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R Quinton

Publications and source records attributed to R Quinton.

At least 19 recordsLinked to original sources
PubMed2004

The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves' disease.

The lymphoid tyrosine phosphatase (LYP), encoded by the protein tyrosine phosphatase-22 (PTPN22) gene, is a powerful inhibitor of T cell activation. Recently, a single nucleotide polymorphism (SNP), encoding a functional arginine to tryptophan residue change at LYP codon 620 has been shown to be associated with type 1 diabetes and other autoimmune disorders. We have used a PCR-restriction fragment (XcmI) assay to examine genotypes at the codon 620 polymorphism in 549 unrelated probands with Graves' disease, 104 unrelated subjects with autoimmune Addison's disease and 429 controls. The T nucleotide at the SNP, encoding the tryptophan 620 residue, was present in 151 of 1098 (13.8%) Graves' disease alleles compared to 67 of 858 (7.8%) control alleles (chi(2) = 17.2, p = 3.4 x 10(-5)' odds ratio = 1.88, 5-95% confidence intervals [CI] 1.39 to 2.55). Similarly, the T nucleotide at the codon 620 SNP was present in 26 of 208 (12.5%) Addison's disease alleles vs 7.8% of controls (chi(2) = 4.63, p = 0.031; odds ratio = 1.69, 5-95% CI 1.04 to 2.73). These data suggest that this LYP polymorphism is a susceptibility allele for Graves' disease with a major effect, and which is likely to have a role in many other autoimmune conditions.

Addison Disease↗
PubMed2001

Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization.

OBJECTIVE: The association of idiopathic hypogonadotrophic hypogonadism (IHH) with congenital olfactory deficit defines Kallmann's syndrome (KS). Although a small proportion of IHH patients have been found to harbour defined genetic lesions, the genetic basis of most IHH cases remains to be elucidated. Genes currently recognized to be involved comprise KAL (associated with X-linked-KS), the GnRH receptor (associated with resistance to GnRH therapy), DAX 1 (associated with adrenohypoplasia congenita) and three loci also associated with obesity, leptin (OB), leptin receptor (DB) and prohormone convertase (PC1). Because of the rarity of the condition and the observation that patients are almost universally infertile without assistance, familial transmission of IHH is encountered infrequently and pedigrees tend to be small. This has constrained the ability of conventional linkage studies to identify other candidate loci for genetic IHH. We hypothesized that a systematic clinical evaluation of a large patient sample might provide new insights into the genetics of this rare disorder. Specifically, we wished to examine the following propositions. First, whether normosmic (nIHH) and anosmic (KS) forms of IHH were likely to be genetically discrete entities, on the basis of quantitative olfactory testing, analysis of autosomal pedigrees and the prevalence of developmental defects such as cryptorchidism and cleft palate. Second, whether mirror movements and/or unilateral renal agenesis were specific phenotypic markers for X-linked-KS. DESIGN AND PATIENTS: We conducted a clinical study of 170 male and 45 female IHH patients attending the endocrinology departments of three London University teaching hospitals. Approximately 80% of data were obtained from case records and 20% collected prospectively. Parameters assessed included olfaction, testicular volume, family history of hypogonadism, anosmia or pubertal delay, and history or presence of testicular maldescent, neurological, renal or craniofacial anomalies. Where possible, the clinical information was correlated with published data on genetic analysis of the KAL locus. RESULTS: Olfactory acuity was bimodally distributed with no evidence for a spectrum of olfactory deficit. Testicular volume, a marker of integrated gonadotrophin secretion, did not differ significantly between anosmic and normosmic patients, at 2.0 ml and 2.2 ml, respectively. Nevertheless, the prevalence of cryptorchidism was nearly three times greater in anosmic (70.3%, of which 75.0% bilateral) than in normosmic (23.2%, of which 43.8% bilateral) patients. Individuals with nIHH, eugonadal isolated anosmia and/or KS were observed to coexist within 6/13 autosomal IHH pedigrees. On three occasions, fertility treatment given to an IHH patient had resulted in the condition being transmitted to the resulting offspring. Mirror movements and unilateral renal agenesis were observed in 24/98 and 9/87 IHH patients, respectively, all of whom were identifiable as X-KS males on the basis of pedigree analysis and/or defective KAL coding sequence. Abnormalities of eye movement and unilateral sensorineural deafness were observed in 10/21 and 6/111 KS patients, respectively, but not in nIHH patients. DISCUSSION: Patients with IHH are almost invariably either anosmic (KS) or normosmic (nIHH), rather than exhibiting intermediate degrees of olfactory deficit. Moreover, the prevalence of cryptorchidism is nearly three times greater in KS than in nIHH despite comparable testicular volumes, suggesting a primary defect of testicular descent in KS independent of gonadotrophin deficiency. Disorders of eye movement and hearing appear only to occur in association with KS. Taken together, these findings indicate a clear phenotypic separation between KS and nIHH. However, pedigree studies suggest that autosomal KS is an heterogeneous condition, with incomplete phenotypic penetrance within pedigrees, and that some cases of autosomal KS, nIHH and even isolated anosmia are likely to have a common genetic basis. The prevalences of anosmia, mirror movements and unilateral renal agenesis among X-KS men are estimated to be 100, 85 and 31%, respectively. In sporadic IHH, mirror movements and unilateral renal agenesis are 100% specific phenotypic markers of de novo X-KS. By comparison, only 7/10 X-KS families harboured KAL coding defects. Clinical ascertainment, using mirror movements, renal agenesis and ichthyosis as X-KS-specific phenotypic markers, suggested that de novo X-KS was unlikely to comprise more than 11% of sporadic cases. The majority of sporadic KS cases are therefore presumed to have an autosomal basis and, hence, the preponderance of affected KS males over females remains unexplained, though reduced penetrance in women would be a possibility.

