Defining the cardiovascular phenotype of adults with Alström syndrome.

BACKGROUND: >40% of infants with Alström Syndrome (AS) present with a transient, severe cardiomyopathy in the first months of life, with apparent recovery in survivors. One in five individuals then develop a later-onset cardiomyopathy but wide clinical variability is observed, even within the same family. The rationale for this study is to provide a comprehensive evaluation of the cardiovascular phenotype in adults with AS. METHODS: Adults attending the National Centre for AS in England were studied. All patients underwent biochemical, 12- lead electrocardiography, echocardiography, and cardiovascular magnetic resonance imaging. RESULTS: 47 adults with AS (64% male; mean age 33 years; 66% white British) were studied. Seven (15%) survived infantile cardiomyopathy and 23 (49%) developed adult-onset cardiomyopathy. Conventional risk factors for cardiovascular disease were present in 39 (83%). Abnormalities were present on biomarkers in 16 (34%), ECG 30 (64%), echocardiography 19 (40%) and CMR 31 (66%). Coronary artery imaging was performed in six (13%), with abnormalities in two. Cardiac, renal, and liver markers were more often impaired in older patients, with impaired left ventricular ejection fraction, reduced global longitudinal strain and late enhancement. 6 (13%) had severe pulmonary hypertension (mean pulmonary artery pressure 46 mmHg) due to left heart disease on invasive testing. CONCLUSION: Cardiomyopathy is common in adults with AS, complicated in a significant proportion by atherosclerotic coronary artery disease and restrictive cardiomyopathy, confirmed on CMR and invasive testing. With advancing age, cardiovascular complications are compounded by contemporaneous renal and liver disease.

Female Alms1-deficient mice develop echocardiographic features of adult but not infantile Alström syndrome cardiomyopathy.

Alström syndrome (AS), a multisystem disorder caused by biallelic ALMS1 mutations, features major early morbidity and mortality due to cardiac complications. The latter are biphasic, including infantile dilated cardiomyopathy and distinct adult-onset cardiomyopathy, and poorly understood. We assessed cardiac function of Alms1 knockout (KO) mice by echocardiography. Cardiac function was unaltered in Alms1 global KO mice of both sexes at postnatal day 15 (P15) and 8 weeks. At 23 weeks, female - but not male - KO mice showed increased left atrial area and decreased isovolumic relaxation time, consistent with early restrictive cardiomyopathy, as well as reduced ejection fraction. No histological or transcriptional changes were seen in myocardium of 23-week-old female Alms1 global KO mice. Female mice with Pdgfra-Cre-driven Alms1 deletion in cardiac fibroblasts and in a small proportion of cardiomyocytes did not recapitulate the phenotype of global KO at 23 weeks. In conclusion, only female Alms1-deficient adult mice show echocardiographic evidence of cardiac dysfunction, consistent with the cardiomyopathy of AS. The explanation for sexual dimorphism remains unclear but might involve metabolic or endocrine differences between sexes.

Glucagon-like peptide-1 analogues in monogenic syndromic obesity: Real-world data from a large cohort of Alström syndrome patients.

AIM: To examine the real-world efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in monogenic obesity in patients with Alström syndrome (ALMS). METHODS: We screened 72 UK adult patients with ALMS and offered treatment to 34 patients meeting one of the following criteria: body mass index of 25 kg/m2 or higher, insulin resistance, suboptimal glycaemic control on antihyperglycaemic medications or non-alcoholic fatty liver disease. RESULTS: In total, 30 patients, with a mean age of 31 ± 11 years and a male to-female ratio of 2:1, completed 6 months of treatment with GLP-1 RAs either in the form of semaglutide or exenatide. On average, treatment with GLP-1 RAs reduced body weight by 5.4 ± 1.7 (95% confidence interval [CI] 3.6-7) kg and HbA1c by 12 ± 3.3 (95% CI 8.7-15.3) mmol/mol, equating to 6% weight loss (P < .01) and 1.1% absolute reduction in HbA1c (P < .01). Significant improvements were also observed in serum total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and alanine aminotransferase. The improvement of metabolic variables in our cohort of monogenic syndromic obesity was comparable with data for polygenic obesity, irrespective of weight loss. CONCLUSIONS: Data from our centre highlight the non-inferiority of GLP-1 RAs in monogenic syndromic obesity to the available GLP-1 RA-use data in polygenic obesity, therefore, these agents can be considered as a treatment option in patients with ALMS, as well as other forms of monogenic obesity.

