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Frontiers in Genetics 2022Alström syndrome (AS) is an ultrarare multisystemic progressive disease caused by autosomal recessive variations of the gene (2p13). AS is characterized by double...
Alström syndrome (AS) is an ultrarare multisystemic progressive disease caused by autosomal recessive variations of the gene (2p13). AS is characterized by double sensory impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, early nonalcoholic fatty liver disease, renal dysfunction, respiratory disease, endocrine and urologic disorders. In female AS patients, hyperandrogenism has been described but fertility issues and conception have not been investigated so far. This case report describes the spontaneous conception, pregnancy, and birth in a 27-year-old woman with AS, characterized by a mild phenotype with late onset of visual impairment, residual perception of light, and hypertension. Before pregnancy, menses were regular with increased levels of dihydrotestosterone and androstanediol glucuronide in the follicular phase, and the ovaries and endometrium were normal during vaginal ultrasound. A thorough clinical follow-up of the maternal and fetal conditions was carried out. A weight gain of 10 kg during pregnancy was recorded, and serial blood and urine tests were all within the normal range, except for mild anemia. The course of pregnancy was uneventful up to 34 weeks of gestation when preeclampsia developed with an abnormally high level of blood pressure and edema in the lower limbs. At 35 weeks + 3 days of gestation, an urgent cesarean section was performed, and a healthy male weighing 1,950 g was born. Histological examination of the placenta showed partial signs of flow obstruction, limited abruption areas, congested fetal vessels and villi, and a small single infarcted area. The present case demonstrates for the first time that conceiving is possible for patients with ALMS. Particular attention should be given to the management of AS systemic comorbidities through the course of pregnancy.
PubMed: 36263420
DOI: 10.3389/fgene.2022.995947 -
Annals of Pediatric Endocrinology &... Sep 2022Based on the genetic contribution, childhood obesity can be classified into 3 groups: common polygenic obesity, syndromic obesity, and monogenic obesity. More genetic...
Based on the genetic contribution, childhood obesity can be classified into 3 groups: common polygenic obesity, syndromic obesity, and monogenic obesity. More genetic causes of obesity are being identified along with the advances in the genetic testing. Genetic obesities including syndromic and monogenic obesity should be suspected and evaluated in children with early-onset morbid obesity and hyperphagia under 5 years of age. Patients with syndromic obesity have early-onset severe obesity associated specific genetic syndromes including Prader-Willi syndrome, Bardet-Biedle syndrome, and Alstrom syndrome. Syndromic obesity is often accompanied with neurodevelopmental delay or dysmorphic features. Nonsyndromic monogenic obesity is caused by variants in single gene which are usually involved in the regulation of hunger and satiety associated with the hypothalamic leptin-melanocortin pathway in central nervous system. Unlike syndromic obesity, patients with monogenic obesity usually show normal neurodevelopment. They would be presented with hyperphagia and early-onset severe obesity with additional clinical symptoms including short stature, red hair, adrenal insufficiency, hypothyroidism, hypogonadism, pituitary insufficiencies, diabetes insipidus, increased predisposition to infection or intractable recurrent diarrhea. Identifying patients with genetic obesity is critical as new innovative therapies including melanocortin 4 receptor agonist have become available. Early genetic evaluation enables to identify treatable obesity and provide timely intervention which may eventually achieve favorable outcome by establishing personalized management.
PubMed: 36203267
DOI: 10.6065/apem.2244188.094 -
BMC Ophthalmology Sep 2022Alström Syndrome (AS) is an autosomal recessive hereditary disease with the characteristics of multiorgan dysfunction. Due to the heterogeneity of clinical...
PURPOSE
Alström Syndrome (AS) is an autosomal recessive hereditary disease with the characteristics of multiorgan dysfunction. Due to the heterogeneity of clinical manifestations of AS, genetic testing is crucial for the diagnosis of AS. Herein, we used whole-exome sequencing (WES) to determine the genetic causes and characterize the clinical features of three affected patients in two Chinese families with Alström Syndrome.
MATERIALS AND METHODS
Three affected patients (initially diagnosed as achromatopsia). and five asymptomatic members were recruited for both genetic and clinical tests. The complete ophthalmic examinations and systemic examinations were performed on all participants. Whole exome sequencing (WES) was performed for mutation detection. The silico analysis was also applied to predict the pathogenesis of identified pathogenic variants.
