Search PubMed⌕ Search

Biomedical subjects

F B Axelrod

Publications and source records attributed to F B Axelrod.

At least 37 records · Page 2Linked to original sources
PubMed1999

Sympathetic skin response differentiates hereditary sensory autonomic neuropathies III and IV.

OBJECTIVE: To evaluate whether sympathetic skin response (SSR) differs in patients with hereditary sensory autonomic neuropathy (HSAN) types III and IV. BACKGROUND: HSAN types III and IV are rare autosomal recessive disorders that cause many similar autonomic, sensory, and motor dysfunctions, but different sweating characteristics. HSAN III patients have preserved and at times, excessive sweating, whereas anhidrosis is characteristic of HSAN IV. SSR reflects the integrity of sympathetic sudomotor fibers and the activation of sweat glands through the change in skin resistance in response to an arousal stimulus. Therefore, SSR is a test method that might facilitate differential diagnosis of HSAN III and IV. METHODS: In 17 HSAN III patients (eight women, nine men; mean age, 20.65+/-5.45 years) and seven HSAN IV patients (five girls, two boys; mean age, 10.0+/-5.45 years) SSR was recorded from the palms and soles after repeated electrical, acoustic, and inspiratory gasp stimulations. In addition, all subjects underwent a neurologic examination; studies of median, peroneal motor, and sural nerve conduction velocities; and determination of vibratory and thermal perception thresholds. RESULTS: Although clinical differences were appreciated between the two types of HSANs, both HSANs had evidence of small-fiber involvement. Both HSANs had abnormal temperature and pain perception. In contrast, SSR was preserved in all HSAN III and absent in all HSAN IV patients. CONCLUSION: SSR provides another parameter to improve differentiation of HSAN III from HSAN IV, and also gives us additional information regarding sympathetic sudomotor fiber function in these developmental diseases.

Adolescent↗
PubMed1999

Electrocardiographic repolarization abnormalities in familial dysautonomia: an indicator of cardiac autonomic dysfunction.

OBJECTIVE: Electrocardiographic repolarization intervals were evaluated to determine the extent of cardiac autonomic dysfunction in patients with familial dysautonomia (FD) and to determine if any of these intervals could serve as a possible predictor of clinical symptoms. METHODS: Thirty-seven electrocardiograms of patients with FD were retrospectively evaluated. QT, JT, rate-corrected QT and JT intervals were calculated as well as QT and QTC dispersion. Results were compared to normative data and electrocardiograms of 20 age-matched control subjects. OBSERVATIONS: In the FD group, prolongation of QTC (>450 msec) was noted in 5/37 (13.5%) patients, as compared to 0/20 normal controls (p = NS), and prolongation of JTc (>340 msec) in 16/37 (43.3%) patients, as compared to 0/20 normal controls (p < 0.001). QT and QTC dispersion were abnormal in 3/37 (8.1%) and 5/37 (13.5%), respectively. In the 16 FD patients with prolonged JTc, six had a positive history of syncope, whereas none of the 21 with normal JTc had syncope or symptoms suggesting arrhythmia (p < 0.003). The positive predictive value of having syncope or symptoms suggestive of arrhythmia with an abnormal JTc is 37.5% (95% CI [15%, 65%]). The negative predictive value is 100% (95% CI [87%, 100%]). CONCLUSION: In the FD population, the electrocardiographic measure of repolarization that was most frequently abnormal was the JTc interval . Prolongation of the JTc interval was significantly more frequent than prolongation of the QTC interval (p < 0.001) QT and QTC dispersions were less significantly affected in the FD population, indicating uniform ventricular recovery time. These results suggest that a prolonged JTc interval may be a more sensitive indicator of abnormal ventricular repolarization and cardiac autonomic dysfunction. Due to the known sympathetic denervation inherent in patients with FD, they are at risk for unopposed parasympathetic predominance. FD patients, therefore, are more likely to have brady arrhythmias and asystole rather than polymorphic ventricular tachycardia. The increased incidence of syncope in patients with prolonged JTc suggests that this measure may serve as a helpful marker to predict which FD patients are at increased risk of serious clinical sequelae including bradyarrhythmias with asystole or sudden death.

