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Background: Alström syndrome (AS) is a rare autosomal recessive disorder that leads to multiple organ fibrosis and failure. Precise diagnosis from the clinical symptoms is challenging due to its highly variabilities and its frequent confusion with other ciliopathies and genetic diseases. Currently, mutations in the ALMS1 gene have been reported as a major cause of AS, thus, it is crucial to focus on the detection and discovery of ALMS1 mutations., Case Presentation: We present a case of a 13-year-old Chinese boy weighing 70 kg and standing 168 cm tall. He has two younger brothers. Their parents hail from different ancestral homes in eastern and northern China. The patient's primary clinical findings included visual impairment at the age of four and progressive hearing loss starting at the age of ten. Subsequently, at the age of twelve, the patient developed hyperlipidaemia and hyperinsulinemia. Ultrasonographic findings indicated the presence of gallstones and mild fatty liver. His Body Mass Index (BMI) significantly increased to 25 kg/m 2 (ref: 18.5-23.9 kg/m 2 ). Additionally, echocardiography revealed mild mitral and tricuspid regurgitation. Ultimately, Whole Exome Sequencing (WES) identified a new missense mutation in the ALMS1 gene (NG_011690.1 (NM_015120): c.9536G > A (p.R3179Q)). This missense mutation generated an aberrant splicer and disrupted the stability and hydrophobicity of proteins, which preliminarily determined as " likely pathogenic". Therefore, considering all the above symptoms and molecular analysis, we deduced that the patient was diagnosed with AS according to the guidelines. We recommended that he continue wearing glasses and undergo an annual physical examination., Conclusion: In this case report, we report a novel homozygous ALMS1 mutation associated with AS in the Chinese population, which expands the mutation spectrum of ALMS1. Genetic testing indeed should be incorporated into the diagnosis of syndromic deafness, as it can help avoid misdiagnoses of AS. While there is no specific treatment for AS, early diagnosis and intervention can alleviate the progression of some symptoms and improve patients' quality of life., (© 2024. The Author(s).)

Alstrom syndrome is a genetic disorder with autosomal recessive inheritance and multiple organ failure. Hearing loss, childhood obesity, diabetes mellitus, and nonalcoholic fatty liver disease are common disorders in this disease. Degree of nonalcoholic fatty liver disease ranges from benign steatosis to cirrhosis. Since it first description in 1959, 89 cases have been reported, and none in the literature underwent liver transplant. In this report, we describe a 19-year-old male patient with a diagnosis of hearingloss, obesity, anddiabetes mellitus startedsince childhood. He was evaluated for bloody vomiting, and grade 3 esophageal varices were detected, with liver cirrhosis findings made with abdominal tomography. The patient had a Model for End-Stage Liver Disease score of 23, and deceased donor liver transplant was planned. After an appropriate donor was identified, the patient underwent liver transplant with an operation lasting approximately 6 hours. Cold ischemia time was about 5 hours, and anastomosis time was about 30 minutes. The patient was extubated on posttransplant day 1. On posttransplant day 10, his vital parameters remained normal, but he had blurred consciousness and loss of orientation. Neurological examination and imaging revealed minimal subdural effusion and mild cerebral cortical dysfunction in electroencephalogram. The patient's symptoms improved after medical treatment, and the patient was discharged on day 13 posttransplant. At the month 24 outpatient follow-up, the patient had no problems. Alstrom syndrome is an autosomal recessive genetic disorder with multiple organ failure. Although various degrees of liver disease have been described in the literature that may progress to cirrhosis of the liver, our present case is considered original because of the absence of liver transplant descriptions in the literature.

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., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Purpose: To report two clinical cases of Alström syndrome (AS) with novel pathogenic variant of the ALMS1 gene not previously reported., Case Description: Patient 1 was a 6-year-old female presenting with poor vision. Ophthalmic examination only showed a visual field (VF) with diffusely decreased sensitivity in both eyes. At age of 15, vision and ophthalmic examination remain stable. Patient 2 was a 2-year-old male with poor vision, photophobia, and nystagmus. ERG showed a severe decrease in cone and rod responses. At age of 6, his vision is lower than 0.1 (decimal scale) and VF is severely constricted. Both of them presented with dilated cardiomyopathy in their first's months of life and patient 2 developed sensorineural deafness along with follow-up. Research genetic testing revealed two loss-of-function heterozygous genetic variants in the ALMS1 gene in both patients, so the diagnosis of AS was made., Conclusions: AS is a rare disease caused by pathogenic variants of ALMS1 gene that causes ocular manifestations in almost 100% of patients. There are many genetic variants of AMLS1 described, but novel pathogenic variants can still be found. Ophthalmologists play an important role in the diagnosis, and AS should be included in the differential diagnosis when retinal dystrophy is suspected.

Alstrom syndrome is a rare autosomal recessive disorder disease caused by mutations in the ALMS1 gene, and its typical clinical manifestations include cone-rod retinal dystrophy, sensorineural deafness, obesity, insulin resistance, diabetes mellitus, hypertriglyceridemia, non-alcoholic fatty liver, dilated cardiomyopathy, and progressive hepatic and renal dysfunction. In this report, we followed up a young male patient presenting with diabetes mellitus, who was later diagnosed with blindness, deafness, hyperlipidemia, obesity, fatty liver, and insulin resistance. Genetic testing revealed a compound heterozygous mutation in ALMS1 from the patient, with an exon 8 c.5535delG (p.S1847Lfs*24) mutation inherited from the maternal side and an exon 16 c.10819C>T (p.R3607X) mutation from the paternal side. Neither of these two mutations had been previously recorded in the known ALMS1 genetic mutation database. Hyperinsulinemic-euglycemic clamp test indicated that the insulin sensitivity index was significantly improved in the patient after taking oral dapagliflozin. By summarizing and analyzing this case, we should consider Alstrom syndrome in clinical adolescent-onset diabetes patients with blindness, deafness, severe insulin resistance, and lipid metabolism disorder. These two new mutation sites identified in this case enrich the genetic mutation database of the ALMS1 gene, and the follow-up data of this study provide new evidence for deciding appropriate glucose-lowering regimens in patients with Alstrom syndrome.

