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PubMed1992

Incomplete bilateral transverse facial cleft--a previously unreported associated defect of the Kallmann's syndrome.

In 1944 Kallmann et al described sex-linked inheritance of hypogonadotropic hypogonadism with anosmia and noted the co-occurrence cleft lip, cleft palate and cranio-facial asymmetry. Since then, other clinical cases associated with various skeletal, ophthalmic, urogenital, cardiovascular and central nervous system disorders have been reported. This article presents the case of a 17-year-old girl with a bilateral incomplete facial cleft in association with the Kallmann's syndrome, a previously unreported connection. We describe the plastic surgical reconstruction of the bilateral incomplete facial cleft. The mechanism of this embryopathologic association of the Kallmann's syndrome is, we suggest, due to a developmental disturbance in the region of the median forebrain organizer and associated structures, possibly in connection with a pleiotropic genetic mechanism.

Adolescent↗
PubMed1991

Juvenile onset diabetes mellitus, central diabetes insipidus and optic atrophy (Wolfram syndrome)--neurological findings and prognostic implications.

The authors report on one case of Wolfram syndrome, a rare condition, which is characterized by juvenile onset diabetes mellitus, diabetes insipidus, optic atrophy and sensorineural deafness. The findings of this 13-year follow-up show that this patient developed typical neurological complications of long-standing diabetes mellitus as in the common type 1 variant. Moreover, some peculiar signs occurred such as anosmia, ophthalmoplegia interna, and central nystagmus. Since Wolfram syndrome is probably part of a more generalized neurodegenerative disorder, long-term prognosis will depend both upon the severity of chronic diabetic complications and upon the rapidity, by which degeneration of cerebellar, pontine and brain stem structures appear. Prognosis of the cardinal clinical signs is such that optic atrophy, though usually quite rapid in the beginning, generally does not lead to complete blindness. Sensorineural hearing loss progresses very slowly so that deafness might be expected exceptionally only. The hearing deficit in classical diabetics, however, is of retrocochlear origin. Therefore, in Wolfram syndrome, a combined inner-ear and retrocochlear hearing loss may occur.

Adolescent↗
PubMed2006

Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2.

Prokineticins, multifunctional secreted proteins, activate two endogenous G protein-coupled receptors PKR1 and PKR2. From in situ analysis of the mouse brain, we discovered that PKR2 is predominantly expressed in the olfactory bulb (OB). To examine the role of PKR2 in the OB, we created PKR1- and PKR2-gene-disrupted mice (Pkr1(-/-) and Pkr2(-/-), respectively). Phenotypic analysis indicated that not Pkr1(-/-)but Pkr2(-/-)mice exhibited hypoplasia of the OB. This abnormality was observed in the early developmental stages of fetal OB in the Pkr2(-/-) mice. In addition, the Pkr2(-/-) mice showed severe atrophy of the reproductive system, including the testis, ovary, uterus, vagina, and mammary gland. In the Pkr2(-/-) mice, the plasma levels of testosterone and follicle-stimulating hormone were decreased, and the mRNA transcription levels of gonadotropin-releasing hormone in the hypothalamus and luteinizing hormone and follicle-stimulating hormone in the pituitary were also significantly reduced. Immunohistochemical analysis revealed that gonadotropin-releasing hormone neurons were absent in the hypothalamus in the Pkr2(-/-) mice. The phenotype of the Pkr2(-/-) mice showed similarity to the clinical features of Kallmann syndrome, a human disease characterized by association of hypogonadotropic hypogonadism and anosmia. Our current findings demonstrated that physiological activation of PKR2 is essential for normal development of the OB and sexual maturation.

Animals↗
PubMed2003

Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54.

Hypogonadotropic hypogonadism is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. In the absence of pituitary or hypothalamic anatomical lesions and of anosmia (Kallmann syndrome), hypogonadotropic hypogonadism is referred to as isolated hypogonadotropic hypogonadism (IHH). A limited number of IHH cases are due to loss-of-function mutations of the gonadotropin-releasing hormone receptor. To identify additional gene defects leading to IHH, a large consanguineous family with five affected siblings and with a normal gonadotropin-releasing hormone receptor coding sequence was studied. Homozygosity whole-genome mapping allowed the localization of a new locus within the short arm of chromosome 19 (19p13). Sequencing of several genes localized within this region showed that all affected siblings of the family carried a homozygous deletion of 155 nucleotides in the GPR54 gene. This deletion encompassed the splicing acceptor site of intron 4-exon 5 junction and part of exon 5. The deletion was absent or present on only one allele in unaffected family members. GPR54 has been initially identified as an orphan G protein-coupled receptor with 40% homology to galanin receptors. Recently, a 54-aa peptide derived from the KiSS1 protein was identified as a ligand of GPR54. The present study shows that loss of function of GPR54 is a cause of IHH, and it identifies GPR54 and possibly KiSS1 protein-derived peptide as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.

