Physiological tremor in human subjects with X-linked Kallmann's syndrome and mirror movements.
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Human physiological tremor consists of mechanical-reflex and neurogenic components. The origin of the neurogenic component, classically detected in the frequency range 7-12 Hz, has been much debated. We have studied six subjects with X-linked Kallmann's syndrome (XKS) and mirror movements. In these subjects unilateral magnetic brain stimulation results in abnormal bilateral EMG responses. Furthermore, abnormal sharing of central nervous inputs between the left and right motoneurone pools results in both abnormal motor unit synchronisation between left and right EMGs and abnormal sharing of long but not short-latency cutaneomuscular reflexes. XKS subjects with mirror movements thus provide a model for studying the central origin of physiological tremor. During sustained co-extension of the left and right index fingers, simultaneous finger tremor and extensor indicis (EI) EMGs were recorded and cross-correlated. The tremor and EMG signals were also subjected to time and frequency domain analysis.Results of frequency domain analysis between ipsilateral finger tremor and EI EMG were similar for both control and XKS subjects. However, in contrast to the controls, short-term synchronisation of left and right EI motor unit activity and significant coherence between left and right EMG, left and right tremor, left EMG and right tremor and right EMG and left tremor were found in XKS subjects. The frequency range (6-40 Hz) and coherence values between left and right were similar to ipsilateral coherence values of rectified EMG and tremor. These data provide strong evidence to support the hypothesis that the neurogenic component of physiological tremor is supraspinal in origin and ranges from 6 to 40 Hz. (+info)
Multicystic dysplastic kidney and Kallmann's syndrome: a new association?
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BACKGROUND: Kallmann's syndrome is characterized by anosmia and hypogonadotrophic hypogonadism. Radiographic studies of teenagers and older subjects with the X-linked form of the syndrome have shown that up to 40% have an absent kidney unilaterally. Although this has been attributed to renal "agenesis", a condition in which the kidney fails to form, little is known about the appearance of the developing urinary tract either pre- or post-natally in individuals with Kallmann's syndrome. METHODS: We describe two brothers who had features of Kallmann's syndrome, most probably of the X-linked variety, who both had a major urinary-tract malformation detected before birth. RESULTS: The brothers were found to have unilateral multicystic dysplastic kidneys on routine antenatal ultrasound scanning and both underwent surgical nephrectomy of these organs post-natally. Immunohistochemical studies on the younger sibling revealed hyperproliferative dysplastic kidney tubules which overexpressed PAX2, a potentially oncogenic transcription factor, and BCL2, a cell-survival factor, surrounded by metaplastic, alpha smooth-muscle actin-positive stroma: similar patterns have been observed in patients with non-syndromic multicystic dysplastic kidneys. CONCLUSIONS: Our results describe a new type of urinary-tract malformation associated with Kallmann's syndrome. However, since multicystic kidneys tend to involute, only when more Kallmann's syndrome patients are screened in utero or in early childhood using structural renal scans, will it be possible to establish whether multicystic kidney disease is a bona-fide part of the syndrome. (+info)
Analysis of the KAL1 gene in 19 Japanese patients with Kallmann syndrome.
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Kallmann syndrome is defined by the association of hypogonadotropic hypogonadism and anosmia. The KAL1 gene is responsible for the X-linked form of Kallmann syndrome. We analyzed the KAL1 gene in 19 Japanese patients with Kallmann syndrome, including 3 patients reported previously, using PCR-direct sequencing method. All of 19 patients were sporadic, except for 2 monozygotic twins. In this study, there were 3 kinds of mutations in the KAL1 gene. One of them was a novel mutation consisting of a G to A substitution in the acceptor site at the junction of intron 6/exon 7. None of the mutations have been reported in countries other than Japan. In male sporadic patients with Kallmann syndrome, the incidence of mutations in Japanese patients (14%: 2 of 14 cases) was slightly higher than that in patients in USA (8%). Also, we found 2 polymorphisms, which were always found together in 6 patients. The severity of hypogonadism was not related to the presence of mutations. Unilateral renal aplasia and mirror movement, which are frequently found in patients with the KAL1 gene mutation, were not related to the sites of mutations. (+info)
High frequency of association of rheumatic/autoimmune diseases and untreated male hypogonadism with severe testicular dysfunction.
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Our goal in the present work was to determine whether male patients with untreated hypogonadism have an increased risk of developing rheumatic/autoimmune disease (RAD), and, if so, whether there is a relation to the type of hypogonadism. We carried out neuroendocrine, genetic, and rheumatologic investigations in 13 such patients and 10 healthy male 46,XY normogonadic control subjects. Age and body mass index were similar in the two groups. Nine of the 13 patients had hypergonadotropic hypogonadism (five of whom had Klinefelter's syndrome [karyotype 47,XXY]) and 4 of the 13 had hypogonadotropic hypogonadism (46,XY). Of these last four, two had Kallmann's syndrome and two had idiopathic cryptorchidism. Eight (61%) of the 13 patients studied had RADs unrelated to the etiology of their hypogonadism. Of these, four had ankylosing spondylitis and histocompatibility B27 antigen, two had systemic lupus erythematosus (in one case associated with antiphospholipids), one had juvenile rheumatoid arthritis, and one had juvenile dermatomyositis. In comparison with the low frequencies of RADs in the general population (about 0.83%, including systemic lupus erythematosus, 0.03%; dermatomyositis, 0.04%; juvenile rheumatoid arthritis, 0.03%; ankylosing spondylitis, 0.01%; rheumatoid arthritis, 0.62%; and other RAD, 0.1%), there were surprisingly high frequencies of such disorders in this small group of patients with untreated hypogonadism (P < 0.001) and very low serum testosterone levels (P = 0.0005). The presence of RADs in these patients was independent of the etiology of their hypogonadism and was associated with marked gonadal failure with very low testosterone levels. (+info)
The Kallmann syndrome gene homolog in C. elegans is involved in epidermal morphogenesis and neurite branching.