Successful Heart Transplant in Dilated Cardiomyopathy Associated With Alström Syndrome: A Case Report.

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.

Alström Syndrome with Early Vision and Hearing Impairement.

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.

Hearing Loss in Adults With Alström Syndrome-Experience From the UK National Alström Service.

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.

Amiodarone-induced multiple organ damage in an Alström syndrome patient with end-stage renal disease and hepatic cirrhosis.

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.

Spinal fusion with motor evoked potential monitoring using remimazolam in Alström syndrome: A case report.

RATIONALE: Alström syndrome is a rare genetic disorder characterized by obesity, diabetes mellitus, cardiomyopathy, and liver dysfunction. Further, scoliosis, a common symptom of Alström syndrome, often requires surgical intervention for functional impairments. Motor evoked potential (MEP) monitoring and other electrophysiological tests are essential when performing surgery for functional scoliosis. However, there are few reports on how to maintain general anesthesia in Alström syndrome. Here, we describe a patient with Alström syndrome who underwent surgery for scoliosis under general anesthesia with remimazolam and MEP monitoring. PATIENT CONCERNS: A 17-year-old woman (height, 140 cm, weight, 64.5 kg) diagnosed with Alström syndrome was scheduled for a posterior spinal fusion for functional scoliosis. Other associated comorbidities of Alström syndrome present were dilated cardiomyopathy, type 2 diabetes mellitus, obesity (body mass index, 32.1 kg/m2), amblyopia (light perception), and hearing impairment (speech awareness threshold 50 dBHL in each ear). DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Posterior spinal fusion was planned for functional scoliosis. While investigating the dilated cardiomyopathy, transthoracic echocardiography showed global wall hypokinesis, with 45% left ventricular ejection fraction. The left ventricle was dilated, with left ventricular end-diastolic and end-systolic diameters of 55 and 42 mm, respectively. This finding along with the hypertriglyceridemia associated with Alström syndrome led us to conclude that propofol should be avoided. Thus, we induced general anesthesia using remimazolam. MEP monitoring was performed, and the patient experienced no motor impairments during the surgery. LESSONS: Myocardial and hepatic dysfunction determine the prognosis of patients with Alström syndrome. Thus, anesthesia that preserves liver function should be selected in such cases. In patients with hypertriglyceridemia, propofol should be avoided, and using remimazolam, an ultrashort-acting benzodiazepine, may be appropriate. In this case, reviewing the Patient State Index with SedLine allowed us to perform MEP monitoring uneventfully, and the posterior spinal fusion was completed without any motor impairment.

[Alström syndrome, a rare cause of renal failure: case report and review of the literature].

We describe the case of a 26-year-old male patient with a previous diagnosis of Alström Syndrome who presented drowsiness, dyspnea, tremors, and a dull abdominal pain, without signs of peritoneal irritation. The patient also presented sensorineural hearing loss, decreased vision, due to chorioretinal dystrophy, difficulty walking with back-lumbar double curve scoliosis, impaired glycemic homeostasis, and a significant deterioration of renal function. Alström syndrome is a multisystem disease characterized by rod-cone dystrophy, hearing loss, obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy, and progressive renal and hepatic dysfunction. Around 450 cases have been identified worldwide. Clinical signs, age of onset and severity can vary significantly between different families and within the same family. Careful nephrological follow-up is necessary in patients with syndromic ciliopathies, since long-term kidney problems can have an impact on other diseases, eg. cardiovascular disease.

Western Diet Promotes Renal Injury, Inflammation, and Fibrosis in a Murine Model of Alström Syndrome.