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., Competing Interests: Disclosures All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This study aimed to investigate the mutation spectrums and ocular features of Alström syndrome (AS) patients. Six AS patients from five unrelated families were included. Ocular and systemic examinations were performed in all subjects. Whole-exome sequencing (WES) was performed in the probands, and Sanger sequencing was performed for mutation validation and segregation analysis. Among the six patients, the first symptoms included nystagmus, poor fixation, and photophobia. Five patients had high hyperopia, four of whom (80%) were initially diagnosed with amblyopia before referral with prescribed corrective lenses and amblyopia treatment, but no improvement was obtained. Optical coherence tomography (OCT) revealed progressive damage to the photoreceptor layer, including blurred ellipsoid zone (EZ) and lack of interdigitation zone (IZ) within the macula, and thorough loss of photoreceptor layer in the peripheral retina. Electroretinograms (ERG) demonstrated severely diminished cone and rod responses. WES identified biallelic variants of ALMS1 in all the six patients, including two novels, c.3892C > T (p.Gln1298*) and c.2888_2897del (p.Ser963Thrfs*15) and five knowns, c.10819C > T (p.Arg3607Trp), c.2090C > A (p.Ser697*), c.4891C > T (p.Gln1631*), c.10825C > T (p.Arg3069*) and c.6430C > T (Arg2146*). In conclusion, this study expanded the ocular features and genotypic spectrum of AS. High hyperopia is a significant and common feature of AS. OCT and ERG are essential accessory techniques for the diagnosis of AS. If a patient had high hyperopia with a noneffective response to amblyopic treatment, the diagnosis of AS should be suspected, and detailed ocular examination, systemic evaluation, and genetic testing recommended., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Alström Syndrome (AS) is an autosomal recessive hereditary disease with the characteristics of multiorgan dysfunction. Due to the heterogeneity of clinical manifestations of AS, genetic testing is crucial for the diagnosis of AS. Herein, we used whole-exome sequencing (WES) to determine the genetic causes and characterize the clinical features of three affected patients in two Chinese families with Alström Syndrome., Materials and Methods: Three affected patients (initially diagnosed as achromatopsia). and five asymptomatic members were recruited for both genetic and clinical tests. The complete ophthalmic examinations and systemic examinations were performed on all participants. Whole exome sequencing (WES) was performed for mutation detection. The silico analysis was also applied to predict the pathogenesis of identified pathogenic variants., Results: In family 1, the proband showed low vision, hyperopia, photophobia, nystagmus, and total color blindness. DNA analysis revealed that she carried a compound heterozygote with two novel pathogenic variants in the ALMS1 gene NM_015120.4:c.10379del (NP_055935.4:p.(Asp2252Tyr)) and NM_015120.4:c.11641_11642del (NP_055935.4:p.(Val3881ThrfsTer11)). Further systemic examinations showed short stature, acanthosis nigricans, and sensorineural hearing loss. In family 2, two affected siblings presented the low vision, hyperopia, photophobia, nystagmus, and total color blindness. DNA analysis revealed that they carried a same compound heterozygote with two novel pathogenic variants in the ALMS1 gene NM_015120.4:c.10379del (NP_055935.4:p.(Asn3460IlefsTer49)), NM_015120.4:c.10819C > T (NP_055935.4:p.(Arg3607Trp)). Further systemic examinations showed obesity and mild abnormalities of lipid metabolism. According to the genetic testing results and further systemic analysis, the three affected patients were finally diagnosed as Alström Syndrome (AS)., Conclusions: We found two new compound heterozygous pathogenic variants of the ALMS1 gene and determined the diagnosis as Alström Syndrome in three patients of two Chinese families. Our study extends the genotypic and phenotypic spectrums for ALMS1 -AS and emphasizes the importance of gene testing in assisting the clinical diagnosis for cases with phenotypic diversities, which would help the AS patients with early diagnosis and treatment to reduce future systemic damage., (© 2022. The Author(s).)

Objective: 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., Method: 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., Results: 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., Conclusion: 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., (© 2022. The Author(s).)

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., (© 2022 Ardiana Beqiri-Jashari et al., published by Sciendo.)

Objective: To characterize the patterns of hearing loss and methods of hearing rehabilitation in the UK national cohort of adults with Alström syndrome., Study Design: Retrospective review of electronic patient records., Setting: UK National multi-disciplinary team (MDT) Alström service held at the Queen Elizabeth Hospital, Birmingham., Patients: Forty one adult patients with a diagnosis of Alström syndrome, confirmed via ALMS1 gene sequencing, are under ongoing review within the UK National MDT Alström service., Main Outcome Measures: Magnitude and type of hearing loss were analyzed using patients' audiometric data. Deterioration of hearing was calculated using serial pure tone audiograms. Methods of hearing rehabilitation used by patients and potential candidacy for cochlear implantation were analyzed., Results: Of 34 patients with available audiograms, all had sensorineural hearing loss (SNHL). Dual sensory (visual and hearing) loss was present in 32/34 (94%) patients. Hearing deteriorated with advancing age, at 1.23 dB/yr. Severe- profound SNHL was present in 9/34 (26%) cases. Air conduction hearing aids were used in 27/34 (79%) cases, and cochlear implants in 2/34 (5%)., Conclusions: Alström syndrome is an ultra-rare genetic disorder with progressive, debilitating multi-system manifestations, including SNHL. The UK National MDT Alström service represents one of the largest reported adult cohorts in the world. SNHL in this group was ubiquitous, showing a rapid decline in hearing with age. Annual audiometric assessment to enable early diagnosis of hearing loss and optimum rehabilitation are paramount to minimize the impact of hearing loss in this condition., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2022, Otology & Neurotology, Inc.)

Alström syndrome (AS) is an extremely rare disease accompanied by blindness, hearing loss, obesity, type 2 diabetes, dilated cardiomyopathy, and progressive hepatic and renal dysfunction. The life span of AS patients rarely exceeds 50 years, and thus there are very few reports describing the implementation of renal replacement therapy for these patients. We here report a case of AS patient who exhibited dilated cardiomyopathy, end-stage renal disease, and hepatic cirrhosis. He underwent hemodialysis therapy more than 3 years. Although he eventually died of amiodarone-induced multiple organ damage in the lungs and liver, the present case suggests that hemodialysis therapy can be a choice of renal replacement therapy for AS patients with end-stage renal disease., (© 2021. Japanese Society of Nephrology.)

