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American Journal of Ophthalmology Case... Mar 2023To describe a case of Alström syndrome arising from maternal uniparental disomy.
PURPOSE
To describe a case of Alström syndrome arising from maternal uniparental disomy.
OBSERVATIONS
A 13-month-old boy with poor vision and nystagmus was diagnosed with Alström syndrome based on genetic testing that identified a homozygous pathogenic variant, c.2141_2141del (p.Ser714Tyrfs*6), that was only found in his mother and not his father. In contrast to the usual autosomal recessive inheritance pattern in which a child inherits a variant from each parent, multi-step genetic testing of the child and both parents confirmed uniparental disomy as the mechanism of inheritance.
CONCLUSIONS AND IMPORTANCE
Confirmation of uniparental disomy in autosomal recessive disorders allows for parental assurance that future offspring will be unaffected.
PubMed: 36636630
DOI: 10.1016/j.ajoc.2022.101745 -
Genes Dec 2022Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) are rare genetic diseases with a number of common clinical features ranging from early-childhood obesity and...
Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) are rare genetic diseases with a number of common clinical features ranging from early-childhood obesity and retinal degeneration. ALMS and BBS belong to the ciliopathies, which are known to have the expression products of genes, encoding them as cilia-localized proteins in multiple target organs. The aim of this study was to perform transcriptomic and proteomic analysis on cellular models of ALMS and BBS syndromes to identify common and distinct pathological mechanisms present in both syndromes. For this purpose, epithelial cells were isolated from the urine of patients and healthy subjects, which were then cultured and reprogrammed into induced pluripotent stem (iPS) cells. The pathways of genes associated with the metabolism of lipids and glycosaminoglycan and the transport of small molecules were found to be concomitantly downregulated in both diseases, while transcripts related to signal transduction, the immune system, cell cycle control and DNA replication and repair were upregulated. Furthermore, protein pathways associated with autophagy, apoptosis, cilium assembly and Gli1 protein were upregulated in both ciliopathies. These results provide new insights into the common and divergent pathogenic pathways between two similar genetic syndromes, particularly in relation to primary cilium function and abnormalities in cell differentiation.
Topics: Child; Humans; Bardet-Biedl Syndrome; Transcriptome; Proteomics; Pediatric Obesity; Alstrom Syndrome; Proteins; Ciliopathies
PubMed: 36553637
DOI: 10.3390/genes13122370 -
Nigerian Journal of Clinical Practice Dec 2022Alstrom syndrome (AS) is one type of monogenic diabetic syndromes caused by mutation in the ALMS1. Due to rare prevalence and overlaps of clinical symptoms, monogenic...
Alstrom syndrome (AS) is one type of monogenic diabetic syndromes caused by mutation in the ALMS1. Due to rare prevalence and overlaps of clinical symptoms, monogenic diabetes is often misdiagnosed. Here, we report a Chinese diabetes patient with poor blood glucose control and insulin resistance. With whole-exome sequencing (WES), this patient was classified into monogenic diabetes and diagnosed as AS with one novel gene mutation identified. This study highlights the clinical application of WES in the diagnosis of monogenic diabetes.
Topics: Humans; Cell Cycle Proteins; Exome Sequencing; East Asian People; Alstrom Syndrome; Diabetes Mellitus; Mutation
PubMed: 36537469
DOI: 10.4103/njcp.njcp_544_22 -
Clinical Case Reports Dec 2022A 32-year-old male case with short stature presented to us with audio-visual impairment, obesity, impaired glucose tolerance, dyslipidemia, and hypogonadism. The...
A 32-year-old male case with short stature presented to us with audio-visual impairment, obesity, impaired glucose tolerance, dyslipidemia, and hypogonadism. The single-gene genetic analysis revealed an ALMS1 gene mutation. A diagnosis of ALMS was reached for meeting one major and four minor criteria.
PubMed: 36514460
DOI: 10.1002/ccr3.6720 -
Frontiers in Endocrinology 2022Patients with the rare syndromic forms of monogenic diabetes: Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) have multiple metabolic abnormalities, including...
BACKGROUND
Patients with the rare syndromic forms of monogenic diabetes: Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) have multiple metabolic abnormalities, including early-onset obesity, insulin resistance, lipid disorders and type 2 diabetes mellitus. The aim of this study was to determine if the expression of circulating miRNAs in patients with ALMS and BBS differs from that in healthy and obese individuals and determine if miRNA levels correlate with metabolic tests, BMI-SDS and patient age.