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Kallmann syndrome is an inherited disorder defined by the association of anosmia and hypogonadism, owing to impaired targeting and migration of olfactory axons and gonadotropin-releasing hormone secreting neurons. The gene responsible for the X-linked form of Kallmann syndrome, KAL-1, encodes a secreted protein of still elusive function. It has been proposed that KAL-1 might be involved in some aspects of olfactory axon guidance. However, the unavailability of a mouse model, and the difficulties in studying cellular and axonal migration in vertebrates have hampered an understanding of its function. We have identified the C. elegans homolog, kal-1, and document its function in vivo. We show that kal-1 is part of a mechanism by which neurons influence migration and adhesion of epidermal cells undergoing morphogenesis during ventral enclosure and male tail formation. We also show that kal-1 affects neurite outgrowth in vivo by modulating branching. Finally, we find that human KAL-1 cDNA can compensate for the loss of worm kal-1 and that overexpression of worm or human KAL-1 cDNAs in the nematode results in the same phenotypes. These data indicate functional conservation between the human and nematode proteins and establish C. elegans as a powerful animal in which to investigate KAL function in vivo. Our findings add a new player to the set of molecules, which appear to underlie both morphogenesis and axonal/neuronal navigation in vertebrates and invertebrates. (+info)
Testosterone substitution of hypogonadal men prevents the age-dependent increases in body mass index, body fat and leptin seen in healthy ageing men: results of a cross-sectional study.
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INTRODUCTION: In healthy men, body weight and total fat content increase with advancing age, while serum testosterone levels decrease. In order to elucidate whether a causal relationship between these phenomena exists, we investigated the influence of testosterone or human chorionic gonadotrophin substitution on body mass index (BMI), total fat mass and serum leptin in testosterone-treated and untreated hypogonadal patients in comparison with ageing eugonadal men. METHODS: In a cross-sectional study, the inter-relationships of body weight, total fat mass, serum sex hormones and leptin were analysed in untreated hypogonadal men (n=24; age 19-65 years), treated hypogonadal men (n=61; age 20-67 years) and healthy eugonadal men (n=60; age 24-78 years). Total fat mass was assessed by bioimpedance measurement. Univariate and multiple linear regression analysis was used to detect possible differences. RESULTS: In eugonadal men, serum testosterone levels decreased with advancing age (correlation coefficients: r=-0.71; P<0.0001), while BMI (r=0.39; P=0.002), total fat content (r=0.51; P<0.0001) and leptin (r=0.48; P<0.0001) increased significantly. In untreated hypogonadal patients, an increase in BMI (r=0.50; P=0.013) and total fat mass (r=0.41; P=0.044) was also observed with advancing age. However, in substituted hypogonadal patients, no age-dependent change in BMI (r=0.067; P=0.606), body fat content (r=-0.083; P=0.522), serum testosterone (r=-0,071; P=0.59) or serum leptin (r=-0.23; P=0.176) was found. CONCLUSION: Since testosterone-substituted older hypogonadal men show BMI and fat mass similar to those of younger eugonadal men and since non-treated hypogonadal men are similar to normal ageing men, testosterone appears to be an important factor contributing to these changes. Thus ageing men should benefit from testosterone substitution as far as body composition is concerned. (+info)
Heparan sulfate proteoglycan-dependent induction of axon branching and axon misrouting by the Kallmann syndrome gene kal-1.
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Kallmann syndrome is a neurological disorder characterized by various behavioral and neuroanatomical defects. The X-linked form of this disease is caused by mutations in the KAL-1 gene, which codes for a secreted molecule that is expressed in restricted regions of the brain. Its molecular mechanism of action has thus far remained largely elusive. We show here that expression of the Caenorhabditis elegans homolog of KAL-1 in selected sensory and interneuron classes causes a highly penetrant, dosage-dependent, and cell autonomous axon-branching phenotype. In a different cellular context, heterologous C. elegans kal-1 expression causes a highly penetrant axon-misrouting phenotype. The axon-branching and -misrouting activities require different domains of the KAL-1 protein. In a genetic modifier screen we isolated several loci that either suppress or enhance the kal-1-induced axonal defects, one of which codes for an enzyme that modifies specific residues in heparan sulfate proteoglycans, namely heparan-6O-sulfotransferase. We hypothesize that KAL-1 binds by means of a heparan sulfate proteoglycan to its cognate receptor or other extracellular cues to induce axonal branching and axon misrouting. (+info)
Anosmin-1, defective in the X-linked form of Kallmann syndrome, promotes axonal branch formation from olfactory bulb output neurons.
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The physiological role of anosmin-1, defective in the X chromosome-linked form of Kallmann syndrome, is not yet known. Here, we show that anti-anosmin-1 antibodies block the formation of the collateral branches of rat olfactory bulb output neurons (mitral and tufted cells) in organotypic cultures. Moreover, anosmin-1 greatly enhances axonal branching of these dissociated neurons in culture. In addition, coculture experiments with either piriform cortex or anosmin-1-producing CHO cells demonstrate that anosmin-1 is a chemoattractant for the axons of these neurons, suggesting that this protein, which is expressed in the piriform cortex, attracts their collateral branches in vivo. We conclude that anosmin-1 has a dual branch-promoting and guidance activity, which plays an essential role in the patterning of mitral and tufted cell axon collaterals to the olfactory cortex. (+info)