Clinical characteristics: Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive bilateral sensorineural hearing impairment, acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy, insulin resistance / type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and chronic progressive kidney disease. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus usually starting between birth and age 15 months. Many individuals lose all perception of light by the end of the second decade, but a minority retain the ability to read large print into the third decade. Children usually have normal birth weight but develop truncal obesity during their first year. Sensorineural hearing loss presents in the first decade in as many as 70% of individuals and may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. Insulin resistance is typically accompanied by the skin changes of acanthosis nigricans, and proceeds to T2DM in the majority by the third decade. Nearly all demonstrate hypertriglyceridemia.
Other findings can include endocrine abnormalities (hypothyroidism, hypogonadotropic hypogonadism in males, and hyperandrogenism in females), urologic dysfunction / detrusor instability, progressive decrease in renal function, and hepatic disease (ranging from elevated transaminases to steatohepatitis/NAFLD). Approximately 20% of affected individuals have delay in early developmental milestones, most commonly in gross and fine motor skills. About 30% have a learning disability. Cognitive impairment (IQ <70) is very rare.
Wide clinical variability is observed among affected individuals, even within the same family.
Diagnosis/testing: The clinical diagnosis of Alström syndrome is based on cardinal clinical features that emerge throughout infancy, childhood, and young adulthood. The molecular diagnosis of Alström syndrome is established in individuals of all ages by identification of biallelic pathogenic variants in ALMS1 on molecular genetic testing.
Management: Treatment of manifestations: No therapy exists to prevent the progressive organ involvement of Alström syndrome. Individuals with Alström syndrome require coordinated multidisciplinary care to formulate management and therapeutic interventions. Red-orange tinted prescription lenses may reduce symptoms of photodysphoria; early educational planning should be based on the certainty of blindness. Obesity and insulin resistance are managed by a healthful, reduced-calorie diet with restricted simple carbohydrate intake and regular aerobic exercise. Myringotomy and/or hearing aids as needed for hearing impairment. Standard therapy for heart failure / cardiomyopathy. Standard treatment of insulin resistance / T2DM as in the general population. Consider nicotinic acid derivatives for hyperlipidemia; consultation with an endocrinologist if pubertal development and/or menses are abnormal; urinary diversion or self-catheterization in those with voiding difficulties; renal transplantation has been successful in a number of cases; appropriate therapy for portal hypertension and esophageal varices.
Surveillance: Routine assessment of vision and hearing; weight, height, and body mass index; heart (including echocardiography and ECG in all individuals, and MRI in those age >18 years); postprandial c-peptide and glucose and HbA1C starting at age four years; lipid profile; plasma ALT, AST, and GGT concentrations; thyroid function. Twice-yearly CBC, electrolytes, BUN, creatinine, cystatin-C, uric acid, urinalysis. Renal and bladder ultrasound examinations every one to two years if symptomatic and/or if urinalysis is abnormal.
Agents/circumstances to avoid: Any substance contraindicated in persons with renal, hepatic, and/or myocardial disease. Therapy directed at one system may have adverse effects on other systems; for example, the use of glitazone therapy in diabetes mellitus is contraindicated in the presence of cardiac failure.
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with Alström syndrome in order to identify as early as possible those who would benefit from prompt evaluation for manifestations of Alström syndrome, initiation of treatment, and/or surveillance for age-related manifestations.
Genetic counseling: Alström syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. When the ALMS1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
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