Reconsidering olfactory bulb magnetic resonance patterns in Kallmann syndrome.

OBJECTIVE: The aim of this retrospective study was to perform magnetic resonance imaging assessment of olfactory pathway and skull base abnormalities in Kallmann syndrome (KS) patients with hypogonadotropic hypogonadism and olfaction disorder. METHODS: Magnetic resonance brain patterns were retrospectively studied in 19 patients clinically classified as KS. Qualitative assessment of olfactory bulb region comprised bulb atrophy and rectus and medial orbital gyrus ptosis; quantitative assessment measured olfactory fossa depth and width, sulcus depth and ethmoid angle. Results were compared to an age- and sex-matched control population (n=19) with no impairment in the region of interest. Sixteen of the 19 KS patients were genetically screened for mutations associated with KS. RESULTS: On the above qualitative criteria, 15 of the 19 patients presented either unilateral (n=2) or bilateral (n=13) olfactory bulb agenesis; 16 showed tract agenesis and 16 showed gyrus malformation (ptosis or absence). On the quantitative criteria, 18 of the 19 patients showed abnormal sulcus depth and/or olfactory fossa malformation and/or abnormal ethmoid angle. CONCLUSION: The presence of malformation abnormalities in the olfactory fossae of 18 of the 19 patients appears to be a key factor for etiological diagnosis of hypogonadotropic hypogonadism, and should enable targeted study of genes involved in KS.

Isolated olfactory bulbs agenesis: an extremely rare entity / Agenesia aislada de los bulbos olfativos: una entidad extremadamente rara

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Ocular and olfactory forebrain abnormalities within a neonatal alpaca (Vicugna pacos).

A 5-day-old Huacaya alpaca cria (Vicugna pacos) was euthanized due to deteriorating health. At birth, the cria had ophthalmologic abnormalities, but had appropriate mentation. At 2 days of age, the cria gradually stopped suckling and began to circle. At 5 days old, the owner elected euthanasia due to declining clinical condition. Grossly, the right iris had a scalloped pupillary margin, and the right olfactory bulb was malformed. Histopathology revealed persistent hyperplastic primary vitreous bilaterally and iridal abnormalities, as well as aplasia of the olfactory ventricle, olfactory tract, and olfactory foramen on the right side.

[Radiological findings in congenital anosmia: a case report]. / Hallazgos radiológicos en la anosmia congénita: a propósito de un caso.

INTRODUCTION: Hypoplasia of the olfactory tracts and bulbs is a rare cause of anosmia in the paediatric population. In most cases it is usually due to an acquired cause and in only a few is it associated to chromosomal disorders (Kallman's syndrome, among others). CASE REPORT: A 10-year-old boy with no chromosomal disorders and a family history of anosmia, who visited because of isolated anosmia; a magnetic resonance scan revealed bilateral hypoplasia of the olfactory tracts and bulbs. CONCLUSIONS: Magnetic resonance imaging allows the anatomy of the olfactory tract to be studied in detail and this makes it a valuable tool in the diagnosis of structural abnormalities in cases of olfactory disorders and also in the planning of treatment.

Hallazgos radiológicos en la anosmia congénita: a propósito de un caso / Radiological findings in congenital anosmia: a case report

Introducción. La hipoplasia de bulbos y tractos olfatorios es una causa rara de anosmia en la población pediátrica. La mayoría de las veces es de causa adquirida, y se asocia en la menor parte de casos a alteraciones cromosómicas (síndrome de Kallman, entre otros). Caso clínico. Niño de 10 años sin alteraciones cromosómicas con antecedentes familiares de anosmia, que acudió por anosmia aislada y cuya resonancia magnética objetivó una hipoplasia bilateral de bulbos y tractos olfatorios. Conclusión. La resonancia magnética permite estudiar la anatomía de la vía olfatoria de manera que constituye una herramienta muy útil en el diagnóstico de anomalías estructurales en casos de trastornos de la olfacción y ayuda también a la planificación del tratamiento (AU)

Introduction. Hypoplasia of the olfactory tracts and bulbs is a rare cause of anosmia in the paediatric population. In most cases it is usually due to an acquired cause and in only a few is it associated to chromosomal disorders (Kallman’s syndrome, among others). Case report. A 10-year-old boy with no chromosomal disorders and a family history of anosmia, who visited because of isolated anosmia; a magnetic resonance scan revealed bilateral hypoplasia of the olfactory tracts and bulbs. Conclusions. Magnetic resonance imaging allows the anatomy of the olfactory tract to be studied in detail and this makes it a valuable tool in the diagnosis of structural abnormalities in cases of olfactory disorders and also in the planning of treatment (AU)

Proboscis lateralis with ipsilateral sinonasal and olfactory pathway aplasia.

