• ALMS1 gene
• Alström syndrome
• Dilated cardiomyopathy
• Whole exome sequencing

• ALMS1
• Alström syndrome
• Copy number variant
• Cor triatriatum sinister
• Microhomology-mediated end joining
• Whole genome sequencing

• Child
• Female
• Humans
• Alstrom Syndrome/genetics
• Cell Cycle Proteins/genetics
• Frameshift Mutation
• Heterozygote
• Whole Genome Sequencing/methods

• Alström syndrome
• cone-rod dystrophy
• dilated cardiomyopathy
• genotype-phenotype correlations
• obesity

• ALMS1
• Alström syndrome
• Cardiomyopathy
• Characterisation
• iPSC

• Humans
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/pathology
• Induced Pluripotent Stem Cells/metabolism
• Alstrom Syndrome/genetics
• Alstrom Syndrome/pathology
• Alstrom Syndrome/metabolism
• Cardiomyopathies/genetics
• Cardiomyopathies/pathology
• Cardiomyopathies/metabolism
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/metabolism
• Calcium/metabolism
• Gene Knockout Techniques
• Infant
• Cardiomyopathy, Dilated/genetics
• Cardiomyopathy, Dilated/metabolism
• Cardiomyopathy, Dilated/pathology

• MR/V009540/1 Medical Research Council

• Alström syndrome
• Cardiovascular

• Humans
• Male
• Female
• Adult
• Phenotype
• Alstrom Syndrome/complications
• Alstrom Syndrome/genetics
• Alstrom Syndrome/physiopathology
• Middle Aged
• Young Adult
• Adolescent
• Electrocardiography
• Echocardiography
• Cardiomyopathies/diagnostic imaging
• Cardiomyopathies/physiopathology

• FS/CDRF/21/21032 British Heart Foundation

• ALMS1
• Alström syndrome
• Ciliopathy
• Sensorineural hearing loss

• Child, Preschool
• Female
• Humans
• Male
• Alstrom Syndrome/genetics
• Cell Cycle Proteins/genetics
• Mutation
• Phenotype
• Infant
• Adult

• Ageing
• Cardiovascular
• Echocardiography
• Phenoage
• Rare diseases

• Humans
• Male
• Aged
• Female
• Ventricular Dysfunction, Left
• Retrospective Studies
• Alstrom Syndrome/diagnostic imaging
• Cross-Sectional Studies
• Diastole
• Echocardiography
• Aging

• FS/CDRF/21/21032 British Heart Foundation
• BB/T00746X/1 Biotechnology and Biological Sciences Research Council

• ALMS, Alström's syndrome
• Meta-analysis
• ciliopathy
• genotype-phenotype
• metabolic disease
• obesity
• rare disease
• retinal disease

• Humans
• Alstrom Syndrome/genetics
• Alstrom Syndrome/pathology
• Cell Cycle Proteins/genetics
• Phenotype
• Exons
• Genetic Association Studies

• Instituto de Salud Carlos III
• Xunta de Galicia
• Ministerio de Educación y Cultura

• ALMS1 gene
• Alström syndrome
• missense variant
• pre-mRNA splicing
• retinal dystrophy

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.

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.

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.

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.

The online version contains supplementary material available at 10.1186/s13023-022-02483-7.

• Connexin 26/genetics
• Connexins/genetics
• Deafness/genetics
• Hearing Loss/genetics
• Humans
• Membrane Proteins/genetics
• Molecular Biology
• Mutation
• Neoplasm Proteins/genetics
• Pakistan/epidemiology
• Serine Endopeptidases/genetics

Alström syndrome (AS, OMIM ID 203800) is a rare disease involving multiple organs in children and is mostly reported in non-Chinese patients. In the Chinese population, there are few reports on the clinical manifestations and pathogenesis of AS. This is the first report on the association between AS and Graves’ hyperthyroidism.

