Sudden Unexpected Death During Sleep in Familial Dysautonomia: A Case-Control Study.

Study Objectives: Sudden unexpected death during sleep (SUDS) is the most common cause of death in patients with familial dysautonomia (FD), an autosomal recessive disease characterized by sensory and autonomic dysfunction. It remains unknown what causes SUDS in these patients and who is at highest risk. We tested the hypothesis that SUDS in FD is linked to sleep-disordered breathing. Methods: We retrospectively identified patients with FD who died suddenly and unexpectedly during sleep and had undergone polysomnography within the 18-month period before death. For each case, we sampled one age-matched surviving subject with FD that had also undergone polysomnography within the 18-month period before study. Data on polysomnography, EKG, ambulatory blood pressure monitoring, arterial blood gases, blood count, and metabolic panel were analyzed. Results: Thirty-two deceased cases and 31 surviving controls were included. Autopsy was available in six cases. Compared with controls, participants with SUDS were more likely to be receiving treatment with fludrocortisone (odds ratio [OR]; 95% confidence interval) (OR 29.7; 4.1-213.4), have untreated obstructive sleep apnea (OR 17.4; 1.5-193), and plasma potassium levels <4 mEq/L (OR 19.5; 2.36-161) but less likely to use noninvasive ventilation at night (OR 0.19; 0.06-0.61). Conclusions: Initiation of noninvasive ventilation when required and discontinuation of fludrocortisone treatment may reduce the high incidence rate of SUDS in patients with FD. Our findings contribute to the understanding of the link between autonomic, cardiovascular, and respiratory risk factors in SUDS.

Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number.

Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase-encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.

Cyclic vomiting associated with excessive dopamine in Riley-day syndrome.

GOALS: To analyze the neurochemical profile during the recurrent attacks of nausea and vomiting in patients with Riley-day syndrome. BACKGROUND: One of the most disabling features of patients with Riley-day syndrome are recurrent attacks of severe nausea/retching/vomiting accompanied by hypertension, tachycardia, and skin flushing, usually triggered by emotional or other stresses. STUDY: We monitored blood pressure and heart rate and measured plasma catecholamines during typical dysautonomic crises triggered by emotionally charged situations. For comparison, measurements were repeated at follow-up after the symptoms had resolved and the patients were feeling calm and well. RESULTS: During a typical attack, patients were hypertensive and tachycardic. In all patients, circulating levels of norepinephrine (P < 0.002) and dopamine (P < 0.007) increased significantly. CONCLUSIONS: Activation of dopamine receptors in the chemoreceptor trigger zone may explain the cyclic nausea/retching/vomiting of patients with Riley-day syndrome.

Plasma catechols in familial dysautonomia: a long-term follow-up study.

This study tested whether familial dysautonomia (FD) involves progressive loss of noradrenergic nerves. Plasma levels of catechols, including dihydroxyphenylglycol (DHPG), norepinephrine (NE), dopamine (DA), and DOPA, were measured in 7 adult patients with FD and 50 healthy control subjects. FD patients were re-tested after a mean follow-up period of 13 years. Compared to controls, FD patients had low plasma levels of DHPG (P < 0.001), high DOPA and DA levels (P = 0.01, P = 0.0002), and high NE:DHPG (P < 0.0001), DA:NE (P = 0.0003), and DOPA:DHPG (P < 0.0001) ratios. At follow-up there were no changes in plasma levels of individual catechols; however, there were further increases in DOPA:DHPG ratios (mean 24 +/- 7%, P = 0.01). In FD, plasma catechol profiles are sufficiently stable, at least over a decade, to be used as a biomarker of disease involvement. An increasing DOPA:DHPG ratio suggests slight but consistent, progressive loss of noradrenergic neurons.

Bone mineral density and metabolism in familial dysautonomia.

