Alstrom syndrome is an autosomal recessive disease. It affects multiple systems, including cardiovascular, renal, endocrine, and eyes. Our patient is a 25-year-old female who presented with elevated creatinine. Her past medical history was significant for hypothyroidism, polycystic ovarian syndrome, blindness, cataracts, hearing loss, and heart problems. She had genetic testing done that revealed that she was homozygous for the ALMS1 gene and was diagnosed with Alstrom syndrome. She was followed by nephrology in the clinic and had chronic kidney disease (CKD) stage V. The patient traveled to Italy and was lost to follow-up.

Mutations in the ALMS1 gene have been linked to isolated inherited retinal dystrophy or Alström syndrome. This report illustrates the unique pattern of ALMS1-associated diseases in a set of three simplex Saudi patients originating from unrelated consanguineous families. A detailed ophthalmological assessment was performed at the Department of Ophthalmology at King Saud University, Riyadh, Saudi Arabia. Next-generation sequencing vision panel revealed recessive ALMS1 mutations (reference sequence NM_015120). As a result, three distinct pathogenic ALMS1 mutations were identified; the first one is a nonsense mutation (c.8158C>T: p.R2720X) which has recently been identified in a Chinese patient, while the other two are known to have a founder effect in the Saudi population (the frameshift: C.848dupA: p.E283fs and the splicing: C.11870-2A>T: p.?). Clinically, a prominent nerve fiber layer was observed in the three studied patients with variable expectations of vessel attenuation. In addition, two of our patients observed unusual presentation of specific retinal pigment epithelium pigmentations in semi/halo-arrangement around the macula. Thus far, our report expands the phenotypic-genotypic spectrum of ALMS1-associated diseases and supports the principles of applying precision medicine in Saudi Arabia by utilizing the fact that common founder mutations were identified and unique phenotype was observed.

BACKGROUND: Alström syndrome (AS) represents an exceptionally rare genetic disorder characterized by a constellation of features including cardiomyopathy, progressive hearing and vision impairment, as well as obesity. This study seeks to elucidate the genetic underpinnings of this syndrome within the Saudi Arabian population.
METHODS: Employing an extended family cohort, we conducted an exhaustive molecular genetic assessment to delineate the presence of Alström syndrome. Additionally, we conducted an extensive review of existing literature from Saudi population to contextualize our findings within the broader understanding of the disorder in our country.
RESULTS: Within our studied extended family, we identified two individuals harboring the homozygous pathogenic mutation (c.2729C>G) in the ALMS1 gene [NM_015120.4:c.2729C>G (p.Ser910*)]. Notably, carrier status was observed in the parents, whereas some siblings exhibited typical alleles while others were carriers of the mutation. Intriguingly, a review of the literature unveiled six distinct reports documenting a total of 20 Alström syndrome patients within the Saudi Arabian population, each presenting with distinct novel mutations.
CONCLUSIONS: In cases featuring cardiomyopathy, obesity, and progressive hearing and vision loss, Alström syndrome merits inclusion within the differential diagnosis. To confirm the diagnosis, molecular genetic assessment of the ALMS1 gene is imperative, offering definitive clarity amidst the complex clinical presentation. This investigation reinforces the importance of genetic scrutiny for precise diagnosis and highlights the unique genetic landscape of Alström syndrome within the Saudi Arabian population.

Alstrom syndrome is a rare autosomal recessive disorder resulting from an ALMS1 gene mutation. Here, we present the clinical data of a case of an infant diagnosed with Alstrom syndrome through whole-exome sequencing. A 2-month-old male infant was admitted to Sichuan Provincial Maternity and Child Health Care Hospital on 30 May 2019 after \"coughing for half a day and dyspnea for 2 hours\". He was diagnosed with severe pneumonia, acute congestive heart failure, Grade III cardiac function, acute respiratory failure, and myocarditis. After treatment, he was discharged with a prescription for oral medication. After a 4-month follow-up, the patient\'s left ventricle exhibited spherical enlargement and a decrease in left ventricular function. The infant\'s whole-exome sequencing results revealed compound heterozygous mutations in the ALMS1 gene: c.2179dup (p. Y727Lfs*12), a frameshift mutation, that was heterozygous and originated from the mother, while c.11140C>T (p. Q3714*) was a heterozygous nonsense mutation that originated from the father. Both mutations are classified as \"category 1-pathogenic mutations\" according to the American College of Medical Genetics and Genomics (ACMG) assessment. A novel ALMS1 mutation was identified in this case report, highlighting the importance of genetic testing for the early diagnosis of Alstrom syndrome.

Purpose: Alström syndrome (AS) is a rare autosomal recessive disorder caused by variants of ALMS1. The objectives of this study were to describe the clinical and genetic characteristics of 19 Chinese patients with biallelic variants in ALMS1. Methods: We recruited 19 probands with biallelic disease-causing ALMS1 variants. All patients underwent ophthalmic and systematic evaluations and comprehensive molecular genetic analysis. Reverse transcriptase-polymerase chain reaction (RT-PCR) assays were performed to observe the effect of a novel missense variant on ALMS1 pre-mRNA splicing. Results: We identified 33 causative variants in ALMS1, including 15 frameshift small indels, 14 non-sense variants, two gross deletions, one splicing variant, and one missense variant. RT-PCR showed that the missense variant c.9542G>A (p.R3181Q) altered pre-mRNA splicing to generate a truncated protein p. (Ser3082Asnfs*6). Retinal dystrophy (RD) was noted in all the patients, followed by metabolism disturbance (obesity or acanthosis nigricans) in 66.7% and hearing impairment in 61.1% of the patients. Patient systemic symptom numbers and their age at evaluation showed a significant positive correlation, and BCVA and age at the last examination showed a moderate correlation. All patients exhibited early-onset RD and severe visual impairment. The exception was one patient carrying homozygous p. R3181Q, who showed a mild visual defect and atypical retinal phenotype. Conclusion: Our findings expand the pathogenic variant spectrum of ALMS1 and provide the first verification of a novel missense variant caused AS by aberrant pre-mRNA splicing. Patients with AS might demonstrate varied clinical spectra; therefore, genetic analysis is vital for the early and accurate diagnosis of patients with atypical AS.