An 8-year-old Chinese girl was diagnosed with AS. Two years later, Graves’ hyperthyroidism developed with progressive liver dysfunction. The patient’s clinical data were collected; DNA from peripheral blood of the proband, parents and sibling was collected for gene mutation detection using the second-generation sequencing method and gene panel for diabetes. The association between the patient’s genotype and clinical phenotype was analyzed. She carried the pathogenic compound heterozygous mutation of ALMS1 (c.2296_2299del4 and c.11460C>A). These stop-gain mutations likely caused truncation of the ALMS1 protein.

The manifestation of hyperthyroidism may suggest rapid progression of AS.

• ALMS1
• Alström syndrome
• Stop-gain mutations
• Protein truncation
• Graves’ hyperthyroidism
• Case report

We present 3 cases of Alström syndrome (ALMS) that highlight the importance of the ophthalmic exam, as well as the diagnostic challenges and management considerations of this ultra-rare disease.

The first case is of a 2-year-old boy with history of spasmus nutans who presented with head bobbing and nystagmus. The second patient is a 5-year-old boy with history of infantile dilated cardiomyopathy status post heart transplant, Burkitt lymphoma status post chemotherapy, obesity, global developmental delay, and high hyperopia previously thought to have cortical visual impairment secondary to heart surgery/possible ischemic event. This patient presented with nystagmus, photophobia, and reduced vision. The third case involves a 8-year-old boy with history of obesity, bilateral optic nerve atrophy, hyperopic astigmatism, exotropia, and nystagmus. Upon presentation to the consulting pediatric ophthalmologist, none of the patients had yet been diagnosed with ALMS. All 3 cases were subsequently found to have an electroretinogram (ERG) that exhibited severe global depression and to carry ALMS1 pathogenic variants.

ALMS is an autosomal recessive disease caused by ALMS1 variations, characterized by cone-rod dystrophy, obesity, progressive sensorineural hearing loss, cardiomyopathy, insulin resistance, and multiorgan dysfunction. Retinal dystrophy diagnosis is critical given clinical criteria and detection rates of genetic testing. Early diagnosis is extremely important because progression to flat ERG leads to the inability to differentiate between rod-cone or cone-rod involvement, either of which have their own differential diagnoses. In our series, the ophthalmic exam and abnormal ERG prompted further genetic testing and the subsequent diagnosis of ALMS. Multidisciplinary care ensures the best possible outcome with the ophthalmologist playing a key role.

• ALMS, Alström Syndrome
• ALMS1 gene
• APD, Afferent pupillary defect
• Alström syndrome
• Autosomal recessive
• BMI, Body mass index
• CHF, Congestive heart failure
• CLIA, Clinical Laboratory Improvement Amendments
• Cone-rod dystrophy
• DA, Dark-adapted
• DFE, Dilated fundus exam
• EEG, Electroencephalogram
• ERG, Electroretinogram
• EUA, Exam under anesthesia
• FAF, Fundus autofluorescence
• IGF, Insulin-like growth factor
• IR, Insulin resistance
• ISCEV, International Society for Clinical Electrophysiology of Vision
• LA, Light-adapted
• MRI, Magnetic resonance imaging
• OCT, Optical coherence tomography
• OD, Right eye
• OPs, Oscillatory potentials
• OS, Left eye
• OU, Both eyes
• RPE, Retinal pigment epithelium
• T2DM, Type II diabetes mellitus
• VA, Visual acuity
• VEP, Visual evoked potential
• VGB, Vigabatrin
• cDNA, complementary DNA

Alström syndrome (ALMS) is a rare ciliopathy characterised by early onset insulin resistance, obesity, and dyslipidaemia and is a model for diseases that have huge social, health and economic impact. Cardiomyopathy develops in the majority, with high rates of morbidity and mortality, the definitive features of which are coarse replacement fibrosis and diffuse myocardial fibrosis (DIF). The pathogenesis of heart failure is thought to involve fibroblast accumulation and expansion of the extracellular matrix with excess protein deposition, leading to distorted organ architecture and impaired contractile function. Consecutive adults with genetically proven ALMS attending the National Centre for Rare Disease in Birmingham, England were studied. All patients underwent serial CMR, echocardiography and venous blood sampling, with computed tomography coronary angiography (CTCA) performed to assess severity of CAD. The aims of this study were: 1) to evaluate changes over time in DIF by cardiovascular magnetic resonance tissue characterization in ALMS; 2) to examine whether changes in DIF are associated with alteration in systolic or diastolic function; and 3) to evaluate the frequency and severity of coronary artery disease as a confounder for progression of ischaemic versus non-ischaemic fibrosis.

