Alstrom Syndrome: Genetics and Clinical Overview

Abstract

Alström syndrome is a rare autosomal recessive genetic disorder characterized by cone-rod dystrophy, hearing loss, childhood truncal obesity, insulin resistance and hyperinsulinemia, type 2 diabetes, hypertriglyceridemia, short stature in adulthood, cardiomyopathy, and progressive pulmonary, hepatic, and renal dysfunction. Symptoms first appear in infancy and progressive development of multi-organ pathology leads to a reduced life expectancy. Variability in age of onset and severity of clinical symptoms, even within families, is likely due to genetic background.Alström syndrome is caused by mutations in ALMS1, a large gene comprised of 23 exons and coding for a protein of 4,169 amino acids. In general, ALMS1 gene defects include insertions, deletions, and nonsense mutations leading to protein truncations and found primarily in exons 8, 10 and 16. Multiple alternate splice forms exist. ALMS1 protein is found in centrosomes, basal bodies, and cytosol of all tissues affected by the disease. The identification of ALMS1 as a ciliary protein explains the range of observed phenotypes and their similarity to those of other ciliopathies such as Bardet-Biedl syndrome.Studies involving murine and cellular models of Alström syndrome have provided insight into the pathogenic mechanisms underlying obesity and type 2 diabetes, and other clinical problems. Ultimately, research into the pathogenesis of Alström syndrome should lead to better management and treatments for individuals, and have potentially important ramifications for other rare ciliopathies, as well as more common causes of obesity and diabetes, and other conditions common in the general population.

A novel ALMS1 splice mutation in a non-obese juvenile-onset insulin-dependent syndromic diabetic patient

“…10,17 The mutation identified in our patient, IVS18-3T4G, is very similar to a splice mutation (IVS18-2A4T) that has been reported in two Saudi Arabian sibs diagnosed with Alström syndrome, presenting obesity and short stature. 18 So, except for the possible exception of dilated cardiomyopathy (DCM), which was absent from these three Novel ALMS1 mutation in atypical Alström syndrome M Sanyoura et al patients, other atypical features in our patients are unlikely to depend on the nature of the mutation.…”

“…Additional modifier effects or risk factors may also modulate disease presentation, as suggested by the variable Alms1 knockout mouse phenotype depending on their genetic background. 10 Interestingly, we determined that this patient was HLA-DRB1*04 positive, and therefore carrier of an independent T1D susceptibility, which may have potentiated insulin dependency in an ALMS1-mutated genetic background.…”

“…In view of the limited number of splice or missense variants reported in Alström patients to date, 10 we cannot exclude that a subset of these may result in atypical Alström presentation. Additional modifier effects or risk factors may also modulate disease presentation, as suggested by the variable Alms1 knockout mouse phenotype depending on their genetic background.…”

“…[9][10][11] Clinical characteristics of these syndromes and of the patient are shown in Table 1. Both syndromes show extensive clinical variability and share impaired glucose metabolism (diabetes), impaired vision and hearing, and neurological abnormalities, which were observed in our patient.…”

Atypical Alstrom syndrome with novel ALMS1 mutations precluded by current diagnostic criteria

“…Childhood hyperphagia has been suggested as a possible issue contributing to obesity, although the evidence remains anecdotal [1] and [12]. It has been proposed that a defective ALMS1 protein in the brain and pancreas could impair normal functioning of satiety factors leading to overeating [5]. Another possible explanation for childhood obesity in AS relates to the role of ALMS1 in ciliary function.…”