RESULTS
In family 1, the proband showed low vision, hyperopia, photophobia, nystagmus, and total color blindness. DNA analysis revealed that she carried a compound heterozygote with two novel pathogenic variants in the ALMS1 gene NM_015120.4:c.10379del (NP_055935.4:p.(Asp2252Tyr)) and NM_015120.4:c.11641_11642del (NP_055935.4:p.(Val3881ThrfsTer11)). Further systemic examinations showed short stature, acanthosis nigricans, and sensorineural hearing loss. In family 2, two affected siblings presented the low vision, hyperopia, photophobia, nystagmus, and total color blindness. DNA analysis revealed that they carried a same compound heterozygote with two novel pathogenic variants in the ALMS1 gene NM_015120.4:c.10379del (NP_055935.4:p.(Asn3460IlefsTer49)), NM_015120.4:c.10819C > T (NP_055935.4:p.(Arg3607Trp)). Further systemic examinations showed obesity and mild abnormalities of lipid metabolism. According to the genetic testing results and further systemic analysis, the three affected patients were finally diagnosed as Alström Syndrome (AS).
CONCLUSIONS
We found two new compound heterozygous pathogenic variants of the ALMS1 gene and determined the diagnosis as Alström Syndrome in three patients of two Chinese families. Our study extends the genotypic and phenotypic spectrums for ALMS1 -AS and emphasizes the importance of gene testing in assisting the clinical diagnosis for cases with phenotypic diversities, which would help the AS patients with early diagnosis and treatment to reduce future systemic damage.
Topics: Alstrom Syndrome; Cell Cycle Proteins; China; Color Vision Defects; DNA; Female; Humans; Hyperopia; Mutation; Pedigree; Photophobia; Vision, Low
PubMed: 36162988
DOI: 10.1186/s12886-022-02597-3 -
Orphanet Journal of Rare Diseases Sep 2022Alström syndrome (ALMS) is a rare autosomal recessive genetic disorder that is caused by homozygous or compound heterozygous mutation in the ALMS1 gene. Dilated... (Review)
Review
OBJECTIVE
Alström syndrome (ALMS) is a rare autosomal recessive genetic disorder that is caused by homozygous or compound heterozygous mutation in the ALMS1 gene. Dilated cardiomyopathy (DCM) is one of the well-recognized features of the syndrome ranging from sudden-onset infantile DCM to adult-onset cardiomyopathy, sometimes of the restrictive hypertrophic form with a poor prognosis. We aimed to evaluate severe cardiomyopathy in Alström syndrome in infancy and display susceptible specific mutations of the disease, which may be linked to severe DCM. Secondarily we reviewed published mutations in ALMS1 with cardiomyopathies in the literature.
METHOD
We represent new mutagenic alleles related to severe cardiomyopathy and cardiac outcome in this patient cohort. We evaluated echocardiographic studies of nine Turkish patients diagnosed with Alström syndrome (between 2014 and 2020, at age two weeks to twenty years). Thus, we examined the cardiac manifestations of a single-centre prospective series of nine children with specific ALMS mutations and multisystem involvement. All patients underwent genetic and biochemical testing, electrocardiograms, and echocardiographic imaging to evaluate systolic strain with speckle tracking.
RESULTS
Four of the patients died from cardiomyopathy. Three patients (including three of the four fatalities) with the same mutation (c.7911dupC [p.Asn2638Glnfs*24]) had cardiomyopathy with intra-familial variability in the severity of cardiomyopathy. Global longitudinal strain, a measure of systolic contractile function, was abnormal in all patients that can be measured.
CONCLUSION
Cardiac function in ALMS patients with infantile cardiomyopathy appears to have different clinical spectrums depending on the mutagenic allele. The c.7911dupC (p. Asn2638Glnfs*24) mutation can be related to severe cardiomyopathy. Parents can be informed and consulted about the progression of severe cardiomyopathy in a child carrying this mutagenic allele.