Base Sequence↗
PubMed1992

X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene.

Kallmann syndrome represents the association of hypogonadotropic hypogonadism with anosmia. This syndrome is from a defect in the embryonic migratory pathway of gonadotropin-releasing hormone synthesizing neurons and olfactory axons. A candidate gene for the X chromosome-linked form of the syndrome was recently isolated by using a positional cloning strategy based on deletion mapping in the Xp22.3 region. With the PCR, two exons of this candidate gene were amplified on the genomic DNAs from 18 unrelated patients affected with the X chromosome-linked Kallmann syndrome. Three different base transitions--all leading to a stop codon--and one single-base deletion responsible for a frameshift were identified. We thus conclude that the candidate gene is the actual KAL gene responsible for the X chromosome-linked Kallmann syndrome. Furthermore, unilateral renal aplasia in two unrelated patients carrying a stop mutation indicates that the KAL gene is itself responsible for this Kallmann syndrome-associated anomaly. The gene is, therefore, also involved in kidney organogenesis. Additional neurologic symptoms in Kallmann patients are also discussed.

Base Sequence↗
PubMed1993

Expression of the KAL gene in multiple neuronal sites during chicken development.

The human KAL gene is responsible for the X chromosome-linked Kallmann syndrome. A partial cDNA sequence from the chicken KAL homologue was determined and used to study expression of the KAL gene, by in situ hybridization, during chicken development, from day 6 of incubation. The KAL gene is mainly expressed in neurons of the central nervous system during the second half of embryonic life. High levels of transcript were detected in mitral neurons of the olfactory bulbs, in striatal neurons, in Purkinje cells of the cerebellum, in retinal neurons, and in isolated neurons of the brainstem and spinal cord. No expression was observed in glial cells. A low level of expression was observed in some mesenchymal derivatives. In the adult, expression is maintained or increased in several neuronal populations, especially in optic tectum and striatum. A possible role for the KAL protein in synaptogenesis at these stages is discussed. These results in the chicken embryo help to elucidate the mechanisms of anosmia and gonadotropin-releasing hormone deficiency, which define Kallmann syndrome. In addition, most of the occasional symptoms described in Kallmann syndrome patients, such as cerebellar ataxia, abnormal ocular movements, abnormal spatial visual attention, mirror movements, and renal aplasia, could be ascribed to malfunction of areas that, in the chicken, express the KAL gene.

Amino Acid Sequence↗
PubMed1993

Probability model for molecular recognition in biological receptor repertoires: significance to the olfactory system.

A generalized phenomenological model is presented for stereospecific recognition between biological receptors and their ligands. We ask what is the distribution of binding constants psi(K) between an arbitrary ligand and members of a large receptor repertoire, such as immunoglobulins or olfactory receptors. For binding surfaces with B potential subsite and S different types of subsite configurations, the number of successful elementary interactions obeys a binomial distribution. The discrete probability function psi(K) is then derived with assumptions on alpha, the free energy contribution per elementary interaction. The functional form of psi(K) may be universal, although the parameter values could vary for different ligand types. An estimate of the parameter values of psi(K) for iodovanillin, an analog of odorants and immunological haptens, is obtained by equilibrium dialysis experiments with nonimmune antibodies. Based on a simple relationship, predicted by the model, between the size of a receptor repertoire and its average maximal affinity toward an arbitrary ligand, the size of the olfactory receptor repertoire (Nolf) is calculated as 300-1000, in very good agreement with recent molecular biological studies. A very similar estimate, Nolf = 500, is independently derived by relating a theoretical distribution of maxima for psi(K) with published human olfactory threshold variations. The present model also has implications to the question of olfactory coding and to the analysis of specific anosmias, genetic deficits in perceiving particular odorants. More generally, the proposed model provides a better understanding of ligand specificity in biological receptors and could help in understanding their evolution.

Animals↗
PubMed2003

Expression and function of gonadotropin-releasing hormone (GnRH) receptor in human olfactory GnRH-secreting neurons: an autocrine GnRH loop underlies neuronal migration.

