Alstrom Syndrome

Alström syndrome is a rare genetic condition that affects many different parts of the body. It is caused by changes (mutations) in a specific gene called ALMS1, which both parents must pass down for a child to have the condition. Because the ALMS1 gene is important for the normal function of cells throughout the body, people with Alström syndrome experience a wide range of medical issues that develop over time. The first signs of the condition usually appear in babies or young children. Infants often have extreme sensitivity to light and rapid, involuntary eye movements, which eventually leads to a progressive loss of vision and complete blindness, often by the teenage years. Hearing loss also typically begins in childhood and gets worse over time. Additionally, children with Alström syndrome often experience rapid weight gain leading to obesity, and they develop a severe resistance to insulin, which frequently results in type 2 diabetes. Other serious health problems associated with Alström syndrome include a form of heart disease that enlarges and weakens the heart muscle, known as dilated cardiomyopathy. This can occur in infancy or later in life. As patients get older, they may also develop slowly worsening problems with their kidneys, liver, and lungs. While there is currently no cure for Alström syndrome, treatments focus on managing the specific symptoms, such as using low vision aids, hearing aids, and medications for heart, kidney, or metabolic issues, to help improve the patient's quality of life.

Condition category: Syndromic IRD

Prevalence: 1 in 1,000,000

Inheritance patterns: Autosomal Recessive

Age of onset: Infancy to early childhood

Clinical overview: Alström syndrome is a rare, complex autosomal recessive genetic disorder characterized by the progressive development of multi-organ pathology. The condition is classified as a ciliopathy, as it is caused by mutations in the ALMS1 gene, which encodes a protein essential for the normal function of primary cilia. The disruption of ciliary function leads to a wide array of systemic issues, making the clinical management of affected individuals highly complex. The key clinical features of Alström syndrome include progressive cone-rod dystrophy leading to early blindness, sensorineural hearing loss, childhood truncal obesity, severe insulin resistance, and type 2 diabetes mellitus. Additionally, patients frequently develop dilated cardiomyopathy, which can present in infancy or later in life, as well as progressive pulmonary, hepatic, and renal dysfunction. A hallmark of the disease is the development of systemic fibrosis of unknown etiology across multiple organs. The clinical significance of Alström syndrome lies in its severe morbidity and reduced life expectancy, primarily driven by cardiac, renal, and hepatic failure. Despite its rarity, studying Alström syndrome provides valuable insights into the molecular mechanisms underlying more common conditions such as obesity, type 2 diabetes, and metabolic syndrome. The disorder is cataloged under OMIM number 203800, with the causative ALMS1 gene listed as OMIM 606844, and it is identified by Orphanet number 64.

Patient and family guide: Alström syndrome is a rare genetic condition that affects many different parts of the body. It is caused by changes (mutations) in a specific gene called ALMS1, which both parents must pass down for a child to have the condition. Because the ALMS1 gene is important for the normal function of cells throughout the body, people with Alström syndrome experience a wide range of medical issues that develop over time. The first signs of the condition usually appear in babies or young children. Infants often have extreme sensitivity to light and rapid, involuntary eye movements, which eventually leads to a progressive loss of vision and complete blindness, often by the teenage years. Hearing loss also typically begins in childhood and gets worse over time. Additionally, children with Alström syndrome often experience rapid weight gain leading to obesity, and they develop a severe resistance to insulin, which frequently results in type 2 diabetes. Other serious health problems associated with Alström syndrome include a form of heart disease that enlarges and weakens the heart muscle, known as dilated cardiomyopathy. This can occur in infancy or later in life. As patients get older, they may also develop slowly worsening problems with their kidneys, liver, and lungs. While there is currently no cure for Alström syndrome, treatments focus on managing the specific symptoms, such as using low vision aids, hearing aids, and medications for heart, kidney, or metabolic issues, to help improve the patient's quality of life.

