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Cancers Jul 2022The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport... (Review)
Review
The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC genes can influence serum and hepatic levels of bile acids. Experimental studies on the gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as , and . Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation.
PubMed: 35884482
DOI: 10.3390/cancers14143421 -
Genes & Diseases Jan 2021Notch is a cell-cell signaling pathway that is involved in a host of activities including development, oncogenesis, skeletal homeostasis, and much more. More... (Review)
Review
Notch is a cell-cell signaling pathway that is involved in a host of activities including development, oncogenesis, skeletal homeostasis, and much more. More specifically, recent research has demonstrated the importance of Notch signaling in osteogenic differentiation, bone healing, and in the development of the skeleton. The craniofacial skeleton is complex and understanding its development has remained an important focus in biology. In this review we briefly summarize what recent research has revealed about Notch signaling and the current understanding of how the skeleton, skull, and face develop. We then discuss the crucial role that Notch plays in both craniofacial development and the skeletal system, and what importance it may play in the future.
PubMed: 33569510
DOI: 10.1016/j.gendis.2020.04.006 -
Annales de Biologie Clinique Dec 2018We report the case of an infant hospitalized for neonatal anoxic ischemia in whom the diagnosis of Alagille syndrome (SAG ; MIM # 118450) was suspected in the presence...
We report the case of an infant hospitalized for neonatal anoxic ischemia in whom the diagnosis of Alagille syndrome (SAG ; MIM # 118450) was suspected in the presence of major cholestasis, cardiac malformations, suggestive facial dysmorphia, and vertebral and ocular abnormalities. This diagnosis was later confirmed by the detection of a heterozygous pathogenic variant in the gene JAG1, i.e. the gene predominantly responsible for this syndrome with autosomal dominant transmission, which affects about 1 in 30 000 births. The purpose of this presentation is to highlight this relatively unknown syndrome, both from the diagnostic and physiopathological points of view. This clinical case is also an opportunity to discuss pseudo-bisalbuminemia, accidentally discovered in the patient during the exploration of serum proteins by capillary electrophoresis. In total, the medical biologist is directly concerned by the multidisciplinary management of this syndrome, which involves biological perturbances in multiple organs.
Topics: Alagille Syndrome; Clinical Laboratory Techniques; Humans; Infant, Newborn; Male; Neonatal Screening
PubMed: 30543192
DOI: 10.1684/abc.2018.1399 -
Proceedings of the National Academy of... Dec 2022Despite the robust healing capacity of the liver, regenerative failure underlies numerous hepatic diseases, including the haploinsufficient disorder, Alagille syndrome...
Despite the robust healing capacity of the liver, regenerative failure underlies numerous hepatic diseases, including the haploinsufficient disorder, Alagille syndrome (ALGS). Cholestasis due to intrahepatic duct (IHD) paucity resolves in certain ALGS cases but fails in most with no clear mechanisms or therapeutic interventions. We find that modulating and allele dosage is sufficient to stratify these distinct outcomes, which can be either exacerbated or rescued with genetic manipulation of Notch signaling, demonstrating that perturbations of Jag/Notch signaling may be causal for the spectrum of ALGS liver severities. Although regenerating IHD cells proliferate, they remain clustered in mutants that fail to recover due to a blunted elevation of Notch signaling in the distal-most IHD cells. Increased Notch signaling is required for regenerating IHD cells to branch and segregate into the peripheral region of the growing liver, where biliary paucity is commonly observed in ALGS. Mosaic loss- and-gain-of-function analysis reveals Sox9b to be a key Notch transcriptional effector required cell autonomously to regulate these cellular dynamics during IHD regeneration. Treatment with a small-molecule putative Notch agonist stimulates Sox9 expression in ALGS patient fibroblasts and enhances hepatic expression, rescues IHD paucity and cholestasis, and increases survival in zebrafish mutants, thereby providing a proof-of-concept therapeutic avenue for this disorder.