Olfactory neurons and gonadotropin-releasing hormone (GnRH) neurons share a common origin during organogenesis. Kallmann's syndrome, clinically characterized by anosmia and hypogonadotropic hypogonadism, is due to an abnormality in the migration of olfactory and GnRH neurons. We recently characterized the human FNC-B4 cell line, which retains properties present in vivo in both olfactory and GnRH neurons. In this study, we found that FNC-B4 neurons expressed GnRH receptor and responded to GnRH with time- and dose-dependent increases in GnRH gene expression and protein release (up to 5-fold). In addition, GnRH and its analogs stimulated cAMP production and calcium mobilization, although at different biological thresholds (nanomolar for cAMP and micromolar concentrations for calcium). We also observed that GnRH triggered axon growth, actin cytoskeleton remodeling, and a dose-dependent increase in migration (up to 3-4-fold), whereas it down-regulated nestin expression. All these effects were blocked by a specific GnRH receptor antagonist, cetrorelix. We suggest that GnRH, secreted by olfactory neuroblasts, acts in an autocrine pattern to promote differentiation and migration of those cells that diverge from the olfactory sensory lineage and are committed to becoming GnRH neurons.

Base Sequence↗
PubMed2005

Structure of human phytanoyl-CoA 2-hydroxylase identifies molecular mechanisms of Refsum disease.

Refsum disease (RD), a neurological syndrome characterized by adult onset retinitis pigmentosa, anosmia, sensory neuropathy, and phytanic acidaemia, is caused by elevated levels of phytanic acid. Many cases of RD are associated with mutations in phytanoyl-CoA 2-hydroxylase (PAHX), an Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes the initial alpha-oxidation step in the degradation of phytenic acid in peroxisomes. We describe the x-ray crystallographic structure of PAHX to 2.5 A resolution complexed with Fe(II) and 2OG and predict the molecular consequences of mutations causing RD. Like other 2OG oxygenases, PAHX possesses a double-stranded beta-helix core, which supports three iron binding ligands (His(175), Asp(177), and His(264)); the 2-oxoacid group of 2OG binds to the Fe(II) in a bidentate manner. The manner in which PAHX binds to Fe(II) and 2OG together with the presence of a cysteine residue (Cys(191)) 6.7 A from the Fe(II) and two further histidine residues (His(155) and His(281)) at its active site distinguishes it from that of the other human 2OG oxygenase for which structures are available, factor inhibiting hypoxia-inducible factor. Of the 15 PAHX residues observed to be mutated in RD patients, 11 cluster in two distinct groups around the Fe(II) (Pro(173), His(175), Gln(176), Asp(177), and His(220)) and 2OG binding sites (Trp(193), Glu(197), Ile(199), Gly(204), Asn(269), and Arg(275)). PAHX may be the first of a new subfamily of coenzyme A-binding 2OG oxygenases.

Aspartic Acid↗
PubMed2000

Functional endoscopic sinus surgery in chronic sinusitis--a series of 237 consecutively operated patients.

From 1989 to 1999, 237 consecutive patients with chronic sinusitis and/or nasal polyposis entered a prospective study on the effect of functional endoscopic sinus surgery (FES). Nasal stenosis associated with massive nasal polyposis was the most frequent problem found in 61% of the patients. The rest had long-lasting symptoms of chronic sinusitis. Duration of symptoms averaged 9.3 years. Most frequent symptoms preoperatively were: nasal stenosis, chronic secretion, anosmia, frontal pain, headache and maxillary pain. All patients had the operation performed under general anaesthesia. 86% of the patients have been operated bilaterally. In 72% the posterior ethmoid was opened, and in 54% the sphenoid was opened. The maxillary ostium has been enlarged in 82% of the patients and the frontal recess opened in 51% of the cases. No serious complications were registered. Annoying bleeding was experienced in 21%, hampering the intended procedure. In three patients rhinoliquore was observed. One case was treated during the procedure; the last two patients were in no need of surgical treatment. At the 1-year follow-up study, 45% of the patients were totally satisfied with the results and without symptoms, and 44% were definitely feeling better.

Adolescent↗
PubMed2002

Applicability of the Scandinavian Odor Identification Test: a Finnish-Swedish comparison.

The possibility of using the Scandinavian Odor Identification Test (SOIT), developed for clinical purposes for use with Swedish subjects, for assessment of another northern European population was studied by comparing test performance between 127 Finnish and 127 Swedish participants, who were matched for age (19-85 years) and gender. The results showed very similar performance between countries and demonstrated, as expected, age- and gender-related differences in performance. Test-retest reliability was as good in Finnish as in Swedish subgroups of participants and no significant difference between countries in terms of diagnostic distribution (normosmia, hyposmia and anosmia) was found when using existing cut-off scores. The findings suggest that the SOIT, with its diagnostic cut-off scores, is reliable and valid for use with Finnish populations.