Objective Alström syndrome is an autosomal recessive genetic disease caused by a mutation in the ALMS1 gene. Alström syndrome is clinically characterized by multisystem involvement, including sensorineural deafness, cone-rod dystrophy, nystagmus, obesity, insulin resistance, type 2 diabetes and hypogonadism. The diagnosis is thus challenging for patients without this characteristic set of clinical symptoms. We explored the effectiveness of whole-exome sequencing in the diagnosis of Alström syndrome. Methods A girl with symptoms of Alström syndrome was tested and diagnosed with the disease by whole-exome sequencing. Results Whole-exome sequencing revealed two novel variants, c.6160_6161insAT: p.Lys2054Asnfs*21 (exon 8) and c.10823_10824 delAG:p.Glu 3608Alafs*9 (exon16) in the ALMS1 gene, leading to premature termination codons and the domain of ALMS1 protein. Blood sample testing of her asymptomatic parents revealed them to be heterozygous carriers of the same mutations. Assembly showed that the mutations on both alleles were located in conserved sequences. A review of the ALMS1 gene nonsense mutation status was performed. Conclusion We herein report two novel variants of the ALMS1 gene discovered in a Chinese Alström syndrome patient that expand the mutational spectrum of ALMS1 and provided new insight into the molecular mechanism underlying Alström syndrome. Our findings add to the current knowledge concerning the diagnosis and treatment of Alström syndrome.

Alström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13. ALMS is a multisystem, progressive disease characterised by visual disturbance, hearing impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, accelerated non-alcoholic fatty liver disease (NAFLD), renal dysfunction, respiratory disease, endocrine and urologic disorders. Clinical symptoms first appear in infancy with great variability in age of onset and severity. ALMS has an estimated incidence of 1 case per 1,000,000 live births and ethnically or geographically isolated populations have a higher-than-average frequency. The rarity and complexity of the syndrome and the lack of expertise can lead to delayed diagnosis, misdiagnosis and inadequate care. Multidisciplinary and multiprofessional teams of experts are essential for the management of patients with ALMS, as early diagnosis and intervention can slow the progression of multi-organ dysfunctions and improve patient quality of life.These guidelines are intended to define standard of care for patients suspected or diagnosed with ALMS of any age. All information contained in this document has originated from a systematic review of the literature and the experiences of the authors in their care of patients with ALMS. The Appraisal of Guidelines for Research & Evaluation (AGREE II) system was adopted for the development of the guidelines and for defining the related levels of evidence and strengths of recommendations.These guidelines are addressed to: a) specialist centres, other hospital-based medical teams and staffs involved with the care of ALMS patients, b) family physicians and other primary caregivers and c) patients and their families.

Background: Alström syndrome is a rare recessively inherited disorder caused by variants in the ALMS1 gene. It is characterized by multiple organ dysfunction, including cone-rod retinal dystrophy, dilated cardiomyopathy, hearing loss, obesity, insulin resistance, hyperinsulinemia, type 2 diabetes mellitus and systemic fibrosis. Heterogeneity and age-dependent development of clinical manifestations make it difficult to obtain a clear diagnosis, especially in pediatric patients., Case Presentation: Here we report the case of a girl with Alström syndrome. Genetic examination was proposed at age 22 months when suspected macular degeneration was the only major finding. Next generation sequencing of a panel of genes linked to eye-related pathologies revealed two compound heterozygous variants in the ALMS1 gene. Frameshift variants c.1196_1202del, p.(Thr399Lysfs*11), rs761292021 and c.11310_11313del, (p.Glu3771Trpfs*18), rs747272625 were detected in exons 5 and 16, respectively. Both variants cause frameshifts and generation of a premature stop-codon that probably leads to mRNA nonsense-mediated decay. Validation and segregation of ALMS1 variants were confirmed by Sanger sequencing., Conclusions: Genetic testing makes it possible, even in childhood, to increase the number of correct diagnoses of patients who have ambiguous phenotypes caused by rare genetic variants. The development of high-throughput sequencing technologies offers an exceptionally valuable screening tool for clear genetic diagnoses and ensures early multidisciplinary management and treatment of the emerging symptoms.

Background: Syndromic dilated cardiomyopathy (DCM) includes a group of complex disorders with a very heterogeneous genetic etiology, leading to delay in definitive diagnosis. Conversely, an early genetic diagnosis is very important in determining the disease course, the prognosis, and may guide personalized treatments and family counseling., Methods: We analyzed two brothers with a multisystemic disorder, including dilated cardiomyopathy, diabetes, bilateral neurosensorial hearing loss, and optic atrophy, using different genetic approaches, namely mitochondrial DNA sequencing, comparative genomic hybridization-array (a-CGH) and whole exome sequencing (WES)., Results: Sequencing of the wide mitochondrial genome revealed, in both brothers, the known homoplasmic variant rs2853826 in the subunit 3 of the NADH dehydrogenase gene (MT-ND3), whose pathogenicity was conflicting. Comparative genomic hybridization-array analysis revealed in both patients and their father two heterozygous deletions in Phosphodiesterase 4d-Interacting Protein (PDE4DIP) and Protocadherin-related 15 (PCDH15) genes, respectively. The use of WES detected a pathogenetic mutation in ALMS1, enabling the definitive diagnosis of Alström syndrome., Conclusion: We demonstrated how the diagnosis of a complex heterogeneous disease may be difficult, due to several overlapping manifestations and the possible interaction of more genetic variants that could lead to a more severe and complex phenotype. This paper strongly evidences how genomics is revolutionizing the diagnosis of rare complex disease, representing one of the most essential steps to enable a definitive diagnosis and to establish the etiology for diseases, such as syndromic DCM., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: We describe the ophthalmologic, clinical, and genetic findings in a patient of Yemenite-Jewish origin diagnosed with Alstrom syndrome due to a novel splice-site mutation 10 years after a clinical misdiagnosis of Leber congenital amaurosis., Methods: Ophthalmological evaluations included visual acuity, cycloplegic refraction, slit-lamp, and optical coherent tomography. Genetic analyses included whole exome sequencing followed by bioinformatics analysis and segregation analysis. An in vitro splicing assay was used to evaluate the effect of the identified mutation on splicing. Taqman assay was used to determine the need for population screening for the identified mutation., Results: Ophthalmologic findings at age 6 were impaired vision, nystagmus, and hyperopia. At age 16 years, the patient presented with obesity, hypothyroidism, and elevated transaminase levels in addition to reduced vision, wandering nystagmus, disc pallor, and degenerative retinal changes. Targeted genetic analysis of ALMS1 revealed a homozygous transversion, c.11544 + 3A>T, suggesting a novel splicing mutation, with elimination of the donor splice site and insertion of 73 nucleotides at the end of exon 16. These changes were validated by Sanger sequencing and co-segregation on family members., Conclusions: Ophthalmologists should be alert to the differential diagnosis of inherited retinal degeneration in young patients who present with impaired vision, especially if systemic symptoms are mild and there is no known family history. In the present case, targeted genetic analysis of a child with a syndromic cone-rod dystrophy yielded a novel splicing mutation in ALMS1 causing Alstrom syndrome.

