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Alström syndrome

Orpha number ORPHA64
Synonym(s) -
Prevalence 1-9 / 1 000 000
Inheritance Autosomal recessive
Age of onset Childhood
Adolescent
Adult
Infancy
Neonatal
ICD-10
  • Q87.8
ICD-O -
OMIM
UMLS
  • C0268425
MeSH
  • D056769
MedDRA
  • 10068783

Summary

Alström syndrome (AS) is a multisystemic disorder characterized by cone-rod dystrophy, hearing loss, obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy (DCM; see this term), and progressive hepatic and renal dysfunction.

Prevalence is unknown. Approximately 950 cases have been identified worldwide.

The clinical features, age of onset, and severity can vary greatly among and within families. Cone-rod retinal dystrophy usually develops within a few weeks after birth, with the first symptoms being nystagmus and extreme photodysphoria or light sensitivity. It is progressive and leads to blindness, usually by the 2nd decade of life. Most patients develop mild-to-moderate slowly progressive bilateral sensorineural hearing loss. DCM manifests in approximately 2/3 of patients, either as infants or as adolescents. Patients are at risk of sudden congestive heart failure at any age. Obesity, insulin resistance and hyperinsulinemia are early and consistent features. Liver dysfunction usually begins in childhood with steatosis (fatty liver). In some cases, cirrhosis, portal hypertension and liver failure can occur. Chronic respiratory illness, pulmonary hypertension, and hypertriglyceridemia are frequent. Slowly progressive nephropathy can lead to end stage renal failure. Patients have distinctive facial characteristics (deep-set eyes with a rounded face, thick ears, premature frontal balding, and thin hair). Most children have characteristic wide, thick, flat feet, and short stubby fingers and toes with no polydactyly or syndactyly. Hypogonadism in males/hyperandrogenism in females is also reported. Most patients have normal intelligence, although some reports have indicated delayed psychomotor and intellectual development. As some phenotypes develop slowly over time, non-classical presentations have also been reported.

AS is caused by mutations in the ALMS1 gene (2p13.1). Its molecular function is currently unknown, although roles in ciliary function, cell cycle control, and intracellular transport have been suggested.

Diagnosis is made on the basis of the clinical features observed (major/minor), usually without genetic confirmation. Family history is considered a major criteria in the diagnosis of AS. The identification of 2 mutated alleles or a single mutated ALMS1 allele in the presence of typical clinical features confirms diagnosis.

Differential diagnoses include Bardet-Biedl syndrome, Biemond syndrome type 2, Wolfram syndrome, Cohen syndrome, familial isolated DCM (see these terms) and mitochondrial disorders.

If the ALMS1 mutations in parents are known, prenatal testing can be offered.

AS is transmitted autosomal recessively and genetic counseling is possible.

Management should include vigilant monitoring and treatment of the emerging clinical manifestations. Red-orange tinted prescription lenses can reduce photophobia. As blindness occurs in all cases, early educational planning to teach patients Braille, computing skills and adaptive living skills is essential. Bilateral digital hearing aids can increase hearing capabilities. Heart failure is mainly treated with angiotensinogen-converting enzyme (ACE) inhibitors, diuretics, and digoxin. Diabetes can be managed with a low-fat, low sugar diet, exercise, metformin, glitazones and incretin analogues (beneficial in 2/3 of cases). Beta-blockers, sclerotherapy of the esophageal veins, and banding usually treat portal hypertension. In unsuccessful cases a transjugular intrahepatic portosystemic shunt may be needed. In those with renal disease, ACE inhibitors can be considered. In several cases, renal transplantation has been successful.

Although the life span of AS patients can be shortened, early diagnosis and intervention can moderate the progression and improve the longevity and quality of life of patients.

Expert reviewer(s)

  • Dr Sebastian BECK
  • Dr Pietro MAFFEI
  • Dr Jan D MARSHALL
  • Pr Jürgen NAGGERT

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Detailed information

Summary information
Clinical practice guidelines
  • ES (2010,pdf)
Practical genetics
  • EN (2007,pdf)
Guidance for genetic testing
  • EN (2013,pdf)
Clinical genetics review
  • EN (2012)
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The documents contained in this web site are presented for information purposes only. The material is in no way intended to replace professional medical care by a qualified specialist and should not be used as a basis for diagnosis or treatment.