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Retinal Cases & Brief Reports Apr 2024Alström Syndrome (AS) is a rare autosomal recessive monogenic ciliopathy which is caused by a mutation of the Alström syndrome 1 (ALMS1) gene. It is a multisystemic...
PURPOSE
Alström Syndrome (AS) is a rare autosomal recessive monogenic ciliopathy which is caused by a mutation of the Alström syndrome 1 (ALMS1) gene. It is a multisystemic disorder characterized by insulin resistance, childhood obesity, cardiomyopathy, progressive hepatic and renal failure, sensorineural hearing loss and retinal degeneration. Herein, we aimed to report a novel variant in ALMS1 gene causing AS in a patient presenting with visual impairment.
METHODS
Case report.
RESULTS
A 10-year-old male patient presented with photophobia and visual impairment in both eyes. Anterior and posterior segment examinations were unremarkable bilaterally. Optical coherence tomography (OCT) showed attenuated ellipsoid zone. Electroretinography revealed diminished cone and rod responses consistent with cone rod dystrophy (CRD). Genetic testing demonstrated a novel homozygous variant in ALMS1 (NM_015120.4) gene. The patient also was found to have early-stage dilated cardiomyopathy through systemic evaluation after the diagnosis of AS.
CONCLUSION
Cone-rod dystrophy in pediatric population is relatively rare condition that can be associated with syndromic ciliopathies. The authors presented a case of AS with a novel variant in ALMS1 gene based on ophthalmic findings. Ophthalmologists play an important role in the diagnosis of this syndrome and early detection of systemic manifestations.
PubMed: 38569205
DOI: 10.1097/ICB.0000000000001578 -
Diabetes/metabolism Research and Reviews May 2024Alström syndrome (AS) is a rare recessive disorder characterised by diabetes, obesity, insulin resistance (IR), and visual and hearing impairments. Mutations in the...
AIMS
Alström syndrome (AS) is a rare recessive disorder characterised by diabetes, obesity, insulin resistance (IR), and visual and hearing impairments. Mutations in the ALMS1 gene have been identified as the causative agents of AS. This study aimed to explore the relationship between rare ALMS1 variants and clinical features in Chinese patients with early-onset type 2 diabetes (age at diagnosis ≤40 years; EOD).
MATERIALS AND METHODS
ALMS1 gene sequencing was performed in 611 Chinese individuals with EOD, 36 with postprandial hyperinsulinemia, and 47 with pre-diabetes and fasting IR. In-silico prediction algorithm and the American College of Medical Genetics Guidelines (ACMG) were used to evaluate the deleteriousness and pathogenicity of the variants.
RESULTS
Sixty-two rare ALMS1 variants (frequency <0.005) were identified in 82 patients with EOD. Nineteen variants were predicted to be deleterious (pD). Patients with EOD carrying pD variants had higher fasting C-peptide, postprandial C-peptide, and HOMA2-IR levels than those without variants. The frequency of ALMS1 pD variants in the subgroup with more insulin-resistant EOD was higher than that in other EOD subgroups. Two patients with EOD, obesity, and IR who carried one heterozygous pathogenic/likely pathogenic rare variant of ALMS1 according to ACMG were identified. Moreover, rare heterozygous pD variants of ALMS1 were found in participants from cohorts of postprandial hyperinsulinemia as well as in pre-diabetes with fasting IR.
CONCLUSIONS
ALMS1 rare pD variants are enriched in the populations with significant IR, which is a major hallmark of diabetes pathogenesis. Accordingly, our exploratory study provides insights and hypotheses for further studies of gene function.
Topics: Humans; Adult; Insulin Resistance; Diabetes Mellitus, Type 2; Prediabetic State; C-Peptide; Cell Cycle Proteins; Alstrom Syndrome; Obesity; Mutation; Hyperinsulinism; China
PubMed: 38546151
DOI: 10.1002/dmrr.3788 -
CircALMS1 Alleviates Pulmonary Microvascular Endothelial Cell Dysfunction in Pulmonary Hypertension.Journal of the American Heart... Mar 2024Circular RNAs can serve as regulators influencing the development of pulmonary hypertension (PH). However, their function in pulmonary vascular intimal injury remains...
