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Alström syndrome (AS), also called Alström–Hallgren syndrome, is a very rare
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
genetic disorder characterised by
childhood obesity Childhood obesity is a condition where excess adipose tissue, body fat negatively affects a child's health or well-being. As methods to determine body fat directly are difficult, the diagnosis of obesity is often based on Body mass index, BMI. ...
and multiple organ dysfunction. Symptoms include early-onset
type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
, cone-rod dystrophy resulting in blindness,
sensorineural hearing loss Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear, sensory organ (cochlea and associated structures), or the vestibulocochlear nerve (Cranial nerves, cranial nerve VIII). SNHL accounts for a ...
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 The cilium (: cilia; ; in Medieval Latin and in anatomy, ''cilium'') is a short hair-like membrane protrusion from many types of eukaryotic cell. (Cilia are absent in bacteria and archaea.) The cilium has the shape of a slender threadlike proj ...
, making Alström syndrome a ciliopathy. At least 239 disease-causing mutations in ''ALMS1'' have been described . 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 In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
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. Prevalence is fewer than 1 in 1,000,000 individuals in the general population, but the disorder is much more common in
Acadians The Acadians (; , ) are an ethnic group descended from the French colonial empire, French who settled in the New France colony of Acadia during the 17th and 18th centuries. Today, most descendants of Acadians live in either the Northern Americ ...
, both in
Nova Scotia Nova Scotia is a Provinces and territories of Canada, province of Canada, located on its east coast. It is one of the three Maritime Canada, Maritime provinces and Population of Canada by province and territory, most populous province in Atlan ...
and
Louisiana Louisiana ( ; ; ) is a state in the Deep South and South Central regions of the United States. It borders Texas to the west, Arkansas to the north, and Mississippi to the east. Of the 50 U.S. states, it ranks 31st in area and 25 ...
. It was first described by Swedish psychiatrist Carl-Henry Alström and his three associates, B. Hallgren, I. B. Nilsson and H. Asander, in 1959.


Signs and symptoms

Symptoms for Alström syndrome generally appear during infancy with great variability in age. Some of the symptoms include: * Heart failure ( dilated cardiomyopathy) in over 60% of cases, usually within the first few weeks after birth, but sometimes the onset is in adolescence or adulthood. * Light sensitivity and vision problems ( cone-rod dystrophy) in all cases, usually within 15 months of birth and progressively worsening until about 20 years of age * Delays in early, developmental milestones in 50% of cases,
learning disabilities Learning disability, learning disorder, or learning difficulty (British English) is a condition in the brain that causes difficulties comprehending or processing information and can be caused by several different factors. Given the "difficulty ...
in about 30% of cases *
Obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
in 100% of cases, apparent by 5 years of age but often apparent in infancy (Alström infants usually have normal birth weights, and by adolescence, weights tend to be in the high-normal to normal range.) * Nystagmus (usually affects the children), one of the first symptoms to occur which causes involuntary rapid eye movement. * Mild to moderate bilateral
sensorineural hearing loss Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear, sensory organ (cochlea and associated structures), or the vestibulocochlear nerve (Cranial nerves, cranial nerve VIII). SNHL accounts for a ...
. * Type 2
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
usually occurs in early childhood. * Hyperinsulinemia/ insulin resistance—development of high level of insulin in blood. * Hypertriglyceridemia * Steatosis (fatty liver) and elevated transaminases (liver enzymes) often develop in childhood and can progress in some patients to cirrhosis and liver failure. * Endocrine dysfunctions may occur where the patient may experience an under or over active thyroid gland, weak growth hormone, increased androgen in females and low testosterone in males. * Slowly progressive kidney failure can occur in the second to fourth decade of life.


Cause

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 The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
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 . 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.


