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Advances in Experimental Medicine and... 2024Tricuspid atresia (TA) is a rare congenital heart condition that presents with a complete absence of the right atrioventricular valve. Because of the rarity of familial...
Tricuspid atresia (TA) is a rare congenital heart condition that presents with a complete absence of the right atrioventricular valve. Because of the rarity of familial and/or isolated cases of TA, little is known about the potential genetic abnormalities contributing to this condition. Potential responsible chromosomal abnormalities were identified in exploratory studies and include deletions in 22q11, 4q31, 8p23, and 3p as well as trisomies 13 and 18. In parallel, potential culprit genes include the ZFPM2, HEY2, NFATC1, NKX2-5, MYH6, and KLF13 genes. The aim of this chapter is to expose the genetic components that are potentially involved in the pathogenesis of TA in humans. The large variability in phenotypes and genotypes among cases of TA suggests a genetic network that involves many components yet to be unraveled.
Topics: Humans; Chromosome Aberrations; Phenotype; Tricuspid Atresia; Univentricular Heart
PubMed: 38884756
DOI: 10.1007/978-3-031-44087-8_54 -
Advances in Experimental Medicine and... 2024Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic... (Review)
Review
Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.
Topics: Humans; Aorta, Thoracic; Aortic Valve; Abnormalities, Multiple; Heart Defects, Congenital; Bicuspid Aortic Valve Disease; Pulmonary Valve Stenosis; Mutation; Receptor, Notch1; Aortic Valve Disease; Heart Valve Diseases; Calcinosis; Hematologic Diseases; Vestibular Diseases
PubMed: 38884747
DOI: 10.1007/978-3-031-44087-8_45 -
Advances in Experimental Medicine and... 2024Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and...
Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.
Topics: Humans; Chromosome Aberrations; DNA Copy Number Variations; Genetic Predisposition to Disease; Heart Septal Defects, Ventricular; Mutation; Transcription Factors
PubMed: 38884729
DOI: 10.1007/978-3-031-44087-8_27 -
European Journal of Case Reports in... 2024Alagille syndrome (ALGS) is a multisystem disorder involving at least three systems among the liver, heart, skeleton, face, and eyes. Common cardiac associations include...
BACKGROUND
Alagille syndrome (ALGS) is a multisystem disorder involving at least three systems among the liver, heart, skeleton, face, and eyes. Common cardiac associations include pulmonary artery stenosis/atresia, atrial septal defect (ASD), ventricular septal defect (VSD) and tetralogy of fallot (ToF). Coarctation of aorta (CoA), renal and intracranial arteries are commonly involved vessels in Alagille syndrome. We present two cases with rare cardiovascular manifestations of Alagille syndrome. .
CASE 1
A 25-year-old female with a history of Alagille syndrome presented to the cardiologist office for progressive exertional dyspnoea, orthopnoea, and palpitations. She was tachycardiac on examination and had an apical diastolic rumble. A transthoracic echocardiogram (TTE) showed a left ventricular ejection fraction (LVEF) of 60% and parachute mitral valve (PMV) with severe mitral stenosis. A transoesophageal echocardiogram (TOE) showed insertion of chordae into the anterolateral papillary muscle, severe mitral stenosis with a valve area of 0.7 cm. She was referred to a congenital heart disease specialist and underwent robotic mitral valve replacement with improvement in her symptoms.
CASE 2
A 27-year-old female with known Alagille syndrome and resistant hypertension presented to the cardiologist office due to progressive exertional dyspnoea for a year. She was hypertensive and had a new 2/6 systolic ejection murmur along the left upper sternal border. TTE revealed an LVEF of 60% and pulmonary artery pressure of 19 mmHg. A CoA was suspected distal to the left subclavian artery due to a peak gradient of 38 mmHg. Cardiac magnetic resonance (CMR) imaging ruled out CoA, and diffuse narrowing of the descending thoracic aorta measuring 13-14 mm in diameter was noted. The patient was referred to a congenital heart disease specialist for further management.
CONCLUSION
PMV presenting as mitral stenosis and mid-aortic syndrome are not commonly described anomalies in association with Alagille syndrome. TTE, TOE and CMR played a key role in diagnosis and management of these patients.
LEARNING POINTS
Alagille syndrome (ALGS) is a complex multisystem disorder involving the liver, heart, skeleton, face, and eyes. Cardiovascular involvement occurs in up to 95% of the patients.Common cardiac associations include pulmonary artery stenosis/atresia, atrial septal defect (ASD), ventricular septal defect (VSD) and tetralogy of fallot (ToF).A parachute mitral valve (PMV) presenting as mitral stenosis and mid-aortic syndrome is not commonly described anomalies in association with ALGS. Here, we present such rare cases.