BACKGROUND
Circular RNAs can serve as regulators influencing the development of pulmonary hypertension (PH). However, their function in pulmonary vascular intimal injury remains undefined. Thus, we aimed to identify specifically expressed circular RNAs in pulmonary microvascular endothelial cells (PMECs) under hypoxia and PH.
METHODS AND RESULTS
Deep RNA sequencing and quantitative real-time polymerase chain reaction revealed that circALMS1 (circular RNA Alstrom syndrome protein 1) was reduced in human PMECs under hypoxia (<0.0001). Molecular biology and histopathology experiments were used to elucidate the roles of circALMS1 in regulating PMEC dysfunction among patients with PH. The circALMS1 expression was decreased in the plasma of patients with PH (=0.0315). Patients with lower circALMS1 levels had higher risk of death (=0.0006). Moreover, the circALMS1 overexpression of adeno-associated viruses improved right ventricular function and reduced pulmonary vascular remodeling in monocrotaline-PH and sugen/hypoxia-PH rats (<0.05). Furthermore, circALMS1 overexpression promoted apoptosis and inhibited PMEC proliferation and migration under hypoxia by directly downregulating miR-17-3p (<0.05). Dual luciferase assay confirmed the direct binding of circALMS1 to miR-17-3p and miR-17-3p binding to its target gene YT521-B homology domain-containing family protein 2 (YTHDF2) (<0.05). The YTHDF2 levels were also downregulated in hypoxic PMECs (<0.01). The small interfering RNA YTHDF2 reversed the effects of miR-17-3p inhibitors on PMEC proliferation, migration, and apoptosis. Finally, the results indicated that, although YTHDF2, as an N(6)-methyladenosine reader protein, contributes to the degradation of many circular RNAs, it could not regulate the circALMS1 levels in PMECs (=0.9721).
CONCLUSIONS
Our study sheds new light on circALMS1-regulated dysfunction of PMECs by the miR-17-3p/YTHDF2 pathway under hypoxia and provides insights into the underlying pathogenesis of PH.
Topics: Humans; Rats; Animals; Hypertension, Pulmonary; MicroRNAs; Endothelial Cells; RNA, Circular; Pulmonary Artery; Hypoxia; Cell Proliferation
PubMed: 38497483
DOI: 10.1161/JAHA.123.031867 -
JACC. Case Reports Mar 2024We present the case of a patient with Alström syndrome who was found to have evidence of a prothrombotic state on autopsy after sudden cardiac death. To the best of our...
We present the case of a patient with Alström syndrome who was found to have evidence of a prothrombotic state on autopsy after sudden cardiac death. To the best of our knowledge, this case of persistent prothrombotic milieu is the first described in a patient with Alström syndrome.
PubMed: 38464801
DOI: 10.1016/j.jaccas.2023.102215 -
Prenatal Diagnosis Apr 2024In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England. This study aimed to explore parent...
OBJECTIVES
In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England. This study aimed to explore parent experiences and their information and support needs from the perspective of parents offered pES and of health professionals involved in its delivery.
METHODS
In this qualitative study, semi-structured interviews were conducted with 42 women and 6 male partners and 63 fetal medicine and genetic health professionals. Interviews were transcribed verbatim and analysed using thematic analysis.
RESULTS
Overall views about pES were positive and parents were grateful to be offered the test. Highlighted benefits of pES included the value of the additional information for pregnancy management and planning for future pregnancies. An anxious wait for results was common, often associated with the need to make decisions near to 24 weeks in pregnancy when there are legal restrictions for late termination. Descriptions of dealing with uncertainty were also common, even when results had been returned. Many parents described pES results as informing decision-making around whether or not to terminate pregnancy. Some professionals were concerned that a non-informative result could be overly reassuring and highlighted that careful counselling was needed to ensure parents have a good understanding of what the result means for their pregnancy. Emotional support from professionals was valued; however, some parents felt that post-test support was lacking.