Elevated blood pressure (BP) and renal dysfunction are complex traits representing major global health problems. Single nucleotide polymorphisms identified by genome-wide association studies have identified the Alström syndrome 1 (ALMS1) gene locus to render susceptibility for renal dysfunction, hypertension, and chronic kidney disease (CKD). Mutations in the ALMS1 gene in humans causes Alström syndrome, characterized by progressive metabolic alterations including hypertension and CKD. Despite compelling genetic evidence, the underlying biological mechanism by which mutations in the ALMS1 gene lead to the above-mentioned pathophysiology is not understood. We modeled this effect in a KO rat model and showed that ALMS1 genetic deletion leads to hypertension. We demonstrate that the link between ALMS1 and hypertension involves the activation of the renal Na+/K+/2Cl- cotransporter NKCC2, mediated by regulation of its endocytosis. Our findings establish a link between the genetic susceptibility to hypertension, CKD, and the expression of ALMS1 through its role in a salt-reabsorbing tubular segment of the kidney. These data point to ALMS1 as a potentially novel gene involved in BP and renal function regulation.

Background: Alström syndrome is a rare autosomal recessive inherited disorder caused by mutations in the ALMS1 gene., Methods: We describe the clinical and five novel mutational screening findings in six patients with Alström syndrome from five families in a single center with distinct clinical presentations of this condition., Results: Five novel mutations in ALMS1 in exon 8 and intron 17 were identified, one of them was a compound heterozygous: c.2259_2260insT, p.Glu754*; c.2035C>T p.Arg679*; c.2259_2260insT, p.Glu754*; c.5969C>G, p.Ser1990*; c.6541C>T, p. Gln2181*/c.11666-2A>G, splicing. One patient had gallstones, this association, to our knowledge, has not been reported in Alström syndrome previously., Conclusions: Early diagnosis of Alström syndrome is often difficult in children and adolescents, because many of the clinical features develop over time. Early diagnosis can initiate an effective managemen of this condition, and it will help to reduce future damage.

Purpose: We aim to describe ophthalmic characteristics and systemic findings in a cohort of seven patients with cone-rod retinal dystrophy (CORD) caused by pathogenic variants in the ALMS1 gene., Methods: Seven patients with Alström syndrome (ALMS) were included in the study. A comprehensive ophthalmological examination was performed, including best-corrected visual acuity (BCVA), a semiautomated kinetic visual field exam, colour vision testing, full-field electroretinography testing according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards, spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging, and slit lamp and dilated fundus examination. DNA samples were analysed using Sanger sequencing or exome sequencing., Results: In our cohort, the ocular phenotype presented with a wide variability in retinal function and disease severity. However, age of symptom onset (i.e. nystagmus and photophobia) was at 6-9 months in all patients. These symptoms mostly mislead to the diagnosis of congenital achromatopsia (ACHM), Leber congenital amaurosis (LCA), isolated CORD or Bardet-Biedl syndrome. The systemic manifestations in our cohort were highly variable., Conclusion: In summary, we can report that most of our ALMS patients primarily presented with nystagmus and severe photophobia since early childhood interestingly without night blindness in the absence of systemic symptoms. Only genetic testing analysing both nonsyndromic retinal disease (RD) genes and syndromic ciliopathy genes by comprehensive panel sequencing can result in the correct diagnosis, genetically and clinically, with important implication for the physical health of the individual., (© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Obesity phenotype can be manifested as an isolated trait or accompanied by multisystem disorders as part of a syndromic picture. In both situations, same molecular pathways may be involved to different degrees. This evidence is stronger in syndromic obesity, in which phenotypes of different syndromes may overlap. In these cases, genetic testing can unequivocally provide a final diagnosis. Here we describe a patient who met the diagnostic criteria for Alström syndrome only during adolescence. Genetic testing was requested at 25 years of age for a final confirmation of the diagnosis. The genetic diagnosis of Alström syndrome was obtained through a Next Generation Sequencing genetic test approach using a custom-designed gene panel of 47 genes associated with syndromic and non-syndromic obesity. Genetic analysis revealed a novel homozygous frameshift variant p.(Arg1550Lysfs*10) on exon 8 of the ALMS1 gene. This case shows the need for a revision of the diagnostic criteria guidelines, as a consequence of the recent advent of massive parallel sequencing technology. Indications for genetic testing reported in these currently accepted diagnostic criteria for Alström syndrome, were drafted when sequencing was expensive and time consuming. Nowadays, Next Generation Sequencing testing could be considered as first line diagnostic tool not only for Alström syndrome but, more generally, for all those atypical or not clearly distinguishable cases of syndromic obesity, thus avoiding delayed diagnosis and treatments. Early diagnosis permits a better follow-up and pre-symptomatic interventions., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Alström syndrome (AS) is a rare autosomal recessive ciliopathy caused by mutations in the ALMS1 gene. Hallmark characteristics include childhood onset of severe retinal degeneration, sensorineural hearing loss, obesity, insulin-resistant diabetes, and cardiomyopathy. Here we comprehensively characterize the auditory and otologic manifestations in a prospective case series of 38 individuals, aged 1.7-37.9 years, with genetically confirmed AS. Hearing loss was preceded by retinal dystrophy in all cases, and had an average age of detection of 7.45 years (range 1.5-15). Audiometric assessments showed mean pure tone averages (0.5, 1, 2, 4 kHz) of 48.6 and 47.5 dB HL in the right and left ears, respectively. Hearing was within normal limits for only 8/74 ears (11%). For the 66 ears with hearing loss, the degree was mild (12%), moderate (54%), or severe (8%). Type of hearing loss was predominantly sensorineural (77%), while three ears had mixed loss, no ears had conductive loss, and type of hearing loss was indeterminate for the remaining 12 ears. Serial audiograms available for 33 patients showed hearing loss progression of approximately 10-15 dB/decade. Our data show that hearing loss associated with AS begins in childhood and is a predominantly symmetric, sensory hearing loss that may progress to a severe degree. Absent otoacoustic emissions, intact speech discrimination, and disproportionately normal auditory brainstem responses suggest an outer hair cell site of lesion. These findings indicate that individuals with AS would benefit from sound amplification and if necessary, cochlear implantation., (© 2017 Wiley Periodicals, Inc.)