Adolescent↗
PubMed1999

Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31.

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by developmental arrest in the sensory and autonomic nervous systems and by Ashkenazi Jewish ancestry. We previously had mapped the defective gene (DYS) to an 11-cM segment of chromosome 9q31-33, flanked by D9S53 and D9S105. By using 11 new polymorphic loci, we now have narrowed the location of DYS to <0.5 cM between the markers 43B1GAGT and 157A3. Two markers in this interval, 164D1 and D9S1677, show no recombination with the disease. Haplotype analysis confirmed this candidate region and revealed a major haplotype shared by 435 of 441 FD chromosomes, indicating a striking founder effect. Three other haplotypes, found on the remaining 6 FD chromosomes, might represent independent mutations. The frequency of the major FD haplotype in the Ashkenazim (5 in 324 control chromosomes) was consistent with the estimated DYS carrier frequency of 1 in 32, and none of the four haplotypes associated with FD was observed on 492 non-FD chromosomes from obligatory carriers. It is now possible to provide accurate genetic testing both for families with FD and for carriers, on the basis of close flanking markers and the capacity to identify >98% of FD chromosomes by their haplotype.

Alleles↗
PubMed1999

Quantitative thermal perception testing in adults.

In 225 adults aged 18 to 80 years, normative warm and cold perception thresholds were assessed at the volar distal forearm, thenar eminence, lower medial calf, and lateral dorsal foot using the method of limits and a Thermotest (Somedic, Stockholm, Sweden). A 1.5-cm x 2.5-cm thermode, a 1 degrees C/s stimulus change rate, and a 32 degrees C baseline temperature were applied. Thresholds of five consecutive stimuli were averaged. At the thenar eminence a 3 degrees C/s stimulation was applied in addition to the 1 degree C/s stimulation. Effects of spatial summation were studied at the calf and forearm by additional testing with a 2.5-cm x 5.0-cm thermode. To evaluate the influence of skin temperature, thresholds were correlated with the pretest skin temperature at the tested sites. Reproducibility of stimulus perception was determined by comparing the lowest to the highest response to five consecutive stimuli. Results showed sufficient accuracy of thermal perception thresholds. Thresholds were higher with the 3 degrees C/s stimulation than with the 1 degree C/s stimulation. Thresholds were lower with the large than with the small probe. Skin temperature had only minimal influence on thresholds. The use of a 32 degrees C baseline temperature and a 1 degree C/s stimulus change rate is recommended. The large probe should be used at body sites where the entire thermode surface adjusts planely to the skin. Warming up the tested skin area is not necessary before thermotesting.

Adolescent↗
PubMed1999

Cold face test demonstrates parasympathetic cardiac dysfunction in familial dysautonomia.

In familial dysautonomia (FD), i.e., Riley-Day syndrome, parasympathetic dysfunction has not been sufficiently evaluated. The cold face test is a noninvasive method of activating trigeminal brain stem cardiovagal and sympathetic pathways and can be performed in patients with limited cooperation. We performed cold face tests in 11 FD patients and 15 controls. For 60 s, cold compresses (0-1 degrees C) were applied to the cheeks and forehead while we monitored heart rate, respiration, beat-to-beat radial artery blood pressure, and laser-Doppler skin blood flow at the first toe pulp. From these measurements heart rate variability parameters were calculated: root mean square of successive differences (RMSSD), coefficient of variation (CV), low- and high-frequency (LF and HF, respectively) power spectra of the electrocardiogram, and the LF transfer function gain between blood pressure and heart rate. All patients perceived cold stimulation and acknowledged discomfort. In controls, heart rate and skin blood flow decreased significantly during cold face test; in patients, both parameters decreased only briefly and not significantly. In controls, blood pressure, RMSSD, CV, and heart rate HF-power spectra increased but remained unchanged in patients. Respiration, as well as heart rate LF power spectra, did not change in either group. In controls, LF transfer function gain between blood pressure and heart rate indicated that bradycardia was not secondary to blood pressure increase. We conclude that the cold face test demonstrated that patients with FD have a reduced cardiac parasympathetic response, which implies efferent parasympathetic dysfunction.

