Alstrom syndrome 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 loss of perception of light (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.
• Birth weight is normal but infants develop truncal obesity by the end of first year.
• Insulin resistance develops in majority of children and is associated with acanthosis nigricans. By the end of third decade of life it eventually proceeds to type 2 diabetes mellitus with associated dyslipidemia.
• Other endocrine abnormalities usually seen in this disorder include hypothyroidism, hypogonadotropic hypogonadism in boys, and polycystic ovaries in girls.
• About 50% of individuals have delay in early developmental milestones; intelligence is normal.
• Liver involvement includes elevation of transaminases, steatosis, hepatosplenomegaly, and steatohepatitis. Portal hypertension and cirrhosis can lead to hepatic encephalopathy and life-threatening esophageal varices.
• Pulmonary dysfunction and severe renal disease may also develop. Pulmonary dysfunction can range from frequent bronchial infections to pulmonary fibrosis and pulmonary hypertension. Renal disease is progressive and the severity of glomerulosclerosis is highly variable. End-stage renal disease (ESRD) can occur as early as the late teens.

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 multi-organ dysfunction.

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