Adolescent↗
PubMed2001

Locomotion evaluation for racing in thoroughbreds.

The potential racing and locomotory profile of a Thoroughbred yearling should be taken into account for its training programme and racing career. A gait test has been designed to assist the trainer in this task. The aim of this study was to investigate the temporal and kinetic locomotory variables of Thoroughbreds at the gallop, in relationship to their racing ability. Thirty Thoroughbred horses in race training were tested at maximal speed during a training session. The training exercise consisted of a warming-up session at trot and canter for 10 min followed by a gallop session at increasing speed on a dirt track 1942 m long. The maximal speed was measured for the last 800 m before the finishing post. An acclerometric device attached to the girth provided quantitative information about the kinetic and temporal variables of the gallop such as: stride length (SL), stride frequency (SF), times elapsed between each hoof midstance phase (HIND, DIAGO, FORE), regularity of the strides (REG), mean vector of propulsion (VPROP), energy of propulsion (EPROP) and energy of loading (ELOAD). The performance records (number of wins, placings and average earning/start [PERF]) were used to analyse the relationship with the gait measurements. The mean maximum speed was 15.26 m/s. Several locomotory variables were significantly (P < 0.05) correlated to the gallop speed: SL (0.90), SF (0.75), DIAGO (0.42), REG (-0.47), VPROP (0.52), ELOAD (0.56) and EPROP (0.65). There were significant correlations between PERF and the following gait variables: REG (0.79), DIAGO (0.43), SF (0.42), SL (-0.32) and ELOAD (-0.40). The horses that won short distance races (< 1400 m) had a larger relative ground contact duration and higher stride frequency than horses that won in longer distance races. The gait test was easy to perform and provided useful locomotory variables that may be used to evaluate the racing ability of the Thoroughbreds in training.

Acceleration↗
PubMed1999

Kallmann's syndrome: mirror movements associated with bilateral corticospinal tract hypertrophy.

OBJECTIVE: To investigate the etiology of mirror movements in patients with X-linked Kallmann's syndrome (xKS) through statistical analysis of pooled white matter data from structural MR images. BACKGROUND: Mirror movements occur in 85% of xKS patients. Previous electrophysiologic studies have suggested an abnormal ipsilateral corticospinal tract projection in xKS patients exhibiting mirror movements. However, an alternative hypothesis has proposed a functional lack of transcallosal inhibitory fibers. METHODS: T1-weighted brain scans were normalized into stereotaxic space with segregation of gray and white matter to allow comparison of pooled white matter data on a voxel-by-voxel basis using SPM-96 software. Nine xKS patients were compared with two age-matched groups of nonmirroring individuals: nine patients with autosomal Kallmann's syndrome (aKS) and nine age-matched normal (healthy) men. RESULTS: Hypertrophy of the corpus callosum was found in both Kallmann's syndrome groups: the anterior and midsection in xKS, and the genu and posterior section in aKS. Bilateral hypertrophy of the corticospinal tract was found only in the group of xKS patients exhibiting mirror movements. SPM analysis was validated by an independent region of interest analysis of corpus callosum size. CONCLUSION: Although morphometry on its own cannot determine the cause of mirror movements, the specific finding of a hypertrophied corticospinal tract in xKS is consistent with electrophysiologic evidence suggesting that mirror movements in xKS result from abnormal development of the ipsilateral corticospinal tract fibers.

