• Inherited retinal degeneration
• Retina
• Retinitis pigmentosa
• Syndrome
• peroxisomal disorders
• rod-cone dystrophy

• 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 gene
• Alstrom syndrome

• Humans
• Alstrom Syndrome/genetics
• Alstrom Syndrome/diagnosis
• Cell Cycle Proteins/genetics
• Extended Family
• Saudi Arabia
• Obesity
• Mutation
• Cardiomyopathies

• 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

• ALMS1
• alström syndrome
• alström–hallgren syndrome
• ciliopathy
• hereditary sensory and motor neuropathy

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.

• ALMS1 gene
• Alström Syndrome
• cone-rod retinal dystrophy
• sensorineural deafness

• Alstrom Syndrome/complications
• Alstrom Syndrome/diagnosis
• Alstrom Syndrome/genetics
• Cell Cycle Proteins/genetics
• Child
• Child, Preschool
• Diabetes Mellitus, Type 2
• Hearing
• Humans
• Male
• Pediatric Obesity

• ALMS1 gene
• Alstrom syndrome (ALMS)
• case report
• diabetes

Alström syndrome (AS) is a rare autosomal recessive disease that is generally induced by mutations of the Alström syndrome 1 (ALMS1) gene. We report a case of AS, extend the spectrum of ALMS1 mutations and highlight the biological role of ALMS1 to explore the relationship between dilated cardiomyopathy (DCM) and mutations in ALMS1.

We present the case of an infant with AS mainly manifesting with DCM that was caused by a novel mutation of the ALMS1 gene. Whole-exome sequencing revealed a simultaneous large deletion and point mutation in ALMS1, leading to frameshift and missense mutations, respectively, rather than nonsense or frameshift mutations, which have been reported previously. Upon optimized anti-remodeling therapy, biohumoral exams and arrhythmic burden of the infant were alleviated at follow-up after 6 mo.

We identified novel mutations of ALMS1 and extended the spectrum of ALMS1 mutations in an infant with AS.

• Alström syndrome
• Dilated cardiomyopathy
• Alström syndrome 1
• Missense mutation
• Frameshift mutation
• Case report

Alström syndrome (ALMS) is a rare inherited metabolic disease and ciliopathy. Large cohorts of ALMS are lacking around the world. Detailed genetic and phenotypic data were obtained from all affected individuals. Olfactory function was evaluated by the Chinese Smell Identification Test and facial pattern was analyzed with Face2gene. Fifty ALMS patients were included in this study, aged from 0.3 to 21.7 years old. Sixty-one ALMS1 variants in 50 patients from 47 different families were confirmed, including 59 truncating and two exon deletions. Twenty-four of those variants were novel. We also summarized all previously reported cases of Chinese ALMS patients (69 patients) and identified specific and common variants within the Chinese population. Besides, the Chinese Smell Identification Test scores in patients was lower than that in controls (11.97 Vs. 10.44, p < .05), indicating olfactory identification impairments in ALMS patients. The facial pattern in ALMS patients was also distinctive from that of the controls (p < .05). In conclusion, this is the largest cohort of Chinese ALMS patients. We have successfully identified both specific and common variants in our cohort. We found a new phenotype of olfactory impairments in ALMS patients through a case-control study.

• ALMS1
• alström syndrome
• next-generation sequencing
• rare disease
• variants

Usher syndrome (USH) is the most common genetic condition responsible for combined loss of hearing and vision. Balance disorders and bilateral vestibular areflexia are also observed in some cases. The syndrome was first described by Albrecht von Graefe in 1858, but later named by Charles Usher, who presented a large number of cases with hearing loss and retinopathy in 1914. USH has been grouped into three main clinical types: 1, 2, and 3, which are caused by mutations in different genes and are further divided into different subtypes. To date, nine causative genes have been identified and confirmed as responsible for the syndrome when mutated: MYO7A, USH1C, CDH23, PCDH15, and USH1G (SANS) for Usher type 1; USH2A, ADGRV1, and WHRN for Usher type 2; CLRN1 for Usher type 3. USH is inherited in an autosomal recessive pattern. Digenic, bi-allelic, and polygenic forms have also been reported, in addition to dominant or nonsyndromic forms of genetic mutations. This narrative review reports the causative forms, diagnosis, prognosis, epidemiology, rehabilitation, research, and new treatments of USH.

