Neuroradiological findings in Alagille syndrome.
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ABSTRACT:
SUBMITTER: D'Amico A
PROVIDER: S-EPMC8722249 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Conjugated hyperbilirubinemia, posterior embryotoxon, and vertebral anomalies are not features of William syndrome (WS). We herein report a preterm infant who presented with features suggestive of Alagille syndrome, but microarray showed findings consistent with WS. This further extends the phenotype of WS and emphasizes the need for microarray analysis.
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Project description:Alagille syndrome (OMIM 118450) is an autosomal dominant disorder associated with abnormalities of the liver, heart, eye, skeleton, and a characteristic facial appearance. Also referred to as the Alagille-Watson syndrome, syndromic bile duct paucity, and arteriohepatic dysplasia, it is a significant cause of neonatal jaundice and cholestasis in older children. In the fully expressed syndrome, affected subjects have intrahepatic bile duct paucity and cholestasis, in conjunction with cardiac malformations (most frequently peripheral pulmonary stenosis), ophthalmological abnormalities (typically of the anterior chamber with posterior embryotoxon being the most common), skeletal anomalies (most commonly butterfly vertebrae), and characteristic facial appearance. Inheritance is autosomal dominant, but expressivity is highly variable. Sibs and parents of probands are often found to have mild expression of the presumptive disease gene, with abnormalities of only one or two systems. The frequency of new mutations appears relatively high, estimated at between 15 and 50%. The disease gene has been mapped to chromosome 20 band p12 based on multiple patients described with cytogenetic or molecular rearrangements of this region. However, the frequency of detectable deletions of 20p12 is low (less than 7%). Progress has been made in the molecular definition of an Alagille syndrome critical region within the short arm of chromosome 20. We will review the clinical, genetic, cytogenetic, and molecular findings in this syndrome.
| S-EPMC1050871 | biostudies-literature
Project description:Background:The spinocerebellar ataxias (SCAs) are a group of autosomal dominant degenerative diseases characterized by cerebellar ataxia. Classified according to gene discovery, specific features of the SCAs - clinical, laboratorial, and neuroradiological (NR) - can facilitate establishing the diagnosis. The purpose of this study was to review the particular NR abnormalities in the main SCAs. Methods:We conducted a literature search on this topic. Results:The main NR characteristics of brain imaging (magnetic resonance imaging or computerized tomography) in SCAs were: (1) pure cerebellar atrophy; (2) cerebellar atrophy with other findings (e.g., pontine, olivopontocerebellar, spinal, cortical, or subcortical atrophy; "hot cross bun sign", and demyelinating lesions); (3) selective cerebellar atrophy; (4) no cerebellar atrophy. Discussion:The main NR abnormalities in the commonest SCAs, are not pathognomonic of any specific genotype, but can be helpful in limiting the diagnostic options. We are progressing to a better understanding of the SCAs, not only genetically, but also pathologically; NR is helpful in the challenge of diagnosing the specific genotype of SCA.
| S-EPMC6765228 | biostudies-literature
Project description:Alagille syndrome (AGS) is a well defined genetic disorder characterised by five major features. An autosomal dominant mode of transmission with reduced penetrance has been suggested by the analysis of a limited number of families. However there has been no statistical analysis. We report here the first segregation analysis of AGS, using 33 families collected through 43 probands. Segregation analysis of these families allowed us to conclude that AGS is transmitted as a dominant disorder with 94% penetrance and 15% of cases are sporadic. The expressivity of the phenotype was variable and 26 persons (15 parents and 11 sibs) were identified as presenting minor forms of the disease. These results are valuable for genetic counselling.