Adult↗
PubMed1999

Kallmann's syndrome: is it always for life?

OBJECTIVE: Kallmann's syndrome (KS) is defined by the association of olfactory deficit with irreversible, congenital gonadotrophin deficiency (IHH). We present evidence for the existence of a variant form of KS, in which endogenous gonadotrophin secretion recovers spontaneously in later life. DESIGN: Longitudinal clinical study. PATIENTS: Five men with anosmia or severe hyposmia, who originally presented in their late teens or early twenties as a result of severe pubertal delay and were thus presumed to have KS. RESULTS: Spontaneous onset of endogenous gonadotrophin secretion, evidenced by progressive normalization of testicular volume and of serum testosterone concentration, occurred in these men over a period of years following the initial diagnosis. CONCLUSIONS: This variant form of Kallman's syndrome is not well recognized and may well be under-diagnosed. Once full virilization has been induced, males with congenital gonadotrophin deficiency whose testes have significantly increased in size should be reassessed, off androgen replacement therapy, to identify those who no longer require treatment.

Adolescent↗
PubMed1999

Gordon Holmes spinocerebellar ataxia: a gonadotrophin deficiency syndrome resistant to treatment with pulsatile gonadotrophin-releasing hormone.

The Gordon Holmes spinocerebellar ataxia syndrome (GHS) is associated with idiopathic hypogonadotrophic hypogonadism (IHH). There are conflicting reports in the literature as to whether the primary neuroendocrine defect is of hypothalamic GnRH secretion, as with most causes of IHH, or of pituitary resistance to GnRH action. Because of the anatomical inaccessibility of the hypophyseal portal circulation, direct measurement of GnRH levels in human subjects is not possible. Previous investigators have attempted to unravel this problem through the use of GnRH stimulation tests and the limitations of this approach may explain the differing results obtained. We used the more physiological approach of treating a male GHS patient for four weeks with GnRH, 7-10 microg/pulse, delivered subcutaneously at 90 minute frequency via a portable minipump. This therapy failed to induce any rise in plasma gonadotrophin and testosterone concentrations. By contrast, eight weeks treatment with exogenous gonadotrophins maintained physiological plasma testosterone concentrations and induced testicular enlargement with induction of spermatogenesis. The data indicate that the primary endocrinopathy in GHS is of pituitary gonadotrophin secretion and not of hypothalamic GnRH. Moreover, the patient did not harbour any mutation of the GnRH receptor gene. Two clinical observations are consistent with progressive involution of gonadotrophic function, rather than a congenital gonadotrophin deficiency. First, the patient's development was arrested at early mid-puberty at the time of original presentation and, second, effective spermatogenesis was induced extremely rapidly during gonadotrophin treatment, suggesting prior exposure of the testes to FSH. Both spinocerebellar ataxia and pituitary dysfunction might thus have been in evolution since late childhood.

Adult↗
PubMed1998

Contrasting expression of KAL in cell-free systems: 5' UTR and coding region structural effects on translation.

We investigated the expression of two different X-linked Kallmann (KAL) gene cDNAs in two different cell-free systems using rabbit reticulocyte lysate: (system A) transcription/translation coupled and (system B) noncoupled. System A yielded a single band of 76 kDa corresponding to anosmin-1, the expected full-length gene product, and upon addition of canine microsomal membranes produced a 85-kDa glycosylated form. System B did not produce any detectable protein band despite the expression of a beta-galactosidase-positive control gene. The first 179 bases of the coding sequence are 74% GC-rich and showed the potential to form imperfect hairpin structures, which in part may explain the translation inhibition of KAL in system B. This has further led us to speculate that coupling transcription to translation may either be preventing translating-inhibiting hairpin formation or be compensating for the lack of certain tissue-specific proteins in reticulocyte lysate that are essential in overcoming inhibitory hairpins during translation. Substitution of the 5'-UTR with an encephalomyocarditis virus internal ribosomal entry site (EMCV IRES) sequence resulted paradoxically in a lower yield of anosmin-1, suggesting that elements in the 5'UTR may be necessary for maintaining a "normal" level of expression. The use of KAL and luciferase reporters (containing different 5'UTRs) demonstrated that the native KAL 5' UTR is not involved in translational efficiency. However, this sequence may influence faithful translation initiation. Theoretical RNA conformation data imply that effective EMCV IRES usage with KAL may require favorable pairing between the IRES and unidentified sequences within the 5' coding region of the gene. This work provides a foundation both for the investigation of KAL regulation and for the characterization of its function.