Symptoms and clinical features: In the early stage, typically during infancy and early childhood, the first symptoms are usually visual. Infants present with nystagmus and extreme photophobia within weeks to months after birth due to cone-rod dystrophy. While birth weight is normal, rapid weight gain and hyperphagia begin in the first year, leading to childhood truncal obesity. Additionally, dilated cardiomyopathy occurs in approximately 60% to 70% of infants, which can cause congestive heart failure but often resolves or abates within the first three years of life. During the intermediate stage, encompassing childhood and adolescence, progressive vision loss continues, with rods typically being destroyed by age five. Slowly progressive bilateral sensorineural hearing loss develops in the first decade, affecting the majority of patients. Metabolic issues emerge prominently, including severe insulin resistance and hyperinsulinemia, which often progress to type 2 diabetes mellitus at a median age of 16, though it can occur as early as age five. Acanthosis nigricans appears as a skin manifestation of insulin resistance, and hypertriglyceridemia develops. Growth slows during this period, resulting in short stature in adulthood. In the advanced stage, during late adolescence and adulthood, complete blindness usually occurs, with no light perception by age 20. Patients experience slowly progressive dysfunction of the kidneys, which can lead to end-stage renal failure. Hepatic dysfunction, including steatohepatitis, cirrhosis, and portal hypertension, as well as pulmonary issues like pulmonary hypertension and chronic obstructive pulmonary disease, may develop. Systemic fibrosis affects multiple organs. There can also be a recurrence or new onset of cardiomyopathy. Urological abnormalities and endocrine issues, such as hypogonadism in males or polycystic ovarian syndrome in females, further complicate the clinical picture.

Molecular pathology: Alström syndrome is caused by mutations in the ALMS1 gene, which encodes a large protein of approximately 0.5 megadaltons. The ALMS1 protein localizes specifically to the proximal end (base) of centrioles and basal bodies. It is widely expressed at low levels in most tissues, which explains the multi-organ involvement characteristic of the disease. ALMS1 is implicated in the maintenance and function of primary cilia, which are centriole-nucleated sensory organelles present on most quiescent human cells. Consequently, Alström syndrome is classified as a ciliopathy. The protein is involved in several critical cellular processes, including endosomal trafficking, actin organization, maintenance of centrosome cohesion, and transcription regulation. At the cellular level, the loss of functional ALMS1 protein leads to significant disruptions. Cells from patients with Alström syndrome exhibit alterations in actin morphology, cytoskeletal disruption, and deficits in endosome-associated recycling of cell components. For instance, impaired recycling of the GLUT4 transporter may contribute to the severe insulin resistance seen in patients. Furthermore, ALMS1 knockout models demonstrate increased cellular contractility, altered calcium extrusion, and impaired glycolytic and mitochondrial function, which likely underlie the pathogenesis of the infantile dilated cardiomyopathy associated with the syndrome.

Genetics: Alström syndrome is inherited in an autosomal recessive pattern, meaning an affected individual must inherit two mutated copies of the causative gene, one from each parent. The disorder is caused exclusively by mutations in the ALMS1 gene, which is located on chromosome 2p13.1. The ALMS1 gene is large, comprising 23 exons, and encodes a protein of 4,169 amino acids. To date, over 200 different pathogenic variants in the ALMS1 gene have been identified. The vast majority of these are nonsense or frameshift mutations that lead to premature termination of translation, resulting in an abnormally short, nonfunctional protein. Almost half of all known mutations occur in exon 8, which is commensurate with its large size, representing 49% of the coding sequence. Other common mutation hotspots include exons 10 and 16. Despite the identification of numerous mutations, there is little evidence of genotype-phenotype correlation in Alström syndrome. The severity of the disease, the age of onset of specific symptoms, and the rate of progression vary significantly among affected individuals, even within families bearing identical ALMS1 mutations. This variability suggests that the clinical phenotype is likely modified by unknown genetic background factors or environmental influences.