Objectives: Alström syndrome (AS) is a rare, multi-system condition characterized by retinal degeneration, sensorineural hearing loss, obesity, insulin-resistant diabetes, hypertriglyceridemia, cardiomyopathy, hepatorenal disease, and recurrent respiratory infections. It belongs to a group of genetic disorders known as primary ciliopathies, which includes autosomal dominant and recessive polycystic kidney diseases, as well as Joubert and Bardet-Biedl syndromes. Prior studies have suggested phenotypic overlap between primary ciliopathies affecting the non-motile, sensory cilia, and primary ciliary dyskinesia (PCD), a motile ciliopathy characterized by respiratory tract disease., Methods: We describe the burden of oto-sino-pulmonary disease in 38 individuals with AS and examines the degree of clinical overlap between PCD and AS. Evaluation at the NIH Clinical Center included clinical examination, chest imaging, and clinical history surveys, as well as measurement of nasal nitric oxide (nNO) in nine patients., Results: Recurrent otitis media was ubiquitous in the AS cohort (92%) with 50% requiring pressure equalization tube placement. A history of bronchitis/pneumonia and sinusitis was reported in 61% and 50% of individuals, respectively. PCD-characterizing symptoms (laterality defects, unexplained neonatal respiratory distress, year-round nasal congestion, and wet cough) were far less prevalent in the AS cohort compared to PCD, and the average nNO production in the AS cohort was 232 ± 57.1 nl/min compared to a cut-off of <77 nl/min for PCD., Conclusions: These data suggest that the oto-sino-respiratory complications in AS are prominent enough to warrant increased clinical attention, but significantly impaired respiratory cilia function as seen in PCD is unlikely in AS. (www.clinicaltrials.gov, trial NCT00068224) Pediatr Pulmonol. 2017;52:487-493. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

In the present study we report on genetic analysis in a patient with developmental delay, truncal obesity and vision problem, to find the causative mutation. Whole exome sequencing was performed on genomic DNA extracted from whole blood of the patient which revealed a homozygous nonsense variant (c.2816T>A) in exon 8 of ALMS1 gene that results in a stop codon and premature truncation at codon 939 (p.L939Ter) of the protein. The mutation was confirmed by Sanger sequencing. Exome sequencing was helpful in establishing diagnosis of Alstrom syndrome in this patient. This case highlights the utility of exome sequencing in clinical practice., (Copyright © 2016 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Background: Alström syndrome is a rare genetic ciliopathy caused by a mutation in the ALMS1 gene. The syndrome is characterized by cone-rod dystrophy, dilated myocardiopathy, childhood obesity and sensorineural hearing loss. To date, cystoid macular edema has not been reported., Methods: A female affected by Alström syndrome developed bilateral cystoid macular edema evidenced by optical coherence tomography. A topical carbonic anhydrase inhibitor was prescribed., Results: Complete resolution of the cystoid macular edema was achieved, though visual acuity did not improve., Conclusions: Topical carbonic anhydrase inhibitors may have a role in the treatment of macular edema in syndromic retinal dystrophies such as Alström syndrome.

Monogenic diabetes is a rare genetic type of diabetes caused by pancreatic β-cells dysfunction. All subtypes of monogenic diabetes are recognized in the pediatric population. They include maturity onset diabetes of the young, permanent neonatal diabetes mellitus and rare syndromic forms of diabetes. An early and proper diagnosis allows to implement an optimal treatment, leads to improved metabolic control and amelioration of related disabilities as well as increases the quality of life of the patients.