Proboscis lateralis is a rare craniofacial malformation characterized by absence of nasal cavity on one side with a trunk-like nasal appendage protruding from superomedial portion of the ipsilateral orbit. High-resolution computed tomography and magnetic resonance imaging are extremely useful in evaluating this congenital condition and the wide spectrum of associated anomalies occurring in the surrounding anatomical regions and brain. We present a case of proboscis lateralis in a 2-year-old girl with associated ipsilateral sinonasal aplasia, orbital cyst, absent olfactory bulb and olfactory tract. Absence of ipsilateral olfactory pathway in this rare disorder has been documented on high-resolution computed tomography and magnetic resonance imaging by us for the first time in English medical literature.

Depth of the olfactory sulcus: a marker of early embryonic disruption in schizophrenia?

Embryonic insults during early gestation increase the risk of schizophrenia. Abnormal forebrain development during this period is often characterized by a shallow olfactory sulcus. The adjacent orbital sulcus does not develop until the third trimester and so is immune to early intrauterine insults. We measured olfactory and orbital sulcal depths in 36 patients and 28 control subjects. Patients had shallower olfactory sulci, but normal orbital sulci. Olfactory and orbital sulcal depths were correlated in controls, but not in patients. Olfactory sulcal depth may therefore be a biomarker denoting an early embryonic disruption in individuals at risk for schizophrenia.

GPC-1, a G protein gamma-subunit, regulates olfactory adaptation in Caenorhabditis elegans.

Caenorhabditis elegans genome carries two Ggamma genes, gpc-1 and gpc-2, and two Gbeta genes, gpb-1 and gpb-2. Of these, gpc-2 and gpb-1 are expressed ubiquitously and are essential for viability. Through a genetic screen, we identified gpc-1 as essential for olfactory adaptation. While wild-type animals show decreased chemotaxis to the odorant benzaldehyde after a short preexposure to the odorant, gpc-1 mutants are still attracted to the odorant after the same preexposure. Cell-specific rescue experiments show that gpc-1 acts in the AWC olfactory neurons. Coexpression of GPC-1 and GPB-1, but not GPB-2, caused enhanced adaptation, indicating that GPC-1 may act with GPB-1. On the other hand, knock down of gpc-2 by cell-targeted RNAi caused reduced chemotaxis to the odorant in unadapted animals, indicating that GPC-2 mainly act for olfactory sensation and the two Ggamma's have differential functions. Nonetheless, overexpression of gpc-2 in AWC neurons rescued the adaptation defects of gpc-1 mutants, suggesting partially overlapping functions of the two Ggamma's. We further tested genetic interaction of gpc-1 with several other genes involved in olfactory adaptation. Our analyses place goa-1 Goalpha and let-60 Ras in parallel to gpc-1. In contrast, a gain-of-function mutation in egl-30 Gqalpha was epistatic to gpc-1, suggesting the possibility that gpc-1 Ggamma may act upstream of egl-30 Gqalpha.

Mechanical obstruction of the olfactory cleft reveals differences between orthonasal and retronasal olfactory functions.

Following up on recent observations in patients with nasal polyposis (NP), the present study aimed to investigate whether a mechanical obstruction of the anterior olfactory cleft (OC) would produce differential effects on orthonasal and retronasal olfactory functions. To this end, we studied 33 healthy subjects in a randomized trial. Sponges with high content of saline were either placed in the OC or on the respiratory epithelium, such that this was blinded to both subject and observer. The results indicated that orthonasal (P = 0.04) but not retronasal (P = 0.15) olfactory identification ability was lower when the OC was blocked. This confirms the idea that differences between orthonasal and retronasal olfactory functions, as observed in NP patients, are, at least to some degree, due to mechanical obstruction of the anterior portion of the OC. The present data also suggest that mechanical obstruction is a means to induce reversible hyposmia void of side effects which can be performed in a blinded fashion. This might become a valuable model of hyposmia for future investigations.

