Alström syndrome (AS) is a very rare multi-system, autosomal recessive genetic disorder characterized by type 2 diabetes, cone-rod dystrophy resulting in blindness, sensorineural hearing loss and cardiomyopathy. Endocrine disorders typically also occur, such as hypergonadotrophic hypogonadism and hypothyroidism, as well as acanthosis nigricans resulting from hyperinsulinemia.
AS is caused by variants in the ALMS1 gene, which is located on the chromosome 2-13 and is involved in the formation of cellular cilia, making Alström syndrome a ciliopathy. At least 300 disease-causing variants in ALMS1 have been described as of 2023. Alström syndrome is sometimes confused with Bardet–Biedl syndrome, another ciliopathy which has similar symptoms, but Bardet–Biedl syndrome tends to be associated with multiple genes, rather than just one like in AS, and includes polydactyly.
There is no cure or specific therapy for Alström syndrome. However, various treatments target the individual symptoms and can include diet, specialized glasses, hearing aids, medications for diabetes and heart issues, and dialysis and/or transplantation in the case of kidney or liver failure. Prognosis varies depending on the specific combination of symptoms, but individuals with Alström syndrome rarely live beyond 50.
Prevalence of AS is cited as 1 in 1,000,000 individuals in the general population, but this is expected to be an underestimation due to the phenotypic variation of the disease and the high rate of misdiagnosis. There is a higher frequency of variants within French Acadians and English populations.
Research Alström Syndrome was first discovered by Swedish psychiatrist, Carl-Henry Alström and his three associates, B. Hallgren, I. B. Nilsson and H. Asander, in 1946. Alström and his colleagues published their first manuscript in 1959, which contained a very thorough investigation of three patients with a recessive combination of retinal degeneration, obesity, sensorineural hearing loss, and diabetes, which are all extremely common symptoms in AS. The syndrome was first known as Alström-Hallgren Syndrome, but has since been more widely known as just Alström Syndrome.
In 2001 Jackson Laboratory in Bar Harbor, Maine, USA with the University of Southampton, UK isolated the single gene (ALMS1) responsible for Alström syndrome. The Jackson Laboratory created the very first mouse model for AS, Alms1-/-, or more colloquially known as "Carl Henry Mouse" in 2004. These mice continue to be used in research studies to simulate the symptoms of an individual with AS.
Cause
Alström syndrome is caused by a mutation in the ALMS1 gene, located on the short arm of chromosome 2p13. The gene mutation is inherited as an autosomal recessive trait. This means both parents have to pass a defective copy of the ALMS1 gene in order for their child to have the syndrome, even though the parents may not show signs or symptoms of the condition.
The ALMS1 gene contains instructions to encode a specific protein known as ALMS1. The protein then is involved in ciliary maintenance and function, cell cycle control, energy balance homeostasis, and intracellular transport. It has a role in the proper function, maintenance and formation of cilia, which are found in all types of cells in the body. Most of these variants have led to the production of a dysfunctional version of the ALSM1 protein which are present in tissues, but at low levels.
Signs and symptoms Symptoms for Alström syndrome can be extremely variable in both age of onset and presentation. Some common symptoms include: Retinal dystrophy (cone-rod dystrophy) in all cases, usually within a few weeks of birth and progressively worsening until about 20 years of age when vision is lost. Nystagmus (often one of the first symptoms identified) and photophobia are also very common. Mild to moderate progressive bilateral sensorineural hearing loss. Hearing impairment is typically diagnosed between the ages of 1 and 10. Congestive heart failure (dilated cardiomyopathy) in over 60% of individuals over the course of their lifetimes. Around 40% of individuals suffer from a severe cardiomyopathy within the first few months of life. For those who survive, cardiomyopathy occurs in 1 of 5 patients with onset in adolescence or adulthood. Hypothyroidism tends to occur in less than half of patients. Growth hormone dysfunction is common in around half of individuals with AS. Thoracic and lumbar scoliosis, kyphosis, or lordosis is present in around 68% of patients. Male hypergonadotropic and hypogonadotropic hypogonadism and female hyperandrogenism. Men can experience microphallus, undescended testes, hypospadias, small testes, and gynecomastia. They are also unlikely to be fertile. Women can experience hirsutism, alopecia, oligomenorrhea/amenorrhea, polycystic ovaries, high testosterone levels, abnormal breast development, precocious puberty, and endometriosis. Female fertility is unlikely and only reported in a few cases. Childhood obesity occurs in most people with AS. Alström infants are usually within the normal birth weight and then experience rapid weight gain within the first 2–36 months. Hyperphagia or polyphagia is common within Alström populations and has been shown to contribute to weight gain. Moderate to severe hypertriglyceridemia occurs in most individuals. Almost all individuals with AS experience insulin resistance and/or hyperinsulinemia to some degree. Therefore, type 2 diabetes mellitus often results as early as 5 years of age with a median onset of 16 years. Non-alcoholic fatty liver disease is common in AS. This often progresses to non-alcoholic steatohepatitis. Upper and lower respiratory tract infections in childhood, which decrease during adulthood. Bronchitis, pneumonia, and sinusitis have also been reported. Increased susceptibility to hypoxemia during or after surgery. Chronic obstructive pulmonary disease, interstitial lung disease, or acute respiratory distress syndrome is also seen in some older patients. Chronic kidney disease is common in some cases that can lead to end-stage renal disease/kidney failure as early as mid-to late teens. Less than half of individuals experience dysuria. Epigastric pain, nausea, and gastroesophageal reflux disease are common. Delays in gross and fine motor skills, learning disabilities, and mixed receptive-expressive language delays are common. Cognitive impairment, however, is very rare. Delays in early, developmental milestones in 50% of cases, learning disabilities in about 30% of cases. Seizures and hyporeflexia have been reported but are less common (20% of individuals).
