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Alström syndrome
This syndrome is typically identified in childhood and can impact the heart, kidneys, and endocrine system. It affects both males and females equally and is caused by genetic changes inherited from both parents.
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Overview
Alström syndrome is a rare genetic disorder that affects multiple parts of the body, often becoming apparent within the first few years of life. Key features frequently include progressive loss of vision and hearing, typically beginning in infancy or early childhood. Individuals with Alström syndrome also commonly develop obesity, insulin resistance leading to type 2 diabetes, and heart muscle disease (cardiomyopathy) [PMID:17918344].
This condition can vary in how it affects different people, even within the same family. It is considered a ciliopathy, a group of disorders caused by defects in cilia, which are tiny, hair-like structures found on the surface of most human cells. Cilia play important roles in cell signalling and many organ functions. Because of the wide range of affected systems, care for individuals with Alström syndrome often involves a team of specialists to manage the various symptoms [PMID:33677242].
The exact prevalence of Alström syndrome is not well established, but it is considered a very rare condition.
Symptoms & clinical features
The symptoms of Alström syndrome are varied and typically progress over time. Vision loss often starts in infancy due to a condition called rod-cone dystrophy, which affects the light-sensitive cells in the retina. This can lead to severe visual impairment or blindness by late childhood or adolescence. Nystagmus (involuntary eye movements) and sensitivity to light are also common eye features.
Progressive hearing loss, usually sensorineural, also commonly begins in childhood and can worsen over time. Heart problems, specifically dilated cardiomyopathy, can develop early in life, sometimes even in infancy, and can be a serious concern. Many individuals with Alström syndrome develop obesity during childhood, which often leads to type 2 diabetes due to insulin resistance.
Other potential symptoms can include kidney dysfunction, liver problems, hypothyroidism (underactive thyroid), and short stature. Some individuals may also experience scoliosis (curvature of the spine) or problems with their teeth and hair. The specific combination and severity of these symptoms can differ significantly among affected individuals.
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Affected organs
Alström syndrome has a broad impact on various body systems and organs. The eyes and ears are consistently affected, leading to progressive vision and hearing impairment. The heart is frequently involved, with dilated cardiomyopathy being a significant concern. The endocrine system is also widely affected, contributing to obesity, insulin resistance, type 2 diabetes, and sometimes hypothyroidism or hypogonadism.
Kidneys can develop progressive renal impairment, and the liver may show signs of fibrosis or steatosis (fatty liver). Other organs that may be affected include the lungs (leading to recurrent infections), the musculoskeletal system (e.g., scoliosis, low bone density), and the central nervous system, though neurological issues are less common than other symptoms.
Risks & severity
Alström syndrome typically presents with symptoms during infancy or early childhood, though the exact timing and progression can vary. Vision impairment often becomes noticeable within the first year of life, and hearing loss usually emerges in early to mid-childhood. The severity of the condition varies widely; for example, cardiomyopathy can range from mild forms to severe, life-threatening heart failure, even at a very young age [PMID:17918344].
Individuals with Alström syndrome face increased risks for several chronic health conditions. These include advanced type 2 diabetes, often developing in adolescence or early adulthood, and progressive kidney and liver disease. Regular monitoring and early intervention are crucial for managing these potential complications and improving long-term health outcomes. Life expectancy can be reduced due to complications impacting the heart, kidneys, or liver, though medical advancements are continually improving management strategies.
Genetic causes
Alström syndrome is caused by pathogenic variants in one specific gene: ALMS1. This gene provides instructions for making the ALMS1 protein, which plays a critical role in the function of cilia, key cellular structures found on many cell types throughout the body. Cilia are involved in a wide range of cellular processes, including cell signalling, development, and maintaining organ function [PMID:33677242].
When there are pathogenic changes in ALMS1, the ALMS1 protein may not be produced correctly or may not function as it should. This disruption of normal ciliary function leads to the diverse range of symptoms seen in Alström syndrome, affecting multiple organs and body systems. The syndrome is classified as a ciliopathy due to this fundamental genetic mechanism.
- ALMS1 ALMS1 centrosome and basal body associated proteinThe ALMS1 gene provides instructions for a protein involved in various cellular processes, with mutations linked to Alström syndrome, a rare inherited disorder.
Inheritance pattern
Alström syndrome follows an autosomal recessive pattern of inheritance. This means that an individual must inherit two copies of a pathogenic ALMS1 variant-one from each parent-to develop the condition. If a person inherits only one pathogenic variant and one typical copy of the gene, they are considered a 'carrier'. Carriers typically do not show symptoms of Alström syndrome.