INTRODUCTION: Alström syndrome is a rare recessive genetic disease caused by mutations in ALMS1, which encodes a protein that is related to cilia function and intracellular endosome trafficking. The syndrome has been linked to impaired glucose metabolism and CKD. Polymorphisms in Alms1 have likewise been linked to CKD, but little is known about the modification of the phenotype by environmental factors. METHODS: To gain further insights, the fat aussie (foz) mouse strain, a genetic murine model of Alström syndrome, was exposed to a normal chow (NC) or to a Western diet (WD, 20% fat, 34% sucrose by weight, and 0.2% cholesterol) and renal outcomes were measured. RESULTS: Body weight and albuminuria were higher in foz than in wild-type (WT) mice on both diets but WD significantly increased the difference. Measurement of plasma creatinine and cystatin C indicated that glomerular filtration rate was preserved in foz versus WT independent of diet. Renal markers of injury, inflammation, and fibrosis were similar in both genotypes on NC but significantly greater in foz than in WT mice on WD. A glucose tolerance test performed in foz and WT mice on WD revealed similar basal blood glucose levels and subsequent blood glucose profiles. CONCLUSIONS: WD sensitizes a murine model of Alström syndrome to kidney injury, inflammation, and fibrosis, an effect that may not be solely due to effects on glucose metabolism. Polymorphisms in Alms1 may induce CKD in part by modulating the deleterious effects of high dietary fat and sucrose on kidney outcome.

Cochlear implantation and mastoid obliteration in a patient with Alström Syndrome.

OBJECTIVES: To describe the outcomes of cochlear implantation with mastoid obliteration in a patient with Alström Syndrome and chronic otorrhea. METHODS: This is a single case discussion of a patient with Alström Syndrome and chronic otorrhea who underwent unilateral cochlear implantation and mastoid obliteration in January 2019. Subsequent contralateral procedure was performed 4 months later. Implantation was pursued due to the progressive sensorineural hearing-loss that is characteristic of Alström Syndrome. Serial Audiograms were obtained before and after procedure. RESULTS: Following implantation, audiological reports improved to near normal thresholds from the previous 60-85 dB sloping hearing loss. The patient's language skills rapidly improved as well as the ability to express her personality. Mastoid obliteration effectively resolved the chronic otorrhea that further complicated this case. CONCLUSION: Cochlear implantation with mastoid obliteration was successful in improving hearing thresholds and resolving chronic otorrhea in a patient with Alström Syndrome.

Cochlear Implants in Alström Syndrome.

OBJECTIVES: Too little is known about hearing loss rehabilitation in patients with Alström syndrome (AS). Benefits of hearing aids (HA) have not been fully documented and only one case treated with a Cochlear Implant (CI) has been described in the proceedings of a conference. Furthermore, comorbidities and risk of complications following surgical intervention may contraindicate Cochlear Implant procedures in these patients.The present case report concerns the first AS patient with CI in the literature. METHODS: After reporting a concise description of the audiological profile of patients with AS described in the literature, the case of a 22-year-old woman with genetically confirmed Alström syndrome who underwent a sequential bilateral CI (Bi-CI) rehabilitation is reported. Audiological results before and after cochlear implantation are described. RESULTS: The patient showed an excellent functional outcome with CIs, which enabled her to achieve communicative, social and academic results comparable with her peers, and no complications occurred. CONCLUSIONS: AS is not necessarily an absolute contraindication to CI. For many AS patients, a good cognitive function and adequate life expectancy represent a clear indication to prompt and adequate hearing rehabilitation with CIs. The description of this type of clinical cases could in the future also generate indications for a tailored audiological treatment of patients with very specific needs, such as patients with Alström Syndrome.

Defining renal phenotype in Alström syndrome.