Animals↗
PubMed1998

Proteinuria, hypertension and chronic renal failure in X-linked Kallmann's syndrome, a defined genetic cause of solitary functioning kidney.

BACKGROUND: Anosmia and hypogonadotrophic hypogonadism are the classic features of X-linked Kallmann's syndrome, a disorder caused by mutations of KAL, a gene expressed during kidney and brain development. About a third of patients have a solitary functioning kidney, but little is known about their renal morbidity. METHODS: We studied seven patients aged 22-35 years with X-linked Kallmann's syndrome and a solitary functioning kidney. RESULTS: Two patients developed significant proteinuria associated with mild to moderate arterial hypertension in the second to third decades of life. In one, proteinuria and renal impairment preceded the appearance of hypertension, and the disorder progressed to chronic renal failure. The remaining five patients had normal plasma creatinine concentrations and no significant proteinuria although four had borderline systolic and/or diastolic hypertension. In two sets of patients from the same kindreds, there was a striking discordance for the occurrence of renal morbidity. CONCLUSIONS: All patients with X-linked Kallmann's syndrome should be screened for renal malformations, and those with solitary kidneys require life-long follow-up to detect hypertension, proteinuria and renal failure.

Adult↗
PubMed1997

Mirror movements in X-linked Kallmann's syndrome. I. A neurophysiological study.

Possible mechanisms underlying the pathological mirror movements that are seen in the majority of patients with X-linked Kallmann's syndrome have been investigated using neurophysiological techniques. An EMG was recorded from the first dorsal interosseous muscle (1DI) during voluntary self-paced abduction of one indexed finger; EMG activity could also be recorded simultaneously from the contralateral 1DI. There was no significant difference between the time of onset of the bursts of voluntary and involuntary mirroring EMG. Focal magnetic stimulation of the hand area of the motor cortex revealed the presence of fast conducting bilateral corticospinal projections from each motor cortex in all subjects. However, both inter- and intra-subject differences exist when considering the ratio of ipsilaterally to contralaterally projecting axons. Cross-correlation analysis of multi-unit EMGs recorded during simultaneous voluntary sustained activation of homologous left and right pairs of distal upper limb muscles was performed. A short duration central peak was seen in the cross-correlograms indicating the presence of a common drive to left and right homologous motor neuron pools. This common drive may result from the synchronous activation of intermingled ipsilaterally and contralaterally projecting corticospinal neurons in the motor cortex. Cutaneomuscular reflexes were recorded from the 1DI following stimulation of the digital nerves of the index finger. Typically each reflex comprises spinal and longer latency trans-cortical components. In these subjects, the long latency components of the reflex response could, in addition, be recorded from the 1DI of the non-stimulated side. We conclude that these subject have a novel ipsilateral at least in part, for the pathological mirroring.

Adolescent↗
PubMed1997

Mirror movements in X-linked Kallmann's syndrome. II. A PET study.

To investigate the mechanism of mirror movements seen in X-linked Kallmann's syndrome, we measured changes of regional cerebral blood flow with H2 15O-PET. We studied six right-handed Kallmann male subjects and six matched, right-handed control subjects during an externally paced finger opposition task. The analyses were done both on a single subject and a group basis. The Kallmann group showed a strong primary motor cortex (M1) activation contralateral to the voluntarily moved hand, but there was also a significant degree of M1 activation ipsilateral to the voluntarily moved hand, i.e. contralateral to the mirroring hand. However, when comparing contralateral to ipsilateral M1 activation, the M1 activation contralateral to the voluntarily moved hand was significantly stronger. In the controls, significant increases in rCBF were seen in the contralateral M1 during voluntary movement of either hand; a small ipsilateral M1 activation was found in two out of six normal subjects when they moved their left hand. In a second experiment it was shown that, in two out of two Kallmann subjects, passive movements of the right hand resulted in left M1 activation that was similar to the activation in the left M1 when subjects made mirror movements with their right hand. This suggests, but does not prove, that the small but significant activation of the ipsilateral M1 in Kallmann's subjects may be due to sensory feedback from the involuntarily mirroring hand.

