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Scientific Reports Jan 2024Alagille Syndrome (ALGS) is a complex genetic disorder characterized by cholestasis, congenital cardiac anomalies, and butterfly vertebrae. The variable phenotypic...
Alagille Syndrome (ALGS) is a complex genetic disorder characterized by cholestasis, congenital cardiac anomalies, and butterfly vertebrae. The variable phenotypic expression of ALGS can lead to challenges in accurately diagnosing affected infants, potentially resulting in misdiagnoses or underdiagnoses. This study highlights novel JAG1 gene mutations in two cases of ALGS. The first case with a novel p.Pro325Leufs*87 variant was diagnosed at 2 months of age and exhibited a favorable prognosis and an unexpected manifestation of congenital hypothyroidism. Before the age of 2, the second patient was incorrectly diagnosed with liver structural abnormalities, necessitating extensive treatment. In addition, he exhibited delays in language acquisition that may have been a result of SNAP25 haploinsufficiency. The identification of ALGS remains challenging, highlighting the importance of early detection and genetic testing for effective patient management. The variant p.Pro325Leufs*87 is distinct from reported variants linked to congenital hypothyroidism in ALGS patients, thereby further confirming the clinical and genetic complexity of ALGS. This emphasizes the critical need for individualized and innovative approaches to diagnosis and medical interventions, uniquely intended to address the complexity of this syndrome.
Topics: Humans; Infant; Male; Alagille Syndrome; China; Congenital Hypothyroidism; Genetic Testing; Jagged-1 Protein
PubMed: 38245625
DOI: 10.1038/s41598-024-52357-0 -
Current Opinion in Cell Biology Feb 2024Notch signaling controls multiple aspects of embryonic development and adult homeostasis. Alagille syndrome is usually caused by a single mutation in the jagged... (Review)
Review
Notch signaling controls multiple aspects of embryonic development and adult homeostasis. Alagille syndrome is usually caused by a single mutation in the jagged canonical Notch ligand 1 (JAG1), and manifests with liver disease and cardiovascular symptoms that are a direct consequence of JAG1 haploinsufficiency. Recent insights into Jag1/Notch-controlled developmental and homeostatic processes explain how pathology develops in the hepatic and cardiovascular systems and, together with recent elucidation of mechanisms modulating liver regeneration, provide a basis for therapeutic efforts. Importantly, disease presentation can be regulated by genetic modifiers, that may also be therapeutically leverageable. Here, we summarize recent insights into how Jag1 controls processes of relevance to Alagille syndrome, focused on Jag1/Notch functions in hepatic and cardiovascular development and homeostasis.
Topics: Humans; Alagille Syndrome; Serrate-Jagged Proteins; Membrane Proteins; Calcium-Binding Proteins; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein
PubMed: 38194749
DOI: 10.1016/j.ceb.2023.102302 -
Hepatology Communications Jan 2024Mitochondrial hepatopathies (MHs) are primary mitochondrial genetic disorders that can present as childhood liver disease. No recognized biomarkers discriminate MH from...
BACKGROUND
Mitochondrial hepatopathies (MHs) are primary mitochondrial genetic disorders that can present as childhood liver disease. No recognized biomarkers discriminate MH from other childhood liver diseases. The protein biomarkers growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) differentiate mitochondrial myopathies from other myopathies. We evaluated these biomarkers to determine if they discriminate MH from other liver diseases in children.
METHODS
Serum biomarkers were measured in 36 children with MH (17 had a genetic diagnosis); 38 each with biliary atresia, α1-antitrypsin deficiency, and Alagille syndrome; 20 with NASH; and 186 controls.
RESULTS
GDF15 levels compared to controls were mildly elevated in patients with α1-antitrypsin deficiency, Alagille syndrome, and biliary atresia-young subgroup, but markedly elevated in MH (p<0.001). FGF21 levels were mildly elevated in NASH and markedly elevated in MH (p<0.001). Both biomarkers were higher in patients with MH with a known genetic cause but were similar in acute and chronic presentations. Both markers had a strong performance to identify MH with a molecular diagnosis with the AUC for GDF15 0.93±0.04 and for FGF21 0.90±0.06. Simultaneous elevation of both markers >98th percentile of controls identified genetically confirmed MH with a sensitivity of 88% and specificity of 96%. In MH, independent predictors of survival without requiring liver transplantation were international normalized ratio and either GDF15 or FGF21 levels, with levels <2000 ng/L predicting survival without liver transplantation (p<0.01).