BACKGROUND: Alström syndrome (AS) is a rare autosomal recessive ciliopathy with a wide spectrum of clinical features, including cone-rod retinal dystrophy, neuronal deafness, severe insulin resistance and major organ failure. The characteristics of renal disease in the syndrome have not been systematically described. The aim of this study is to define the onset and progression of renal disease in AS. METHOD: Prospective observational cohort study. SETTING AND PARTICIPANTS: Thirty-two adult subjects from a national specialist clinic in UK and 86 subjects from an international AS registry were studied. OUTCOMES: First, an international registry cross-sectional study across all age groups to determine change in kidney function was performed. Secondly, a detailed assessment was carried out of adult AS patients with serial follow-up to determine incidence, aetiology and progression of renal disease. ANALYTICAL APPROACH: Generalized estimating equations were used to evaluate the relationship between age and estimated glomerular filtration rate (eGFR). Associations between patient factors and eGFR levels were then assessed in the adult AS cohort. RESULTS: The international registry study of the renal function of 118 subjects with AS (median age 21 years) showed a rapid decline with age, at an average of -16.7 and -10.9 mL/min/1.73 m2 per decade in males and females, respectively. In a UK national cohort of 32 patients with AS (median age 22 years), 20/32 (63%) had chronic kidney disease (CKD) Stage 3 or above based on eGFR <60 mL/min/1.73 m2 or evidence of albuminuria. Hyperuricaemia was noted in 25/32 (79%). Structural abnormalities such as nephrocalcinosis without hypercalcaemia and cysts were observed in 20/32 (63%) subjects. Lower urinary tract symptoms were frequent in 17/19 (70%) of AS patients. Histological evidence showed mixed tubulo-interstitial and glomerular disease. CONCLUSIONS: This is the first study to demonstrate that renal disease is the hallmark of AS, which starts early and progresses with age, leading to a high prevalence of advanced CKD at young age. AS should be considered in the differential diagnosis of rare genetic renal diseases.

Alström Syndrome Presenting as Isolated Dilated Cardiomyopathy.

Cardiomyopathy is an etiologically heterogeneous condition, and non-syndromic as well as syndromic genetic causes are identified in a significant proportion of cases without a known acquired cause. The present report describes a 2-mo-old boy who presented initially with a referral diagnosis of isolated dilated cardiomyopathy, without any associated dysmorphism or malformations, and with history of similar cardiac disease and early infantile death in an elder male sibling. Next generation sequencing (NGS) based multigene panel testing of the cardiomyopathy-associated genes was done which revealed the diagnosis of Alström syndrome, based on which appropriate management and surveillance could be planned for the child and accurate genetic counseling could be provided to the parents. This report reiterates the fact that genetic testing for cardiomyopathy without an obvious acquired cause helps in identification of the underlying etiology, appropriate management, early diagnosis of syndromic forms, and monitoring and pre-symptomatic intervention for associated extracardiac complications.

Alström syndrome: Renal findings in correlation with obesity, insulin resistance, dyslipidemia and cardiomyopathy in 38 patients prospectively evaluated at the NIH clinical center.

Alström Syndrome is a ciliopathy associated with obesity, insulin resistance/type 2 diabetes mellitus, cardiomyopathy, retinal degeneration, hearing loss, progressive liver and kidney disease, and normal cognitive function. ALMS1, the protein defective in this disorder, localizes to the cytoskeleton, microtubule organizing center, as well as the centrosomes and ciliary basal bodies and plays roles in formation and maintenance of cilia, cell cycle regulation, and endosomal trafficking. Kidney disease in this disorder has not been well characterized. We performed comprehensive multisystem evaluations on 38 patients. Kidney function decreased progressively; eGFR varied inversely with age (p = 0.002). Eighteen percent met the definition for chronic kidney disease (eGFR < 60 mL/min/1.73 m2 and proteinuria); all were adults with median age of 32.8 (20.6-37.9) years. After adjusting for age, there were no significant associations of kidney dysfunction with type 2 diabetes mellitus, dyslipidemia, hypertension, cardiomyopathy or portal hypertension suggesting that kidney disease in AS is a primary manifestation of the syndrome due to lack of ALMS1 protein. Approximately one-third of patients had hyperechogenicity of the renal parenchyma on imaging. While strict control of type 2 diabetes mellitus may decrease kidney-related morbidity and mortality in Alström syndrome, identification of novel targeted therapies is needed.

Comprehensive Endocrine-Metabolic Evaluation of Patients With Alström Syndrome Compared With BMI-Matched Controls.

