Alstrom syndrome
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]
Synonyms and keywords: Alstrom-Hallgren syndrome; ALMS; ALSS
Overview
Alström syndrome is a rare genetic disorder caused by mutations in the gene ALMS1 which is located on the chromosome 2. It is among the rarest genetic disorders.
Historical Perspective
It was first described by Carl-Henry Alström in Sweden in 1959.
Epidemiology and Demographics
It is among the rarest genetic disorders in the world, as currently it has only 266 reported cases in medical literature and only 800 known cases in 54 countries.
Pathophysiology
The Jackson Laboratory in Bar Harbor, Maine, USA with the University of Southampton, UK isolated the single gene (ALMS1) responsible for Alstrőm Syndrome. The gene is recessive; it must be passed from both parents for the syndrome to manifest.
The key features are childhood obesity, blindness due to congenital cone-rod retinal dystrophy, and sensorineural hearing loss. Associated endocrinologic features include hyperinsulinemia, early-onset type 2 diabetes, and hypertriglyceridemia. Thus, AS shares several features with the common metabolic syndrome, namely obesity, hyperinsulinemia, and hypertriglyceridemia. Mutations in the ALMS1 gene have been found to be causative for AS with a total of 79 disease-causing mutations having been described.[1]
The cone-rod retinal dystrophy usually develops within the first few weeks after birth and the symptoms include nystagmus and extreme photodysphoria (light sensitivity). It is progressive and by the second decade of life leads to blindness. Most patients slowly develop bilateral sensorineural hearing loss. Dilated cardiomyopathy can develop at any age (infants or adolescents). It is seen in at least two-thirds of the patients and can lead to sudden cardiac failure.
Genetics
ALMS1 encodes a protein whose function is unknown. Mutations in this gene can lead to production of a dysfunctional protein that might be responsible for the signs and symptoms of Alstrom disease. Alström syndrome (AS) is a rare autosomal recessive disease characterized by multiorgan dysfunction.
Differentiating Alstrom syndrome from other Diseases
Alstrom syndrome is sometimes confused with Bardet-Biedl syndrome, which has similar symptoms. Bardet-Biedl syndrome tends to have later onset in its symptoms. Alstrom syndrome is a ciliopathy. Other ciliopathies that should be differentiated from Alstrom syndrome include:
- Primary ciliary dyskinesia
- Polycystic kidney disease
- Polycystic liver disease
- Nephronophthisis
- Meckel-Gruber syndrome
- Biemond II syndrome
- Wolfram syndrome
- Cohen syndrome
- Sporadic infantile DCM
- Mitochondrial disorders
- Some forms of retinal degeneration[2]
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 only diagnosed clinically, since genetic testing is still rare 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 electroretinography (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.
Symptoms
Early Symptoms
- 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
- Developmental delays in 50% of cases, learning disabilities in about 30% of cases
- Obesity 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)
Later Symptoms
- Progressive hearing loss
- Kidney problems
- Liver problems
- Insulin resistance/Type 2 diabetes
Physical Examination
Appearance of the Patient
Patients have distinctive facial characteristics (deep-set eyes with a rounded face, thick ears, premature frontal balding, and thin hair).
Extremities
Wide, thick, flat feet, and short stubby fingers and toes
References
- ↑ Joy T, Cao H, Black G, Malik R, Charlton-Menys V, Hegele RA, Durrington PN (2007). "Alstrom syndrome (OMIM 203800): a case report and literature review" (PDF). Orphanet Journal of Rare Diseases. 2 (1): 49. doi:10.1186/1750-1172-2-49. PMC 2266715. PMID 18154657.
- ↑ Badano, Jose L. (September 2006). "The Ciliopathies : An Emerging Class of Human Genetic Disorders". Annual Review of Genomics and Human Genetics. 7: 125–148. doi:10.1146/annurev.genom.7.080505.115610. PMID 16722803. Retrieved 2008-06-15. Unknown parameter
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