PubMed: 38846669
DOI: 10.12890/2024_004545 -
Andes Pediatrica : Revista Chilena de... Apr 2024Alagille syndrome (ALGS) is an autosomal dominant, multisystem disorder that typically presents with cholestasis, cardiac, ocular, skeletal, vascular and renal...
UNLABELLED
Alagille syndrome (ALGS) is an autosomal dominant, multisystem disorder that typically presents with cholestasis, cardiac, ocular, skeletal, vascular and renal abnormalities, and distinct facial features. Most cases are due to variants in the JAG1 gene, with only a small percentage involving a complete gene deletion.
OBJECTIVE
to contribute to the phenotype delineation and interpretation of a microdeletion not previously described in the literature on chromosome 20.
CLINICAL CASE
A 4-month-old female patient was diagnosed with a heart murmur. An echocardiogram revealed pulmonary artery stenosis, which, combined with a prominent forehead observed on physical examination, determined her referral to clinical genetics. Because ALGS was suspected, complementary studies were performed, revealing butterfly vertebras and a genetic panel identified a pathogenic heterozygous deletion, encompassing the entire coding sequence of the JAG1 gene. To rule out a more extensive deletion, a chromosome microarray was performed, confirming a pathogenic microdeletion on chromosome 20 of 378 kb (arr[GRCh37] 20p12.2(10414643_10792802)x1).
CONCLUSIONS
A targeted sequencing panel followed by confirmation with a chromosome microarray allowed the identification and delineation of a pathogenic microdeletion not previously reported in the literature, including the complete JAG1 gene in a Chilean patient whose phenotype is consistent with ALGS.
Topics: Humans; Alagille Syndrome; Jagged-1 Protein; Female; Gene Deletion; Infant; Phenotype
PubMed: 38801368
DOI: 10.32641/andespediatr.v95i2.4820 -
International Journal of Molecular... Apr 2024The hepatic deletion of Rbpjκ () in the mouse leads to exhibition of the Alagille syndrome phenotype during early postnatal liver development with hyperlipidemia and...
The hepatic deletion of Rbpjκ () in the mouse leads to exhibition of the Alagille syndrome phenotype during early postnatal liver development with hyperlipidemia and cholestasis due to attenuated disruption of NOTCH signaling. Given the roles of NRF2 signaling in the regulation of lipid metabolism and bile ductal formation, it was anticipated that these symptoms could be alleviated by enhancing NRF2 signaling in the mouse by hepatic deletion of in compound mice. Unexpectedly, these mice developed higher hepatic and plasma cholesterol levels with more severe cholestatic liver damage during the pre-weaning period than in the mice. In addition, hypercholesterolemia and hepatic damage were sustained throughout the growth period unlike in the mouse. These enhanced abnormalities in lipid metabolism appear to be due to NRF2-dependent changes in gene expression related to cholesterol synthetic and subsequent bile acid production pathways. Notably, the hepatic expression of and genes involved in bile acid homeostasis was significantly reduced in compared to mice. The accumulation of liver cholesterol and the weakened capacity for bile excretion during the 3 pre-weaning weeks in the mice may aggravate hepatocellular damage level caused by both excessive cholesterol and residual bile acid toxicity in hepatocytes. These results indicate that a tuned balance of NOTCH and NRF2 signaling is of biological importance for early liver development after birth.
Topics: Animals; Kelch-Like ECH-Associated Protein 1; Mice; Hypercholesterolemia; Liver; Hepatomegaly; Immunoglobulin J Recombination Signal Sequence-Binding Protein; NF-E2-Related Factor 2; Lipid Metabolism; Gene Deletion; Signal Transduction; Cholesterol; Mice, Knockout; Male; Bile Acids and Salts
PubMed: 38731931
DOI: 10.3390/ijms25094712 -
Stem Cell Research Jun 2024Alagille syndrome (ALGS) is an autosomal dominant, multisystemic disorder due to haploinsufficiency in JAG1 or less frequently, mutations in NOTCH2. The disease has been...
Alagille syndrome (ALGS) is an autosomal dominant, multisystemic disorder due to haploinsufficiency in JAG1 or less frequently, mutations in NOTCH2. The disease has been difficult to diagnose and treat due to variable expression. The generation of this iPSC line (TRNDi036-A) carrying a heterozygous mutation (p.Cys693*) in the JAG1 gene provides a means of studying the disease and developing novel therapeutics towards patient treatment.