Familial dysautonomia (FD) patients suffer from multiple fractures and have reduced bone pain, which defers the diagnosis. The pathogenesis of bone fragility in FD is unknown. This study aimed to characterize bone mineral metabolism and density in FD. Seventy-nine FD patients aged 8 months to 48 years (mean age 13.9 +/- 10.4 years, median 12.3) were studied. Clinical data included weight, height, bone age, weekly physical activity and history of fractures. Bone mineral density (BMD) of the lumbar spine (n = 43), femoral neck (n = 26), total hip (n = 22) and whole body (n = 15) were determined by dual-energy X-ray absorptiometry. Serum 25-hydroxyvitamin D3, osteocalcin, bone alkaline phosphatase (B-ALP), parathyroid hormone and urinary N-telopeptide cross-linked type 1 collagen (NTx) were determined in 68 patients and age- and sex-matched controls. Forty-two of 79 patients (53%) sustained 75 fractures. Twenty-four of 43 patients had a spine Z-score < -2.0, and 13 of 26 had a femoral neck Z-score < -2.0. Mean femoral neck BMD Z-score was lower in patients with fractures compared with those without (-2.5 +/- 0.9 vs -1.5 +/- 1.0, p = 0.01). Mean body mass index (BMI) was 16 kg/m2 in prepubertal patients and 18.4 kg/m2 in postpubertal patients. Bone age was significantly lower than chronological age (75.5 vs 99.3 months in prepubertal patients, p < 0.001; 151 vs 174 in postpubertal patients, p < 0.05). NTx and osteocalcin levels were higher in FD patients compared with controls (400 +/- 338 vs 303 +/- 308, BCE/mM creatinine p < 0.02; 90 +/- 59.5 vs 61.8 +/- 36.9 ng/ml, p < 0.001, respectively). B-ALP was lower in FD patients compared with controls (44.66 +/- 21.8 vs 55.36 +/- 36.6 ng/ml, p < 0.04). Mean spine Z-score was significantly lower in physically inactive compared with active patients (-3.00 +/- 1.70 vs -1.77 +/- 1.3, respectively, p = 0.05). We conclude that fractures in FD patients are associated with reduced BMD. FD patients have increased NTx and osteocalcin. Contributing factors include reduced BMI, failure to thrive and reduced physical activity. Preventive therapy and early diagnosis are essential.

Calcitonin gene related peptide in familial dysautonomia.

Familial dysautonomia (FD) patients have diminished sensory C-fibers. Calcitonin gene related peptide (CGRP) is a widely distributed neuropeptide and prominent neurotransmitter in C-fibers. We show that plasma CGRP levels measured by radioimmunoassay is significantly lower in 51 FD patients compared to controls (P<0.001). In 11/51 FD patients with FD crisis and in 19/51 FD patients with pneumonia, the mean CGRP levels rose significantly as compared to their baseline (P<0.003, P<0.001, respectively). The deficiency of CGRP in FD patients is consistent with their depletion of C-fibers, and may explain some of their symptoms, either directly or via modulation of sympathetic activity.

Gynecological aspects of female familial dysautonomia.

BACKGROUND: Familial dysautonomia is a genetic disease in which there is a defect in the autonomic and sensory nervous systems. These systems have a major role in the reproductive system. OBJECTIVE: To study the inter-relationship of autonomic and sensory dysfunction and gynecological function. METHODS: The gynecological histories of 48 women with familial dysautonomia were analyzed retrospectively. Their mean age was 22.25 years (range 12-47). Thirty-three women (65%) were available for further questioning and investigation of hormonal status. RESULTS: Menarche had occurred in 32 of the 48 (66.7%). Their average age of menarche was significantly delayed as compared to their unaffected mothers (15.5 vs. 13.6 years respectively, P = 0.002). The most prominent finding was the very high prevalence, 81.2%, of premenstrual symptoms. Seven of 26 had premenstrual syndrome symptoms of dysautonomic crisis. Blood sex hormone levels were normal in 27 of the 33 patients studied. None reached natural menopause. One patient had adenomyosis, and another, dysgerminoma. Three patients became pregnant and delivered healthy infants. CONCLUSION: Menarche is delayed in women with FD, and the physiological monthly hormonal fluctuations may disturb autonomic homeostasis sufficiently to precipitate dysautonomic crisis.

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.

Atrial natriuretic peptide response to postural change and medication in familial dysautonomia.

Circulating atrial natriuretic peptide (ANP) was assayed before and after postural change and exercise in 54 patients with familial dysautonomia (FD) and 20 controls. ANP levels were compared with blood pressure, heart rate, plasma catecholamines and parameters of renal function. Compared with controls supine FD subjects had elevated blood pressures, heart rates and ANP levels (39 +/- 4 pg/ml vs. 23 +/- 3 pg/ml, p < 0.01). With the erect posture and exercise in FD subjects, blood pressure fell below control values, with ANP lowered. In FD subjects, blood pressure was correlated with ANP levels when supine and when erect and with heart rate post exercise. In controls, ANP levels did not correlate with other parameters. In FD patients on metoclopramide, supine and erect blood pressure and ANP levels were higher. FD subjects treated with fludrocortisone, had elevated supine and erect noradrenaline (p < 0.05 and p = 0.06); and those on diazepam had lower erect and post exercise noradrenaline (p < 0.05), but ANP levels were similar. In conclusion, sympathetic denervation may increase FD patients' responsiveness to other regulators of cardiovascular integrity, such as ANP. In addition, circulating ANP and catecholamines in FD subjects appear to be influenced by commonly used medications, such as metoclopramide.