Diagnosis

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 Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
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 Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and ...
(MRI) or
X-ray An X-ray (also known in many languages as Röntgen radiation) is a form of high-energy electromagnetic radiation with a wavelength shorter than those of ultraviolet rays and longer than those of gamma rays. Roughly, X-rays have a wavelength ran ...
s 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.


Related disorders

Recent findings in genetic research have suggested that a large number of
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...
s, 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 Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These cy ...
and
liver disease Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground gla ...
, nephronophthisis, Meckel–Gruber syndrome and some forms of retinal degeneration.


Diagnostic criteria

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: # ''ALMS1'' mutation in 1 allele and/or family history of Alström syndrome # Vision pathology (nystagmus, photophobia). Minor criteria are: # Obesity # Dilated cardiomyopathy with congestive heart failure. 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: # ''ALMS1'' mutation in 1 allele and/or family history of Alström syndrome, # Vision pathology ( nystagmus,
photophobia Photophobia is a medical symptom of abnormal intolerance to visual perception of light. As a medical symptom, photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence o ...
, diminished acuity). If old enough for testing: cone dystrophy by ERG. Minor criteria: #
Obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
and/or insulin resistance and/or
Type 2 Diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
# History of dilated cardiomyopathy with
congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF typically pr ...
#
Hearing loss Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spo ...
#
Liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
dysfunction # Kidney failure # Advanced bone age 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: # ''ALMS1'' mutation in 1 allele and/or family history of Alström syndrome. # Vision pathology (history of nystagmus in infancy/childhood, legal blindness, cone and rod dystrophy by ERG). Minor criteria: # Obesity and/or insulin resistance and/or Type 2 Diabetes # History of dilated cardiomyopathy with congestive heart failure. # Hearing loss # Hepatic dysfunction # Renal failure # Short stature # Males: hypogonadism, Females: irregular menses and/or hyperandrogenism 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

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.


Treatment

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: * Corrective lenses: tinted lenses that help with the sensitivity from bright lights. The patients may have to adapt to reading in Braille, use adaptive equipment, mobility aids and adaptive computing skills. * Education: patients with Alström syndrome who have intellectual disabilities must have access to education. They must be able to receive free and appropriate education. Some Alström syndrome patients are educated in normal classrooms. Other patients have to take special education classes or attend to specialized schools that are prepared to teach children with disabilities. Staff members from schools have to consult with patient's parents or caregivers in order to design an education plan based on the child's needs. In addition, the school may document the progress of the child in order to confirm that the child's needs are being met. * Hearing aids: the battery-operated devices are available in three styles: behind the ear, in the ear and inside the ear canal. Behind the ear aims for mild-to-profound hearing loss. In the ear aims for mild to severe hearing loss. Lastly, the canal device is aimed for mild to moderately severe hearing loss. Patients that have severe hearing loss may benefit from a cochlear implant. * Diet: an appropriate and healthy diet is necessary for individuals with Alström syndrome because it could potentially decreases chances of obesity or diabetes. * Occupational therapy: the therapist helps the child learn skills to help him or her perform basic daily tasks like eating, getting dressed and communicating with others. * Physical Activity: exercising reduces chances of being obese and helping control blood sugar levels. * Dialysis: helps restore filtering function. With hemodialysis, a patient's blood circulates into an external filter and clean. The filtered blood is then returned into the body. With peritoneal dialysis, fluid containing
dextrose Glucose is a sugar with the molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae during photosynthesis from water an ...
is introduced into the abdomen by a tube. The solution then absorbs the wastes into the body and is then removed. * Transplantation: patients that endure a kidney failure may undergo a kidney transplantation. * Surgery: if the patient endures severe scoliosis or
kyphosis Kyphosis () is an abnormally excessive convex curvature of the Spinal column, spine as it occurs in the Thoracic spine, thoracic and sacrum, sacral regions. Abnormal inward concave ''lordotic'' curving of the Cervical spine, cervical and Lumba ...
, surgery may be required.