Adult↗
PubMed2004

Correspondence between three olfactory tests and suprathreshold odor intensity ratings.

OBJECTIVES: The capability of three olfactory tests (European Test of Olfactory Capabilities, Sniffin' Sticks and Cross-Cultural Smell Identification Test) to similarly classify subjects as normosmics, hyposmics and anosmics as well as the relation between test performance and suprathreshold ortho- and retronasal odor intensity ratings were examined. MATERIAL AND METHODS: A total of 48 subjects (age range 15-84 years; mean age 49.5 years) completed the 3 olfactory tests, rated aqueous solutions of vanilla (0-0.31%) and lemon aroma (0-0.17%) for odor and flavor intensity and filled in a background questionnaire. Ten subjects had case histories indicating anosmia, with the remainder having subjectively normal olfaction. RESULTS: The test results were highly correlated and differentiated anosmic, hyposmic and normosmic subjects. At an individual level, some discrepancy was seen in the olfactory diagnoses given by the three tests. In principal component analysis, olfactory measurements were loaded on three components: (i) odor detection, discrimination and identification; (ii) suprathreshold intensity ratings; and (iii) threshold for n-butanol. Advanced age was related to impaired olfactory performance. CONCLUSIONS: Although the three olfactory tests diagnosed the individuals slightly differently, all were considered to be valid for clinical evaluation of olfactory capabilities. The tests separated anosmics and normosmics highly significantly, and permitted an assessment of hyposmia. The suprathreshold odor intensity ratings reflected a different dimension of olfaction than the three olfactory tests.

Adolescent↗
PubMed2006

Functional inferior turbinosurgery (FITS) for the treatment of resistant chronic rhinitis.

CONCLUSIONS: Modified vidian neurectomy combined with inferior turbinoplasty provided an optimal surgical outcome as a treatment for intractable chronic rhinitis as evidenced by a relatively long-term follow-up. OBJECTIVE: The study was designed to determine the efficacy of submucosal reduction of the inferior turbinate and resection of the posterior nasal nerve for the treatment of resistant chronic rhinitis. PATIENTS AND METHODS: Fifty-six consecutive patients (37 males and 19 females; mean+/-SD age, 26+/-11 years) with resistant allergic rhinitis or nonallergic rhinitis with eosinophilia syndrome despite medical treatment. Symptomatic improvement including nasal obstruction, nasal discharge, sneezing, smell perception, and quality of life and objective evaluation of nasal airway resistance and nasal provocation test before and after surgery were investigated. RESULTS: The patients showed a remarkable improvement of > or = 80%, with the exception of two patients who had an approximately 50% reduction of the total symptomatic scores. Four of eight patients with anosmia subjectively improved whereas the other four patients felt unchanged. All patients who underwent rhinomanometry (n=15) and nasal provocation testing (n = 15) both before and after surgery showed a significant improvement. There were no intraoperative complications. Postoperative epistaxis occurred in one patient. One patient complained of a transient hypesthesia of the soft palate and dry eye. Nasal mucosal tears were observed in approximately 30% of the patients who otherwise showed no severe synechia or persistent crusting.

Adolescent↗
PubMed1998

The Scandinavian Odor-Identification Test: development, reliability, validity and normative data.

The Scandinavian Odor-Identification Test (SOIT) was developed to address the need for a culturally valid odor-identification test for clinical use on the Scandinavian population that (i) has good ability to generalize performance to olfactory status, (ii) assesses olfactory and trigeminal function separately, (iii) requires only limited cognitive demands, (iv) has normative data and good sensitivity and specificity, and (v) is fast, easy to administer and inexpensive. Sixteen odorous test stimuli were selected that were relatively identifiable, familiar, strong in intensity and pleasant according to healthy participants. Four response alternatives were then selected for each test stimulus based on a confusion matrix of identification rates obtained from healthy participants, in a manner that controlled for task difficulty. Results on the SOIT from healthy persons and hyposmic patients showed satisfactory test-retest reliability, split-half reliability and validity. Cut-off scores for olfactory diagnosis (normosmia, hyposmia, anosmia) based on normative data obtained from 171 healthy persons showed a satisfactory sensitivity and specificity of the SOIT. Assessment of 22 anosmic patients with the SOIT revealed that three of the test stimuli were significant trigeminal stimulants.

Adolescent↗
PubMed1999

Olfactory dysfunction in head injured workers.

