scholarly journals A Case Report of two siblings with Alstrom syndrome without hearing loss associated with two new ALMS1 variants

2019 ◽  
Author(s):  
Maria Fedorovna Shurygina ◽  
Maria A. Parker ◽  
Catie Schlechter ◽  
Rui Chen ◽  
Yumei Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Late Onset ◽  
Light Sensitivity ◽  
Clinical Findings ◽  
Alström Syndrome ◽  
Mild Developmental Delay ◽  
Novel Variants ◽  
Normal Stature ◽  
Alstrom Syndrome

Abstract Background Alström syndrome (AS) is a rare monogenic disorder characterized by progressive multi-organ pathology including retinal degeneration, hearing impairment and type 2 diabetes. Here we present clinical features in two siblings diagnosed with Alström syndrome associated with novel biallelic changes in ALMS1. Case presentation Two siblings originally diagnosed as having achromatopsia presented with mild light sensitivity, nonspecific otitis media, and mild developmental delay during the first decade of life with a relatively stable ocular appearance during second decade, late onset of nystagmus and dyschromatopsia (after 20 years) and preserved vision during the third decade of life. One sibling had late onset hearing loss and both siblings had symmetric high myopia, normal stature, and ptosis. Clinical findings revealed structural and functional tests consistent with a cone-rod dystrophy. Novel variants c.9894dupC (p.S3298fs) and c.10769delC (p.T3590fs) in ALMS1 gene were found. Conclusions Two North American siblings who presented with a mild clinical phenotype of Alström syndrome were found to have novel mutations in ALMS1. These two frame-shift mutations segregated with the disease phenotype lending evidence to their pathogenicity.

scholarly journals A Case Report of two siblings with Alstrom syndrome without hearing loss associated with two new ALMS1 variants

2019 ◽  
Author(s):  
Maria Fedorovna Shurygina ◽  
Maria A. Parker ◽  
Catie Schlechter ◽  
Rui Chen ◽  
Yumei Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Late Onset ◽  
Light Sensitivity ◽  
Clinical Findings ◽  
Alström Syndrome ◽  
Mild Developmental Delay ◽  
Novel Variants ◽  
Normal Stature ◽  
Alstrom Syndrome

Abstract Background Alström syndrome (AS) is a rare monogenic disorder characterized by progressive multi-organ pathology including retinal degeneration, hearing impairment and type 2 diabetes. Here we present clinical features in two siblings diagnosed with Alström syndrome associated with novel biallelic changes in ALMS1. Case presentation Two siblings originally diagnosed as having achromatopsia presented with mild light sensitivity, nonspecific otitis media, and mild developmental delay during the first decade of life with a relatively stable ocular appearance during second decade, late onset of nystagmus and dyschromatopsia (after 20 years) and preserved vision during the third decade of life. One sibling had late onset hearing loss and both siblings had symmetric high myopia, normal stature, and ptosis. Clinical findings revealed structural and functional tests consistent with a cone-rod dystrophy. Novel variants c.9894dupC (p.S3298fs) and c.10769delC (p.T3590fs) in ALMS1 gene were found. Conclusions Two North American siblings who presented with a mild clinical phenotype of Alström syndrome were found to have novel mutations in ALMS1. These two frame-shift mutations segregated with the disease phenotype lending evidence to their pathogenicity.

scholarly journals A Case Report of two siblings with Alstrom syndrome without hearing loss associated with two new ALMS1 variants

2019 ◽  
Author(s):  
Maria Fedorovna Shurygina ◽  
Maria A. Parker ◽  
Catie Schlechter ◽  
Rui Chen ◽  
Yumei Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Late Onset ◽  
Light Sensitivity ◽  
Clinical Findings ◽  
Alström Syndrome ◽  
Mild Developmental Delay ◽  
Novel Variants ◽  
Normal Stature ◽  
Alstrom Syndrome

