A girl with obesity and other characteristic signs of Alström syndrome was found to have two very unusual mutations in the ALMS1 gene, both largely unreported in this disease, according to a case study.
Its researchers suggest their findings support genetic testing to help diagnose Alström syndrome and other rare diseases with gradually emerging symptoms.
The study, “Whole exome sequencing identified two homozygous ALMS1 mutations in an Iranian family with Alström syndrome,” was published in the journal Gene.
Alström syndrome is a recessive genetic disease, meaning a person must inherit two altered copies (a homozygous mutation) of the ALMS1 gene, one from the mother and one from the father. It is extremely rare, with a prevalence of less than 1 to 10 per million in the general population.
Added to its slow clinical onset, Alström syndrome’s rareness makes a correct diagnosis particularly challenging.
DNA sequencing techniques can be helpful. Examples include an approach called Sanger sequencing and whole exome sequencing (WES), a technique that analyzes small DNA bits (exons) that contain information to make proteins.
Researchers in Iran described the case of a 12-year old girl, whose parents were cousins. She showed progressive loss of visual acuity and vision problems that included nystagmus (repetitive and uncontrolled eye movements), photophobia (discomfort or pain in the eyes due to light), and cone dystrophy, a group of disorders that affect the cone cells (responsible for color and fine detail) of the retina.
Hyperphagia (excessive eating) and considerable weight gain began in her first year of life, and led to obesity by age 4. At age 12, her weight was 68.3 kg (about 150 lbs.) and her body mass index was 29.5 kg/m2, which fell within the overweight/obese range.
The girl had other complications suggestive of Alström syndrome, including type 2 diabetes, insulin resistance, hearing loss, cardiomyopathy (heart muscle disease), progressive kidney failure, and acanthosis nigricans (a skin condition characterized by areas of dark, velvety discoloration).
Unlike previously reported cases of Alström syndrome, she did not show any signs of epilepsy, liver disease, or problems with cognition.
Using both WES and Sanger sequencing, researchers found two homozygous mutations in the ALMS1 gene. Both mutations — p.(Ser2421Ile) and p.(Glu2435Valfs*7) — are extremely rare in the Iranian population, they wrote.
The girl’s parents had mutations in one ALMS1 copy (heterozygous), and were clinically normal.
Computational modeling revealed that the p.(Ser2421Ile) mutation was within a conserved gene region, meaning that it is identical across different species. This is a missense mutation that changes the amino acid sequence of the ALMS1 protein.
The p.(Glu2435Valfs*7) mutation either impairs production of the ALMS1 protein or disrupts its function by lacking two conserved regions.
“In conclusion, by using WES, we identified two homozygous mutations … in a child from a consanguineous marriage,” the researchers wrote.
“It should be reminded that WES is very useful in the accurate and early diagnosis of diseases with gradually emerging symptoms such as AS [Alström syndrome], and this is very important for the effective clinical management of patients,” they added.