Alström syndrome

Rare genetic disorder involving childhood obesity and multiple organ dysfunction

Alström syndrome (AS), also called Alström–Hallgren syndrome, is a very rare autosomal recessive genetic disorder characterised by childhood obesity and multiple organ dysfunction. Symptoms include early onset type 2 diabetes, cone rod dystrophy resulting in blindness, sensorineural hearing loss and dilated cardiomyopathy. Endocrine disorders typically also occur, such as hypergonadotrophic hypogonadism and hypothyroidism, as well as acanthosis nigricans resulting from hyperinsulinemia. Developmental delay is seen in almost half of people with Alström syndrome. It is caused by mutations in the gene ALMS1, which is involved in the formation of cellular cilia, making Alström syndrome a ciliopathy. At least 239 disease causing mutations in ALMS1 have been described as of 2015. Alström syndrome is sometimes confused with Bardet–Biedl syndrome, another ciliopathy which has similar symptoms, but Bardet–Biedl syndrome tends to have later onset in its symptoms, includes polydactyly and is caused by mutations in BBS genes. There is no cure for Alström syndrome. Treatments target the individual symptoms and can include diet, corrective lenses, hearing aids, medications for diabetes and heart issues and dialysis and 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. At least 900 cases have been reported. It was first described by Swedish psychiatrist Carl Henry Alström and his three associates, B. Hallgren, I. B. Nilsson and H. Asander, in 1959.

Alström syndrome is caused by a mutation in the ALMS1 gene, located on the short arm of chromosome 2 (2p13.2). 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 function, cell cycle control and intracellular transport. In addition, the protein is expressed in all organ tissues of the body. It has a role in the proper function, maintenance and formation of cilia, which are found in all types of cells in the body. At least 239 disease causing mutations in ALMS1 have been described as of 2015.

It is possible to clinically detect Alström syndrome in infancy, but more frequently, it is detected much later, as doctors tend to detect symptoms as separate problems. Currently, Alström syndrome is often diagnosed clinically, since genetic testing is costly and only available on a limited basis. Family and personal medical history are required. Information about the health of an individual is crucial because it provides traces to a genetic diagnosis. Laboratory tests, particularly genetic testing, are performed to diagnose genetic disorders. Some of the types of genetic testing are molecular, biochemical and chromosomal. Other laboratory tests performed may measure levels of certain substances in urine and blood that can also help suggest a diagnosis.

Recent findings in genetic research have suggested that a large number of genetic disorders, both genetic syndromes and genetic diseases, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical root cause of the widely varying, phenotypically observed disorders. Thus, Alstrom syndrome is a ciliopathy. Other known ciliopathies include primary ciliary dyskinesia, Bardet–Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Meckel–Gruber syndrome and some forms of retinal degeneration.

Prevention for Alström syndrome is considered to be harder compared to other diseases/syndromes because it is an inherited condition. However, there are other options that are available for parents with a family history of Alström syndrome. Genetic testing and counseling are available where individuals are able to meet with a genetic counselor to discuss risks of having the children with the disease. The genetic counselor may also help determine whether individuals carry the defective ALSM1 gene before the individuals conceive a child. Some of the tests the genetic counselors perform include chorionic villus sampling (CVS), preimplantation genetic diagnosis (PGD) and amniocentesis. With PGD, the embryos are tested for the ALSM1 gene and only the embryos that are not affected may be chosen for implantation via in vitro fertilization.

There is no cure for Alström syndrome; however, there are treatment aims to reduce the symptoms and prevent further complications. Some of these treatment aims include:
Heart medications: Angiotensin converting enzyme (ACE) inhibitors, diuretics, digoxin and beta blockers may help with the management of cardiomyopathy and heart failure.

The Jackson Laboratory in Bar Harbor, Maine, USA with the University of Southampton, UK isolated the single gene (ALMS1) responsible for Alström syndrome.