METHODS
We quantified miRNA expression (Qiagen, Germany) in four groups of patients: with ALMS (n=13), with BBS (n=7), patients with obesity (n=19) and controls (n=23). Clinical parameters including lipids profile, serum creatinine, cystatin C, fasting glucose, insulin and C-peptide levels, HbA1c values and insulin resistance (HOMA-IR) were assessed in patients with ALMS and BBS.
RESULTS
We observed multiple up- or downregulated miRNAs in both ALMS and BBS patients compared to obese patients and controls, but only 1 miRNA (miR-301a-3p) differed significantly and in the same direction in ALMS and BBS relative to the other groups. Similarly, 1 miRNA (miR-92b-3p) was dysregulated in the opposite directions in ALMS and BBS patients, but diverged from 2 other groups. We found eight miRNAs (miR-30a-5p, miR-92b-3p, miR-99a-5p, miR-122-5p, miR-192-5p, miR-193a-5p, miR-199a-3p and miR-205-5p) that significantly correlated with at least of the analyzed clinical variables representing an association with the course of the diseases.
CONCLUSIONS
Our results show for the first time that serum miRNAs can be used as available indicators of disease course in patients with ALMS and BBS syndromes.
Topics: Humans; Bardet-Biedl Syndrome; Diabetes Mellitus, Type 2; Insulin Resistance; Circulating MicroRNA; MicroRNAs; Obesity; Disease Progression
PubMed: 36506055
DOI: 10.3389/fendo.2022.1057056 -
Frontiers in Endocrinology 2022The diagnosis of neonatal hypocalcemic seizures (HS) in newborns is made based on clinical signs and serum calcium level. Their etiology is broad and diverse, and timely...
BACKGROUND
The diagnosis of neonatal hypocalcemic seizures (HS) in newborns is made based on clinical signs and serum calcium level. Their etiology is broad and diverse, and timely detection and initiation of treatment is essential.
METHODS
We retrospectively reviewed 1029 patients admitted to the neonatal intensive care unit. Neonatal HS were diagnosed in 16 patients, and we compared etiologies and clinical outcomes, including clinical seizures and neurodevelopment at least over 1 year old.
RESULTS
The etiologies can be broadly categorized into 5 syndromic and 11 non-syndromic neonatal HS. Syndromic neonatal HS included 3 Digeorge syndrome, 1 Kleefstra syndrome and 1 Alström syndrome. Non-syndromic neonatal HS included 8 vitamin D deficiency, 1 hypoparathyroidism, and 2 hypoxic-ischemic encephalopathy. Patients with syndromic neonatal HS were found to have worse clinical outcomes than those with nonsyndromic HS. In eight patients with vitamin D deficiency, neurodevelopment was normal. Five of five patients (100%) with syndromic HS used two or more antiseizure drugs. However, among patients with non-syndromic neonatal HS, only one of 11 (9.1%) used more than one drug ( 0.001).
CONCLUSION
This finding highlighted that syndromic hypocalcemic seizures in newborns have worse neurodevelopmental outcomes and are more often difficult to manage, and would benefit from a genetic diagnostic approach.
Topics: Infant; Humans; Infant, Newborn; Retrospective Studies; Seizures; Vitamin D Deficiency
PubMed: 36440223
DOI: 10.3389/fendo.2022.998675 -
Transplantation Proceedings Dec 2022Alström syndrome is a rare, multisystemic genetic disorder, and dilated cardiomyopathy occurs in approximately two-thirds of patients with this condition. Because of...
Alström syndrome is a rare, multisystemic genetic disorder, and dilated cardiomyopathy occurs in approximately two-thirds of patients with this condition. Because of donor organ shortage and unfavorable prognosis of multiple organ dysfunction, heart transplant is not the most desirable therapeutic option for patients with dilated cardiomyopathy with Alström syndrome. However, eliminating heart dysfunction elements at an appropriate time itself plays a pivotal role in preventing or even reversing other organ failures. Herein, we report the case of a 17-year-old boy who underwent successful isolated heart transplant despite severe liver dysfunction.
Topics: Male; Humans; Adolescent; Alstrom Syndrome; Cardiomyopathy, Dilated; Cardiomyopathies; Heart Transplantation
PubMed: 36371280
DOI: 10.1016/j.transproceed.2022.09.028 -
The Lancet. Diabetes & Endocrinology Dec 2022Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period.
BACKGROUND
Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare genetic diseases associated with hyperphagia and early-onset severe obesity. We aimed to evaluate the effect of setmelanotide on bodyweight in these patients.
