Alstrom syndrome
Encyclopedia
Alström syndrome is a rare genetic disorder caused by mutations in the gene ALMS1. It is among the rarest genetic disorders in the world, as currently it has only 266 reported cases in medical literature and over 501 known cases in 47 countries. It was first described by Carl-Henry Alström
in Sweden in 1959. Alstrom syndrome is sometimes confused with Bardet-Biedl syndrome
, which has similar symptoms. Bardet-Biedl syndrome tends to have later onset in its symptoms.
According to a 2007 article by Joy et al. publilshed in the Oprhanet Journal of Rare Diseases:
in Bar Harbor, Maine
, USA with the University of Southampton
, UK isolated the single gene
(ALMS1
) responsible for Alström Syndrome. The gene is recessive
; it must be passed from both parents for the syndrome to manifest.
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.
Birth – 2 years:
Minimum diagnosis requires 2 major criteria or 1 major and 2 minor criteria.
Major criteria are:
1) ALMS1 mutation in 1 allele and/or family history of Alström Syndrome
2) Vision pathology (nystagmus, photophobia).
Minor criteria are:
1) Obesity
2) 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:
1) ALMS1 mutation in 1 allele and/or family history of Alström Syndrome,
2) Vision pathology (nystagmus, photophobia, diminished acuity). If old enough for testing: cone dystrophy by ERG.
Minor Criteria:
1) Obesity and/or insulin resistance and/or Type 2 Diabetes
2) History of dilated cardiomyopathy with congestive heart failure
3) Hearing loss
4) Hepatic dysfunction
5) Renal failure
6) 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:
1) ALMS1 mutation in 1 allele and/or family history of Alström Syndrome.
2) Vision pathology (history of nystagmus in infancy/childhood, legal blindness, cone and rod dystrophy by ERG).
Minor criteria:
1) Obesity and/or insulin resistance and/or Type 2 Diabetes
2) History of dilated cardiomyopathy with congestive heart failure.
3) Hearing loss
4) Hepatic dysfunction
5) Renal failure
6) Short stature
7) 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.
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
and liver disease
, nephronophthisis
, Meckel-Gruber syndrome and some forms of retinal degeneration
..
Carl-Henry Alström
Carl-Henry Alström was a Swedish psychiatrist who described a syndrome now named for him, Alström syndrome, an hereditary disorder that characteristically includes obesity in childhood, nerve deafness and retinal degeneration .-External links:* biographical sketch on site*...
in Sweden in 1959. Alstrom syndrome is sometimes confused with Bardet-Biedl syndrome
Bardet-Biedl syndrome
The Bardet–Biedl syndrome is a ciliopathic human genetic disorder that produces many effects and affects many body systems. It is characterized principally by obesity, retinitis pigmentosa, polydactyly, mental retardation, hypogonadism, and renal failure in some cases.-Summary of the...
, which has similar symptoms. Bardet-Biedl syndrome tends to have later onset in its symptoms.
According to a 2007 article by Joy et al. publilshed in the Oprhanet Journal of Rare Diseases:
"Alström syndrome (AS) is a rare autosomal recessive disease characterized by
multiorgan dysfunction. The key features are childhood obesity, blindness due to
congenital retinal dystrophyDystrophyDystrophy is any condition of abnormal development, often denoting the degeneration of muscles.-Types:* Muscular dystrophy* Duchenne muscular dystrophy* Becker's muscular dystrophy* Reflex neurovascular dystrophy* Retinal dystrophy* Conal dystrophy...
, and sensorineural hearing lossSensorineural hearing lossSensorineural hearing loss is a type of hearing loss in which the root cause lies in the vestibulocochlear nerve , the inner ear, or central processing centers of the brain....
. Associated endocrinologicEndocrinologyEndocrinology is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions called hormones, the integration of developmental events such as proliferation, growth, and differentiation and the coordination of...
features include hyperinsulinemiaHyperinsulinemiaHyperinsulinemia, or hyperinsulinaemiais a condition which there is excess levels of insulin circulating in the blood than expected relative to the level of glucose. While it is often mistaken for diabetes or hypoglycaemia, hyperinsulinemia can result from a variety of metabolic diseases and...
, early-onset type 2 diabetes, and hypertriglyceridemiaHypertriglyceridemiaIn medicine, hypertriglyceridemia denotes high blood levels of triglycerides, the most abundant fatty molecule in most organisms. It has been associated with atherosclerosis, even in the absence of hypercholesterolemia . It can also lead to pancreatitis in excessive concentrations In medicine,...
.
Thus, AS shares several features with the common metabolic syndrome, namely
obesity, hyperinsulinemia, and hypertriglyceridemia. Mutations in the ALMS1ALMS1Alstrom syndrome 1 also known as ALMS1 is a protein which in humans is encoded by the ALMS1 gene.- Molecular biology :The gene is located on the short arm of chromosome 2 on the plus strand. It is 224,161 bases in length organised into 23 exons. The encoded protein has 4,167 amino acids and...
gene have
been found to be causative for AS with a total of 79 disease-causing mutations having
been described."
Diagnosis
The Jackson LaboratoryJackson Laboratory
The Jackson Laboratory was founded in Bar Harbor, Maine in 1929 by former University of Maine and University of Michigan president C. C. Little under the name Roscoe B...
in Bar Harbor, Maine
Maine
Maine is a state in the New England region of the northeastern United States, bordered by the Atlantic Ocean to the east and south, New Hampshire to the west, and the Canadian provinces of Quebec to the northwest and New Brunswick to the northeast. Maine is both the northernmost and easternmost...
