Neurologic findings in men with isolated hypogonadotropic hypogonadism

Schwankhaus, John D.; Currie, James Michael Stevenson; Jaffe, Myles J.; Rose, Shelley; Sherins, Richard J.

doi:10.1212/wnl.39.2.223

Cited by 96 publications

(32 citation statements)

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“…9,18,19 Finally, a variety of non-reproductive non-olfactory additional anomalies are present in only a fraction of KS patients. These disorders include involuntary upper limb mirror movements (bimanual synkinesis), 17,20 -22 abnormal eye movements, 21,23 congenital ptosis, 24,25 abnormal visual spatial attention, 26 hearing impairment, 5,6,8,27 -29 agenesis of the corpus callosum, 7,13 unilateral (occasionally bilateral) renal agenesis, 30 -32 cleft lip or palate, [5][6][7]33 agenesis of one or several teeth (hypodontia), 7,24,33,34 obesity 6,10 and other less documented anomalies (see reference 35 for review).…”

Section: Clinical Overviewmentioning

confidence: 99%

Kallmann syndrome

2008

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The Kallmann syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked recessive form of the disease. Mutations in FGFR1 or FGF8, encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance. Finally, mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic/oligogenic KS transmission modes. Notably, mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered.

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Section: Clinical Overviewmentioning

confidence: 99%

Kallmann syndrome

2008

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“…A number of additional neurologic symptoms have been described in Kallmann patients (17,18). The Previous reports have established the common embryonic origin and migratory pathway for GnRH-synthesizing neurons and olfactory axons (13)(14)(15).…”

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confidence: 97%

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

Hardelin

Levilliers

Castillo

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

173

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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 ofthe 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.

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“…They include neurological symptoms such as mirror movements (17,18), abnormal spatial visual attention (19), uncoordinated eye movements, sensory neural hearing loss, cerebellar ataxia, pes cavus deformity (20), minor epilepsy, spastic paraplegia (21), and nonneurological symptoms such as high arched palate, cleft lip and/or palate (22), and unilateral renal aplasia (23 (15 ,um thick) were done through the head and trunk. The sections were thawed onto poly-L-lysine-coated slides (50 ug/ml) and treated for hybridization as described (24).…”

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confidence: 99%

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

Legouis

Lièvre

Leibovici

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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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.Kallmann syndrome (KS) is an inherited disease defined by the association of hypogonadotropic hypogonadism and anosmia (absence of the sense of smell). The hypogonadism is due to a deficiency in gonadotropin-releasing hormone (GnRH) (1) and the anosmia has been related to aplasia of the olfactory bulbs and olfactory tracts (2). A positional cloning strategy was used to isolate the gene responsible for the X chromosome-linked form of the disease (KAL gene) (3)(4)(5) Embryological studies in several species (9-11), including chicken (12, 13), have established that GnRH-synthesizing neurons derive from the olfactory placodes. In mammals, three other types of neurons-namely, the nervus terminalis, the olfactory, and the vomeronasal neurons-derive from the olfactory epithelium. Their axons reach, respectively, the preoptic area, the olfactory bulbs, and the accessory olfactory bulbs and form a bridge of neural cell adhesion molecule immunoreactive fibers between the olfactory pit and the developing forebrain. GnRH neurons, which originate from the same part of the olfactory pit as the vomeronasal and terminalis nerves, leave the olfactory epithelium, migrating to the brain along these nerves, and ultimately reach the preoptic and hypothalamic areas (14). Histological analysis of a human male fetus carrying a deletion of the KAL gene has revealed that neither the GnRH neurons nor the axon terminals of the olfactory, terminalis, and vomeronasal neurons were present in the brain (15). This observation can account for the absence of olfactory bulbs in KS patients, since contact between the ingrowing olfactory axons and the forebrain is required for...

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Neurologic findings in men with isolated hypogonadotropic hypogonadism

Cited by 96 publications

References 0 publications

Kallmann syndrome

Kallmann syndrome

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

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

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