| S-EPMC1049922 | biostudies-other
Project description:BackgroundAlagille syndrome (ALGS) is a dominant, multisystem disorder caused by mutations in the Jagged1 (JAG1) ligand in 94% of patients, and in the NOTCH2 receptor in <1%. There are only two NOTCH2 families reported to date. This study hypothesised that additional NOTCH2 mutations would be present in patients with clinical features of ALGS without a JAG1 mutation.MethodsThe study screened a cohort of JAG1-negative individuals with clinical features suggestive or diagnostic of ALGS for NOTCH2 mutations.ResultsEight individuals with novel NOTCH2 mutations (six missense, one splicing, and one non-sense mutation) were identified. Three of these patients met classic criteria for ALGS and five patients only had a subset of features. The mutations were distributed across the extracellular (N=5) and intracellular domains (N=3) of the protein. Functional analysis of four missense, one nonsense, and one splicing mutation demonstrated decreased Notch signalling of these proteins. Subjects with NOTCH2 mutations demonstrated highly variable expressivity of the affected systems, as with JAG1 individuals. Liver involvement was universal in NOTCH2 probands and they had a similar prevalence of ophthalmologic and renal anomalies to JAG1 patients. There was a trend towards less cardiac involvement in the NOTCH2 group (60% vs 100% in JAG1). NOTCH2 (+) probands exhibited a significantly decreased penetrance of vertebral abnormalities (10%) and facial features (20%) when compared to the JAG1 (+) cohort.ConclusionsThis work confirms the importance of NOTCH2 as a second disease gene in ALGS and expands the repertoire of the NOTCH2 related disease phenotype.
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Project description:While previous research has investigated neuroradiological findings in autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), the entire range of neurodevelopmental disorders (NDDs) has not yet been well-studied using magnetic resonance imaging (MRI). Considering the overlap among NDDs and simultaneous development of the brain and face, guided by molecular signaling, we examined the relationship of actionable and incidental (non-actionable) MRI findings and NDD diagnoses together with facial morphological variants and genetic copy number variants (CNVs). A cross-sectional study was conducted with a twin cohort 8-36 years of age (57% monozygotic, 40% dizygotic), including 372 subjects (46% with NDDs; 47% female) imaged by MRI, 280 with data for facial morphological variants, and 183 for CNVs. Fifty-one percent of participants had MRI findings. Males had a statistically significantly higher percentage of MRI findings (57.7%) compared with females (43.8%, p = 0.03). Twin zygosity was not statistically significantly correlated with incidence or severity of specific MRI findings. No statistically significant association was found between MRI findings and any NDD diagnosis or facial morphological variants; however, MRI findings were statistically significantly associated with the number of CNVs (OR 1.20, 95% CI 1.00-1.44, p = 0.05, adjusted OR for sex 1.24, 95% CI 1.03-1.50, p = 0.02). When combining the presence of MRI findings, facial morphological variants, and CNVs, statistically significant relationships were found with ASD and ADHD diagnoses (p = 0.0006 and p = 0.002, respectively). The results of this study demonstrate that the ability to identify NDDs from combined radiology, morphology, and CNV assessments may be possible. Additionally, twins do not appear to be at increased risk for neuroradiological variants.
| S-EPMC7772336 | biostudies-literature
Project description:Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, is a multisystem disorder due to defects in components of the Notch signalling pathway, most commonly due to mutation in JAG1 (ALGS type 1), but in a small proportion of cases mutation in NOTCH2 (ALGS type 2). The main clinical and pathological features are chronic cholestasis due to paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis, minor vertebral segmentation anomalies, characteristic facies, posterior embryotoxon/anterior segment abnormalities, pigmentary retinopathy, and dysplastic kidneys. It follows autosomal dominant inheritance, but reduced penetrance and variable expression are common in this disorder, and somatic/germline mosaicism may also be relatively frequent. This review discusses the clinical features of ALGS, including long-term complications, the clinical and molecular diagnosis, and management.
