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Olfactory Dysfunction in Type I Pseudohypoparathyroidism: Dissociation from G_s Protein Deficiency¹

Smell and Taste Center and Department of Otorhinolaryngology: Head and Neck Surgery (R.L.D., A.D.F., D.A.M.), School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; Department of Medicine (M.A.L.), Division of Endocrinology and Metabolism, Johns Hopkins University, Baltimore, Maryland 21205; Department of Medicine (A.M.), College of Medicine, State University of New York Health Science Center, Syracuse, New York 13210

Address correspondence to Richard L. Doty, Ph.D., Director, Smell and Taste Center, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, Pennsylvania 19104.

The discovery of variably decreased olfactory ability in Type Ia pseudohypoparathyroidism (PHP), a syndrome in which generalized hormone resistance is associated with deficiency of the alpha chain of the stimulatory guanine nucleotide-binding protein (G_s) of adenylyl cyclase, has been used to support the hypothesis that G_s plays a major role in human olfactory transduction. However, only a limited number of olfactory tests have been administered to such patients, and these patients have other problems that might cause or contribute to their olfactory dysfunction, including an unusual constellation of skeletal and developmental deficits termed Albright hereditary osteodystrophy (AHO). In this study, we administered tests of odor detection, identification, and memory to (i) 13 patients with Type Ia PHP; (ii) 8 patients with Type Ib PHP; (iii) 7 patients with pseudopseudohypoparathyroidism (PPHP); and (iv) 3 sets of normal controls matched to these groups on the basis of age, gender, and smoking history. Although we confirm that PHP Type Ia patients evidence olfactory dysfunction, we also demonstrate that (i) patients with Type Ib PHP, who have no AHO, no generalized hormone resistance, and normal G_s activity, also evidence olfactory dysfunction relative to matched controls; and (ii) patients with PPHP, who have AHO, no generalized hormone resistance, and deficient G_s protein activity, have relatively normal olfactory function. These observations do not support the hypothesis that the olfactory dysfunction associated with PHP is the result of generalized G_s protein deficiency and imply that other mechanisms (e.g. ones associated with PTH or PTHrP resistance) are responsible for the olfactory deficits of this disorder.

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