CONCLUSION
Parents and professionals welcomed the introduction of pES. Results inform parents' decision-making around the termination of pregnancy. When there are no diagnostic findings or uncertain findings from pES, personalised counselling that considers scans and other tests are crucial. Directing parents to reliable online sources of information and providing emotional support throughout could improve their experiences of care.
Topics: Pregnancy; Humans; Male; Female; State Medicine; Exome Sequencing; Parents; England; Counseling; Qualitative Research
PubMed: 38441167
DOI: 10.1002/pd.6537 -
Brazilian Journal of Otorhinolaryngology 2024To report two new variants of ALMS1 gene and to discuss the audiological evolution and clinical phenotype in two pairs of siblings with Alström syndrome.
OBJECTIVES
To report two new variants of ALMS1 gene and to discuss the audiological evolution and clinical phenotype in two pairs of siblings with Alström syndrome.
REPORT
This paper is a multi-disciplinary diagnostic evaluation, with genetic and audiological analysis that aims to report two new variants of the ALMS1 gene and to discuss the audiological evolution and clinical phenotype in a case series of patients with familial Alström syndrome. Therefore, we describe 4 cases presenting a complete audiometric profile of two pairs of unrelated siblings, to provide a better understanding of this very rare disease. Additionally, the present study identified two heterozygous mutations in the ALMS1 gene.
CONCLUSION
This Clinical Capsule Report highlights the importance of audiological monitoring throughout the development of patients with Alström syndrome. The two variants found were not previously reported in the literature, which expands the spectrum of ALMS1 variants in Alström syndrome.
Topics: Child, Preschool; Female; Humans; Male; Alstrom Syndrome; Cell Cycle Proteins; Mutation; Phenotype; Infant; Adult
PubMed: 38428329
DOI: 10.1016/j.bjorl.2024.101402 -
Diabetes, Obesity & Metabolism Apr 2024Bardet-Biedl syndrome (BBS) is a genetic disorder characterized by early-onset obesity, polydactyly, genital and kidney anomalies, developmental delay and vision loss... (Review)
Review
Bardet-Biedl syndrome (BBS) is a genetic disorder characterized by early-onset obesity, polydactyly, genital and kidney anomalies, developmental delay and vision loss due to rod-cone dystrophy. BBS is an autosomal recessive disorder with >20 implicated genes. The genotype-phenotype relationship in BBS is not clear, and there may be additional modifying factors. The underlying mechanism is dysfunction of primary cilia. In BBS, receptor trafficking in and out of the cilia is compromised, affecting multiple organ systems. Along with early-onset obesity, hyperphagia is a prominent symptom and contributes significantly to clinical morbidity and caregiver burden. While there is no cure for BBS, setmelanotide is a new pharmacotherapy approved for treatment of obesity in BBS. The differential diagnosis for BBS includes other ciliopathies, such as Alstrom syndrome, and other genetic obesity syndromes, such as Prader-Willi syndrome. Careful clinical history and genetic testing can help determine the diagnosis and a multidisciplinary team is necessary to guide clinical management.
Topics: Humans; Bardet-Biedl Syndrome; Obesity; Obesity, Morbid
PubMed: 38383825
DOI: 10.1111/dom.15494 -
Journal of AAPOS : the Official... Apr 2024We report the case of an otherwise healthy 6-year-old girl presenting with poor visual acuity, photophobia, and abnormal eye and head movements who was initially...
We report the case of an otherwise healthy 6-year-old girl presenting with poor visual acuity, photophobia, and abnormal eye and head movements who was initially diagnosed with spasmus nutans. A remote history of presumed viral cardiomyopathy and further electroretinography testing raised suspicion for Alström syndrome. She was diagnosed with a novel ALMS1 variant.