In total, 30/32 adults (63% male; 67% White British) participated. The median age at first scan was 21.3 years (interquartile range: 19.0–32.6) and participants were followed for a maximum of 67 months. Only 4 patients had significant coronary artery stenosis on post-mortem, invasive coronary angiography or CTCA. Mid short axis myocardial T1 times, myocardial extracellular volume, and left ventricular mass increased significantly over time, by an average of 21.8 ms (95% CI 17.4–26.1; p < 0.001), 1.1 percentage points (0.6–1.6, p < 0.001), and 2.8 g/m² (1.9–3.7; p < 0.001) per year, respectively. These changes were not associated with significant deterioration in myocardial structure or function.

This is the first comprehensive prospective study demonstrating progression of DIF in ALMS over time, although no structural or functional consequences were noted within a median three and a half years’ follow up. Further study is warranted to define whether DIF is a by-stander or the driver to impaired contractile function, heart failure and death.

• Alström syndrome
• Cardiovascular magnetic resonance
• Diffuse interstitial fibrosis
• Extracellular volume
• Ischaemic heart disease
• Progression

• ALMS1
• Alstrom syndrome
• Chinese

• clinics
• genetics
• syndromic obesity
• therapy

• ethnic diversity
• genetic susceptibility
• obesity

Ciliopathies are a group of rare disorders characterized by a high genetic and phenotypic variability, which complicates their molecular diagnosis. Hence the need to use the latest powerful approaches to faster identify the genetic defect in these patients. We applied whole exome sequencing to six consanguineous families clinically diagnosed with ciliopathy-like disease, and for which mutations in predominant Bardet-Biedl syndrome (BBS) genes had previously been excluded. Our strategy, based on first applying several filters to ciliary variants and using many of the bioinformatics tools available, allowed us to identify causal mutations in BBS2, ALMS1 and CRB1 genes in four families, thus confirming the molecular diagnosis of ciliopathy. In the remaining two families, after first rejecting the presence of pathogenic variants in common cilia-related genes, we adopted a new filtering strategy combined with prioritisation tools to rank the final candidate genes for each case. Thus, we propose CORO2B, LMO7 and ZNF17 as novel candidate ciliary genes, but further functional studies will be needed to confirm their role. Our data show the usefulness of this strategy to diagnose patients with unclear phenotypes, and therefore the success of applying such technologies to achieve a rapid and reliable molecular diagnosis, improving genetic counselling for these patients. In addition, the described pipeline also highlights the common pitfalls associated to the large volume of data we have to face and the difficulty of assigning a functional role to these changes, hence the importance of designing the most appropriate strategy according to each case.

• Biomarkers/metabolism
• Cell Cycle Proteins
• Cilia/metabolism
• Cilia/pathology
• Ciliopathies/diagnosis
• Ciliopathies/genetics
• Ciliopathies/pathology
• Consanguinity
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Exome
• Eye Proteins/genetics
• Eye Proteins/metabolism
• Female
• Gene Expression
• Genome, Human
• Genotype
• High-Throughput Nucleotide Sequencing
• Humans
• LIM Domain Proteins/genetics
• LIM Domain Proteins/metabolism
• Male
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Microfilament Proteins/genetics
• Microfilament Proteins/metabolism
• Nerve Tissue Proteins/genetics
• Nerve Tissue Proteins/metabolism
• Phenotype
• Proteins/genetics
• Proteins/metabolism
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Tripartite Motif Proteins
• Ubiquitin-Protein Ligases

• Instituto de Salud Carlos III
• Ministerio de Educación, Cultura y Deporte
• Secretaría de Estado de Investigación, Desarrollo e Innovación
• Centro Nacional de Análisis Genómico