Topics: Alagille Syndrome; Humans; Jagged-1 Protein; Induced Pluripotent Stem Cells; Heterozygote; Mutation; Cell Line; Male; Female
PubMed: 38703666
DOI: 10.1016/j.scr.2024.103429 -
The Lancet. Gastroenterology &... Jul 2024In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome.
METHODS
The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 μg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0-4) from baseline to weeks 21-24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed.
FINDINGS
Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21-24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of -1·7 (95% CI -2·0 to -1·3) for odevixibat and -0·8 (-1·3 to -0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0·9 [95% CI -1·4 to -0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 μmol/L [SD 115] with odevixibat vs 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] vs 271 μmol/L [167]; LS mean change -90 μmol/L [95% CI -133 to -48] with odevixibat vs 22 μmol/L [-35 to 80] with placebo; difference in LS mean change -113 μmol/L [95% CI -179 to -47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths.
INTERPRETATION
Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study.
FUNDING
Albireo Pharma, an Ipsen company.
Topics: Humans; Double-Blind Method; Alagille Syndrome; Male; Female; Child; Adolescent; Pruritus; Treatment Outcome; Bile Acids and Salts; Adult; Child, Preschool; Young Adult; Carrier Proteins; Membrane Glycoproteins; Methylamines; Thiazepines
PubMed: 38670135
DOI: 10.1016/S2468-1253(24)00074-8 -
Journal of the American Heart... Apr 2024We aimed to describe the frequency and yield of genetic testing in supravalvar aortic stenosis (SVAS) following negative evaluation for Williams-Beuren syndrome (WS).
BACKGROUND
We aimed to describe the frequency and yield of genetic testing in supravalvar aortic stenosis (SVAS) following negative evaluation for Williams-Beuren syndrome (WS).
METHODS AND RESULTS
This retrospective cohort study included patients with SVAS at our institution who had a negative evaluation for WS from May 1991 to September 2021. SVAS was defined as (1) peak supravalvar velocity of ≥2 meters/second, (2) sinotubular junction or ascending aortic score <-2.0, or (3) sinotubular junction score <-1.5 with family history of SVAS. Patients with complex congenital heart disease, aortic valve disease as the primary condition, or only postoperative SVAS were excluded. Genetic testing and diagnoses were reported. Of 162 patients who were WS negative meeting inclusion criteria, 61 had genetic testing results available (38%). Chromosomal microarray had been performed in 44 of 61 and was nondiagnostic for non-WS causes of SVAS. Sequencing of 1 or more genes was performed in 47 of 61. Of these, 39 of 47 underwent sequencing, 20 of 39 (51%) of whom had a diagnostic variant. Other diagnoses made by gene sequencing were Noonan syndrome (3 , 1 , Alagille syndrome (3 ), neurofibromatosis (1 ), and homozygous familial hypercholesterolemia (1 ). Overall, sequencing was diagnostic in 29 of 47 (62%).
CONCLUSIONS
When WS is excluded, gene sequencing for SVAS is high yield, with the highest yield for the gene. Therefore, we recommend gene sequencing using a multigene panel or exome analysis. Hypercholesterolemia can also be considered in individuals bearing the stigmata of this disease.
Topics: Humans; Williams Syndrome; Aortic Stenosis, Supravalvular; Retrospective Studies; Genetic Testing; Aorta
PubMed: 38591341
DOI: 10.1161/JAHA.123.034048 -
World Journal of Gastroenterology Mar 2024Several diseases originate from bile duct pathology. Despite studies on these diseases, certain etiologies of some of them still cannot be concluded. The most common... (Review)
Review
Several diseases originate from bile duct pathology. Despite studies on these diseases, certain etiologies of some of them still cannot be concluded. The most common disease of the bile duct in newborns is biliary atresia, whose prognosis varies according to the age of surgical correction. Other diseases such as Alagille syndrome, inspissated bile duct syndrome, and choledochal cysts are also time-sensitive because they can cause severe liver damage due to obstruction. The majority of these diseases present with cholestatic jaundice in the newborn or infant period, which is quite difficult to differentiate regarding clinical acumen and initial investigations. Intraoperative cholangiography is potentially necessary to make an accurate diagnosis, and further treatment will be performed synchronously or planned as findings suggest. This article provides a concise review of bile duct diseases, with interesting cases.
Topics: Infant; Child; Infant, Newborn; Humans; Bile Ducts; Biliary Atresia; Choledochal Cyst; Bile Duct Diseases; Cholangiography
PubMed: 38577180
DOI: 10.3748/wjg.v30.i9.1043