Olfactory dysfunction following trauma has been widely reported and is currently compensable according to existing American Medical Association guidelines when it occurs in the occupational setting. Its presence and the risk factors for its development, however, have not been clearly delineated in occupationally head injured workers. In order to assess this phenomenon, a series of 365 consecutive head injured workers from 1993-1997 was assessed in order to determine the incidence of post-traumatic olfactory dysfunction and its association with the severity of the head injury, the mechanism of injury and other neurotological abnormalities in the same cohort group. Olfactory dysfunction was identified in 13.7% (9.3% with anosmia, 4.4% with hyposmia/dysosmia). It was more likely where the loss of consciousness > 1 h (p < 0.002), in more severe head injuries (grades II-V) (p < 0.001) and when skull fracture (p < 0.001) occurred. The direction of the blow applied to the skull did not influence its presence, although radiologically confirmed skull fractures in the frontal, occipital, skull base and midface were twice as likely as temporal and parietal fractures to result in an olfactory change. From a neurotologic perspective, approximately 21.9% of head injured workers were determined to have recognizable evidence of cochleovestibular dysfunction. Olfactory dysfunction as a physical finding post-head injury compares favourably with the presence of post-traumatic benign positional paroxysmal vertigo (BPPV) and its atypical variants in 11.2% of head injured workers.

Craniocerebral Trauma↗
PubMed2004

A Rasch analysis of the Stanford Hypnotic Susceptibility Scale, Form C.

The psychometric structure of the Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C) was tested in a Rasch analysis using data from 279 subjects. The Rasch model is the model of choice because it justifies the use of the sum of the item scores as a measure for the underlying construct. Rasch analysis revealed that use of a single sum score (number of suggestions passed) to express hypnotic ability is not sufficiently justified. However, the omission of the mosquito-hallucination and anosmia items (Items 3 and 9) rendered this short 10-item form of the SHSS:C sufficiently compatible with requirements of one-dimensionality, local stochastic independence,and equi-discriminability. Hence, the 10-item form justifies use of a sum score.

Factor Analysis, Statistical↗
PubMed1999

Measuring change in the subjective experience of hypnosis.

The authors indexed the subjective experience of hypnosis through the use of a continuous behavioral measure of the strength of the participant's experience at the time of the suggestion. Specifically, subjects turned a dial to indicate changes in their experience of the suggested effect during that experience. Thirty-three high, 47 medium, and 28 low hypnotizable subjects were asked to use the dial during the suggestion, test, and cancellation phases of three hypnotic items: arm levitation, arm rigidity, and anosmia. The pattern of ratings differed according to the nature of the suggestion. Also, across the items, subjects who passed according to behavioral criteria experienced the suggested effect to a greater degree than those who failed. Notably, whereas the ratings of highs and mediums did not differ for any item, they differed from lows on all three items. The authors discuss the implications of these findings in terms of the potential for this method to provide insight into the experience of hypnosis.

Adult↗
PubMedDate not supplied

Olfactory mucosal necrosis in male CD rats following acute inhalation exposure to hydrogen sulfide: reversibility and the possible role of regional metabolism.

Hydrogen sulfide (H2S) is a potent inhibitor of cytochrome oxidase (CO) and is associated with dysosmia and anosmia in humans and nasal lesions in exposed rodents. An improved understanding of the pathogenesis of these lesions is needed to determine their toxicological relevance. We exposed 10-week-old male CD rats to 0, 30, 80, 200, or 400 ppm H2S for 3 hours/day for 1 or 5 days consecutively. The nose was histologically examined 24 hours after H2S exposure, and lesion recovery was assessed at 2 and 6 weeks following the 5-day exposure. A single 3-hour exposure to > or = 80 ppm H2S resulted in regeneration of the respiratory mucosa and full thickness necrosis of the olfactory mucosa localized to the ventral and dorsal meatus, respectively. Repeated exposure to the same concentrations caused necrosis of the olfactory mucosa with early mucosal regeneration that extended from the dorsal medial meatus to the caudal regions of the ethmoid recess. Acute exposure to 400 ppm H2S induced severe mitochondrial swelling in sustentacular cells and olfactory neurons, which progressed to olfactory epithelial necrosis and sloughing. CO immunoreactive cells were more frequently observed in regions of the olfactory mucosa commonly affected by H2S than in regions that were not. These findings demonstrate that acute exposure to >80 ppm H2S resulted in reversible lesions in the respiratory and olfactory mucosae of the CD rat and that CO immunoreactivity may be a susceptibility factor for H2S-induced olfactory toxicity in the rat.

Administration, Inhalation↗