Topics: Female; Humans; Child; Nystagmus, Pathologic; Alstrom Syndrome; Spasms, Infantile; Electroretinography; Diagnosis, Differential; Cell Cycle Proteins
PubMed: 38378129
DOI: 10.1016/j.jaapos.2024.103853 -
Current Obesity Reports Jun 2024Syndromic obesity refers to obesity occurring with additional clinical findings, such as intellectual disability/developmental delay, dysmorphic features, and congenital... (Review)
Review
Syndromic obesity refers to obesity occurring with additional clinical findings, such as intellectual disability/developmental delay, dysmorphic features, and congenital malformations. PURPOSE OF REVIEW: To present a narrative review regarding the genetic etiology, clinical description, and molecular diagnosis of syndromic obesity, which is a rare condition with high phenotypic variability and genetic heterogeneity. The following syndromes are presented in this review: Prader-Willi, Bardet-Biedl, Pseudohypoparathyroidism, Alström, Smith-Magenis, Cohen, Temple, 1p36 deletion, 16p11.2 microdeletion, Kleefstra, SIM1-related, Börjeson-Forssman-Lehmann, WAGRO, Carpenter, MORM, and MYT1L-related syndromes. RECENT FINDINGS: There are three main groups of mechanisms for syndromic obesity: imprinting, transcriptional activity regulation, and cellular cilia function. For molecular diagnostic, methods of genome-wide investigation should be prioritized over sequencing of panels of syndromic obesity genes. In addition, we present novel syndromic conditions that need further delineation, but evidences suggest they have a higher frequency of obesity. The etiology of syndromic obesity tends to be linked to disrupted neurodevelopment (central) and is associated with a diversity of genes and biological pathways. In the genetic investigation of individuals with syndromic obesity, the possibility that the etiology of the syndromic condition is independent of obesity should be considered. The accurate genetic diagnosis impacts medical management, treatment, and prognosis, and allows proper genetic counseling.
Topics: Humans; Obesity; Intellectual Disability; Syndrome; Phenotype; Bardet-Biedl Syndrome; Prader-Willi Syndrome; Developmental Disabilities; Alstrom Syndrome
PubMed: 38277088
DOI: 10.1007/s13679-023-00543-y -
European Journal of Endocrinology Feb 2024SOFT syndrome (MIM#614813), denoting Short stature, Onychodysplasia, Facial dysmorphism, and hypoTrichosis, is a rare primordial dwarfism syndrome caused by biallelic...
OBJECTIVE
SOFT syndrome (MIM#614813), denoting Short stature, Onychodysplasia, Facial dysmorphism, and hypoTrichosis, is a rare primordial dwarfism syndrome caused by biallelic variants in POC1A, encoding a centriolar protein. SOFT syndrome, characterized by severe growth failure of prenatal onset and dysmorphic features, was recently associated with insulin resistance. This study aims to further explore its endocrinological features and pathophysiological mechanisms.
DESIGN/METHODS
We present clinical, biochemical, and genetic features of 2 unrelated patients carrying biallelic pathogenic POC1A variants. Cellular models of the disease were generated using patients' fibroblasts and POC1A-deleted human adipose stem cells.
RESULTS
Both patients present with clinical features of SOFT syndrome, along with hyperinsulinemia, diabetes or glucose intolerance, hypertriglyceridemia, liver steatosis, and central fat distribution. They also display resistance to the effects of IGF-1. Cellular studies show that the lack of POC1A protein expression impairs ciliogenesis and adipocyte differentiation, induces cellular senescence, and leads to resistance to insulin and IGF-1. An altered subcellular localization of insulin receptors and, to a lesser extent, IGF1 receptors could also contribute to resistance to insulin and IGF1.
CONCLUSIONS
Severe growth retardation, IGF-1 resistance, and centripetal fat repartition associated with insulin resistance-related metabolic abnormalities should be considered as typical features of SOFT syndrome caused by biallelic POC1A null variants. Adipocyte dysfunction and cellular senescence likely contribute to the metabolic consequences of POC1A deficiency. SOFT syndrome should be included within the group of monogenic ciliopathies with metabolic and adipose tissue involvement, which already encompasses Bardet-Biedl and Alström syndromes.
Topics: Humans; Cell Cycle Proteins; Cytoskeletal Proteins; Insulin-Like Growth Factor I; Insulin Resistance; Ciliopathies; Abnormalities, Multiple; Insulins
PubMed: 38245004
DOI: 10.1093/ejendo/lvae009