• disease heterogeneity
• genetic elucidation
• quality of evidence
• syndromic obesity

• ALMS1
• Alström syndrome
• DNA sequencing
• Microarray analysis
• Mutation

• ALMS1
• Alström Syndrome
• SNV
• ciliopathy

• Adolescent
• Adult
• Alstrom Syndrome/genetics
• Cell Cycle Proteins
• Child
• Exons
• Humans
• Mutation
• Pedigree
• Proteins/genetics
• Young Adult

• U19 HD077693 NICHD NIH HHS
• P30 CA034196 NCI NIH HHS
• R01 HD036878 NICHD NIH HHS
• P20 GM130422 NIGMS NIH HHS
• HD36878 NICHD NIH HHS
• KL2 TR001448 NCATS NIH HHS

• Alström syndrome
• Leber congenital amaurosis
• Sanger sequencing
• cone-rod dystrophy
• null mutations
• whole exome sequencing

• Animals
• Cell Cycle/genetics
• Cell Cycle/physiology
• Cell Cycle Proteins
• Cell Differentiation/genetics
• Cell Differentiation/physiology
• Cells, Cultured
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Humans
• Immunohistochemistry
• Mice
• Molecular Sequence Data
• Mutation
• Myocytes, Cardiac/cytology
• Myocytes, Cardiac/metabolism
• Proteins/genetics
• Proteins/metabolism
• Reverse Transcriptase Polymerase Chain Reaction

• 4R00HL09223 NHLBI NIH HHS
• U54 HG006542 NHGRI NIH HHS
• R01 HL111198 NHLBI NIH HHS
• R01 HD036878 NICHD NIH HHS
• T32 HL007227 NHLBI NIH HHS
• R00 HL092234 NHLBI NIH HHS
• HD036878 NICHD NIH HHS
• 5U54HG006542 NHGRI NIH HHS
• HHSN268200782096C NHLBI NIH HHS
• R01HL111198 NHLBI NIH HHS

• alström syndrome
• dilated cardiomyopathy
• autosomal recessive
• alms1 gene

• ALMS1
• Alström syndrome
• ciliopathy
• truncal obesity.

• R01 HD036878 NICHD NIH HHS

• Alstrom Syndrome/genetics
• Alstrom Syndrome/pathology
• Alstrom Syndrome/physiopathology
• Animals
• Bardet-Biedl Syndrome/genetics
• Bardet-Biedl Syndrome/metabolism
• Bardet-Biedl Syndrome/physiopathology
• Cell Cycle Proteins
• Diabetes Mellitus, Type 2/genetics
• Diabetes Mellitus, Type 2/metabolism
• Humans
• Mutation
• Obesity/genetics
• Obesity/metabolism
• Proteins/genetics

• Adolescent
• Alstrom Syndrome/diagnosis
• Cell Cycle Proteins
• Consanguinity
• Female
• Humans
• Proteins/genetics

A case series of the cardiac magnetic resonance imaging findings in seven adult Alström patients.

Seven patients from the National Specialist Commissioning Group Centre for Alström Disease, Torbay, England, UK, completed the cardiac magnetic resonance imaging protocol to assess cardiac structure and function in Alström cardiomyopathy.

All patients had some degree of left and right ventricular dysfunction. Patchy mid wall gadolinium delayed enhancement was demonstrated, suggesting an underlying fibrotic process. Some degree of cardiomyopathy was universal. No evidence of myocardial infarction or fatty infiltration was demonstrated, but coronary artery disease cannot be completely excluded. Repeat scanning after 18 months in one subject showed progression of fibrosis and decreased left ventricular function.

Adult Alström cardiomyopathy appears to be a fibrotic process causing impairment of both ventricles. Serial cardiac magnetic resonance scanning has helped clarify the underlying disease progression and responses to treatment. Confirmation of significant mutations in the ALMS1 gene should lead to advice to screen the subject for cardiomyopathy, and metabolic disorders.