Alström syndrome is a clinically complex disorder characterized by progressive degeneration of sensory functions, resulting in visual and audiological impairment as well as metabolic disturbances. It is caused by recessively inherited mutations in the ALMS1 gene, which codes for a centrosomal/basal body protein. The purpose of this study was to investigate the genetic and clinical features of two Tunisian affected siblings with Alström syndrome. Detailed clinical examinations were performed including complete ophthalmic examination, serial audiograms and several biochemical and hormonal blood tests. For the molecular study, first genomic DNA was isolated using a standard protocol. Then, linkage analysis with microsatellite markers was performed and DNA array was used to detect known mutations. Subsequently, all ALMS1 exons were simultaneously sequenced for one affected patient with the TaGSCAN targeted sequencing panel. Finally, segregation of the causal variant was performed by Sanger sequencing. Both affected siblings had cone rod dystrophy with impaired visual acuity, sensorineural hearing loss and truncal obesity. One affected individual showed insulin resistance without diabetes mellitus. Other clinical features including cardiac and pulmonary dysfunction, hypothyroidism, hyperlipidemia, acanthosis nigricans, renal and hepatic dysfunction were absent. Genetic analysis showed the presence of a homozygous splice site mutation (c.10388-2A > G) in both affected siblings. Although Alström syndrome is relatively well characterized disease, this syndrome is probably misdiagnosed in Tunisia. Here, we describe the first report of Tunisian patients affected by this syndrome and carrying a homozygous ALMS1 mutation. The diagnosis was suspected after long-term clinical follow-up and confirmed by genetic testing., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Bardet-Biedl Syndrome (BBS) and Alström Syndrome are two pleiotropic ciliopathies with significant phenotypic overlap between them across many tissues. Although BBS and Alström genes are necessary for the proper function of primary cilia, their role in defects across multiple organ systems is unclear., Methods: To provide insight into the pathways underlying BBS and Alström phenotypes, we carried out whole organism transcriptome analysis by RNA sequencing in established zebrafish models of the syndromes., Results: We analyzed all genes that were significantly differentially expressed and found enrichment of phenotypically significant pathways in both models. These included multiple pathways shared between the two disease models as well as those unique to each model. Notably, we identified significant downregulation of genes in pathways relevant to visual system deficits and obesity in both disorders, consistent with those shared phenotypes. In contrast, neuronal pathways were significantly downregulated only in the BBS model but not in the Alström model. Our observations also suggested an important role for G-protein couple receptor and calcium signaling defects in both models., Discussion: Pathway network analyses of both models indicate that visual system defects may be driven by genetic mechanisms independent of other phenotypes whereas the majority of other phenotypes are a result of genetic players that contribute to multiple pathways simultaneously. Additionally, examination of genes differentially expressed in opposing directions between the two models suggest a deficit in pancreatic function in the Alström model, that is not present in the BBS model., Conclusions: These findings provide important novel insight into shared and divergent phenotypes between two similar but distinct genetic syndromes.

Unlabelled: To report novel mutations in two Saudi children with clinical features of Leber congenital amaurosis (LCA) and Alström syndrome., Case Reports: Case 1 was a child with phenotypic features of LCA including oculodigital sign, bilateral enophthalmos, nystagmus, pale disc, and retinal changes. Direct sequencing of the coding sequence of GUCY2D revealed a missense mutation affecting highly conserved position (c. 743C > T; p.S248 L). Case 2 describes a girl with marked nystagmus, photophobia, and retinal changes in both eyes with short and stubby fingers tapering at the distal phalanges. The electroretinograms were nonrecordable in each eye. She had a hearing aid in the left ear, mid-facial hypoplasia, bilateral enophthalmos, and insulin dependent diabetes. Mutation screening of candidates genes revealed a pathogenic mutation in ALMS1 gene (c. 8441C > A, p.S2814). Two novel mutations causing phenotypic LCA and Alström syndrome in Saudi patients from consanguineous families expand the genotypic spectrum of congenital retinal dystrophies.

Context: Alström syndrome is characterized by increased risk of cardiovascular disease from childhood., Objective: To explore the association between risk factors for cardiovascular disease, aortic pulse wave velocity, and vascular events in Alström syndrome., Design: Cross-sectional analyses with 5-year follow-up., Setting: The UK NHS nationally commissioned specialist clinics for Alström syndrome., Patients: Thirty-one Alström patients undertook vascular risk assessment, cardiac studies, and aortic pulse wave velocity measurement. Subsequent clinical outcomes were recorded., Interventions: Insulin resistance was treated with lifestyle intervention and metformin, and diabetes with the addition of glitazones, glucagon-like peptide 1 agonists, and/or insulin. Thyroid and T deficiencies were corrected. Dyslipidemia was treated with statins and nicotinic acid derivatives. Cardiomyopathy was treated with standard therapy as required., Main Outcome Measures: The associations of age, gender, and risk factors for cardiovascular disease with aortic pulse wave velocity were assessed and correlated with the effects of reduction in left ventricular function. Vascular events were monitored for 5 years., Results: Aortic pulse wave velocity was positively associated with the duration of diabetes (P = .001) and inversely with left ventricular ejection fraction (P = .036). Five of the cohort with cardiovascular events had higher aortic pulse wave velocity (P = .0247), and all had long duration of diabetes., Conclusions: Duration of diabetes predicted aortic pulse wave velocity in Alström syndrome, which in turn predicted cardiovascular events. This offers hope of secondary prevention because type 2 diabetes can be delayed or reversed by lifestyle interventions.

Idiopathic dilated cardiomyopathy is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. Dilated cardiomyopathy typically exhibits autosomal dominant inheritance, yet frequently remains clinically silent until adulthood. We sought to discover the molecular basis of idiopathic, non-syndromic dilated cardiomyopathy in a one-month-old male presenting with severe heart failure. Previous comprehensive testing of blood, urine, and skin biopsy specimen was negative for metabolic, mitochondrial, storage, and infectious etiologies. Ophthalmologic examination was normal. Chromosomal microarray and commercial dilated cardiomyopathy gene panel testing failed to identify a causative mutation. Parental screening echocardiograms revealed no evidence of clinically silent dilated cardiomyopathy. Whole exome sequencing was carried out on the family trio on a research basis, filtering for rare, deleterious, recessive and de novo genetic variants. Pathogenic compound heterozygous truncating mutations were identified in ALMS1, diagnostic of Alström syndrome and prompting disclosure of genetic findings. Alström syndrome is a known cause for dilated cardiomyopathy in children yet delayed and mis-diagnosis are common owing to its rarity and age-dependent emergence of multisystem clinical manifestations. At six months of age the patient ultimately developed bilateral nystagmus and hyperopia, features characteristic of the syndrome. Early diagnosis is guiding clinical monitoring of other organ systems and allowing for presymptomatic intervention. Furthermore, recognition of recessive inheritance as the mechanism for sporadic disease has informed family planning. This case highlights a limitation of standard gene testing panels for pediatric dilated cardiomyopathy and exemplifies the potential for whole exome sequencing to solve a diagnostic dilemma and enable personalized care., (© 2015 Wiley Periodicals, Inc.)