Olfactory bulb mitral cell dendritic pruning abnormalities in a mouse model of the Fragile-X mental retardation syndrome: further support for FMRP's involvement in dendritic development.

The Fragile-X mental retardation syndrome is the leading form of inherited mental retardation. Dendritic analysis in a mouse model (FraX) found abnormal pruning in somatosensory cortex. To further characterize dendritic abnormalities and assess their occurrence in other brain regions, we examined mitral cells in FraX mice olfactory bulbs. FraX mice exhibited dendritic abnormalities consistent with somatosensory cortex, suggesting that deficient pruning is found in multiple brain regions.

Ontogeny of GnRH and olfactory neuronal systems in man: novel insights from the investigation of inherited forms of Kallmann's syndrome.

GnRH embryonic neuronal fate is determined by discreet spatio-temporal expression patterns and interactions of axonal guidance and cell adhesion molecules and extracellular matrix proteins. Expression of several transcription factors, locally derived growth factors and neurotransmitters influence GnRH ontogeny and rostral forebrain specification. In man, disrupted GnRH neuronal ontogeny can be caused by several monogenic disorders leading to isolated hypogonadotrophic hypogonadism (IHH); these include mutations within KAL-1, GnRH-R, and FGFR1. Mutations in KAL-1 and its encoded protein anosmin-1, causes X-linked Kallmann's syndrome (XKS) characterized by IHH, anosmia, synkinesis, and unilateral renal agenesis. Anosmin-1 has an obligate functional interaction with membrane associated heparan sulphate proteoglycans (HSPG) and FGFR-1 (KAL-2) whose mutations lead to the autosomal dominant form of KS (AKS). FGFR1 and anosmin-1 may interact via a HSPG dependent mechanism raising the possibility of interaction between two single gene defects cause similar phenotypic abnormalities.

Magnetic resonance imaging for diagnosis of congenital anosmia.

Magnetic Resonance Imaging (MRI) was performed on 9 patients who lacked a sense of smell since birth. Seven of them, including two patients with Kallmann syndrome, exhibited abnormality of the olfactory bulb, olfactory tract, olfactory sulcus, or rectus gyrus, with some variation among patients in type and degree of abnormality. The other two patients exhibited normal olfactory pathway morphology, and for them the possibility of acquired sensorineural anosmia could not be ruled out. MRI is useful for determining whether patients with congenital anosmia have olfactory pathway anomalies. Many patients with congenital anosmia and hypoplasty or aplasty of the olfactory pathway nevertheless had no gonadal or endocrinological disorders.

The transcriptional repressor Mecp2 regulates terminal neuronal differentiation.

Rett syndrome (RTT) is a severe neurodevelopmental disorder with features of autism that results from mutation of the gene encoding the transcriptional repressor methyl-CpG binding protein (MECP2). The consequences of loss of a transcription factor may be complex, affecting the expression of many proteins, thus limiting understanding of this class of diseases and impeding therapeutic strategies. This is true for RTT. Neither the cell biological mechanism(s) nor the developmental stage affected by MECP2 deficiency is known. In vivo analysis of the olfactory system demonstrates that Mecp2 deficiency leads to a transient delay in the terminal differentiation of olfactory neurons. This delay in maturation disrupts axonal targeting in the olfactory bulb, resulting in abnormal axonal projections, subglomerular disorganization, and a persistent reduction in glomerular size. These results indicate a critical cell biological function for Mecp2 in mediating the final stages of neuronal development.

A longitudinal descriptive study of self-reported abnormal smell and taste perception in pregnant women.