Abstract Background Alström syndrome (AS) is a rare monogenic disorder characterized by progressive multi-organ pathology including retinal degeneration, hearing impairment and type 2 diabetes. Here we present clinical features in two siblings diagnosed with Alström syndrome associated with novel biallelic changes in ALMS1. Case presentation Two siblings originally diagnosed as having achromatopsia presented with mild light sensitivity, nonspecific otitis media, and mild developmental delay during the first decade of life with a relatively stable ocular appearance during second decade, late onset of nystagmus and dyschromatopsia (after 20 years) and preserved vision during the third decade of life. One sibling had late onset hearing loss and both siblings had symmetric high myopia, normal stature, and ptosis. Clinical findings revealed structural and functional tests consistent with a cone-rod dystrophy. Novel variants c.9894dupC (p.S3298fs) and c.10769delC (p.T3590fs) in ALMS1 gene were found. Conclusions Two North American siblings who presented with a mild clinical phenotype of Alström syndrome were found to have novel mutations in ALMS1. These two frame-shift mutations segregated with the disease phenotype lending evidence to their pathogenicity.

scholarly journals A case report of two siblings with Alstrom syndrome without hearing loss associated with two new ALMS1 variants

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Maria F. Shurygina ◽  
Maria A. Parker ◽  
Catie L. Schlechter ◽  
Rui Chen ◽  
Yumei Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Late Onset ◽  
Light Sensitivity ◽  
Clinical Findings ◽  
Alström Syndrome ◽  
Mild Developmental Delay ◽  
Novel Variants ◽  
Normal Stature ◽  
Alstrom Syndrome

Abstract Background Alström syndrome (AS) is a rare monogenic disorder characterized by progressive multi-organ pathology including retinal degeneration, hearing impairment and type 2 diabetes. Here we present clinical features in two siblings diagnosed with Alström syndrome associated with two novel changes in ALMS1. Case presentation Two siblings originally diagnosed as having achromatopsia presented with mild light sensitivity, nonspecific otitis media, and mild developmental delay during the first decade of life with a relatively stable ocular appearance during second decade, late onset of nystagmus and dyschromatopsia (after 20 years) and preserved vision during the third decade of life. One sibling had late onset hearing loss and both siblings had symmetric high myopia, normal stature, and ptosis. Clinical findings revealed structural and functional tests consistent with a cone-rod dystrophy. Novel variants c.9894dupC (p.S3298 fs) and c.10769delC (p.T3590 fs) in ALMS1 gene were found. Conclusions Two North American siblings who presented with a mild clinical phenotype of Alström syndrome were found to have novel mutations in ALMS1. These two frame-shift mutations segregated with the disease phenotype lending evidence to their pathogenicity.

scholarly journals Prevalent ALMS1 Pathogenic Variants in Spanish Alström Patients

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 282
Author(s):  
Brais Bea-Mascato ◽  
Carlos Solarat ◽  
Irene Perea-Romero ◽  
Teresa Jaijo ◽  
Fiona Blanco-Kelly ◽  
...  
Keyword(s):  
High Frequency ◽  
Haplotype Analysis ◽  
Genetic Diagnosis ◽  
Allelic Frequency ◽  
Structural Protein ◽  
Alström Syndrome ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Alstrom Syndrome

Alström syndrome (ALMS) is an ultrarare disease with an estimated prevalence lower than 1 in 1,000,000. It is associated with disease-causing mutations in the Alström syndrome 1 (ALMS1) gene, which codifies for a structural protein of the basal body and centrosomes. The symptomatology involves nystagmus, type 2 diabetes mellitus (T2D), obesity, dilated cardiomyopathy (DCM), neurodegenerative disorders and multiorgan fibrosis. We refined the clinical and genetic diagnosis data of 12 patients from 11 families, all of them from Spain. We also studied the allelic frequency of the different variants present in this cohort and performed a haplotype analysis for the most prevalent allele. The genetic analysis revealed 2 novel homozygous variants located in the exon 8, p.(Glu929Ter) and p.(His1808GlufsTer20) in 2 unrelated patients. These 2 novel variants were classified as pathogenic after an in silico experiment (computer analysis). On the other hand, 2 alleles were detected at a high frequency in our cohort: p.(Tyr1714Ter) (25%) and p.(Ser3872TyrfsTer19) (16.7%). The segregation analysis showed that the pathogenic variant p.(Tyr1714Ter) in 3 families is linked to a rare missense polymorphism, p.(Asn1787Asp). In conclusion, 2 novel pathological mutations have been discovered in homozygosis, as well as a probable founder effect in 3 unrelated families.