, USA with the University of Southampton
University of Southampton
The University of Southampton is a British public university located in the city of Southampton, England, a member of the Russell Group. The origins of the university can be dated back to the founding of the Hartley Institution in 1862 by Henry Robertson Hartley. In 1902, the Institution developed...
, UK isolated the single gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
(ALMS1
ALMS1
Alstrom syndrome 1 also known as ALMS1 is a protein which in humans is encoded by the ALMS1 gene.- Molecular biology :The gene is located on the short arm of chromosome 2 on the plus strand. It is 224,161 bases in length organised into 23 exons. The encoded protein has 4,167 amino acids and...
) responsible for Alström Syndrome. The gene is recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
; it must be passed from both parents for the syndrome to manifest.
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
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
is costly and only available on a limited basis.
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:
1) ALMS1 mutation in 1 allele and/or family history of Alström Syndrome
2) Vision pathology (nystagmus, photophobia).
Minor criteria are:
1) Obesity
2) 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:
1) ALMS1 mutation in 1 allele and/or family history of Alström Syndrome,
2) Vision pathology (nystagmus, photophobia, diminished acuity). If old enough for testing: cone dystrophy by ERG.
Minor Criteria:
1) Obesity and/or insulin resistance and/or Type 2 Diabetes
2) History of dilated cardiomyopathy with congestive heart failure
3) Hearing loss
4) Hepatic dysfunction
5) Renal failure
6) 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:
1) ALMS1 mutation in 1 allele and/or family history of Alström Syndrome.
2) Vision pathology (history of nystagmus in infancy/childhood, legal blindness, cone and rod dystrophy by ERG).
Minor criteria:
1) Obesity and/or insulin resistance and/or Type 2 Diabetes
2) History of dilated cardiomyopathy with congestive heart failure.
3) Hearing loss
4) Hepatic dysfunction
5) Renal failure
6) Short stature
7) 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.
Early symptoms
- Heart failure (Dilated cardiomyopathyCardiomyopathyCardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
) in over 60% of cases, usually within the first few weeks after birth, but sometimes the onset is in adolescence or adulthood. - Light sensitivityLight sensitivityLight sensitivity or photosensitivity is an increase in the reactivity of the skin to sunlight. Apart from vision, human beings have many physiological and psychological responses to light. In rare individuals an atypical response may result in serious discomfort, disease, or injury. Some drugs...
and vision problems (Cone-rod dystrophy) in all cases, usually within 15 months of birth and progressively worsening until about 20 years of age - Developmental delays in 50% of cases, learning disabilities in about 30% of cases
- ObesityObesityObesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
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)
Relation to other rare genetic disorders
Recent findings in genetic research have suggested that a large number of genetic disorderGenetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
s, both genetic syndromes
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
and genetic diseases
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
root cause of the widely-varying, phenotypically
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
-observed disorders. Thus, Alstrom syndrome is a ciliopathy
Ciliopathy
A ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies, or of ciliary function.Although ciliopathies are usually considered to involve proteins that localize to the primary cilia or centrosomes, it is possible for ciliopathies to be associated...
. Other known ciliopathies include primary ciliary dyskinesia
Primary ciliary dyskinesia
Primary ciliary dyskinesia , also known as immotile ciliary syndrome or Kartagener Syndrome ', is a rare, ciliopathic, autosomal recessive genetic disorder that causes a defect in the action of the cilia lining the respiratory tract and fallopian tube, and also of the flagella of sperm in...
, Bardet-Biedl syndrome
Bardet-Biedl syndrome
The Bardet–Biedl syndrome is a ciliopathic human genetic disorder that produces many effects and affects many body systems. It is characterized principally by obesity, retinitis pigmentosa, polydactyly, mental retardation, hypogonadism, and renal failure in some cases.-Summary of the...
, polycystic kidney
Polycystic kidney disease
Autosomal dominant polycystic kidney disease is an inherited systemic disorder that predominantly affects the kidneys, but may affect other organs including the liver, pancreas, brain, and arterial blood vessels...
and liver disease
Polycystic liver disease
Polycystic liver disease usually describes the presence of multiple cysts scattered throughout normal liver tissue, in association with polycystic kidney disease.-Pathophysiology:Associations with PRKCSH and SEC63 have been described....
, nephronophthisis
Nephronophthisis
Nephronophthisis is a genetic disorder of the kidneys which affects children. It is classified as a medullary cystic kidney disease.The disorder is inherited in an autosomal recessive fashion and, although rare, is the most common genetic cause of childhood kidney failure.It is a form of...
, Meckel-Gruber syndrome and some forms of retinal degeneration
Retinal degeneration
The term retinal degeneration may refer to:* One of several eye diseases or eye disorders in humans* Progressive retinal atrophy, an eye disease in dogs-See also:*List of human eye diseases and disorders...
..
External Links
- GeneReviews/NCBI/NIH/UW entry on Alstrom syndrome
- OMIM entries on Alström syndrome
- Alström Syndrome International home page
- The UK Alström Syndrome Support Group Home page
- Alström syndrome in the Swedish Rare Disease Database
- Alstrom Syndrome. Eur J Hu Genet (Practical Genetics): 15, 2007, S. 1193–1202