Adolescent↗
PubMed1998

Normative values of vibratory perception in 530 children, juveniles and adults aged 3-79 years.

Impaired vibratory perception is an early and frequent finding in various neuropathies. Quantitative vibratory threshold assessment refines the diagnosis of neuropathies but is based on psychophysical techniques requiring patient cooperation. Large, age and sex matched normative data bases are needed to better identify abnormal vibratory perception. In this study vibratory perception was tested at the second metacarpal bone and above the first metatarsal bone of 530 children, juveniles and adults aged 3.3-79.2 years. Thresholds assessed with a 128 Hz graded Rydel-Seiffer tuning fork, TF, were compared to three Vibrameter values, the vibration perception thresholds, VPT, determined with increasing vibration stimuli, the vibration disappearance threshold, VDT, determined with decreasing supraliminal stimuli, and the vibration threshold VT which equals the mean of VPT and VDT. The influence of gender, age, body height, weight and skin temperature at the tested site on thresholds was studied. Retest reliability was tested in 73 children aged 3.3-6.9 years and in 20 volunteers aged 5.2-66.1 years who were also tested for the influence of pretest skin warming on thresholds and for differences between results of the left and right body side. TF, VPT, VDT, VT were closely correlated with each other (Spearman: -0.67<Rs<-0.47; P<0.01). The skin temperature, body side, weight and height did not influence thresholds. In adults, thresholds increased with age and were higher in men above the age of 50 than in women of the same age. Thresholds at the feet were higher than at the hands (Wilcoxon: P<0.001). Retest reliability was high and did not depend on the retest interval. The study provides important normative data for the widespread use of quantitative vibration testing.

Adolescent↗
PubMed1998

Assessing microcirculation in familial dysautonomia by laser Doppler flowmeter.

Microcirculatory vasomotor responses to an alpha-adrenergic agonist and an antagonist were assessed in 11 familial dysautonomia and nine control subjects by laser Doppler flowmetry. Using two iontophoresis machines, blood flow in the midclavicular areas was continuously monitored by two channel laser Doppler flowmeter. Simultaneously, the alpha-antagonist (0.5 mM phentolamine hydrochloride) and a control solution (0.9% saline) were iontophoresed at 200 microA for 15 min. The alpha-agonist (0.5 mM norepinephrine bitartrate) was then iontophoresed (20 microA) to both pretreated areas for progressively longer pulses separated by 3-min observation intervals (15, 30, 60, 90, 120 s). The familial dysautonomia subject group had higher mean baseline perfusion with widely fluctuating baselines, especially on the phentolamine pretreated side (P = 0.03). Saline iontophoresis significantly increased perfusion in the control group, but not in the familial dysautonomia group (ANOVA: P = 0.02 and 0.15, respectively). There was > 100% increase in flow by the end of the saline observation period in seven of nine controls, but in only three of 11 familial dysautonomia subjects. Phentolamine iontophoresis differentiated familial dysautonomia subjects into responders and nonresponders by 7-8 min when all nine control subjects, but only five of 11 familial dysautonomia subjects, had > 200% increase in blood flow. Irrespective of pretreatment type, norepinephrine decreased blood flow in both familial dysautonomia and control groups (ANOVA: P < 0.0001), but the final mean change after saline was greater in the control group, P = 0.02. The final mean changes of flow after phentolamine pretreatment were not different between the two groups and were comparable to the familial dysautonomia group's smaller response after saline pretreatment. Higher baseline perfusion suggests dilation may be intrinsic to familial dysautonomia vasculature. Two populations of familial dysautonomia subjects are noted; those who like controls increase blood flow with iontophoresis of the alpha-antagonist and those who are refractory. In addition, in familial dysautonomia subjects, the microcirculatory constrictive response to alpha-agonist iontophoresis is less than that observed for controls. These data suggest that some familial dysautonomia subjects may have decreased or dysfunctional adrenoceptors as well as decreased innervation.