CONCLUSIONS
GDF15 and FGF21 are significantly higher in children with MH compared to other childhood liver diseases and controls and, when combined, were predictive of MH and had prognostic implications.
Topics: Child; Humans; Alagille Syndrome; Biliary Atresia; Biomarkers; Growth Differentiation Factor 15; Non-alcoholic Fatty Liver Disease; Mitochondrial Diseases
PubMed: 38180987
DOI: 10.1097/HC9.0000000000000361 -
Hepatology (Baltimore, Md.) Jun 2024Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter... (Comparative Study)
Comparative Study
BACKGROUND AND AIMS
Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study.
APPROACH AND RESULTS
Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings.
CONCLUSIONS
This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.
Topics: Humans; Alagille Syndrome; Female; Male; Retrospective Studies; Child; Infant; Child, Preschool; Progression-Free Survival; Adolescent; Carrier Proteins; Membrane Glycoproteins
PubMed: 38146932
DOI: 10.1097/HEP.0000000000000727 -
Nature Metabolism Dec 2023The thyroid functions as an apex endocrine organ that controls growth, differentiation and metabolism, and thyroid diseases comprise the most common endocrine disorders....
The thyroid functions as an apex endocrine organ that controls growth, differentiation and metabolism, and thyroid diseases comprise the most common endocrine disorders. Nevertheless, high-resolution views of the cellular composition and signals that govern the thyroid have been lacking. Here, we show that Notch signalling controls homeostasis and thermoregulation in adult mammals through a mitochondria-based mechanism in a subset of thyrocytes. We discover two thyrocyte subtypes in mouse and human thyroids, identified in single-cell analyses by different levels of metabolic activity and Notch signalling. Therapeutic antibody blockade of Notch in adult mice inhibits a thyrocyte-specific transcriptional program and induces thyrocyte defects due to decreased mitochondrial activity and ROS production. Thus, disrupting Notch signalling in adult mice causes hypothyroidism, characterized by reduced levels of circulating thyroid hormone and dysregulation of whole-body thermoregulation. Inducible genetic deletion of Notch1 and 2 in thyrocytes phenocopies this antibody-induced hypothyroidism, establishing a direct role for Notch in adult murine thyrocytes. We confirm that hypothyroidism is enriched in children with Alagille syndrome, a genetic disorder marked by Notch mutations, suggesting that these findings translate to humans.
Topics: Adult; Child; Humans; Mice; Animals; Thyroid Epithelial Cells; Mammals; Hypothyroidism; Homeostasis
PubMed: 38123718
DOI: 10.1038/s42255-023-00937-1 -
Radiology Case Reports Feb 2024Middle aortic syndrome (MAS), an uncommon cause of secondary hypertension, is defined by obstructive narrowing of the abdominal aorta and ostia of its major branches...
Middle aortic syndrome (MAS), an uncommon cause of secondary hypertension, is defined by obstructive narrowing of the abdominal aorta and ostia of its major branches like the renal and splanchnic arteries. Most of the cases of MAS are categorized as idiopathic; however, genetic disorders like Williams syndrome, mucopolysaccharidosis, neurofibromatosis type 1 (NF1), and Alagille syndrome, and acquired inflammatory diseases such as Takayasu arteritis and other nonspecific arteritis can also lead to MAS. MAS is commonly seen in children and young adults presenting with severe hypertension, congestive heart failure, renal failure, or severe leg claudication. The diagnosis of MAS on CT, MR, and conventional angiography is fairly straightforward. However, the spectrum of sonographic findings in MAS can be varied. Since ultrasound is frequently utilized as a first-line investigation for secondary causes of hypertension, it is especially crucial to understand the sonographic features of MAS. Here, we report a case of a young female who presented to our hospital with severe hypertension. On the Renal Doppler scan, the only clue of the renovascular etiology of her secondary hypertension was the "tardus-parvus waveform'' in the intrarenal arteries.