Adolescent↗
PubMed1997

Gonadotropin-releasing hormone immunoreactivity in the nasal epithelia of adults with Kallmann's syndrome and isolated hypogonadotropic hypogonadism and in the early midtrimester human fetus.

GnRH-secreting neurons are known to originate in the epithelium of the medial olfactory placode, whence they migrate along the axons of the terminal nerve via the forebrain and into the hypothalamus. Synaptic contact between the developing olfactory bulbs and fascicles of the vomeronasal, terminal, and olfactory nerves does not occur in Kallmann's syndrome. Consequently, there is migration arrest of GnRH cells and partial or complete failure of formation of the olfactory bulbs, resulting in severe olfactory deficit and hypogonadotropic hypogonadism. In the present study, using an immunofluorescent, double immunostaining technique and confocal laser scanning microscopy, we observed GnRH-immunoreactive neurons in the hypothalamus of a 14-week-old human fetus. However, migration of GnRH neurons was not complete, and indeed, such cells were seen to be migrating along terminal nerve fascicles beneath the cribriform plate in a 16-week-old fetus. The same immunofluorescent technique demonstrated the presence of GnRH cells in biopsies of nasal mucosa obtained from three adults with Kallmann's syndrome, one normosmic subject with hypogonadotropic hypogonadism, and a eugonadal male cadaver. These findings are consistent with two different interpretations: the nasal GnRH neurons may be vestigial, representing cells that failed to migrate during embryogenesis; alternatively, they may have been generated de novo later in life, a possibility consistent with the recognized plasticity of human postnatal olfactory neuroepithelium. They also reveal that subjects with the normosmic (i.e. non-Kallmann's) form of GnRH deficiency are able to synthesize immunologically recognizable GnRH, implying that failure of GnRH synthesis is not responsible for this type of hypogonadotropic hypogonadism.

Adult↗
PubMed1997

X-linked ichthyosis with hypogonadism: not always Kallmann's syndrome.

We describe two males with congenital ichthyosis secondary to steroid sulphatase deficiency who also manifested delayed puberty with biochemical features of hypogonadotrophic hypogonadism. In the first patient a history of cryptorchidism and the clinical findings of anosmia, micropenis and bimanual synkinesis suggested a contiguous gene syndrome, comprising X-linked Kallmann's syndrome and X-linked ichthyosis. An X-Y chromosomal translocation involving the Xp22.3 locus was identified; deletions of the STS locus and of exons 10-14 of the KAL locus were subsequently demonstrated. The second patient was euosmic and, although the STS locus was deleted in association with a pericentric inversion involving Xp22.3, no deletions were detected at the KAL locus. Clinically, he was felt to have constitutionally delayed puberty rather than hypogonadotropic hypogonadism and this diagnosis was substantiated by his subsequent development.

Adolescent↗
PubMed1996

The neuroradiology of Kallmann's syndrome: a genotypic and phenotypic analysis.

A detailed neurological investigation of patients with Kallmann's syndrome (KS) has been performed in an attempt to relate phenotypic characterization with genotype. Twenty-seven subjects with KS were studied (including 12 males with X-linked disease and 3 females). Six male and 2 female normosmics with isolated GnRH deficiency, 1 male with KS variant, and 1 obligate female carrier were also imaged. Evidence for X-linked disease was derived both from analysis of pedigree and by mutation analysis at the KAL locus. The female carrier and all 8 normosmics had normal olfactory bulbs and sulci, as did 3 male KS. The study, therefore, confirms the value of magnetic resonance imaging in the diagnosis of KS, but suggests that the technique is not sufficiently sensitive to differentiate KS from the normosmic form of GnRH deficiency in all cases. Phenotypic characterization of KS was more effectively achieved by accurate estimation of olfactory status. Three new mutations at the KAL locus were identified, 2 single exon deletions and 1 point mutation. In 2 pedigrees with clear X-linked inheritance, no coding sequence mutations were detected; it may be that these harbor mutations of pKAL, the recently characterized 5'-promoter region. No clear relationship could be established between specific phenotypic anomalies and particular KAL mutations. Involuntary, mirror movements of the upper limbs were present in 10 of 12 cases of X-linked KS, but in none of the other subjects. Although this phenomenon has been ascribed to an abnormality of the corpus callosum, in the present study magnetic resonance imaging demonstrated no quantitative or qualitative morphological anomalies of this structure.

Base Sequence↗