Adolescent↗
PubMed1998

Familial dysautonomia: a 47-year perspective. How technology confirms clinical acumen.

A historical perspective of familial dysautonomia is presented, highlighting the early contributions of Dr. Joseph Dancis. As further investigations proceeded, his original observations have withstood the test of time and may contribute to determining the molecular abnormality in this rare genetic disorder. Dr. Dancis's work in this area serves as a model of how observations based on clinical acumen and critical thinking can be verified by future technological advances.

Adult↗
PubMed1998

Highly abnormal thermotests in familial dysautonomia suggest increased cardiac autonomic risk.

OBJECTIVE: Patients with familial dysautonomia have an increased risk of sudden death. In some patients with familial dysautonomia, sympathetic cardiac dysfunction is indicated by prolongation of corrected QT (QTc) interval, especially during stress tests. As many patients do not tolerate physical stress, additional indices are needed to predict autonomic risk. In familial dysautonomia there is a reduction of both sympathetic neurons and peripheral small nerve fibres which mediate temperature perception. Consequently, quantitative thermal perception test results might correlate with QTc values. If this assumption is correct, quantitative thermotesting could contribute to predicting increased autonomic risk. METHODS: To test this hypothesis, QTc intervals were determined in 12 male and eight female patients with familial dysautonomia, aged 10 to 41 years (mean 21.7 (SD 10.1) years), in supine and erect positions and postexercise and correlated with warm and cold perception thresholds assessed at six body sites using a Thermotest. RESULTS: Due to orthostatic presyncope, six patients were unable to undergo erect and postexercise QTc interval assessment. The QTc interval was prolonged (>440 ms) in two patients when supine and in two additional patients when erect and postexercise. Supine QTc intervals correlated significantly with thermal threshold values at the six body sites and with the number of sites with abnormal thermal perception (Spearman's rank correlation p<0.05). Abnormal Thermotest results were more frequent in the four patients with QTc prolongation and the six patients with intolerance to stress tests. CONCLUSION: The results suggest that impaired thermal perception correlates with cardiac sympathetic dysfunction in patients with familial dysautonomia. Thus thermotesting may provide an alternative, albeit indirect, means of assessing sympathetic dysfunction in autonomic disorders.

Adolescent↗
PubMed1996

Pattern of plasma levels of catecholamines in familial dysautonomia.

This report extends previous investigations of endogenous catecholamine levels in patients with orthostatic hypotension due to familial dysautonomia (FD), to define better the neurochemical phenotype and elucidate possible pathophysiological mechanisms. Ten FD patients (age 26.1 +/- 2.6 (SEM) years) and eight control subjects (age 29.5 +/- 3.7 years) were studied. Heart rate, blood pressure and venous blood samples were obtained while supine and after 5 min in the upright position. Plasma levels of dihydroxyphenylalanine (DOPA), noradrenaline (NA), adrenaline (A), dopamine (DA), dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC) were measured. When supine, the FD group had greater NA and DOPA levels, and lower DHPG levels. Plasma NA did not increase with erect posture in FD patients. Individual FD mean blood pressures were correlated positively with plasma NA levels when supine and with plasma DA and DOPAC when upright. In FD, DOPA:DHPG ratios were above the range found in normal subjects or that reported in patients with acquired forms of dysautonomia regardless of posture, whereas DOPAC:DHPG ratios remained normal. Thus FD patients have a characteristic neurochemical pattern which probably reflects either decreased vesicular storage of catecholamines or limited oxidative deamination despite normal or increased tyrosine hydroxylation.

Adolescent↗
PubMed1996

Mitochondrial encephalomyopathies presenting with features of autonomic and visceral dysfunction.

Three children are reported with mitochondrial encephalomyopathy who presented with autonomic dysfunction. Autonomic dysfunction included gastrointestinal dysmotility, apnea, cardiac arrhythmias, decreased lacrimation, supersensitivity to metacholine, altered sweating, and postural hypotension. These patients illustrate that in some mitochondrial encephalomyopathies autonomic features may be prominent and can mimic the clinical features associated with hereditary sensory and autonomic neuropathies.