• Abnormalities, Multiple/genetics
• Base Sequence
• Cohort Studies
• DNA Primers
• Exons
• Female
• Genotype
• Haplotypes
• Humans
• Male
• Mutation
• Pedigree
• Phenotype
• Polymorphism, Single Nucleotide
• Syndrome

• CA34196 NCI NIH HHS
• HD36878 NICHD NIH HHS

• Cell Cycle Proteins
• Child
• Exudates and Transudates
• Eye Diseases, Hereditary/genetics
• Female
• Humans
• Mutation
• Proteins/genetics
• Retinal Degeneration/genetics
• Syndrome
• Telangiectasis/genetics

Premature truncation alleles in the ALMS1 gene are a frequent cause of human Alström syndrome. Alström syndrome is a rare disorder characterized by early obesity and sensory impairment, symptoms shared with other genetic diseases affecting proteins of the primary cilium. ALMS1 localizes to centrosomes and ciliary basal bodies, but truncation mutations in Alms1/ALMS1 do not preclude formation of cilia. Here, we show that in vitro knockdown of Alms1 in mice causes stunted cilia on kidney epithelial cells and prevents these cells from increasing calcium influx in response to mechanical stimuli. The stunted-cilium phenotype can be rescued with a 5′ fragment of the Alms1 cDNA, which resembles disease-associated alleles. In a mouse model of Alström syndrome, Alms1 protein can be stably expressed from the mutant allele and is required for cilia formation in primary cells. Aged mice developed specific loss of cilia from the kidney proximal tubules, which is associated with foci of apoptosis or proliferation. As renal failure is a common cause of mortality in Alström syndrome patients, we conclude that this disease should be considered as a further example of the class of renal ciliopathies: wild-type or mutant alleles of the Alström syndrome gene can support normal kidney ciliogenesis in vitro and in vivo, but mutant alleles are associated with age-dependent loss of kidney primary cilia.

Alström syndrome is a rare genetic disorder caused by mutations in the ALMS1 gene. The disease is characterized by blindness, deafness, and metabolic disorders. These symptoms are reminiscent of diseases affecting the primary cilium, a cellular appendage with a role in sensing changes to the extracellular environment. In addition, kidney failure is a frequent cause of death in Alström syndrome patients, and recent studies have suggested a causal relationship between defects in primary cilia and cystic kidney diseases. In this paper, we show that ALMS1 protein is required to form cilia in kidney cells. Mutant alleles of the gene that are similar to those seen in the human disease are able to support cilia formation in cell culture and in animals. However, a defect in the function of the disease alleles is uncovered in older mice: cilia are lost from the kidney cells, and this is associated with an increase in cellular proliferation and cell death. The data are consistent with a requirement for ALMS1 in ciliogenesis and suggest inclusion of Alström syndrome among the growing class of cilia-related pathologies.

• Abnormalities, Multiple/pathology
• Aging/metabolism
• Animals
• Cell Cycle Proteins
• Cilia/genetics
• Cilia/metabolism
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Gene Expression Regulation
• Homeostasis
• Humans
• Kidney/abnormalities
• Kidney/cytology
• Kidney/metabolism
• Kidney/pathology
• Mechanotransduction, Cellular
• Mice
• Mice, Mutant Strains
• Molecular Sequence Data
• Peptide Fragments/metabolism
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• RNA, Small Interfering/metabolism
• Syndrome
• Transcription, Genetic

• Absorptiometry, Photon
• Adipose Tissue
• Adolescent
• Adult
• Aging
• Anthropometry
• Body Composition
• Body Mass Index
• Cell Cycle Proteins
• Child
• Child, Preschool
• DNA Mutational Analysis
• Diabetes Mellitus/genetics
• Diabetes Mellitus/physiopathology
• Female
• Founder Effect
• Genotype
• Hearing Loss, Sensorineural/genetics
• Humans
• Hyperinsulinism/genetics
• Hypertension/genetics
• Hypertriglyceridemia/genetics
• Insulin Resistance/genetics
• Male
• Mutation
• Obesity/genetics
• Obesity/physiopathology
• Phenotype
• Proteins/genetics
• Syndrome
• United Kingdom