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Alstrom syndrome

Alstrom syndrome (AS), also called Alstrom-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 Alstrom syndrome.

It is caused by mutations in the gene ALMS1, which is involved in the formation of cellular cilia, making Alstrom syndrome a ciliopathy. At least 239 disease-causing mutations in ALMS1 have been described as of 2015[update]. Alstrom 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 Alstrom 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 Alstrom syndrome rarely live beyond 50.[medical citation needed]

At least 900 cases have been reported. Prevalence is fewer than 1 in 1,000,000 individuals in the general population, but the disorder is much more common in Acadians, both in Nova Scotia and Louisiana. It was first described by Swedish psychiatrist Carl-Henry Alstrom and his three associates, B. Hallgren, I. B. Nilsson and H. Asander, in 1959.

Symptoms for Alstrom syndrome generally appear during infancy with great variability in age. Some of the symptoms include:[medical citation needed]

Alstrom 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[update]. Most of these mutations have led to the production of a dysfunctional version of the ALSM1 protein which are present in tissues, but at low levels.

It is possible to clinically detect Alstrom syndrome in infancy, but more frequently, it is detected much later, as doctors tend to detect symptoms as separate problems. Currently, Alstrom syndrome is often diagnosed clinically, since genetic testing is costly and only available on a limited basis.

A physical examination would be needed to properly diagnose the patient. Certain physical characteristics can determine if the patient has some type of genetic disorder. Usually, a geneticist would perform the physical examination by measuring the distance around the head, distance between the eyes and the length of arms and legs. In addition, examinations for the nervous system or the eyes may be performed. Various imaging studies like computerized tomography scans (CT), Magnetic Resonance Imaging (MRI) or X-rays are used to see the structures within the body.

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.

Marshall JD et al. provided a comprehensive guidance for diagnostic criteria in their 2007 publication.

Birth - 2 years:

Minimum diagnosis requires 2 major criteria or 1 major and 2 minor criteria.

Major criteria are:

Minor criteria are:

Other variable supportive evidence:
Recurrent pulmonary infections, normal digits, delayed developmental milestones.

At 3-14 years of age:

2 major criteria or 1 major and 3 minor criteria.

Major criteria are:

Minor criteria:

Variable supportive evidence:
Recurrent pulmonary infections, normal digits, delayed developmental milestones, hyperlipidemia, scoliosis, flat wide feet
hypothyroidism, hypertension, recurrent urinary tract infection, growth hormone deficiency.

Presentation 15 years - adulthood:

2 major and 2 minor criteria or 1 major and 4 minor criteria.

Major criteria are:

Minor criteria:

Other supportive features:

Recurrent pulmonary infections, normal digits, history of developmental delay, hyperlipidemia, scoliosis, flat wide feet,
hypothyroidism, hypertension, recurrent urinary tract infections/urinary dysfunction, growth hormone deficiency, alopecia.

Prevention for Alstrom 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 Alstrom 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 Alstrom syndrome; however, there are treatment aims to reduce the symptoms and prevent further complications. Some of these treatment aims include:

A prognosis for Alstrom syndrome is complicated because it widely varies. Any person that has the syndrome have different set of disorders. Permanent blindness, deafness and type 2 diabetes may occur. Liver and kidney failure can progressively get worse. The life expectancy is usually reduced and the patients rarely live past 50 years old.

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

Research was conducted in 2014 on Alstrom syndrome patients regarding degeneration and plasticity of the optic pathway. The functional and structural changes have been investigated on the optic pathway in Alstrom syndrome by using magnetic resonance imaging to provide better insight on the underlying pathogenic mechanisms. Eleven patients with the syndrome (mean age of 23 years, 5 females, 6 males) underwent a brain MRI. The protocol also included conventional sequences, resting-state functional MRI and diffusion tensor imaging. Results found that patients with Alstrom syndrome had occipital regions with decreased white matter volume as well as decreased gray matter volume sparing the occipital poles. The diffused fractional anisotropy decreased and the radial diffusivity increased while mean and axial diffusivities were normal. Lastly, the reduced connectivity in the medial visual network was strikingly sparing the occipital poles. The conclusion of the research was that the protean occipital brain changes in patients with Alstrom syndrome. They are likely to reflect coexistence of diffuse primary myelin derangement, anterograde trans-synaptic degeneration and complex cortical reorganization that affect the posterior and anterior visual cortex.

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