| S-EPMC3283172 | biostudies-literature
Project description:A new mouse mutant was identified at the Munich ENU mutagenesis project due to hyperactivity, head tossing, and circling behaviour. Neurological and gross morphological phenotyping of these mutant mice revealed impairment of the vestibular system. Using whole genome exome sequencing and a custom-made variant calling pipeline, we identified the causative mutation as an A->T substitution on the chromosome 2 at the position 128 in the exon 6 of jagged 1 (Jag1) gene. This introduces a premature termination codon at the position 883 of the cDNA. In humans, mutations in the JAG1 gene are associated with Alagille syndrome (ALGS1 ), a multisystem developmental disorder mainly affecting small bile ducts in the liver, but also heart, skeleton, and eyes, and occasionally also kidney or inner ears. Further examination of the Jag1K295*/+ mutant mouse line disclosed multiorgan deficiencies, such as cardiac liver congestion, bile duct hypoplasia, mild nephropathy, subvalvular hypertrophy of the right ventricle, and mild growth retardation. No skeletal abnormalities could be detected. In summary, we report a novel mouse model for Alagille syndrome, Jag1K295*/+, which resembles most of the features of the mild form of Alagille syndrome observed in patients.
2014-10-01 | GSE55602 | GEO
Project description:A new mouse mutant was identified at the Munich ENU mutagenesis project due to hyperactivity, head tossing, and circling behaviour. Neurological and gross morphological phenotyping of these mutant mice revealed impairment of the vestibular system. Using whole genome exome sequencing and a custom-made variant calling pipeline, we identified the causative mutation as an A->T substitution on the chromosome 2 at the position 128 in the exon 6 of jagged 1 (Jag1) gene. This introduces a premature termination codon at the position 883 of the cDNA. In humans, mutations in the JAG1 gene are associated with Alagille syndrome (ALGS1 ), a multisystem developmental disorder mainly affecting small bile ducts in the liver, but also heart, skeleton, and eyes, and occasionally also kidney or inner ears. Further examination of the Jag1K295*/+ mutant mouse line disclosed multiorgan deficiencies, such as cardiac liver congestion, bile duct hypoplasia, mild nephropathy, subvalvular hypertrophy of the right ventricle, and mild growth retardation. No skeletal abnormalities could be detected. In summary, we report a novel mouse model for Alagille syndrome, Jag1K295*/+, which resembles most of the features of the mild form of Alagille syndrome observed in patients. Total RNA obtained from liver of 4 male heterozygous Jag1K295*/+ and 4 male wildtype mice
2014-10-01 | E-GEOD-55602 | biostudies-arrayexpress
Project description:Krabbe disease is an autosomal recessive neurodegenerative disorder due to a defect of the lysosomal enzyme β-galactocerebrosidase (β-GALC). Depending on the age of onset, the disease is classified into infantile and later-onset forms. We report neuroradiological, neurophysiological and molecular findings in two Greek patients with the infantile form of Krabbe disease. The index patients presented at the age of 3.5 and 6 months, respectively, due to developmental delay. Magnetic resonance imaging (MRI) of the first patient's brain demonstrated signs of leukodystrophy, while nerve conduction velocities (NCVs) were significantly decreased. The second patient's MRI at the age of 4 months was initially normal, but at 18 months demonstrated leukodystrophic alterations as well, whereas NCVs were also significantly delayed. In both patients, a severe decrease in β-GALC, activity supported the diagnosis of Krabbe disease, while the final diagnosis was confirmed by molecular genetic testing. Two homozygous mutations of the GALC gene, the c.411_413delTAA [p.K139del] mutation in the first patient, and the c.749T>C [p.I250T] mutation in the second patient, were identified. At their last follow-up visit at the age of 4 and 6 years, respectively, both patients were bedridden and quadri-plegic, suffering from frequent respiratory tract infections and fed through a gastrostomy. Both mutations found in homozygosity in these two unrelated patients of Greek ancestry, could pinpoint a common origin. Genotyping of patients with Krabbe disease is important, in order to contribute to the creation of a European mutation database and to further study possible genotype-phenotype correlations of the disease.
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