Imagine life without odors. Food tastes the same regardless of how congested your nasal passages are or how damaged your nose is. Perfume and other fragrances simply do not exist. There are no mouthwatering aromas, no bad breath or body odor, and no subconscious sense that someone is scared or sick.
A missing sense of smell is called anosmia. It can occur as a result of trauma or illness, as described in books like “Remembering Smell: A Memoir of Losing—And Discovering—The Primal Sense” or “Season to Taste: How I Lost my Sense of Smell and Found My Way”.
But sometimes the cause is genetic and starts at birth. Affected people simply never smell anything, a condition known as congenital anosmia. Not surprisingly, sense of taste is severely impacted, to such an extent that food is mostly about texture. Other effects include missing “emotional connections associated with smell and cannot enjoy the pleasurable aspects of smell, from the scent of lilacs in the spring to the smell of babies’ heads.”
Congenital anosmia is a rare disorder, thought to affect 1 in 5,000 to 1 in 10,000 people. It was previously believed to primarily be a result of genetic disorders like Kallmann syndrome, a form of hypogonadotrophic hypogonadism in which puberty is delayed or absent.
But recent research has shown that congenital anosmia has a complex molecular basis. In particular, congenital anosmia that occurs in otherwise healthy individuals is known as “isolated congenital anosmia” and is extremely rare. In some cases, brain MRIs of affected individuals show an absence or severe hypoplasia of the olfactory bulb, but in others, olfactory structures are largely intact. The genetic basis of this disorder is becoming better understood.
A study in the European Journal of Human Genetics from late in 2017 involving next-generation sequencing of patients with congenital anosmia found “involvement of 6 syndromic Kallmann genes in isolated anosmia.” This suggests that the gene defects in Kallmann syndrome may also play a role in isolated congenital anosmia because some of the genes that cause Kallmann are involved in the development of olfactory neurons, nerve cells specialized to handle the sense of smell.
A separate study in Clinical Genetics looking specifically at congenital general anosmia found a “rare X-linked missense mutation in the TENM1 (teneurin 1) gene.” This combined with work in Drosophila melanogaster and in mice points to loss-of-function mutations in TENM1 as a possible sole cause of congenital general anosmia. Research in Drosophila shows that TENM1 “functions in synaptic-partner-matching between axons of olfactory sensory neurons and target projection neurons and is involved in synapse organization in the olfactory system.”
The NaV1.7 sodium channel gene SCN9A implicated. In the book “Chasing Men on Fire: The Story of a Search for a Pain Gene”, neuroscientist Stephen Waxman, PhD, writes “NaV1.7 was known to be present in olfactory sensory neurons which are essential for our sense of smell, and, consistent with this, anosmia—loss of the sense of smell—was also observed in these loss-of-function patients” who have a mutation in the SCN9A gene that causes hereditary small fiber neuropathy.
Whole exome sequencing has added important information, too. A 2017 study in Nature found that a stop gain mutation in CNGA2 as the cause of isolated congenital anosmia in a large Iranian family. This built on earlier work published in Clinical Genetics in 2015, finding a novel X-linked stop mutation in CNGA2 in two brothers with isolated congenital anosmia. The gene CNGA2 encodes the alpha subunit of a cyclic nucleotide-gated olfactory channel, though its exact role in olfaction remains to be clarified.
The above genetics demonstrates how complex the sense of smell is. Genes are involved in the formation and function of the olfactory bulb in the brain and sensory neurons in the nose. Mutations in any of these genes are now thought to be possible explanations for congenital anosmia.
This presents a challenge in clinical medicine. After more probable causes of apparent congenital anosmia are eliminated, in particular early-life trauma or illness, the list of possible genetic causes is still long. Ruling out disorders like Kallmann syndrome is important, but that still leaves distinguishing between isolated congenital anosmia and various rare disorders that are more complicated.
For instance, Refsum disease presents with anosmia, but also includes retinitis pigmentosa, progressive muscle wasting, arrhythmias, and neurological manifestations. Refsum disease is an inborn error of metabolism that causes an over-accumulation of phytanic acid, leading to a variety of progressively severe neurological manifestations. Treatment involves a phytanic acid-restricted diet and possibly plasmapheresis. Although this does not restore sense of smell, it does greatly improve quality of life, making early diagnosis important.
Thus, anosmia is about far more than not being able to smell the roses. An absent sense of smell from birth is almost always genetic and can be an early sign of a serious disorder. Or it can be isolated, a result of a single failure in a complex system that is more vulnerable than generally recognized.
Roger Chriss is a technical consultant in Washington state, where he specializes in mathematics and research