Autonomic Nervous System Diseases↗
PubMed1995

Prenatal diagnosis of familial dysautonomia by analysis of linked CA-repeat polymorphisms on chromosome 9q31-q33.

Familial Dysautonomia (FD) is an autosomal recessive sensory neuropathy that affects about 1 in 3,700 individuals of Ashkenazi Jewish ancestry. The underlying biochemical and genetic defects are unknown, thereby precluding prenatal diagnosis in at-risk families. Recently, the FD gene (DYS) was mapped with strong linkage disequilibrium to polymorphic markers in the chromosome 9 region q31-q33. In this report, the use of these markers for the prenatal diagnosis of FD by linkage analysis in families with a previously affected child was evaluated. Genomic DNA from appropriate family members was analyzed to construct haplotypes using informative CA repeat polymorphisms closely linked to and flanking the FD locus. The calculation of risk for the prenatal diagnoses was performed by linkage analysis. All seven FD families were informative for the closely linked polymorphic markers and fetal diagnoses were made in eight pregnancies. Six fetal diagnoses were predicted with > 98% accuracy, while two with recombinations were predicted with at least 88% and 92% accuracy. Use of these closely linked markers permitted the reliable prenatal diagnosis of FD in families with a previously affected child.

Abortion, Eugenic↗
PubMed1995

Preliminary observations on the use of midodrine in treating orthostatic hypotension in familial dysautonomia.

Midodrine, a peripheral alpha-adrenergic agonist, was evaluated in 7 female and 2 male patients with familial dysautonomia (FD), a disorder characterized by decreased sympathetic innervation. Prior to and after three months of midodrine treatment, each patient's response to postural change was assessed by arteriosonde readings of blood pressure and heart rate, corrected QT-interval measurements, Doppler evaluation of renal blood flow and circulating atrial natriuretic peptide (ANP) levels. The initial midodrine dose (2.5 mg three times daily) was raised until subjective symptoms improved. Doses were reduced if patients felt jittery or developed erect hypertension (systolic > 180 mmHg or diastolic > 110 mmHg). Midodrine, at an average dose of 0.25 mg/kg per day, improved subjective symptoms in all patients. With treatment, magnitude of blood pressure responses was variable. Although mean erect blood pressure did not increase significantly for the aggregate, it did increase in six of nine patients. In addition, the QTc interval normalized and erect renal perfusion improved. Changes in supine mean blood pressure and supine circulating ANP correlated directly. We judge midodrine to be useful in management of orthostatic hypotension in patients with familial dysautonomia.

Adolescent↗
PubMed1995

The human gene for neurotrophic tyrosine kinase receptor type 2 (NTRK2) is located on chromosome 9 but is not the familial dysautonomia gene.

The neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene is a member of the trk family of tyrosine protein kinases, which encode receptors for the nerve growth factor-related proteins known as neurotrophins. The neurotrophins and their receptors have long been considered candidate genes for familial dysautonomia (FD), a hereditary sensory neuropathy resulting from the congenital loss of both sensory and autonomic neurons. The DYS gene has recently been mapped to human chromosome 9q31-q33, and therefore we set out to determine the chromosomal localization of the candidate gene NTRK2. A mouse trkB probe was hybridized to both somatic cell hybrids containing human chromosome 9 and a human chromosome 9 flow-sorted cosmid library. The human homologue of trkB, NTRK2, was assigned to chromosome 9. To localize the NTRK2 gene further, a dinucleotide repeat polymorphism was identified within a cosmid that contains NTRK2 exon sequences. This marker was genotyped in the CEPH reference pedigrees and places the NTRK2 gene near D9S1 on the proximal long arm of human chromosome 9. The NTRK2 gene is located approximately 22 cm proximal to DYS and shows several recombinants in disease families. Therefore, the NTRK2 gene can now be excluded as a candidate gene for familial dysautonomia.

Animals↗