Circadian hormonal rhythms in two new cases of fatal familial insomnia.

We used a chronobiological inferential statistical method to investigate circadian rhythms of hypophyseal hormones, cortisol, melatonin and catecholamines in two females of the same family affected by fatal familial insomnia. Case 1 (confirmed at autopsy) presented an absent or progressive loss of circadian rhythms of all hormones. In case 2 there was a loss of GH circadian rhythm and a less significant rhythm for melatonin, catecholamines and gonadotropins. These results confirm the role of the thalamus in regulating hormonal circadian rhythm.

Dysautonomia in an infant with secondary hyperammonemia due to propionyl coenzyme A carboxylase deficiency.

A male infant who had vomiting and coma in the absence of ketoacidosis was initially thought to have dysautonomia because of abnormal responses to methacholine and histamine, as well as abnormal urinary catecholamine excretion. Following an episode of hyperammonemia, a liver biopsy was performed which revealed a partial deficiency of carbamyl phosphate synthetase activity. The patient was treated with a protein-restricted diet supplemented with a mixture of ketoacid analogues of the essential amino acids, which precipitated ketosis and acidosis. A primary deficiency of propionyl coenzyme A (CoA) carboxylase was subsequently demonstrated. Because disorders of propionate metabolism may not initially present with ketoacidosis, we recommend examination of both plasma and urine for metabolites of this pathway, as well as direct measurement of propionyl CoA carboxylase activity in peripheral blood leukocytes, before performing a liver biopsy to evaluate urea cycle enzyme activities, and particularly before adding keto acid/amino acid mixtures to a protein-restricted diet.

[Evaluation of the state of the parasympathetic branch of the autonomic nervous system by cholinergic blood activity]. / Otsenka sostoianiia parasimpaticheskogo otdela vegetativnoi nervnoi sistemy po kholinergicheskoi aktivnosti krovi.

On the basis of the data obtained during a determination of the cholinergic blood activity in different physiological and pathological conditions of the organism it was possible to evaluate the state (tone and reactivity) of the parasympathetic part of the vegetative nervous system. The conducted studies demonstrate that the cholinergic blood activity depends upon the quantitative relationships between the separate components of the "acetylcholine system" which consists of the free acetylcholine content, bound erythrocytes, the activity of the acetylcholine esterase and the capability of blood in vitro to fixate the added acetylcholine. The pathogenetic therapy in the different forms of disturbed cholinergic blood activity (conditions of parasympathicotonia and parasympathicoatonia) should be directed to a restitution of normal relationships within the acetylcholine complex.

Plasma levels of norepinephrine.

Plasma norepinephrine derives from sympathetic nerves, but the proportion reaching the circulation before being metabolized varies with the type of nerve ending-effector junctions in the tissue. Plasma levels of norepinephrine also will fluctuate because of rapid metabolism rates and environmental, emotional, and endogenous stimuli provoking a sympathetic response. The responses of plasma catecholamines in spontaneously hypertensive rats and in normotensive rats of the same strain were compared after exposure to a variety of stressors. Drugs that inhibit monoamine oxidase, catechol-O-methyl transferase, or neuronal uptake were administered to show the effects of metabolic enzymes and neuronal uptake on the amounts of catecholamines reaching the circulation. Sympathetic nervous activity and the ability of the sympathetic nervous system to respond to a uniform stimulus are studied in hypertensive and normotensive subjects. A survey of the plasma levels of norepinephrine in a variety of neurologic disorders is given.

Salt conservation in familial dysautonomia (Riley-Day syndrome).

In some patients with familial dysautonimia, plasma renin activity shows a paradoxical response to postural stimuli, i.e., levels of plasma renin activity are high when the patient is in the supine position and fall significantly during subsequent ambulation. Furthermore, there is no coordinated release of plasma renin activity and aldosterone. The aim of the present study was to determine whether these findings are accompanied by a disturbance of salt conservation. Six patients were studied in a summer camp while on normal and low-salt diets. Plasma and urinary aldosterone levels rose sharply and appropriately when four of the patients were placed on a low-sodium diet. In these subjects, urinary sodium output fell sharply although three of them failed to attain sodium equilibrium by the third day of the low-sodium regimen. Elevation of early morning plasma renin activity appeared to correlate with an inversion in the normal day-night rhythm in urinary volume.