Alström syndrome is a rare ciliopathy affecting about 1 in 1,000,000 individuals. It is characterised by cone-rod dystrophy, insulin resistance, diabetes mellitus, cardiomyopathy, renal failure and hypogonadism. Progressive multi-organ dysfunction eventually leads to death. Only about 800 patients with this disorder have been identified so far. The diagnosis of Alström syndrome is critical as it can easily be overlooked because of the many features it shares with metabolic syndrome. The gene affected in this autosomal recessive disease is ALMS1, the protein product of which is involved in intracellular trafficking and ciliary function. Alström syndrome is being studied as a model which would potentially shed light on the pathophysiology of diabetes mellitus. In this report, we describe a patient with features of Alström syndrome and a clinical picture suggestive of a recurrent, severe, steroid responsive myopathy which, to the best of our knowledge, has not been reported so far.

Objective: The study focuses on theory-of-mind in adolescents and young adults with Alström syndrome (ALMS). ALMS, an autosomal recessive syndrome causes juvenile blindness, sensorineural hearing loss, cardiomyopathy, endocrinological disorders and metabolic dysfunction. Theory-of-mind (ToM) refers to the ability to impute mental states to one self and to others. Clinical observations have revealed an increased occurrence of deviances in mental state understanding in ALMS. In the present study ToM will be examined and related to working memory (WM), verbal ability and sensory loss., Methods: Twelve young individuals (16-37 years) with ALMS and 24 nondisabled individuals matched on age, gender and educational level participated. ToM was assessed by means of a multiple task that taxes the ability to understand thoughts and feelings of story characters'. WM was examined by means of a reading span task and verbal ability by means of a vocabulary test., Results: The ALMS group performed at significantly lower levels in ToM tasks and displayed a higher variability in performance than the control group. Individuals with ALMS and a relatively poor level performance provided fewer correct mental state inferences in ToM tasks than ALMS individuals with relatively higher performance levels. ALMS individuals with relatively high performance levels made as many correct inferences in ToM tasks as the control group, but their inferences were more often incomplete. Vocabulary skills and educational level, but not WM-capacity predicted ToM performance. Degree of deafblindness did not have an impact on ToM. Age of onset of visual loss but not hearing loss related to ToM., Conclusions: The individuals with ALMS display a high degree of heterogeneity in terms of ToM, where some individuals reached performance levels comparable to nondisabled individuals. The results are discussed with respect to how cognitive and verbal abilities and factors related to the disability affect ToM., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Alström syndrome (Online Mendelian Inheritance in Man ALMS #203800) is a rare hereditary disorder caused by mutations in the gene ALMS1. This rare disorder's characteristics are cone-rod dystrophy resulting in blindness in childhood, insulin-resistant type 2 diabetes mellitus, truncal obesity, progressive sensorineural hearing loss, dilated cardiomyopathy, craniofacial features, hypothyroidism, elevation in liver transaminases, renal insufficiency, gonadal dysfunction, and menstrual irregularities. A 13.5-year-old girl was admitted to the hospital for complaints of excessive water consumption and urination over the previous 2 years. The patient's parents were third-degree relatives. At physical examination, hyperpigmentation was present over the areola and acanthosis nigricans under the arms and on the neck. Audiologic examination revealed bilateral sensorineural hearing loss, and bilateral cataract was determined at ocular examination. The patient was monitored by the chest diseases department due to bronchiectasis. HbA1c was 13.1%. In mutation screening study, 2 novel mutations c.5586T>G; p.Tyr1862* and c.2905insT; p.L968fs*4 were detected in the ALMS1 gene. Saccharin test was positive. We emphasize that Alström syndrome may be complicated by bronchiectasis.

We report on clinical and genetic studies in a non-consanguineous Irish sib-pair with infantile dilated cardiomyopathy and retinopathy. A diagnosis of Alström Syndrome (AS) was considered and diagnostic testing pursued. The Alströms gene (ALMS1) is very large (23 exons) and diagnostic testing of mutational hotspots (exon 6, 8 and 10) was negative. Furthermore the siblings were tall and did not have the typical phenotype of nystagmus, photophobia, obesity or hearing loss and so the AS diagnosis was removed. We then sought to identify the causative gene in this family using whole exome sequencing. Unexpectedly, the exome analysis identified novel compound heterozygous ALMS1 mutations in exon 5 (c.777delT:p.D260fs*26) and exon 20 (c.12145&#95;12146insC:p.S4049fs*36) that segregated with the phenotype. Although the siblings show some clinical overlap with AS, their phenotype is not classical. It is plausible that their atypical presentation may be due to the location of the ALMS1 mutations outside the usual mutational hotspots. Our findings show how atypical cases of AS may be missed under the current diagnostic guidelines and support consideration of complete ALMS1 sequencing in children with two or more features, even if all of the core clinical features of AS are not present., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background: Alström syndrome is a recessively inherited condition characterised by severe insulin resistance and metabolic syndrome with progression to type 2 diabetes, hepatic dysfunction and coronary artery disease. The metabolic responses to lifestyle changes in the syndrome have not been reported., Case Reports: We describe the effects on glycaemia of intense cycling in two insulin treated Alström patients with diabetes, and the effects of opposite lifestyle changes over one year in two others., Methods: After practise and clinical assessment two patients aged 21 and 39 years undertook a 380 km cycle ride over 4 days by tandem. The effects of planned reductions in insulin therapies and increased regular carbohydrate ingestion were monitored by frequent capillary blood glucose measurements. Two siblings aged 22 and 25 years underwent assessment of glycaemia, C-peptide/glucose ratio serum lipids, hepatic function and ultrasound, Enhanced Liver Fibrosis test and measures of insulin resistance. Measurements were repeated one year later after profound lifestyle changes., Results: Aerobic exercise strikingly improved blood glucose control despite reduction in insulin dose and increased carbohydrate intake. Increase in exercise and exclusion of fast foods improved all aspects of the metabolic syndrome and induced remission of diabetes in one sibling. Reduction in exercise and consumption of high energy foods in the other resulted in development of type 2 diabetes, severe metabolic syndrome and fatty liver in the other., Conclusions: Despite dual sensory loss and genetic basis for insulin resistance, Alström patients can successfully ameliorate the metabolic syndrome with lifestyle changes., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background: Alström Syndrome (ALMS) is an extremely rare multiorgan disease caused by mutations in ALMS1. Dilated cardiomyopathy (DCM) is a common finding but only one series has been investigated by Cardiac Magnetic Resonance (CMR)., Methods: Eight genetically proven ALMS patients (ages 11-41) underwent CMR performed by standard cine steady state, T1, T2 and late gadolinium enhancement (LGE) sequences. Ejection fraction (EF), Diastolic Volume (EDV) and Systolic Volume normalized for body surface area (ESV), and mass indices were determined, as well as EDV/Mass ratio, an index expressing the adequacy of cardiac mass to heart volume. Regional fibrosis was assessed by LGE; diffuse fibrosis was measured by a TI scout sequence acquired at 5, 10 and 15 min after gadolinium by comparing inversion time values (TI) at null time in ALMS and control group., Results: In one patient severe DCM was present with diffuse LGE. There were seven cases without clinical DCM. In these patients, EF was at lower normal limits or slightly reduced and ESV index increased; six patients had decreased mass index and EDV/Mass ratio. Mild regional non ischemic fibrosis was detected by LGE in three cases; diffuse fibrosis was observed in all cases, as demonstrated by shorter TI values in ALMS in comparison with controls (5 min: 152 ± 12 vs 186 ± 16, p 0.0002; 10 min: 175 ± 8 vs 204 ± 18, p 0.0012; 15 min: 193 ± 9 vs 224 ± 16, p 0.0002)., Conclusions: Cardiac involvement in ALMS is characterized by progressive DCM, associated with systolic dysfunction, myocardial fibrosis and reduced myocardial mass., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Alström syndrome (ALMS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene. We report two brothers, 3 and 4 years of age and diagnosed with ALMS, who initially presented in infancy with severe dilated cardiomyopathy during febrile respiratory infection. The disease course in the two siblings was marked by significant intrafamilial variability. Although cardiomyopathy in the older sibling has mainly resolved thus allowing for the discontinuation of medical therapy, heart function in the younger sibling continues to deteriorate despite maximal drug support with furosemide, carvedilol, captopril, and aldospirone. Genetic analysis revealed homozygous mutations, c.8008C>T (R2670X), in ALMS1 resulting in premature protein truncation. This report further emphasizes the exceptional intrafamilial variability of ALMS, mainly during the natural course of cardiac disease.