Patients with complex rare genetic syndromes (CRGS) have combined medical problems affecting multiple organ systems. Pediatric multidisciplinary (MD) care has improved life expectancy, however, transfer to internal medicine is hindered by the lack of adequate MD care for adults. We have launched an MD outpatient clinic providing syndrome-specific care for adults with CRGS, which, to our knowledge, is the first one worldwide in the field of internal medicine. Between 2015 and 2020, we have treated 720 adults with over 60 syndromes. Eighty-nine percent of the syndromes were associated with endocrine problems. We describe case series of missed diagnoses and patients who had undergone extensive diagnostic testing for symptoms that could actually be explained by their syndrome. Based on our experiences and review of the literature, we provide an algorithm for the clinical approach of health problems in CRGS adults. We conclude that missed diagnoses and needless invasive tests seem common in CRGS adults. Due to the increased life expectancy, an increasing number of patients with CRGS will transfer to adult endocrinology. Internist-endocrinologists (in training) should be aware of their special needs and medical pitfalls of CRGS will help prevent the burden of unnecessary diagnostics and under- and overtreatment.

• intellectual disability
• internal medicine
• medical overuse
• missed diagnosis
• multidisciplinary care
• syndrome

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

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.

• Alström syndrome
• ciliopathies
• founder effect
• metabolic disease
• novel mutations

• ALMS1
• Alström syndrome
• Saudi Arabia
• rare variant
• splice site mutation

• Alström syndrome
• Blindness
• Cardiomyopathy
• Deafness
• Guidelines
• Insulin resistance
• Non-alcoholic fatty liver disease
• Obesity
• Rare disease

• ALMS1
• Alström syndrome
• Iran
• Whole exome sequencing

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.

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.

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.

• ALMS1 gene
• Alström syndrome
• Case report
• Cone-rod dystrophy

• ALMS1 gene
• Alstrom syndrome
• Autosomal recessive
• Genetic heterogeneity
• Whole exome sequencing

• ALMS motif
• Actinin
• Bardet-Biedl syndrome
• C-Nap1
• C10orf90
• CART complex
• CEP250
• CEP295
• Centriole
• Centrosome
• Cilia
• Ciliopathy
• Diabetes
• Endosomal recycling
• Fibrosis
• GLUT4
• Insulin resistance
• KIAA1731
• Mitogenic cardiomyopathy
• Notch
• Obesity
• Pericentrin
• RFX
• Rootlet

• Adolescent
• Adrenal Insufficiency/epidemiology
• Adrenal Insufficiency/genetics
• Adult
• Alstrom Syndrome/blood
• Alstrom Syndrome/complications
• Body Mass Index
• Case-Control Studies
• Child
• Child, Preschool
• Diabetes Mellitus, Type 2/epidemiology
• Diabetes Mellitus, Type 2/genetics
• Female
• Humans
• Hyperandrogenism/epidemiology
• Hyperandrogenism/genetics
• Hypogonadism/epidemiology
• Hypogonadism/genetics
• Hypothyroidism/epidemiology
• Hypothyroidism/genetics
• Insulin Resistance
• Male
• Metabolic Syndrome/epidemiology
• Metabolic Syndrome/genetics
• Obesity/epidemiology
• Obesity/genetics
• Prevalence
• Young Adult

