Genetic testing early in life can improve the diagnosis of conditions such as Alström syndrome, a rare form of genetic obesity, a case report suggests.
Advanced technologies such as next-generation sequencing (NGS), which can examine thousands of genes at once, may help find the most adequate treatment options and ensure multidisciplinary disease management, scientists said.
The study, “A very early diagnosis of Alstrom syndrome by next generation sequencing,” was published in the journal BMC Medical Genetics.
The changes in the ALMS1 gene that cause Alström syndrome have a variety of effects, including obesity, type 2 diabetes, widespread fibrosis (scarring), and heart disease. Such varied clinical symptoms complicate diagnosis, but the availability of high-throughput sequencing technologies provides a valuable way to identify the disorder with accuracy.
Researchers in Italy described the case of a 22-month-old girl who was ultimately diagnosed with Alström syndrome following NGS screening.
The girl was born via cesarian section and developed normally at first. Her pediatrician found a bright red birthmark called a hemangioma when she was 6 months old. She was recovering from several episodes of acute bronchitis, or chest colds, that had gotten worse.
When she was a year old, her parents consulted an ophthalmologist out of concern for her tendency to squint in the light and randomly hit objects. She was examined for macular degeneration, and was found to have convergent concomitant strabismus in the right eye, a condition in which the deviation of the squinting eye relative to the other eye is always the same, regardless of the gaze direction. Further examination found evidence of cone dystrophy, a group of disorders that affect the cone cells of the retina, which are responsible for color and fine detail.
A genetic test was suggested when she was 22 months, which focused on a panel of genes linked to disorders of the eye.
The test revealed two ALMS1 mutations, one in each of the two inherited gene copies. Each variant caused the protein-making process from ALMS1 to end prematurely. The patient’s 5-year-old sister did not have these mutations.
After her diagnosis, the patient was examined more closely by physicians. Ultrasonography revealed borderline heart dimensions for her weight and lower function of her left ventricle. Yet, the team found no signs of dilated cardiomyopathy — in which the heart is enlarged and pumps less effectively — or of heart failure.
No therapy was prescribed at this point, but the girl was monitored every six to 12 months.
She continued to need diapers at age 3. The girl also showed intellectual disabilities with attention deficit and hyperactivity.
Blood tests showed high cholesterol and high levels of fatty molecules called triglycerides, a condition called hypertriglyceridemia. The doctors then recommended a low-calorie, low-fat diet rich in omega-3s.
Further evaluation also found chronic inflammation of the middle ear, which was treated by inserting tiny tubes called grommets into her eardrum.
A lung exam showed bronchial asthma. Finally, a microscopy examination of throat and upper airway tissue found a low number of cilia, hair-like appendages that extend from cells of the airways to clear mucus and dirt. Notably, studies of the various functions of the ALMS1 protein have suggested that Alström syndrome belongs to a class of genetic disorders linked to dysfunctions of the cilia, known as ciliopathies.
The ophthalmologist prescribed the girl dark orange glasses with corrective lenses for farsightedness and astigmatism. A genital fungal infection developed at a later age.
Overall, “early genetic diagnosis based on a sensitive and relatively low cost approach allows clinicians to determine the best available therapeutic options without delay, which can be crucial in [validating] rare genetic disorders like [Alström syndrome],” the scientists wrote.
Such approaches, the team added, offer “an exceptionally valuable screening tool for clear genetic diagnoses and ensures early multidisciplinary management and treatment of the emerging symptoms.”
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