Medication

* Antibiotics: patients with lung problems will be prescribed antibiotics because they are more prone to infections like bronchitis. * Oral diabetes medications: are taken by mouth to treat diabetes. Can be taken combined into a single pill, which may be more effective and convenient for people with diabetes. It is usually taken once or twice daily before meals. Some of these medications includes: ** Meglitinides (repaglinide and nateglinide): taken to stimulate the cells found in the pancreas to release insulin. These drugs are taken by mouth daily before each meal and could cause a drop in blood sugar. ** Metformin (biguanide): decreases the amount blood sugar being released by the liver and by stimulating the cells within muscles to take up blood sugar. Taken twice daily. ** Thiazolidinediones (rosiglitazone and pioglitazone): taken to help insulin work more efficiently in muscle and fat cells causing the liver to release less glucose. Is associated with heart failure. ** Dipeptidyl peptidase IV (DPP-4) inhibitors (sitagliptin): helps with improving blood sugar levels by decreasing the action of an enzyme breaking down
GLP-1 Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certai ...
(lowers the blood sugar level). ** Injected diabetes medicine: taken by an injection into the fat below the skin. Sometimes referred as subcutaneous injections. Some of these medications include the following: ** Pramlintide (Symlin): is an Amylin agonist. It acts centrally (via the brain) to reduce food intake and blood sugar. It is most commonly used at mealtimes by people with type 1 and type 2 diabetes. ** Exenatide (Byetta): synthetic form of exendin-4 ( a GLP-1 receptor agonist that increases secretion of insulin, decreases the secretion of glucagon from the pancreas and reduces food intake). * Cholesterol-lowering medications: is necessary when cholesterol levels are high. HMG-CoA reductase inhibitors, also called "statins," effectively lower levels of low-density lipoprotein, cholesterol and triglycerides. High-dose nicotinic acid (niacin) may also reduce cholesterol levels. * Heart medications:
Angiotensin-converting enzyme Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasocon ...
(ACE) inhibitors, diuretics,
digoxin Digoxin (better known as digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart disease, heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. ...
and beta-blockers may help with the management of cardiomyopathy and heart failure.


Prognosis

A prognosis for Alström 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.


Research

The Jackson Laboratory in Bar Harbor,
Maine Maine ( ) is a U.S. state, state in the New England region of the United States, and the northeasternmost state in the Contiguous United States. It borders New Hampshire to the west, the Gulf of Maine to the southeast, and the Provinces and ...
, USA with the
University of Southampton The University of Southampton (abbreviated as ''Soton'' in post-nominal letters) is a public university, public research university in Southampton, England. Southampton is a founding member of the Russell Group of research-intensive universit ...
, UK isolated the single
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
('' ALMS1'') responsible for Alström syndrome. Research was conducted in 2014 on Alström syndrome patients regarding degeneration and plasticity of the optic pathway. The functional and structural changes have been investigated on the optic pathway in Alström 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 Alström syndrome had occipital regions with decreased white matter volume as well as decreased gray matter volume sparing the occipital poles. The diffused fractional
anisotropy Anisotropy () is the structural property of non-uniformity in different directions, as opposed to isotropy. An anisotropic object or pattern has properties that differ according to direction of measurement. For example, many materials exhibit ve ...
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 Alström syndrome. They are likely to reflect coexistence of diffuse primary
myelin Myelin Sheath ( ) is a lipid-rich material that in most vertebrates surrounds the axons of neurons to insulate them and increase the rate at which electrical impulses (called action potentials) pass along the axon. The myelinated axon can be lik ...
derangement, anterograde trans-synaptic degeneration and complex cortical reorganization that affect the posterior and anterior visual cortex.


References


Further reading

* {{DEFAULTSORT:Alstrom Syndrome Ciliopathy Syndromes with obesity Syndromes with sensorineural hearing loss Syndromes affecting the retina Syndromes including diabetes mellitus Rare genetic syndromes Diseases named after discoverers