Topics: Adult; Alstrom Syndrome; Cardiomyopathies; Cardiomyopathy, Dilated; Child; Homozygote; Humans; Mutation
PubMed: 36109815
DOI: 10.1186/s13023-022-02483-7 -
International Journal of Molecular... Aug 2022Cerebral visual impairments (CVIs) is an umbrella term that categorizes miscellaneous visual defects with parallel genetic brain disorders. While the manifestations of... (Review)
Review
Cerebral visual impairments (CVIs) is an umbrella term that categorizes miscellaneous visual defects with parallel genetic brain disorders. While the manifestations of CVIs are diverse and ambiguous, molecular diagnostics stand out as a powerful approach for understanding pathomechanisms in CVIs. Nevertheless, the characterization of CVI disease cohorts has been fragmented and lacks integration. By revisiting the genome-wide and phenome-wide association studies (GWAS and PheWAS), we clustered a handful of renowned CVIs into five ontology groups, namely ciliopathies (Joubert syndrome, Bardet-Biedl syndrome, Alstrom syndrome), demyelination diseases (multiple sclerosis, Alexander disease, Pelizaeus-Merzbacher disease), transcriptional deregulation diseases (Mowat-Wilson disease, Pitt-Hopkins disease, Rett syndrome, Cockayne syndrome, X-linked alpha-thalassaemia mental retardation), compromised peroxisome disorders (Zellweger spectrum disorder, Refsum disease), and channelopathies (neuromyelitis optica spectrum disorder), and reviewed several mutation hotspots currently found to be associated with the CVIs. Moreover, we discussed the common manifestations in the brain and the eye, and collated animal study findings to discuss plausible gene editing strategies for future CVI correction.
Topics: Animals; Bardet-Biedl Syndrome; Cerebellum; Comorbidity; Neuromyelitis Optica; Pathology, Molecular
PubMed: 36077104
DOI: 10.3390/ijms23179707 -
NIHR Open Research 2022Prenatal exome sequencing (ES) for the diagnosis of fetal anomalies was implemented nationally in England in October 2020 by the NHS Genomic Medicine Service (GMS). is...
BACKGROUND
Prenatal exome sequencing (ES) for the diagnosis of fetal anomalies was implemented nationally in England in October 2020 by the NHS Genomic Medicine Service (GMS). is the GMS is based around seven regional Genomic Laboratory Hubs (GLHs). Prenatal ES has the potential to significantly improve NHS prenatal diagnostic services by increasing genetic diagnoses and informing prenatal decision-making. Prenatal ES has not previously been offered routinely in a national healthcare system and there are gaps in knowledge and guidance.
METHODS
Our mixed-methods evaluation commenced in October 2020, aligning with the start date of the NHS prenatal ES service . Study design draws on a framework developed in previous studies of major system innovation. There are five interrelated workstreams. Workstream-1 will use interviews and surveys with professionals, non-participant observations and documentary analysis to produce in-depth case studies across all GLHs. Data collection at multiple time points will track changes over time. In Workstream-2 qualitative interviews with parents offered prenatal ES will explore experiences and establish information and support needs. Workstream-3 will analyse data from all prenatal ES tests for nine-months to establish service outcomes (e.g. diagnostic yield, referral rates, referral sources). Comparisons between GLHs will identify factors (individual or service-related) associated with any variation in outcomes. Workstream-4 will identify and analyse practical ethical problems. Requirements for an effective ethics framework for an optimal and equitable service will be determined. Workstream-5 will assess costs and cost-effectiveness of prenatal ES versus standard tests and evaluate costs of implementing an optimal prenatal ES care pathway. Integration of findings will determine key features of an optimal care pathway from a service delivery, parent and professional perspective.
DISCUSSION
The proposed formative and summative evaluation will inform the evolving prenatal ES service to ensure equity of access, high standards of care and benefits for parents across England.
PubMed: 35935673
DOI: 10.3310/nihropenres.13247.2 -
Case Reports in Ophthalmological... 2022Bardet-Biedl syndrome is a rare autosomal recessive form of syndromic obesity which is characterized by retinal degeneration, obesity, polydactyly, cognitive impairment,...
Bardet-Biedl syndrome is a rare autosomal recessive form of syndromic obesity which is characterized by retinal degeneration, obesity, polydactyly, cognitive impairment, and renal and urogenital anomalies. In this study, we used whole-exome sequencing (WES) to investigate the underlying mutations in four Iranian children from consanguineous families with a clinical diagnosis of Bardet-Biedl syndrome (BBS). In three out of four children, we identified one previously reported frameshifting variant in the gene (c.265-266delTT, p.L89fs) and two novel nonsense variants in (c.1196T>G, p.L399X) and genes (c.1636C>T, p.Q546X). In the other child, no mutations were detected in known genes for BBS. However, we identified a novel variant in the gene (c.10996delC, p.Q3666fs) indicative of Alström syndrome. All variants were interpreted as pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines and confirmed through Sanger sequencing. In conclusion, our results not only expand the spectrum of mutations in BBS and genes but also accentuate the importance of genetic testing for differentiating BBS from Alström syndrome.
PubMed: 35912300
DOI: 10.1155/2022/6110775 -
Prilozi (Makedonska Akademija Na... Jul 2022Alström syndrome (ALMS) is an autosomal recessive disorder characterized by multiple organ involvement, including progressive cone-rod dystrophy, sensorineural hearing...