Background: Alström syndrome (AS), a monogenic form of obesity, is caused by recessive mutations in the centrosome- and basal body-associated gene ALMS1. AS is characterized by retinal dystrophy, sensory hearing loss, cardiomyopathy, childhood obesity, and metabolic derangements. Objective: We sought to characterize the endocrine and metabolic features of AS while accounting for obesity as a confounder by comparing patients with AS to body mass index (BMI)-matched controls. Methods: We evaluated 38 patients with AS (age 2 to 38 years) who were matched with 76 controls (age 2 to 48 years) by age, sex, race, and BMI. Fasting biochemistries, mixed meal test (MMT), indirect calorimetry, dual-energy X-ray absorptiometry, and MRI/magnetic resonance spectroscopy were performed. Results: Frequent abnormalities in AS included 76% obesity, 37% type 2 diabetes mellitus (T2DM), 29% hypothyroidism (one-third central, two-thirds primary), 3% central adrenal insufficiency, 57% adult hypogonadism (one-third central, two-thirds primary), and 25% female hyperandrogenism. Patients with AS and controls had similar BMI z scores, body fat, waist circumference, abdominal visceral fat, muscle fat, resting energy expenditure (adjusted for lean mass), free fatty acids, glucagon, prolactin, ACTH, and cortisol. Compared with controls, patients with AS were shorter and had lower IGF-1 concentrations (Ps ≤ 0.001). Patients with AS had significantly greater fasting and MMT insulin resistance indices, higher MMT glucose, insulin, and C-peptide values, higher HbA1c, and higher prevalence of T2DM (Ps < 0.001). Patients with AS had significantly higher triglycerides, lower high-density lipoprotein cholesterol, and a 10-fold greater prevalence of metabolic syndrome (Ps < 0.001). Patients with AS demonstrated significantly greater liver triglyceride accumulation and higher transaminases (P < 0.001). Conclusion: Severe insulin resistance and T2DM are the hallmarks of AS. However, patients with AS may present with multiple other endocrinopathies affecting growth and development.

Kidney Transplantation in Alström Syndrome: Case Report.

The Alström syndrome is a rare genetic disorder, inherited in an autosomal recessive manner. It has recently been classified as a ciliopathic disorder. Alström syndrome is a multiorgan pathology characterized by cone-rod dystrophy, hearing loss, childhood truncal obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dyslipidemia, short stature in adulthood, hypothyroidism, hypogonadism, dilated or restrictive cardiomyopathy, and progressive pulmonary, hepatic, and renal dysfunction. End-stage renal disease can occur as early as the late teens and is the leading cause of death. More than 900 people with Alström syndrome have been reported worldwide. We present a case of a 42-year-old man affected by this syndrome with end-stage renal disease, type 2 diabetes mellitus, and loss of visual function and hearing who received a kidney transplant from a cadaveric donor. Basiliximab and steroid were used as induction therapy. Tacrolimus, mycophenolate mofetil, and steroid were used as maintenance therapy. No complications were reported during the recovery. In selected patients affected by Alström syndrome, renal transplantation can be a successful treatment for chronic kidney disease.

Variable clinical course of identical twin neonates with Alström syndrome presenting coincidentally with dilated cardiomyopathy.

Alström Syndrome (AS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene. We report monozygotic twin infants who presented concurrently with symptoms of congestive heart failure (CHF) due to dilated cardiomyopathy (DCM). Following their initial presentation, one twin improved both echocardiographically and functionally while the other twin showed a progressive decline in ventricular function and worsening CHF symptoms requiring multiple hospitalizations and augmentation of heart failure therapy. Concordant findings of nystagmus, vision loss, and developmental delay were noted in both twins. Additional discordant findings included obesity and signs of insulin resistance in one twin. Genetic testing on one sibling confirmed AS. These twins underscore the importance of considering AS in any child presenting with DCM, particularly in infancy, and highlights that, even in monozygotic twins, the clinical course of AS is variable with regard to both the cardiac and non-cardiac manifestations of the disease.