Diagnostic evaluation: Diagnosis of Alström syndrome is established clinically by the presence of two mutated alleles or a single mutated ALMS1 allele alongside specific primary and secondary features. The clinical workup involves a multidisciplinary approach. Fundoscopy in the early stages may appear normal or near-normal, but as the disease progresses, it reveals optic disc pallor, attenuation of retinal blood vessels, and pigmentary changes such as retinal pigment epithelial mottling, bone spicules, and bull's eye maculopathy. Optical coherence tomography (OCT) imaging typically demonstrates thinning of the macula and an early arrest of macular development with immature retinal structural organization. Electroretinography (ERG) is crucial for diagnosis; initially, it shows severe cone impairment with mild or no rod involvement, characteristic of cone-rod dystrophy. Over time, the ERG progresses to severely reduced or extinguished responses for both cones and rods. Genetic testing confirms the diagnosis through molecular analysis of the ALMS1 gene. Screening strategies often target exons 8, 10, and 16, where the majority of mutations occur. The differential diagnosis includes other ciliopathies and retinal dystrophies, such as Bardet-Biedl syndrome (BBS), Leber congenital amaurosis (LCA), and achromatopsia. Notably, Alström syndrome can be distinguished from BBS by the absence of polydactyly and mental retardation.

Differential diagnosis: Differential diagnosis of Alström syndrome includes: (1) Bardet-Biedl syndrome — retinal dystrophy and obesity but with polydactyly, cognitive impairment, no cardiomyopathy; BBS gene mutations. (2) Cohen syndrome — retinal dystrophy, obesity, but with characteristic facial features, neutropenia; VPS13B mutations. (3) Wolfram syndrome — optic atrophy (not retinal dystrophy), diabetes mellitus, hearing loss; WFS1 mutations. (4) Prader-Willi syndrome — obesity, hypotonia, but no retinal dystrophy or cardiomyopathy. (5) Isolated dilated cardiomyopathy — no retinal or metabolic features.

Natural history: The natural history of Alström syndrome is characterized by the sequential onset of multi-organ pathology. In the first 15 months of life, infants typically present with nystagmus, extreme photophobia, and cone-rod dystrophy. While birth weight is normal, rapid weight gain and hyperphagia begin in the first year. Additionally, infantile dilated cardiomyopathy may occur during this period, which can cause congestive heart failure but often resolves or abates within three years. During the first decade of life, slowly progressive bilateral sensorineural hearing loss begins to develop. Insulin resistance and truncal obesity become prominent clinical features. By the second decade, complete blindness usually occurs. It is also during adolescence and early adulthood that type 2 diabetes mellitus, hypertriglyceridemia, and progressive dysfunction of the kidneys, liver, and lungs begin to manifest or significantly worsen. The prognosis is heavily dictated by the severity and progression of organ failure. The primary causes of morbidity and mortality are congestive heart failure, due to either dilated or restrictive cardiomyopathy, and end-stage renal or hepatic failure. Interestingly, while body mass index tends to moderate with age, this moderation does not correlate with a delay in the onset of renal failure, heart failure, or type 2 diabetes.