Background: Bardet-Biedl syndrome (BBS) is a pleiotropic recessive disorder that belongs to the rapidly growing family of ciliopathies. It shares phenotypic traits with other ciliopathies, such as Alström syndrome (ALMS), nephronophthisis (NPHP) or Joubert syndrome. BBS mutations have been detected in 16 different genes (BBS1-BBS16) without clear genotype-to-phenotype correlation. This extensive genetic heterogeneity is a major concern for molecular diagnosis and genetic counselling. While various strategies have been recently proposed to optimise mutation detection, they either fail to detect mutations in a majority of patients or are time consuming and costly., Method: We tested a targeted exon-capture strategy coupled with multiplexing and high-throughput sequencing on 52 patients: 14 with known mutations as proof-of-principle and 38 with no previously detected mutation. Thirty genes were targeted in total including the 16 BBS genes, the 12 known NPHP genes, the single ALMS gene ALMS1 and the proposed modifier CCDC28B., Results: This strategy allowed the reliable detection of causative mutations (including homozygous/heterozygous exon deletions) in 68% of BBS patients without previous molecular diagnosis and in all proof-of-principle samples. Three probands carried homozygous truncating mutations in ALMS1 confirming the major phenotypic overlap between both disorders. The efficiency of detecting mutations in patients was positively correlated with their compliance with the classical BBS phenotype (mutations were identified in 81% of 'classical' BBS patients) suggesting that only a few true BBS genes remain to be identified. We illustrate some interpretation problems encountered due to the multiplicity of identified variants., Conclusion: This strategy is highly efficient and cost effective for diseases with high genetic heterogeneity, and guarantees a quality of coverage in coding sequences of target genes suited for diagnosis purposes.

Introduction: Early onset retinal degeneration associated with obesity can present a diagnostic challenge in paediatric ophthalmology practice. Clinical overlap between Bardet-Biedl syndrome (BBS) and Alström syndrome has been described, although the two entities are genetically distinct. To date, 16 genes are known to be associated with BBS (BBS1-16) and only one gene has been identified for Alström syndrome (ALMS1)., Materials and Methods: In collaboration with the French National Center for Sequencing (CNS, Evry), all coding exons and flanking introns were sequenced for 27 ciliopathy genes (BBS1-12, MGC1203, TTC21b, AHI1, NPHP2-8 (NPHP6=BBS14), MKS1(BBS13), MKS3, C2ORF86, SDCCAG8, ALMS1) in 96 patients referred with a clinical diagnosis of BBS. ALMS1 gene analysis included sequencing of all coding exons., Results: BBS known gene mutations were found in 44 patients (36 with two mutations and 8 heterozygous). ALMS1 mutations were found in four cases. The rate of ALMS1 mutations among patients suspected of having BBS was 4.2%., Discussion: Clinically, all four patients presented early-onset severe retinal degeneration with congenital nystagmus associated with obesity. The difficult early differential diagnosis between the two syndromes is outlined. One mutation had already been reported (c.11310delAGAG/p.R3770fsX) and three were novel (c.2293C > T/p.Q765X, c.6823insA/p.R2275fsX, c.9046delA/p.N3016fsX)., Conclusions: Ciliopathy genes sequencing can be very helpful in providing a timely diagnosis in this group of patients, hence appropriate genetic counselling for families and adequate medical follow-up for affected children.

Alström syndrome (AS) is a ciliopathy and an uncommon cause of syndromic retinal dystrophy. This case reports findings in a 5-year-old boy with severe early onset retinal dystrophy, and how the recognition of extraocular features with genetic analysis led to the correct diagnosis of AS after 4 years of investigation.

Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, polydactyly, renal abnormalities, and cognitive impairment for which 15 causative genes have been identified. Here we present the results of a mutational analysis of our multiethnic cohort of 83 families (105 cases); 75.9% of them have their mutations identified including 26 novel changes. Comprehensive phenotyping of these patients demonstrate that the spectrum of clinical features is greater than expected and overlapped with the features of other ciliopathies; specifically Alström and McKusick-Kauffman syndromes.