Impaired Smell in HAE Types 1, 2 Likely Unrelated to Gene Changes

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by Margarida Maia |

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One in three patients with hereditary angioedema (HAE) may have an impaired sense of smell, but this does not appear to be tied to changes in the genes responsible for odor detection, a small study found.

The scientists said more research is needed, in larger patient populations, to better understand what factors cause people with HAE to lose their sense of smell.

“Further studies should investigate non-genetic underlying mechanisms of impaired smell in HAE patients and the impact of different therapeutic approaches,” the investigators wrote.

The study, “Analysis of genetic impact on smell impairment in patients with hereditary angioedema type 1 and 2,” was published in the Journal of the German Society of Dermatology.

There are three types of HAE, categorized based on their underlying causes. Types 1 and 2 are due to mutations in SERPING1, a gene located on chromosome 11 — which is home to the most “smell genes” in the human genome.

The genome is the group of all genes present in human DNA. Chromosome 11 houses the human genome’s highest number of olfactory receptor genes, or ORGs, which provide instructions for making proteins that are able to bind odorants, or molecules capable of evoking a smell.

A previous study has shown that patients with HAE may partially lose their sense of smell — a condition known as hyposmia. Some may even lose their sense of smell entirely, and develop what is known as anosmia.

“The burden of HAE affects patients in many aspects of their daily lives. This includes smell impairment,” the researchers wrote.

Now, the investigators wanted to know if changes in HAE patients’ sense of smell might be related to alterations in ORG gene expression — the process by which information is relayed from genes to RNA, and then finally into proteins. Of note, RNA is the molecule that cells use as a template to create proteins.

The study included 30 adults with HAE and 30 healthy people, matched for sex and age, who served as controls. Among the HAE patients, 28 had type 1 disease and two had type 2.

First, the researchers tested the participants’ ability to detect odors using the Sniffin’ Sticks test. Consistent with the previous study, they found that a higher proportion of patients with HAE had hyposmia compared with healthy controls (33% vs. 6.7%).

Typically, people with type 1 or 2 HAE have lower levels or function of C1 inhibitor — a protein found in the blood that is encoded by the SERPING1 gene. In the study, patients with HAE (and controls) who had a normal sense of smell, or normosmia, had more C1 inhibitor circulating in the bloodstream than those with hyposmia, whose sense of smell was impaired. The protein’s activity also was higher in those with normosmia.

Next, changes in ORG gene expression were assessed and compared between patients and controls, using a technique called gene expression array. The results showed that the gene expression of three different ORGs was similar between patients with normosmia and those with hyposmia.

“The olfactory impairment in HAE patients appears to be independent of ORG expression levels,” the researchers wrote.

One limitation of the study, according to researchers, was its small size, while another was the heterogeneity in the therapies used, which made it more challenging to assess their effects.