Management and treatment research: ### Current management and standard of care There is currently no cure or treatment that reverses Alström syndrome. Care is multidisciplinary and focuses on monitoring complications, treating symptoms, preserving independence, and supporting quality of life. Because Alström syndrome can affect vision, hearing, heart function, metabolism, kidneys, liver, and other body systems, regular follow-up with appropriate specialists is important. Management may include: - **Vision support:** Low-vision services, magnifiers and other assistive technology, orientation and mobility training, Braille instruction when helpful, and school or workplace accommodations for progressive cone-rod dystrophy. - **Hearing support:** Regular hearing assessments, hearing aids, and consideration of cochlear implants for some people with severe hearing loss. - **Metabolic care:** Individualized nutrition and physical-activity support, along with standard treatment for obesity, insulin resistance, type 2 diabetes, high cholesterol, and high triglycerides. Treatment may include diabetes medicines, insulin, and lipid-lowering medicines when appropriate. - **Heart care:** Dilated cardiomyopathy and heart failure are managed using standard cardiology approaches. These may include medicines such as ACE inhibitors or ARBs, beta-blockers, diuretics, and other heart-failure treatments. Ongoing cardiac monitoring is important. - **Kidney and liver care:** Kidney function, blood pressure, urine protein, and liver health should be monitored regularly. Advanced kidney disease may require dialysis or kidney transplantation. Severe liver disease may require specialist evaluation, including transplant assessment in selected cases. - **Other support:** Care may also address sleep problems, endocrine concerns, breathing difficulties, musculoskeletal issues, mental-health needs, and social or educational support. ### Approved therapies No therapies are currently approved specifically to treat Alström syndrome or its underlying genetic cause. Medicines and procedures used for diabetes, heart failure, kidney disease, hearing loss, and other complications are standard treatments for those individual health conditions. ### Investigational research and clinical studies There are no disease-specific treatment candidates in the current pipeline. Current recruiting studies include registries and research cohorts that may improve understanding of Alström syndrome and help prepare for future treatment studies. - **Translational research cohort:** **NCT04461444** is recruiting people with Bardet-Biedl syndrome and Alström syndrome for a translational research study at University Hospital Strasbourg in France. Translational research connects information collected from participants with laboratory research to better understand disease mechanisms and identify possible future diagnostic or treatment approaches. - **Natural-history registry:** **NCT01793168** is a recruiting rare-disease patient registry and natural-history study coordinated by Sanford Health. Natural-history studies collect long-term information about symptoms, medical complications, and outcomes. These data can help researchers understand how a condition changes over time and plan future clinical trials. - **MC4R agonist therapy in severe genetic obesity:** **NCT07674290** is a recruiting Phase 4 study of real-world effects of melanocortin-4 receptor (MC4R) agonist therapy in Bardet-Biedl syndrome and severe genetic obesity. MC4R is part of a brain signaling pathway involved in appetite and body-weight regulation. The study title does not specifically list Alström syndrome; potential eligibility should be confirmed with the study team. ### Considering clinical trial participation Clinical studies may involve monitoring, examinations, imaging, laboratory testing, or collection of health information rather than a new treatment. Participation is voluntary, and eligibility may depend on age, genetic findings, health status, location, and prior treatments. Families can discuss research opportunities with their Alström syndrome care team and contact study sites listed under the relevant NCT number.

Outlook: The prognosis for individuals with Alström syndrome is generally poor due to the progressive and severe nature of the multi-organ involvement. Life expectancy is significantly reduced, with few affected individuals living beyond the age of 40 to 50 years. The primary causes of mortality are congestive heart failure, resulting from dilated or restrictive cardiomyopathy, and end-stage renal or hepatic failure. Quality of life is severely impacted by the early onset of blindness and progressive hearing loss, which present significant sensory challenges. Furthermore, the burden of managing multiple chronic and life-threatening conditions, including severe insulin resistance, type 2 diabetes, and progressive organ dysfunction, requires intensive, lifelong medical care. Early diagnosis and proactive, multidisciplinary management are essential to mitigate complications, delay organ failure, and optimize the quality of life for patients.

Epidemiology: Alström syndrome is an ultra-rare genetic disorder with an estimated prevalence of less than 1 in 1,000,000 in the general population, although some estimates range from 1 in 100,000 to 1 in 1,000,000. The exact incidence remains unknown, but approximately 950 to 1,200 cases have been reported worldwide. The condition affects males and females equally. While it occurs globally, it is more frequently observed in certain isolated populations due to founder effects. Higher frequencies have been noted among the French Acadians of Yarmouth County, Nova Scotia, and Louisiana, as well as in specific populations in Saudi Arabia.

Selected references: 1. Marshall JD, Maffei P, Collin GB, Naggert JK. Alström Syndrome: Genetics and Clinical Overview. Curr Genomics. 2011. PMID: 22043170 2. Hearn T. ALMS1 and Alström syndrome: a recessive form of metabolic, neurosensory and cardiac deficits. J Mol Med (Berl). 2019. PMID: 30421101 3. Joy T, Cao H, Black G, et al. Alstrom syndrome (OMIM 203800): a case report and literature review. Orphanet J Rare Dis. 2007. PMID: 18154657 4. Tahani N, Maffei P, Dollfus H, et al. Consensus clinical management guidelines for Alström syndrome. Orphanet J Rare Dis. 2020. PMID: 32941034 5. Khan AO, Bifari IN, Bolz HJ. Ophthalmic features of children not yet diagnosed with Alström syndrome. Ophthalmology. 2015. PMID: 25986797 6. Michaud JL, Héon E, Guilbert F, et al. Natural history of Alström syndrome in early childhood: onset with dilated cardiomyopathy. J Pediatr. 1996. PMID: 8636816