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Introduction

Congenital smell loss is a condition characterized by inability to detect or recognize odors since birth and affects about 500,000 individuals in the US . In about 12% of cases (Type I), the condition is familial and occurs in conjunction with other severe congenital neurological defects and somatic abnormalities including hypogonadotropic hypogonadism . Multiple genetic abnormalities have been associated with these patients . The remaining 88% of congenital smell loss cases (Type II) occur without gonadal and somatic abnormalities, usually without familial association; no genetic abnormalities have been associated with Type II patients .

Type I congenital smell loss was first reported in 1856 . In the 20th century, it was further characterized by Kallmann and later De Morsier . Kallmann syndrome patients exhibit hypogonadotropic hypogonadism, anosmia/hyposmia, color blindness, and other X-linked congenital abnormalities; they also exhibit low levels of sex and gonadotropin hormones, and suffer from absent or severely diminished smell function . Patients with Type I congenital smell loss demonstrate a hereditary pattern, but they appear sporadically. They are the result of a complex genetic–environmental relationship probably involving oligogenic inheritance in many cases. Most of the responsible mutations are in genes that code for G-protein coupled receptors (GPCR) and their ligands. They appear to cause the primary developmental defects observed. Smell loss has been demonstrated to be related to anatomical changes mediated in part by these biochemical abnormalities . Indeed magnetic resonance (MR) imaging of patients with Type I congenital smell loss revealed severe malformation or complete agenesis of key brain olfactory structures formed in utero including aplasty or hypoplasty of the olfactory bulbs and insufficient deepening of the olfactory sulci .

The pathogenesis of smell loss in patients with Type I congenital smell loss is heterogeneous. A model involving the failure of gonadotropin-releasing hormone (GnRH) synthesizing neurons to properly direct the morphogenesis of the brain structures has been established . The failure of the neurite-directing protein anosmin-1 has also been implicated . Various olfactory epithelial defects have also frequently been found in these patients including its absence, diminished size, and histological/anatomical abnormalities .

Type II congenital smell loss was first described nearly 100 years ago and since then others have reported patients who display no clinical abnormalities other than congenital decreased or absent response to olfactory stimuli . A family history of olfactory or gustatory disorders has usually not been discovered among these patients . Genetic screening of several dozen individuals affected by Type II congenital smell loss in which a familial trait was present revealed no association between the disease state and mutations of 3 key olfactory signal transduction genes: cyclic nucleotide-gated channel alpha 2 (CNGA2), adenylate cyclase-stimulating G alpha protein, olfactory type (GNAL), and adenylyl cyclase type III (ADCY3) . To date, genetic factors that might be associated with Type II congenital smell loss have remained elusive and most of the biology of the condition is still unknown.

MR imaging of Type II congenital smell loss patients revealed a heterogeneous group of olfactory CNS abnormalities including hypoplasia of olfactory bulbs, grooves, and sulci . However, while frequent, olfactory CNS abnormalities in Type II congenital smell loss patients were not as common or as severe as those observed in Type I congenital smell loss patients; anatomical components of the normal olfactory system were found present in each patient .

The purpose of the present study is to investigate a possible basis for genetic changes that might be present in patients with Type II congenital smell loss. To do this we determined the erythrocyte membrane antigens in these patients and compared their rates of occurrence to those expected based on published control data.

We have collected blood samples for erythrocyte antigen analysis in patients with congenital smell loss beginning in 1980. Although more comprehensive techniques for studying genetic factors in disease are currently available, these techniques were not available at the time we initiated these studies. Thus, we studied erythrocyte antigen expression frequencies in these patients in an attempt to obtain some genetic information among these patients. By analyzing the expression frequencies of 16 antigens in these patients, we were able to obtain some information about their genomes and to determine whether some aspect of specific genes might be expressed similarly or in a different manner to a large control group. Statistically significant deviations in erythrocyte antigen expression frequencies between the patients and the control group would indicate a probability that the condition might be genetically associated. This technique has previously been employed to study genetic factors present in patients suffering from chronic kidney disease .

The antigens A and B (of the ABO blood group), M, N, S, and s (of the MNS blood group), Fy ^a and Fy ^b (of the Duffy blood group), D (of the RhD blood group), C, c, E, and e (of the RhCE blood group), K (of the Kell blood group), and Jk ^a and Jk ^b (of the Kidd blood group) were chosen for study because they exhibit a wide range of expression frequencies among a control group and have reliable serology techniques for their detection . Although the antigens and the genes responsible for their expression may not be directly involved with olfaction or gustation, analysis of their expression patterns among the congenital smell loss patients may reflect a manifestation of genetic tendencies in this group of patients.