METHODS
This multicentre, randomised, 14-week double-blind, placebo-controlled, phase 3 trial followed by a 52-week open-label period, was performed at 12 sites (hospitals, clinics, and universities) in the USA, Canada, the UK, France, and Spain. Patients aged 6 years or older were included if they had a clinical diagnosis of Bardet-Biedl syndrome or Alström syndrome and obesity (defined as BMI >97th percentile for age and sex for those aged 6-15 years and ≥30 kg/m for those aged ≥16 years). Patients were randomly assigned (1:1) using a numerical randomisation code to receive up to 3·0 mg of subcutaneous setmelanotide or placebo once per day during the 14-week double-blind period, followed by open-label setmelanotide for 52 weeks. The primary endpoint, measured in the full analysis set, was the proportion of patients aged 12 years or older who reached at least a 10% reduction in bodyweight from baseline after 52 weeks of setmelanotide treatment. This study is registered with ClinicalTrials.gov, NCT03746522.
FINDINGS
Between Dec 10, 2018, and Nov 25, 2019, 38 patients were enrolled and randomly assigned to receive setmelanotide (n=19) or placebo (n=19; 16 with Bardet-Biedl syndrome and three with Alström syndrome in each group). In terms of the primary endpoint, 32·3% (95% CI 16·7 to 51·4; p=0·0006) of patients aged 12 years or older with Bardet-Biedl syndrome reached at least a 10% reduction in bodyweight after 52 weeks of setmelanotide. The most commonly reported treatment-emergent adverse events were skin hyperpigmentation (23 [61%] of 38) and injection site erythema (18 [48%]). Two patients had four serious adverse events (blindness, anaphylactic reaction, and suicidal ideation); none were considered related to setmelanotide treatment.
INTERPRETATION
Setmelanotide resulted in significant bodyweight reductions in patients with Bardet-Biedl syndrome; however, these results were inconclusive in patients with Alström syndrome. These results support the use of setmelanotide and provided the necessary evidence for approval of this drug as the first treatment for obesity in patients with Bardet-Biedl syndrome.
FUNDING
Rhythm Pharmaceuticals.
Topics: Humans; Receptor, Melanocortin, Type 4; Alstrom Syndrome; Bardet-Biedl Syndrome; Treatment Outcome; Obesity
PubMed: 36356613
DOI: 10.1016/S2213-8587(22)00277-7 -
Frontiers in Molecular Biosciences 2022is a ubiquitous gene associated with Alström syndrome (ALMS). The main symptoms of ALMS affect multiple organs and tissues, generating at last, multi-organic fibrosis...
is a ubiquitous gene associated with Alström syndrome (ALMS). The main symptoms of ALMS affect multiple organs and tissues, generating at last, multi-organic fibrosis in the lungs, kidneys and liver. TGF-β is one of the main pathways implicated in fibrosis, controlling the cell cycle, apoptosis, cell migration, cell adhesion and epithelial-mesenchymal transition (EMT). Nevertheless, the role of gene in fibrosis generation and other implicated processes such as cell migration or cell adhesion the TGF- β pathway has not been elucidated yet. Initially, we evaluated how depletion of affects different processes like apoptosis, cell cycle and mitochondrial activity in HeLa cells. Then, we performed proteomic profiling with TGF-β stimuli in HeLa -/- cells and validated the results by examining different EMT biomarkers using qPCR. The expression of these EMT biomarkers were also studied in hTERT-BJ-5ta -/-. Finally, we evaluated the SMAD3 and SMAD2 phosphorylation and cell migration capacity in both models. Depletion of generated apoptosis resistance to thapsigargin (THAP) and C2-Ceramide (C2-C), and G2/M cell cycle arrest in HeLa cells. For mitochondrial activity, results did not show significant differences between and . Proteomic results showed inhibition of downstream pathways regulated by TGF-β. The protein-coding genes (PCG) were associated with processes like focal adhesion or cell-substrate adherens junction in HeLa. showed an opposite pattern to what would be expected when activating the EMT in HeLa and BJ-5ta. Finally, in BJ-5ta model a reduced activation of SMAD3 but not SMAD2 were also observed. In HeLa model no alterations in the canonical TGF-β pathway were observed but both cell lines showed a reduction in migration capacity. has a role in controlling the cell cycle and the apoptosis processes. Moreover, the depletion of affects the signal transduction through the TGF-β and other processes like the cell migration and adhesion capacity.
PubMed: 36325276
DOI: 10.3389/fmolb.2022.992313 -
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