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.

Alström syndrome (AS) is a rare autosomal recessive monogenic disorder caused by mutations of the Alström syndrome 1 (ALMS1) gene, located on chromosome 2p13. It is a progressive multisystemic disease characterized mostly by obesity, sensorineural hearing loss, visual impairments, cardiomyopathy, insulin resistance and/or type 2 diabetes mellitus (T2DM), metabolic dysfunctions, non-alcoholic fatty liver disease, and chronic progressive kidney disease. Generally, the first clinical symptoms of the disease appear in the first years of life with a major variation of onset age. In this study, we aimed to examine the molecular diagnosis of a 6-year-old patient with suspected AS clinical symptoms. After applying clinical exome sequencing (CES) in the patient we found a homozygous deletion in exon 8 at the ALMS1 gene (c.2311_2312del). We identified a homozygous frameshift mutation. The reported variant was pathogenic according to the criteria of the American College of Medical Genetics and Genomics (ACMG). Thus, the patient was diagnosed with AS as a result of the combined clinical phenotype and genetic tests results. We hope the variant we found can expand the spectrum of ALMS1 variants in AS.

UNASSIGNED: Alstrom syndrome (ALMS) is a rare genetic disorder. ALMS is characterized by progressive bilateral sensorineural hearing impairment, cone-rod dystrophy, infantile-onset cardiomyopathy, hypertriglyceridemia, accelerated non-alcoholic fatty liver disease, renal dysfunction and insulin-resistant diabetes mellitus (DM). DM typically develop in childhood or adolescence. Dilated cardiomyopathy may arise in infancy. Clinical symptoms appear with great variability and severity. Several cases have been reported worldwide; however, diagnosis remains challenging.
UNASSIGNED: We report an 8-year-and-11-month-old female diagnosed with ALMS who had a long history of obesity and amblyopia from infancy. We found high levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in this patient. She showed no hearing disfunction. Recently, she presented with sudden-onset insulin-resistant DM. Genetic analysis revealed the heterozygous mutations c.8366delT, p.L2789* and c.6829C>T, p.R2277*. c.8366delT, which results in premature protein termination, has not been reported previously in ALMS1. Although the patient\'s two sisters died of acute heart failure following infection at 4 and 14 months respectively, she showed no signs of cardiomyopathy until now.
UNASSIGNED: This case provides an unusual cause of genetic syndrome associated with diabetes. A detailed medical history, physical examination and appropriate gene analysis are critical for diagnosis. Our case identifies a novel ALMS1 mutation and reaffirms the great clinical variation of this disease even within families.

Alström syndrome (ALMS) is an ultra-rare metabolic disorder caused by biallelic loss-of-function in the Alms1 gene which encodes a ubiquitously expressed centrosomal protein of the primary cilium. Although ALMS is characterised by several metabolic and hormonal dysfunctions that can lead to an increased risk of developing osteoporosis and bone fracture, an increased BMD have been observed. The aim of this study was to characterise the anthropometric, clinical, genetic and densitometric features of bone health in a large adult UK cohort of subjects with ALMS.
Twenty-three patients with ALMS and 23 age-matched male control subjects were recruited. Lumbar spine (LS) and total hip (TH) bone mineral density (BMD) were evaluated by DXA in all subjects. A CT scan to assess the spinal bone architecture was performed in ALMS patients with raised lumbar density. Blood analysis for biochemical parameters and thyroid and sex hormones was performed in all ALMS patients.
LS Z-score levels were higher than +2 SD in 35% of all ALMS study participants, of whom 75% were men and 25% were women. TH Z-scores were higher than +1 SD 13% of patients and all of them have higher than expected lumbar Z-score. An extremely high BMD was found in two of the oldest patients (LS Z-score +10.8 and +15.3 SD).
ALMS patients tend to have high levels of BMD that increase with age, in particular of the trabecular bones. Although obesity and lifelong IR can be responsible for the increase in BMD, at least in part, of a possible signalling role of Alms1 protein as a bone-forming factor is plausible.

Alström syndrome (ALMS) is a rare autosomal recessive multi-organ syndrome considered to date as a ciliopathy and caused by variations in ALMS1. Phenotypic variability is well-documented, particularly for the systemic disease manifestations; however, early-onset progressive retinal degeneration affecting both cones and rods (cone-rod type) is universal, leading to blindness by the teenage years. Other features include cardiomyopathy, kidney dysfunction, sensorineural deafness, and childhood obesity associated with hyperinsulinemia and type 2 diabetes mellitus. Here, we present an unusual and delayed retinal dystrophy phenotype associated with ALMS in a 14-year-old female, with affected cone function and surprising complete preservation of rod function on serial electroretinograms (ERGs). High-throughput sequencing of the affected proband revealed compound heterozygosity with two novel nonsense variations in the ALMS1 gene, including one variant of de novo inheritance, an unusual finding in autosomal recessive diseases. To confirm the diagnosis in the context of an unusually mild phenotype and identification of novel variations, we demonstrated the biallelic status of the compound heterozygous variations (c.[286C > T];[1211C > G], p.[(Gln96*)];[(Ser404*)]). This unique case extends our knowledge of the phenotypic variability and the pathogenic variation spectrum in ALMS patients.