When both parents are carriers of an ALMS1 pathogenic variant, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two affected copies and therefore develop Alström syndrome. There is a 50% (2 in 4) chance that their child will be a carrier, and a 25% (1 in 4) chance that their child will inherit two typical copies of the gene and will not develop the condition nor be a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosing Alström syndrome typically involves a combination of clinical evaluation and genetic testing. A healthcare professional may suspect the condition based on the presence of key features like early-onset vision loss, hearing loss, obesity, and dilated cardiomyopathy. Detailed assessments by specialists, such as ophthalmologists, audiologists, and cardiologists, contribute to the clinical picture.
Confirmation of Alström syndrome relies on identifying two pathogenic variants in the ALMS1 gene through genetic testing. This testing is often arranged through a clinical genetics service following a referral from a GP or specialist. Genetic testing for Alström syndrome falls under the NHS Genomic Medicine Service, with specific R-codes for genomic testing where clinically appropriate. A genetic counsellor can provide support and information throughout the diagnostic process, helping families understand the implications of a diagnosis.
Management & lifestyle
While there is currently no cure for Alström syndrome, management focuses on addressing specific symptoms and preventing complications through regular monitoring and supportive care. A multidisciplinary team of healthcare professionals is typically involved, which may include ophthalmologists, audiologists, cardiologists, endocrinologists, nephrologists, and dietitians.
For vision and hearing loss, assistive devices such as low-vision aids, hearing aids, or cochlear implants may be recommended. Heart conditions like cardiomyopathy are managed with medications and regular cardiac assessments. Diabetes is treated with standard therapies, including diet, exercise, and medication such as insulin if necessary. Obesity is managed through dietary advice and lifestyle modifications. Regular screening for kidney and liver function is also important, along with monitoring for other potential issues like hypothyroidism.
Individuals and families can access support through NHS care pathways, often coordinated by clinical genetics departments. Genetic counsellors play a vital role in providing information, support, and guidance on living with Alström syndrome.
UK care pathway
In the UK, suspected cases of Alström syndrome would typically be referred by a GP or specialist to a regional Clinical Genetics service. This service can arrange for genomic testing, which is available through the NHS Genomic Medicine Service (GMS) pathways. The specific R-codes for genomic testing for Alström syndrome would be reviewed to ensure appropriate testing is undertaken.
Clinical geneticists and genetic counsellors within these services provide expert care, including diagnosis, genetic counselling for families, and coordination of multidisciplinary management plans. They can also offer information about the condition, its inheritance, and implications for other family members.
Frequently asked questions
What is the life expectancy for someone with Alström syndrome?
Life expectancy can vary significantly depending on the severity of symptoms, particularly heart, kidney, and liver involvement. With early diagnosis and comprehensive management, the prognosis has improved, though complications can still be life-limiting. Regular monitoring and appropriate medical interventions are crucial.
Can Alström syndrome be prevented?
No, Alström syndrome is a genetic condition caused by inherited variants in the ALMS1 gene and cannot be prevented. For families with a known history, genetic counselling can provide information about the risks of passing the condition on and discuss options like prenatal diagnosis or pre-implantation genetic diagnosis.
Is Alström syndrome always severe?
The severity of Alström syndrome can vary greatly, even among individuals within the same family. While many experience significant health challenges, the specific combination and progression of symptoms like vision loss, hearing loss, and organ involvement can differ, leading to a spectrum of experiences.
What kind of support is available for families affected by Alström syndrome?
Families can access support through their NHS clinical genetics team and genetic counsellors, who can help navigate care pathways. Patient organisations and charities specific to rare genetic conditions or ciliopathies may also offer valuable information, resources, and community networks for affected individuals and their families.
How common is Alström syndrome?
Alström syndrome is considered a very rare genetic condition. The exact prevalence is not precisely known, but it affects a very small number of people worldwide. It is much less common than many other types of genetic conditions.
References
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- Tsang SH, Aycinena ARP, Sharma T. Ciliopathy: Alström Syndrome. Advances in experimental medicine and biology. 2018. PMID: 30578508
- Shoemaker A. Bardet-Biedl syndrome: A clinical overview focusing on diagnosis, outcomes and best-practice management. Diabetes, obesity & metabolism. 2024. PMID: 38383825
- Markham A. Setmelanotide: First Approval. Drugs. 2021. PMID: 33638809
- Haqq AM, Chung WK, Dollfus H. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. The lancet. Diabetes & endocrinology. 2022. PMID: 36356613
- Vaisse C, Reiter JF, Berbari NF. Cilia and Obesity. Cold Spring Harbor perspectives in biology. 2017. PMID: 28096262
- Marshall JD, Beck S, Maffei P. Alström syndrome. European journal of human genetics : EJHG. 2007. PMID: 17940554
- Engle SE, Bansal R, Antonellis PJ. Cilia signaling and obesity. Seminars in cell & developmental biology. 2021. PMID: 32466971