PubMed: 38074442
DOI: 10.1016/j.radcr.2023.11.008 -
Gastroenterology Nursing : the Official...
PubMed: 38064423
DOI: 10.1097/SGA.0000000000000799 -
Hepatology Communications Dec 2023Alagille syndrome and progressive familial intrahepatic cholestasis are conditions that can affect multiple organs. Advancements in molecular testing have aided in the...
Alagille syndrome and progressive familial intrahepatic cholestasis are conditions that can affect multiple organs. Advancements in molecular testing have aided in the diagnosis of both. The impairment of normal bile flow and secretion leads to the various hepatic manifestations of these diseases. Medical management of Alagille syndrome and progressive familial intrahepatic cholestasis remains mostly targeted on supportive care focusing on quality of life, cholestasis, and fat-soluble vitamin deficiency. The most difficult therapeutic issue is typically related to pruritus, which can be managed by various medications such as ursodeoxycholic acid, rifampin, cholestyramine, and antihistamines. Surgical operations were previously used to disrupt enterohepatic recirculation, but recent medical advancements in the use of ileal bile acid transport inhibitors have shown great efficacy for the treatment of pruritus in both Alagille syndrome and progressive familial intrahepatic cholestasis.
Topics: Humans; Alagille Syndrome; Quality of Life; Cholestasis; Pruritus
PubMed: 38055640
DOI: 10.1097/HC9.0000000000000314 -
JPGN Reports Nov 2023Biliary atresia (BA) remains the most common indication for pediatric liver transplantation. Early diagnosis is essential for a favorable long-term prognosis for...
BACKGROUND
Biliary atresia (BA) remains the most common indication for pediatric liver transplantation. Early diagnosis is essential for a favorable long-term prognosis for patients with BA. Preliminary data suggests that measurement of direct bilirubin (DB) in newborns may be an effective screening tool for neonatal cholestasis, particularly BA, allowing for early referral and diagnosis. The objective of our study was to establish a cutoff DB value to predict diagnosis of cholestatic liver disease (CLD) with high sensitivity and specificity, as well as, to evaluate whether newborns with elevated DB received appropriate follow-up in our health system.
METHODS
Baseline data were collected on infants born between 2016 and 2019 who had serum total bilirubin and DB drawn in the nursery, and who continued to follow in our health system. Sensitivity, specificity, and positive and negative predictive values were examined using cutoff values of 0.5, 0.6, and 0.7 mg/dL for identifying infants at risk for CLD. Patients' charts were reviewed to note whether they had follow-up levels drawn by their pediatrician or by the hepatology team within 2 months of age and whether they were diagnosed with CLD.
RESULTS
Serum total bilirubin and DB levels were drawn from 11 965 infants during their hospitalizations. Three infants from this cohort were diagnosed with CLD: 2 with BA and 1 with Alagille syndrome. DB cutoff values of 0.5, 0.6, and 0.7 mg/dL had sensitivity of 100% and specificity of 96.83% (95% confidence interval [CI], 96.69%-97.53%), 99.08% (95% CI, 98.81%-99.30%), and 99.63% (95% CI, 99.4%-99.7%), respectively. Given that a DB of 0.6 mg/dL had a sensitivity of 100% and specificity of 99%, this value was chosen as the cutoff value to monitor for DB follow-up and diagnosis of CLD. Out of 60 infants who met criteria for DB ≥0.6 mg/dL, only 15 (25%) had a repeat level drawn after nursery discharge; 3 (5%) were eventually diagnosed with CLD.
CONCLUSIONS
A DB cutoff value of 0.6 mg/dL yielded high sensitivity and specificity for identifying patients with CLD. All 3 patients diagnosed with CLD had elevated DB at hospital discharge. The data revealed that the majority (75%) of eligible newborns did not receive follow-up for their elevated DB in the outpatient setting.
PubMed: 38034462
DOI: 10.1097/PG9.0000000000000345