Diagnosis Diagnosis typically occurs in the first few years of life and should be confirmed with a review of symptoms as well as genetic testing with targeted panels that include the ALMS1 gene as well as other ciliopathies, retinal diseases, cardiomyopathy, and obesity. Typically, the first symptoms to be observed are nystagmus, photophobia, impaired vision, and/or infantile cardiomyopathy within the first two years of life. Obesity and/or sensorineural hearing loss are often next and should be followed by genetic/molecular testing to try and identify two pathogenic variants of ALMS1 to confirm or deny the presence of the disease.
However, the rarity of the disease, variability of symptoms, and lack of experts can make diagnosis very difficult. Additionally, since it can be difficult to identify both biallelic pathogenic variants in the ALMS1 gene, there is existing diagnostic criteria as shown below. +Alström Syndrome Diagnostic Criteria by Age Chart from 2019 Gene ReviewAge RangeMajor Diagnostic CriteriaMinor Diagnostic CriteriaMinimum Required0 – 2 years -1 ALMS1 variant OR family history of Alström syndrome -Visual impairment
-Infantile cardiomyopathy -Obesity -Hearing loss -2 major criteria OR -1 major + 2 minor criteria3–14 years -1 ALMS1 variant OR family history of Alström syndrome -Visual impairment
-History of infantile cardiomyopathy -Hearing loss -Obesity AND/OR its complications
-Restrictive cardiomyopathy
-Decreased renal function -2 major criteria OR -1 major + 3 minor criteria 15 years - adult -1 ALMS1 variant OR family history of Alström syndrome -Visual impairment -Hearing loss -Restrictive cardiomyopathy AND/OR history of infantile cardiomyopathy
-Obesity AND/OR its complications
-Chronic kidney disease -2 major + 2 minor criteria OR -1 major + 4 minor criteria
Assessment Due to Alström Syndrome's effect on nearly every organ system of the body, experts strongly recommend a multidisciplinary team of professionals with experience caring for those with AS when possible. The following multidisciplinary assessment is recommended for those with AS: +Specialists and Assessment Recommendations 2020 Consensus GuidelinesDisciplineFeatures of AS for which this discipline may be of assistanceInitial AssessmentFollow-upPrimary Care PhysicianProvide oversight & coordinate specialistsFirst referral at time of diagnosis6 months or less as per clinical needGeneticists/clinical scientistsPrenatal screening, AS diagnosis, counseling for familiesFirst referral prenatal or during childhood. Initial assessment: detection of two ALMS1 variants. Then, possible investigation of parental genotypic informationAs per request or clinical needOpthalamologistsBlindness, nystagmus, photophobia, retinal dystrophyFirst referral before the age of one. Initial assessment includes: standard evaluation, imaging, and testing AnnuallyENT specialistProgressive bilateral sensorineural hearing lossFirst referral usually during childhood. Assessment includes otologic and audiologic evaluation of both ears.AnnuallyCardiologistInfantile, juvenile, or adult onset cardiomyopathy, hypertension, coronary artery disease, heart failureFirst referral before the age of one. Initial assessment: natriuretic peptides, transthoracic echocardiography (TTE), ECG. In older children and adult, include CMRECG - yearly TTE - yearly or per clinical needPulmonologistAssess for pulmonary fibrosis, restrictive lung disease, pulmonary hypertensionFirst referral during adulthood. Initial assessment includes Conventional Pulmonary Function test (cPFT) and chest X-ray, and HRCT Thorax when needed.HRCT Thorax - as per clinical needEndocrinologist/Metabolic Specialist Assess and treatment of metabolic complications (obesity, insulin-resistance, type II diabetes, non-alcoholic fatty liver disease, dyslipidemia) and endocrine disorders (hypothyroidism, GH deficiency, male hypogonadism, female hypoandrogenism)First referral during childhood. Initial assessment: Body measurements, thyroid Function Test (TFT), pituitary and sexual hormones, glucose levels, HbA1c, and lipid profile. Every 6–12 months in children, then yearly Gastroenterologist/hepatologistAssess for liver fibrosis/cirrhosis and associated complications (portal hypertension, cancer, liver failure).First referral: From childhood to adulthood Initial assessment: Liver function tests, platelet count, liver ultrasound, transient elastography and ELF test. Upper endoscopy (EGD) in case of cirrhosis Yearly or per clinical need Liver ultrasound yearly or as per clinical need NephrologistAssess for progressive renal dysfunction and Chronic Kidney DiseaseFirst referral: from mid-childhood to adulthood Initial assessment: Kidney function test and renal ultrasonographyYearly or per clinical needNeurologistAssess of developmental milestones, learning disability, mixed receptive-expressive language delays, seizure, and hyporeflexiaFirst referral during childhood.