Self-reported abnormal sensitivity, qualitative distortions and phantom sensations with respect to smell and taste was assessed with a longitudinal design, based on questions referring to gestational weeks 13-16 and 31-34 of pregnancy in comparison with 9-12 weeks post partum and with non-pregnant women with corresponding time durations and intervals. The results show that abnormal smell and/or taste perception was reported by 76% of the pregnant women, typically believed to be caused by their pregnancy. Increased smell sensitivity was found to be very common at the early stage of pregnancy (67% of all pregnant respondents) and occasionally accompanied by qualitative smell distortions (17%) and phantom smells (14%). The smell abnormalities were less common at the late pregnancy stage and almost absent post partum. Abnormal taste sensitivity was fairly commonly reported (26%), often described as increased bitter sensitivity and decreased salt sensitivity. These results, suggesting that abnormal smell and/or taste perception is experienced by a large majority of pregnant women, imply that further research is needed to understand to what extent these chemosensory changes may underlie food aversions and craving with implications for food intake during pregnancy.

Defective neuronogenesis in the absence of Dlx5.

Dlx genes play an important role in the control of the development of the central nervous system (CNS). Single or compound inactivation of Dlx1, Dlx2, or Dlx5 in the mouse causes defects of neuronal migration and differentiation. Dlx5, in particular, is essential for the correct development of the olfactory system. Targeted inactivation of Dlx1 and Dlx2 in the mouse results in abnormal neuronal differentiation in the embryonic subcortical forebrain and is associated to the loss of Dlx5 and Dlx6 expression. So far, however, it has been impossible to investigate the role of Dlx genes on late neurogenesis, as their inactivation leads to perinatal death. We have now generated cultures of neural stem cells (NSCs) derived from embryonic and newborn Dlx5-null mice, and we have compared their capacity to differentiate in vitro to that of equivalent cells derived from normal littermates. We show here that in the absence of Dlx5, NSCs derived from newborn animals have a severely reduced capacity to generate neurons. This is not the case for cells derived from E12.5 embryos. Forced expression of Dlx5 in cultures of newborn mutant NSCs fully restores their neuronogenic potential. Our data suggest that Dlx5 is essential for secondary (postnatal) neuronogenesis.

Differences and similarities in insular and temporal pole MRI gray matter volume abnormalities in first-episode schizophrenia and affective psychosis.

CONTEXT: Whether psychoses associated with schizophrenia and affective disorder represent manifestations of different disorders or the same disorder is an important but unresolved question in psychiatry. Results of previous volumetric magnetic resonance imaging investigations indicate that gray matter volume reductions in neocortical regions may be specific to schizophrenia. OBJECTIVE: To simultaneously evaluate multiple olfactocentric paralimbic regions, which play crucial roles in human emotion and motivation, in first-episode patients with schizophrenia and affective psychosis. DESIGN: A cross-sectional study using high-spatial resolution magnetic resonance imaging in patients with schizophrenia and affective psychosis at their first hospitalization. SETTING: Inpatient units at a private psychiatric hospital. PARTICIPANTS: Fifty-three first-episode patients, 27 with schizophrenia and 26 with affective (mainly manic) psychosis, and 29 control subjects. MAIN OUTCOME MEASURES: Using high-spatial resolution magnetic resonance imaging, the gray matter volumes of 2 olfactocentric paralimbic regions of interest, the insular cortex and the temporal pole, were evaluated. RESULTS: A bilateral volume reduction in insular cortex gray matter was specific to first-episode patients with schizophrenia. In contrast, both first-episode psychosis groups showed a volume reduction in left temporal pole gray matter and an absence of normal left-greater-than-right asymmetry. Region of interest correlations showed that only patients with schizophrenia lacked a positive correlation between left temporal pole and left anterior amygdala-hippocampal complex gray matter volumes, whereas both psychosis groups were similar in lacking normal positive correlations between left temporal pole and left anterior superior temporal gyrus gray matter volumes. CONCLUSIONS: These partially different and partially similar patterns of structural abnormalities in olfactocentric paralimbic regions and their associated abnormalities in other temporolimbic regions may be important factors in the differential and common manifestations of the 2 psychoses.

Phenotype of the zebrafish masterblind (mbl) mutant is dependent on genetic background.