scholarly journals A Case Report of two siblings with Alstrom syndrome without hearing loss associated with two new ALMS1 variants

2019 ◽  
Author(s):  
Maria Fedorovna Shurygina ◽  
Maria A. Parker ◽  
Catie Schlechter ◽  
Rui Chen ◽  
Yumei Li ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Hearing Loss ◽  
Case Report ◽  
Retinal Degeneration ◽  
Hearing Impairment ◽  
Clinical Features ◽  
Monogenic Disorder ◽  
Alström Syndrome ◽  
Alstrom Syndrome

Abstract Alström syndrome (AS) is a rare monogenic disorder characterized by progressive multi-organ pathology including retinal degeneration, hearing impairment and type 2 diabetes. Here we present clinical features in two siblings diagnosed with Alström syndrome associated with two novel changes in ALMS1.

scholarly journals Genomic knockout of alms1 in zebrafish recapitulates Alström syndrome and provides insight into metabolic phenotypes

2018 ◽  
Author(s):  
Jessica E. Nesmith ◽  
Timothy L. Hostelley ◽  
Carmen C. Leitch ◽  
Maggie S. Matern ◽  
Saumil Sethna ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Single Gene ◽  
Loss Of Function ◽  
Β Cells ◽  
Zebrafish Model ◽  
Alström Syndrome ◽  
Alstrom Syndrome

SCIENTIFIC ABSTRACTAlström syndrome is an autosomal recessive obesity ciliopathy caused by loss-of-function mutations in the ALMS1 gene. In addition to multi-organ dysfunction, such as cardiomyopathy, retinal degeneration, and renal dysfunction, the disorder is characterized by high rates of obesity, insulin resistance and early onset type 2 diabetes mellitus (T2DM). To investigate mechanisms linking disease phenotypes we generated a loss-of-function deletion of alms1 in the zebrafish using CRISPR/Cas9. We demonstrate conserved phenotypic effects including cardiac defects, retinal degeneration, and metabolic deficits that included propensity for obesity and fatty livers in addition to hyperinsulinemia and glucose response defects. Gene expression changes in β-cells isolated from alms1−/− mutants revealed changes consistent with insulin hyper-secretion and glucose sensing failure, which were also identified in cultured murine β-cells lacking Alms1. These data present a zebrafish model to assess etiology and new secretory pathway defects underlying Alström syndrome-associated metabolic phenotypes. Given the hyperinsulinemia and reduced glucose sensitivity in these animals we also propose the alms1 loss-of-function mutant as a monogenic model for studying T2DM phenotypes.AUTHOR SUMMARYThese data comprise a thorough characterization of a zebrafish model of Alström syndrome, a human obesity syndrome caused by loss-of-function deletions in a single gene, ALMS1. The high rates of obesity and insulin resistance found in these patients suggest this disorder as a single-gene model for Type 2 Diabetes Mellitus (T2DM), a disorder caused by a variety of environmental and genetic factors in the general population. We identify a propensity for obesity, excess lipid storage, loss of β-cells in islets, and hyperinsulinemia in larval and adult stages of zebrafish alms1 mutants. We isolated β-cells from the alms1 mutants and compared the gene expression profiles from RNASeq datasets to identify molecular pathways that may contribute to the loss of β-cells and hyperinsulinemia. The increase in genes implicated in generalized pancreatic secretion, insulin secretion, and glucose transport suggest potential β-cell exhaustion as a source of β-cell loss and excess larval insulin. We propose this mutant as a new genetic tool for understanding the metabolic failures found in Type 2 Diabetes Mellitus.