• ZIA HD000641 Intramural NIH HHS
• ZIA HD008898 Intramural NIH HHS

• clinics
• genetics
• syndromic obesity
• therapy

Alström syndrome (AS) is a rare autosomal recessive disorder that shares clinical features with other ciliopathy-related diseases. Genetic mutation analysis is often required in making differential diagnosis but usually costly in time and effort using conventional Sanger sequencing. Herein we describe a Taiwanese patient presenting cone-rod dystrophy and early-onset obesity that progressed to diabetes mellitus with marked insulin resistance during adolescence. Whole exome sequencing of the patient's genomic DNA identified a novel frameshift mutation in exons 15 (c.10290_10291delTA, p.Lys3431Serfs^*10) and a rare mutation in 16 (c.10823_10824delAG, p.Arg3609Alafs^*6) of ALMS1 gene. The compound heterozygous mutations were predicted to render truncated proteins. This report highlighted the clinical utility of exome sequencing and extended the knowledge of mutation spectrum in AS patients.

• ALMS1 gene
• Alström syndrome
• childhood obesity
• ciliopathy
• retinitis pigmentosa
• whole exome sequencing

• Alström Syndrome
• Congenital Retinal Dystrophy
• Leber Congenital Amaurosis

• Adolescent
• Adult
• Alstrom Syndrome/genetics
• Alstrom Syndrome/pathology
• Cell Cycle Proteins
• Child
• Consanguinity
• Female
• Heterozygote
• Homozygote
• Humans
• Male
• Mutation/genetics
• Pedigree
• Phenotype
• Prognosis
• Proteins/genetics
• Siblings
• Turkey
• Young Adult

• AMP-Activated Protein Kinases/genetics
• Adolescent
• Adult
• Age Factors
• Aged
• Amides
• Autoantigens/genetics
• Cell Cycle Proteins
• Chromosomes, Human, X/genetics
• Codon, Nonsense
• Energy Metabolism/genetics
• Fatty Acids
• Female
• Gene Frequency
• Genes, X-Linked/genetics
• Genetic Variation
• Genotype
• Humans
• Hypogonadism/genetics
• Immunoglobulins/genetics
• Laminin/genetics
• Membrane Proteins/genetics
• Menarche/genetics
• Middle Aged
• Mutation, Missense
• Penetrance
• Phenotype
• Proteins/genetics
• RNA Interference
• RNA-Binding Proteins/genetics
• Receptors, Neurokinin-3/genetics
• Signal Transduction/genetics
• White People/genetics
• Young Adult

• 16563 Cancer Research UK
• MC_UP_A100_1003 Medical Research Council
• P30 CA015704 NCI NIH HHS
• MC_UU_12015/1 Medical Research Council
• MC_UU_12015/2 Medical Research Council
• CZD/16/6/4 Chief Scientist Office
• R21 AG032598 NIA NIH HHS
• MC_UU_12015/5 Medical Research Council
• 001 World Health Organization
• MC_U106179471 Medical Research Council
• MR/K026992/1 Medical Research Council
• 11174 Cancer Research UK
• UL1 TR001108 NCATS NIH HHS
• 16565 Cancer Research UK
• R01 AG029451 NIA NIH HHS
• MC_PC_U127561128 Medical Research Council
• MC_U106179472 Medical Research Council
• UM1 CA182913 NCI NIH HHS

Alström syndrome (ALMS) is a rare genetic disorder that has been included in the ciliopathies group, in the last few years. Ciliopathies are a growing group of diseases associated with defects in ciliary structure and function. The development of more powerful genetic approaches has been replaced the strategies to follow for getting a successful molecular diagnosis for these patients, especially for those without the typical ALMS phenotype. In an effort to deepen the understanding of the pathogenesis of ALMS disease, much work has been done, in order to establish the biological implication of ALMS1 protein, which is still being elucidated. In addition to its role in ciliary function and structure maintenance, this protein has been implicated in intracellular trafficking, regulation of cilia signaling pathways, and cellular differentiation, among others. All these progresses will lead to identifying therapeutic targets, thus opening the way to future personalized therapies for human ciliopathies.

• ALMS1 gene
• ALMS1 protein
• Alström syndrome
• ciliopathies
• molecular diagnosis

• 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