The zebrafish masterblind (mbl) mutant is characterized by the lack of olfactory placodes and optic vesicles, reduced telencephalon, an expanded epiphysis (Heisenberg et al. [1996] Development 123:191-203), and enlarged jaw. To understand the cellular events giving rise to the olfactory placode defect of this mutant, we examined the expression pattern of the distal-less-3 (dlx3) gene in mbl. In the mutant, dlx3, which is normally expressed in the developing nose and ear, showed reduced expression in the olfactory placode field, but normal expression in the developing ear. To determine whether the loss of dlx3 expression was due to cell loss, we assayed cell death by using TUNEL labeling. Although cell death in the mutant was not concentrated in the region of dlx3 expression, there was increased cell death in the forebrain, epiphysis, and jaw region, as compared with that in wild-type controls. This cell death phenotype was cyclical in nature, showing an increase and decrease in cell death on a roughly 24-hr cycle. Further analysis showed that this cyclical phenotype was specific to the genetic background. The severity of the mbl phenotype, including cell death, expanded epiphysis, and enlarged jaw, decreased when the mutation was moved from the original "TL" background to the "AB" background. Thus, the severity of developmental defects in the mbl mutant is strongly dependent on genetic background. We examined the contribution of cell death to the morphologic defects of mbl by blocking cell death by using zVADfmk, a known caspase inhibitor. We found that this treatment partially rescued the expanded jaw defect and that this rescue was dependent on the genetic background. Therefore, the mbl mutant phenotypes result, in part, from genetic background effects that alter the pattern of programmed cell death early in development.

Sox1-deficient mice suffer from epilepsy associated with abnormal ventral forebrain development and olfactory cortex hyperexcitability.

Mutations in several classes of embryonically-expressed transcription factor genes are associated with behavioral disorders and epilepsies. However, there is little known about how such genetic and neurodevelopmental defects lead to brain dysfunction. Here we present the characterization of an epilepsy syndrome caused by the absence of the transcription factor SOX1 in mice. In vivo electroencephalographic recordings from SOX1 mutants established a correlation between behavioral changes and cortical output that was consistent with a seizure origin in the limbic forebrain. In vitro intracellular recordings from three major forebrain regions, neocortex, hippocampus and olfactory (piriform) cortex (OC) showed that only the OC exhibits abnormal enhanced synaptic excitability and spontaneous epileptiform discharges. Furthermore, the hyperexcitability of the OC neurons was present in mutants prior to the onset of seizures but was completely absent from both the hippocampus and neocortex of the same animals. The local inhibitory GABAergic neurotransmission remained normal in the OC of SOX1-deficient brains, but there was a severe developmental deficit of OC postsynaptic target neurons, mainly GABAergic projection neurons within the olfactory tubercle and the nucleus accumbens shell. Our data show that SOX1 is essential for ventral telencephalic development and suggest that the neurodevelopmental defect disrupts local neuronal circuits leading to epilepsy in the SOX1-deficient mice.

Widespread defects in the primary olfactory pathway caused by loss of Mash1 function.

MASH1, a basic helix-loop-helix transcription factor, is widely expressed by neuronal progenitors in the CNS and PNS, suggesting that it plays a role in the development of many neural regions. However, in mice lacking a functional Mash1 gene, major alterations have been reported in only a few neuronal populations; among these is a generalized loss of olfactory receptor neurons of the olfactory epithelium. Here, we use a transgenic reporter mouse line, in which the cell bodies and growing axons of subsets of central and peripheral neurons are marked by expression of a tau-lacZ reporter gene (the Tattler-4 allele), to look both more broadly and deeply at defects in the nervous system of Mash1-/- mice. In addition to the expected lack of olfactory receptor neurons in the main olfactory epithelium, developing Mash1-/-;Tattler-4+/- mice exhibited reductions in neuronal cell number in the vomeronasal organ and in the olfactory bulb; the morphology of the rostral migratory stream, which gives rise to olfactory bulb interneurons, was also abnormal. Further examination of cell proliferation, cell death, and cell type-specific markers in Mash1-/- animals uncovered parallels between the main olfactory epithelium and the vomeronasal organ in the regulation of sensory neuron development. Interestingly, this analysis also revealed that, in the olfactory epithelium of Mash1-/- animals, there is an overproduction of proliferating cells that co-express markers of both neuronal progenitors and supporting cells. This finding suggests that olfactory receptor neurons and olfactory epithelium supporting cells may share a common progenitor, and that expression of Mash1 may be an important factor in determining whether these progenitors ultimately generate neurons or glia.