Alström syndrome (ALMS) is an autosomal recessive disorder characterized by multiple organ involvement, including progressive cone-rod dystrophy, sensorineural hearing loss, childhood obesity, and type 2 diabetes mellitus. Pathogenic variants in the ALMS1 gene are the known cause for the occurrence of this devastating condition. Here we report on a 12 year old boy referred to the University Clinic with early signs of impaired hearing and vision, obesity, and scoliosis. Central vision was first affected, followed by peripheral vision. In addition, his weight began increasing after the age of two years, reaching 78 kg at a height of 157 cm (BMI 31.64). No polydactyly was present. His mental development was normal in spite of his hearing and vision impairments. There was acanthosis nigricans on the neck. ECG and the cardiac ultrasound were normal. At the age of 12 years, his testicles are 12 ml and his pubertal status is P2 A2. OGTT revealed impaired glucose tolerance with elevated insulin concentrations 121ulU/mL (reference range 2,00-29,1 ulU/mL). Renal function was unaffected, liver functions were normal. Uric acid and lipids were within normal plasma concentrations. A Whole Exome Sequencing was performed and a homozygous ALMS1 pathogenic, frameshift gene variant (LRG_741t1(ALMS1):c.4156dup; p.Thr1386AsnfsTer15) was determined as the cause of the disease. Both parents were carriers for the variant. The absence of mental retardation and polydactyly differentiates Alström and Bardet-Biedle syndrome.
Topics: Alstrom Syndrome; Cell Cycle Proteins; Child; Child, Preschool; Diabetes Mellitus, Type 2; Hearing; Humans; Male; Pediatric Obesity
PubMed: 35843912
DOI: 10.2478/prilozi-2022-0028 -
Frontiers in Endocrinology 2022The primary cilium is a narrow organelle located at the surface of the cell in contact with the extracellular environment. Once underappreciated, now is thought to... (Review)
Review
The primary cilium is a narrow organelle located at the surface of the cell in contact with the extracellular environment. Once underappreciated, now is thought to efficiently sense external environmental cues and mediate cell-to-cell communication, because many receptors, ion channels, and signaling molecules are highly or differentially expressed in primary cilium. Rare genetic disorders that affect cilia integrity and function, such as Bardet-Biedl syndrome and Alström syndrome, have awoken interest in studying the biology of cilium. In this review, we discuss recent evidence suggesting emerging roles of primary cilium and cilia-mediated signaling pathways in the regulation of pancreatic β- and α-cell functions, and its implications in regulating glucose homeostasis.
Topics: Cilia; Glucagon-Secreting Cells; Insulysin; Pancreatic Hormones; Signal Transduction
PubMed: 35832432
DOI: 10.3389/fendo.2022.922825 -
Bone Reports Dec 2022Causative variants in genes responsible for Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) cause damage to primary cilia associated with correct functioning of...
OBJECTIVES
Causative variants in genes responsible for Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) cause damage to primary cilia associated with correct functioning of cell signaling pathways in many tissues. Despite differences in genetic background, both syndromes affect multiple organs and numerous clinical manifestations are common including obesity, retinal degeneration, insulin resistance, type 2 diabetes and many others. The aim of the study was to evaluate bone metabolism abnormalities and their relation to metabolic disorders based on bone turnover markers and presence of mandibular atrophy in patients with ALMS and BBS syndromes.
MATERIAL AND METHODS
In 18 patients (11 with ALMS and 7 with BBS aged 5-29) and in 42 age-matched ( < 0.05) healthy subjects, the following markers of bone turnover were assessed: serum osteocalcin (OC), osteoprotegerin (OPG), s-RANKL and urinary deoxypyridinoline - DPD. In addition, a severity of alveolar atrophy using dental panoramic radiograms was evaluated.
RESULTS
Lower serum OC ( = 0.0004) and urinary DPD levels ( = 0.0056) were observed in the study group compared to controls. In ALMS and BBS patients, serum OC and urinary DPD values negatively correlated with the HOMA-IR index, while a positive correlation between the OC and 25-OHD levels and a negative correlation between s-RANKL and fasting glucose concentrations were found. A significant difference in the incidence of low-grade mandibular atrophy between patients with ALMS and BBS and controls ( < 0.0001) was observed.
CONCLUSIONS
The identification of bone metabolism disorders in patients with ALMS and BBS syndromes indicates the necessity to provide them with appropriate diagnosis and treatment of these abnormalities.
PubMed: 35818441
DOI: 10.1016/j.bonr.2022.101600