scholarly journals alms1 mutant zebrafish do not show hair cell phenotypes seen in other cilia mutants

2020 ◽  
Author(s):  
Lauren Parkinson ◽  
Tamara M. Stawicki
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Intraflagellar Transport ◽  
Cell Loss ◽  
Cell Types ◽  
Mutant Mice ◽  
Alström Syndrome ◽  
Metabolic Defects ◽  
Alstrom Syndrome

ABSTRACTMultiple cilia-associated genes have been shown to affect hair cells in zebrafish (Danio rerio), including the human deafness gene dcdc2, the radial spoke gene rsph9, and multiple intraflagellar transport (IFT) and transition zone genes. Recently a zebrafish alms1 mutant was generated. The ALMS1 gene is the gene mutated in the ciliopathy Alström Syndrome a disease that causes hearing loss among other symptoms. The hearing loss seen in Alström Syndrome may be due in part to hair cell defects as Alms1 mutant mice show stereocilia polarity defects and a loss of hair cells. Hair cell loss is also seen in postmortem analysis of Alström patients. The zebrafish alms1 mutant has metabolic defects similar to those seen in Alström syndrome and Alms1 mutant mice. We wished to investigate if it also had hair cell defects. We, however, failed to find any hair cell related phenotypes in alms1 mutant zebrafish. They had normal lateral line hair cell numbers as both larvae and adults and normal kinocilia formation. They also showed grossly normal swimming behavior, response to vibrational stimuli, and FM1-43 loading. Mutants also showed a normal degree of sensitivity to both short-term neomycin and long-term gentamicin treatment. These results indicate that cilia-associated genes differentially affect different hair cell types.

scholarly journals Recessive LOXHD1 Variants Cause a Milder Prelingual Hearing Loss: Genotype-Phenotype Correlation and Three Additional Patients With Novel Variants

2020 ◽  
Author(s):  
Sha Yu ◽  
Wen-xia Chen ◽  
Yun-Fei Zhang ◽  
Chao Chen ◽  
Yihua Ni ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Late Onset ◽  
Protein Domain ◽  
Low Frequencies ◽  
Genotype Combination ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Splicing Variants ◽  
Novel Variants ◽  
Children With Hearing Loss

Abstract BackgroundBiallelic mutations in LOXHD1 have been identified as the cause of DFNB77 (deafness, autosomal recessive 77). It is a novel, progressive, severe-profound, and late-onset non-syndromic hearing loss, and is genetically and phenotypically highly heterogeneous. This study aimed to provide an additional three cases of DFNB77 to analyze this complex disease.MethodsWe presented three cases of pediatric patients with prelingual milder form of the DFNB77 with residual hearing at low frequencies. Trio whole-exome sequencing (WES) was conducted to identify the pathogenic variants. Additionally, we reviewed the literature to further analyze the relationships between the genotype and audiology phenotype of LOXHD1 worldwide.ResultsSix novel possible pathogenic LOXHD1 variants in three patients were identified by WES, including three missense, one nonsense, and two splicing variants. The literature review showed that 68.5% of DFNB77 patient onset before five years old; Most variants (60%) were associated with a milder phenotype, particularly variants in the protein domain of PLAT 7 and PLAT 9. We found that compared with homozygous LOXHD1 variants, individuals with heterozygous compound variants had a significantly milder phenotype, especially individuals carrying one missense and one splicing or bi-allelic missense variants (P <0.05). Audiometric analysis at different ages showed that the hearing loss degree was aggravated at all frequencies in adulthood and more severe in elderhood.ConclusionsWe report three children with hearing loss carrying six novel LOXHD1 variants identified by WES. Furthermore, our work indicates that DFNB77 may be milder than previously reported, and recommends considering the genotype combination and mutation location of LOXHD1 and race-specificity in DFNB77 molecular diagnoses and management.

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