Topics: Animals; Humans; Alagille Syndrome; Jagged-1 Protein; Mosaicism; SOX9 Transcription Factor; Zebrafish; Receptors, Notch; Signal Transduction; Regeneration; Bile Ducts, Intrahepatic; Fibroblasts
PubMed: 36469766
DOI: 10.1073/pnas.2201097119 -
Case Reports in Psychiatry 2016Alagille syndrome is a rare multisystem disorder affecting the liver, heart, vertebrae, eyes, and face. Alagille syndrome shares multiple phenotypic variants of other...
Alagille syndrome is a rare multisystem disorder affecting the liver, heart, vertebrae, eyes, and face. Alagille syndrome shares multiple phenotypic variants of other congenital or chronic childhood illnesses such as DiGeorge syndrome, Down syndrome, spina bifida, type 1 diabetes mellitus, and cystic fibrosis. All of these chronic illnesses have well-established links to psychiatric conditions. There are few community resources for Alagille patients, as it is an extremely rare condition. Despite the overlap with other chronic childhood illnesses, the psychiatric manifestations of Alagille syndrome have not been previously discussed in literature. The current study is a case report of a twelve-year-old female hospitalized in our pediatric psychiatric hospital for suicidal ideation with intent and plan. The patient had major depressive disorder, anxiety, other specified feeding and eating disorder, and attention-deficit/hyperactive disorder.
PubMed: 28018696
DOI: 10.1155/2016/1657691 -
JGH Open : An Open Access Journal of... Dec 2022Alagille syndrome (ALGS) is a multisystem disorder with variable clinical courses. This study investigated the clinical and genetic features of ALGS patients with...
BACKGROUND AND AIM
Alagille syndrome (ALGS) is a multisystem disorder with variable clinical courses. This study investigated the clinical and genetic features of ALGS patients with different outcomes and analyzed the liver pathology at liver transplantation (LT) compared with that in biliary atresia (BA).
METHODS
We report the clinical characteristics, outcomes, and genetic mutations of 25 children with ALGS followed for a median of 7.3 years. Patients were classified into (i) jaundice-free (JF) group (resolving jaundice after 2 years of age); (ii) progressive disease (PD) group (persistent jaundice or progressive cholestasis). In addition, we analyzed the explant liver in 10 ALGS patients compared with 20 age-matched BA patients at the time of LT.
RESULTS
Nine patients (36%) in the JF group had a favorable outcome, with longer native liver survival than patients with PD ( = 16, < 0.001). Fourteen of the PD group patients received LT or died. We identified 18 different mutations in 22 patients. Three unrelated probands in the JF group had the same de novo mutation in , c.2122-2125delCAGT. Compared with BA children, ALGS patients had lower METAVIR scores in liver pathology, higher serum albumin levels, and lower weight-for-age -scores when receiving LT.
CONCLUSION
One-third of ALGS patients had JF and a favorable course. Children with ALGS presenting with persistent jaundice beyond 2 years of age should be cautioned for poor prognosis. ALGS patients tend to have a lesser extent of cirrhosis, and more growth problems than BA patients at the time of LT.
PubMed: 36514505
DOI: 10.1002/jgh3.12830 -
Tissue Engineering. Part C, Methods Mar 2021Notch is an evolutionary, conserved, cell-cell signaling pathway that is central to several biological processes, from tissue morphogenesis to homeostasis. It is... (Review)
Review
Notch is an evolutionary, conserved, cell-cell signaling pathway that is central to several biological processes, from tissue morphogenesis to homeostasis. It is therefore not surprising that several genetic mutations of Notch components cause inherited human diseases, especially cardiovascular disorders. Despite numerous efforts, current models are still insufficient to unravel the underlying mechanisms of these pathologies, hindering the development of utmost needed medical therapies. In this perspective review, we discuss the limitations of current murine models and outline how the combination of microphysiological systems (MPSs) and targeted computational models can lead to breakthroughs in this field. In particular, while MPSs enable the experimentation on human cells in controlled and physiological environments, models can provide a versatile tool to translate the findings to the more complex setting. As a showcase example, we focus on Notch-related cardiovascular diseases, such as Alagille syndrome, Adams-Oliver syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Impact statement In this review, a comprehensive overview of the limitations of current models of genetic Notch cardiovascular diseases is provided, followed by a discussion over the potential of microphysiological systems and computational models in overcoming these limitations and in potentiating drug testing and modeling of these pathologies.
