Congenital General Anosmia

In addition to the human inter-individual diversity in perceiving specific odorants, humans also vary in their general olfactory capabilities. This covers a wide range of phenomena, from general anosmia through hyposmia (diminished sensitivity to smell). At the other end of the scale is general hyperosmia (enhanced smell sensitivity) (30). Moreover, during aging, a general olfactory loss occurs, which is also a feature of several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases (31).

It is estimated that approx 1% of the Western world population suffers from chemosensory disorders. Most of the people suffering from smell disorders have an acquired condition, which develops during life, owing to allergy, viral upper respiratory tract infection, nasal sinus diseases, head trauma, inhalation of noxious chemicals, or medicinal drug intake (32,33). A much smaller minority is born without a sense of smell, an affliction referred to here as congenital general anosmia (CGA). Two broad categories of CGA can be considered: CGA occurring with other anomalies (syndromic) and CGA seen as an isolated condition. Prevalence for isolated CGA is roughly estimated to be between 1:5000 and 1:20,000. Several past reports have described the condition, including a few familial cases. One of them shows 22 patients with 8 being familial (34). On examination by biopsy of the olfactory region in several anosmic patients, their respiratory epithelium was found to be normal, but not their olfactory epithelium, some of them lacking it totally. In all cases, axonal abnormalities and the absence of mature olfactory sensory neurons were observed. It has been proposed that the olfactory epithelium may degenerate because of functional failure in olfaction (34,35). Another study found a large four-generation family with 27 CGA-affected individuals (36), and recently, two Iranian families with isolated CGA have been reported with a suggested 46-cm linkage interval on chromosome 18 (37). A parallel study (38) has collected 27 individuals in 10 families and 56 sporadic cases of CGA. The three major candidate genes (ADCY3, GNCA2, GNAL) were screened in these individuals, but no causative mutations for CGA could be found. Although the number of affected families and individuals is small, all familial cases described are consistent with an autosomal dominant mode of inheritance with partial penetrance.

The most well studied group of syndromic CGA is related to the Kallmann syndrome. Such patients exhibit hypogonadotropic hypogonadism and anosmia, secondary to failure of gona-dotropin-releasing hormone (GnRH)-producing neurons to migrate from the olfactory placode to the brain, and to agenesis of the olfactory bulbs. The prevalence of the disease has been estimated at 1 in 10,000 in males and five to seven times lower in females. Three different modes of inheritance have been reported in familial cases of Kallmann Syndrome, X chromosome-linked, autosomal dominant, and autosomal recessive (39). The X-linked form of the Kallmann Syndrome has been well characterized, being caused by mutations in the gene KALI (chromosome Xp22.3) (40-42). The KALI protein, anosmin-1, is a locally restricted component of basement membranes and/or extracellular matrices during the organogenesis period (39). It has been found to enhance axonal branching from olfactory bulb output neurons (43) and to affect the migratory activity of GnRH-producing neurons (44).

To date, no causative genes have been described for isolated human CGA. However in mouse, three transduction genes have revealed behavioral phenotypes consistent with general anosmia when they are inactivated. Mice generated by homologous recombination, lacking the functional olfactory cyclic nucleotide-gated channel (Cnga2) (45), the stimulatory olfactory G-protein (Gnal), (46) or enzyme adenylyl cyclase III (Adcy3) (47), display profound reductions or even absence of physiological responses to odorants. Most ofthe homozygously deficient mice die within a few days after birth owing to an apparent inability to locate their mother's nipple and suckle.

Congenital and progressive blindness have been studied much more extensively. Inherited forms of blindness can be caused by anomalies in the central nervous system (48) or in different parts of the eye: cornea, iris, lens, retina, and the optic nerve. About 140 genomic loci have been associated with retinal dystrophies and more than 60 genes have been identified. The partial similarity in the transduction processes between olfaction and vision may facilitate the future identification of some of the causative genes of CGA and its mode of genetic transmission.

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