atrophy and congenital blindness. Initial results from a clinical trial on Crigler-Najjar syndrome suggest that AAV-based gene therapy could serve as a potential alternative treatment for this life-threatening disease [1,7]. The treatment, which is currently being tested, was developed by Généthon** researchers. It involves providing liver cells with a copy of the UGT1A1 gene, which encodes an enzyme that facilitates the removal of bilirubin. Initial observations from the CureCN study (“Adeno-Associated Virus Vector-Mediated Liver Gene Therapy for Crigler-Najjar Syndrome”) suggest that gene therapy could be a potential alternative treatment. “We are very excited about the results achieved so far in this study of AAV-mediated [Adeno-assoziiertes Virus] gene therapy for the treatment of Crigler-Najjar syndrome,” noted Dr. D’Antiga [1]. “The treatment has been shown to be safe at appropriate doses and capable of targeting the disease to such an extent that the first patient was able to stop her daily phototherapy, eliminating the risk of neurological damage. The degree of improvement in the second patient suggests that she too may soon be able to stop phototherapy” [1].

** Genethon is part of the Biotherapies Institute for Rare Diseases (BIRD)

An article published in 2024 by Di Dato et al. [6] also assesses gene therapy as a promising potential treatment alternative, although the authors point out that there are still some unanswered questions regarding the efficacy and safety of this treatment approach, which are the subject of current investigations (box).

Literature:

“Clinical study gives hope to people suffering from a rare genetic liver disease”, https://cordis.europa.eu/article/id/430456-clinical-trial-gives-hope-to-sufferers-of-rare-genetic-liver-disease/de,(last accessed 29.08.2024) .
“Crigler-Najjar syndrome”, https://liverfoundation.org,(last accessed 29.08.2024).
“UDP-glucuronyltransferase mutation (UGT1A1*28)”,www.labor-duesseldorf.de/examination/view/udp-glukuronyltransferase-mutation-ugt1a128,(last accessed 29.08.2024).
“Crigler-Najjar syndrome”, https://flexikon.doccheck.com,(last accessed 29.08.2024).
Rijal D, et al: A rare case of Crigler-Najjar syndrome type 2: A case report and literature review. Clin Case Rep 2023; Nov 13; 11(11): e8176.
Di Dato F, D’Uonno G, Iorio R: Crigler-Najjar syndrome: looking to the future does not make us forget the present. Orphanet J Rare Dis. 2024 Mar 7; 19(1): 102.
D’Antiga L, et al: Gene Therapy in patients with the Crigler-Najjar Syndrome. NEJM 2023; 389(7): 620-631.
Aronson SJ, Ronzitti G, Bosma PJ: What’s next in gene therapy for Crigler-Najjar syndrome? Expert Opin Biol Ther 2023; 23(2): 119-121.
George LA, et al: Long-term Follow-Up of the First in Human Intravascular Delivery of AAV for Gene transfer: AAV2-hFIX16 for severe Hemophilia B. Mol Ther 2020; 28(9): 2073-2082.
Sabatino DE, et al: Evaluating the state of the science for adeno-associated virus integration: an integrated perspective. Mol Ther 2022; 30(8): 2646-2663.
Wikipedia: Kernicterus, https://en.wikipedia.org,(last accessed 29.08.2024).