Topics: Animals; Cardiovascular Diseases; Ectodermal Dysplasia; Humans; Limb Deformities, Congenital; Mice; Receptors, Notch; Signal Transduction
PubMed: 33403934
DOI: 10.1089/ten.TEC.2020.0327 -
Journal of Medical Case Reports Apr 2023Chromosome 5p partial monosomy (5p-syndrome) and chromosome 6p partial trisomy are chromosomal abnormalities that result in a variety of symptoms, but liver dysfunction...
BACKGROUND
Chromosome 5p partial monosomy (5p-syndrome) and chromosome 6p partial trisomy are chromosomal abnormalities that result in a variety of symptoms, but liver dysfunction is not normally one of them. Alagille syndrome (OMIM #118450) is a multisystem disorder that is defined clinically by hepatic bile duct paucity and cholestasis, in association with cardiac, skeletal, and ophthalmologic manifestations, and characteristic facial features. Alagille syndrome is caused by mutations in JAG1 on chromosome 20 or NOTCH2 on chromosome 1. Here, we report a preterm infant with karyotype 46,XX,der(5)t(5,6)(p15.2;p22.3) and hepatic dysfunction, who was diagnosed as having incomplete Alagille syndrome.
CASE PRESENTATION
The Japanese infant was diagnosed based on the cardiac abnormalities, ocular abnormalities, characteristic facial features, and liver pathological findings. Analysis of the JAG1 and NOTCH sequences failed to detect any mutations in these genes.
CONCLUSIONS
These results suggest that, besides the genes that are known to be responsible for Alagille syndrome, other genetic mutations also may cause Alagille syndrome.
Topics: Infant; Humans; Infant, Newborn; Alagille Syndrome; Jagged-1 Protein; Infant, Premature; Karyotype
PubMed: 37101309
DOI: 10.1186/s13256-023-03810-7 -
Korean Journal of Pediatrics Oct 2015Alagille syndrome is a complex hereditary disorder that is associated with cardiac, hepatic, skeletal, ocular, and facial abnormalities. Mutations in the Notch signaling...
PURPOSE
Alagille syndrome is a complex hereditary disorder that is associated with cardiac, hepatic, skeletal, ocular, and facial abnormalities. Mutations in the Notch signaling pathway, such as in JAG1 and NOTCH2, play a key role in embryonic development. A cardiac or hepatic presentation is a critical factor for determining the prognosis.
METHODS
We conducted a retrospective study of 41 patients with Alagille syndrome or a JAG1 mutation between 1983 and 2013.
RESULTS
The first presentations were jaundice, murmur, cyanosis, and small bowel obstruction at a median age of 1.0 months (range, 0-24 months). The JAG1 mutation was found in 27 of the 28 genetically-tested patients. Cardiovascular anomalies were identified in 36 patients, chronic cholestasis was identified in 34, and liver transplantation was performed in 9. There was no significant correlation between the severity of the liver and cardiac diseases. The most common cardiovascular anomaly was peripheral pulmonary stenosis (83.3%), with 13 patients having significant hemodynamic derangement and 12 undergoing surgical repair. A total bilirubin level of >15 mg/dL with a complex surgical procedure increased the surgical mortality (P=0.022). Eight patients died after a median period of 2.67 years (range, 0.33-15 years). The groups with fetal presentation and with combined severe liver and heart disease had the poorest survival (P<0.001).
CONCLUSION
The group with combined severe liver and heart disease had the poorest survival, and a multidisciplinary approach is necessary to improve the outcome.
PubMed: 26576184
DOI: 10.3345/kjp.2015.58.10.392 -
JHEP Reports : Innovation in Hepatology Feb 2023Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs),...
BACKGROUND & AIMS
Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship.
METHODS
From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS.
RESULTS
The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 75% in BSEP1/1 and 23% in BSEP3/3 (0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; 0.001).
CONCLUSIONS
Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment.
IMPACT AND IMPLICATIONS
This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.
PubMed: 36687469
DOI: 10.1016/j.jhepr.2022.100626