Introduction
Family members
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Subject I:1 was reported by the descendants to have been suffering from a young age from episodes of dizziness when rising up and sometimes syncope; details not known.
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Subject II:1 is alive, aged 93 years, but symptoms are not reported in this intermediate generation.
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Subject IV:1 (index patient) was born after normal gestation and delivery. From the age of 10 years onwards he noticed a tendency for repeated fainting when rising and standing that increased in severity with age. At age 15 years he suffered from marked orthostatic intolerance, and OH was documented. Innumerable faints occurred, associated with paleness, palpitations and sometimes cold sweat, indicating at least partially intact autonomic functions. The patient was 20 years old at referral. He was tall (193 cm), with a body mass index (BMI) of 18.8 kg/m2. A physical examination revealed no abnormality except for OH (see below) and excavated feet. He constantly experienced mild lightheadedness when standing still, and he could not rise abruptly from lying to standing without a risk of fainting. There were periods of exaggerated orthostatic intolerance lasting days through weeks. He reported normal urinary bladder and sexual functions, normal sweating and no heat intolerance.Polyneuropathy had initially been suspected due to pes excavatus but was not confirmed at repeated clinical and neurophysiological examinations. The patient had tried dihydroergotamine, salt supplementation and fludrocortisone as treatment for OH, without any effect of practical benefit. Compressive garments (knee stockings) brought about some subjective improvement but no obvious increase in tolerance to rapid postural challenge.
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Subject IV:3, the youngest brother of the proband, was referred for clinical evaluation at the age of 17 years. Similar to his above-mentioned brother, he is slim and tall for age (194 cm; BMI 16.1 kg/m2) with excavated feet from birth. He was otherwise healthy until the age of 14 years, when he successively developed a strong tendency to faint in the upright position. Bouts of exaggerated orthostatic intolerance occurred, which on a few occasions were reversed by rapid infusion of Ringer’s solution. The orthostatic intolerance, together with other seemingly intact autonomic functions, was phenomenologically identical to that of the index patient.
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Subject IV:2 is the middle and healthy brother without postural symptoms. He is less slim than his brothers but slightly taller (196 cm, BMI 25.0 kg/m2), and foot configuration was normal. He was referred at the age of 21 years as part of the family investigation.
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Subject III:1 is the father of the proband and was referred at the age of 53 years as part of the family investigation. At the examination, he exhibited a similar slender and tall body constitution (192 cm, BMI 23.1 kg/m2) as his sons, and he had experienced lightheadedness and occasional fainting from late adolescence onwards. The orthostatic intolerance varied, as for the sons, sometimes from one day to another. No detailed examination related to OH had been conducted prior to the present referral. The orthostatic intolerance was never as severe as that of his sons. Bladder and sexual functions were intact.
Methods
Examination of the additional family members
Results
Subject IV:1 (index patient)
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Neurography, electromyography and sensory thresholds were normal.
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Autonomic test results according to clinical signs, including sweating detected by galvanic skin response (GSR; electrodermal response), palmar and plantar skin vasoconstriction (photoelectric plethysmography; van Gogh, Amsterdam, Netherlands) and RR-interval variation during deep breathing and Valsalva, were normal.
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Routine BP measurements revealed a supine resting BP of 127/73 mmHg, which was 96/78 mmHg after 2 min of standing upright. The corresponding HR were 61 and 118 beats per minute (bpm), respectively. BP measurements were obtained from the following tests:
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Routine tilt test according to the “Italian protocol” [23] revealed a pronounced fall in BP with immediate more than doubling of HR (54 to 128 bpm); administration of nitroglycerine caused faint with unmeasurable BP.
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Active rise to standing position with continuous BP recording showed showed a similar drop in BP and increased HR. Typical BP reactions with continuous BP measurement are shown in Fig. 2A. Leg crossing with the thighs pressed together at standing [24] strongly reduced the fall in BP (Fig. 2A part c). The BP and HR changes, measured using the Finapres device, varied with rising speed from the lying to standing position (Table 1). A normalization of BP, HR and subjective feeling was always achieved within 5–10 s after resuming a recumbent position. Table 1 also shows BP reactions after he administration of oral midodrine, 60–90 min after stepwise dose increases of 2.5 to 5–10 mg, as well as the marked stabilizing effect of BP by standing with crossed legs; no effect on BP was recorded in standing position after midodrine administration.
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Test cycling in the sitting position showed a marked increase in HR (56–184 bpm), a weak and slow systolic BP reaction (105–130 mmHg), but for age a good working capacity; the patient reported slight light-headedness. Test cycling in lying position brought about normal increases in both HR (56–159 bpm) and systolic BP (100–159 mmHg); no light-headedness.
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BP reaction to sustained handgrip during 2 min was qualitatively normal in both the lying and sitting position, with an increase in BP and HR (Fig. 2B).
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BP reactions to apnoea and Valsalva manoeuvres were both qualitatively normal (Fig. 2c, D; a detailed description is provided below).
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Ultrasound cardiography was normal in the recumbent position. In a sitting position, slightly bent forward, a markedly reduced preload was noted, without significantly reduced BP, thus suggestive of a low venous return.
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Colour Doppler ultrasonography of leg veins showed normal anatomy, ordinary valves and no sign of leakage. A similar Doppler ultrasonography of carotid and vertebral arteries revealed no abnormality.
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Abdominal computed tomography (lying position) did not reveal any abnormal dilatation of pelvic veins (abdominal organs normal as well).
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Direct recording of sympathetic signals was performed with microneurography in the peroneal nerve. MNSA and, after electrode adjustment, SSNA, were recorded. Both types of activity occurred in the respective normal burst pattern: MSNA bursts displaying cardiac rhythmicity and an inverse relationship to BP fluctuations (Fig. 2c, D); SSNA bursts in an irregular pattern, with clear arousal response (Fig. 2E). MSNA outflow (burst frequency) at supine rest was 30 bursts/min (somewhat higher than mean outflow in subjects of the patient’s age [25, 26]. Apnoea induced an increase in MSNA with subsequent rise in BP (Fig. 2c), and a Valsalva manoeuvre brought about a normal pattern (Fig. 2D), i.e. a reduction in BP inducing an initial increase in MSNA, followed by an increase of BP during the ongoing manoeuvre, and a final inhibition of sympathetic outflow with normal post-manoeuvre rebound rise in BP. Strength of individual bursts, measured as mean amplitude (mm) in the neurogram, increased 59% during apnoea and 39% during Valsalva.
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Serum noradrenaline level at rest was slightly above the upper normal limit (mean of 2 analyses: 2.25 nmol/L; reference interval: 0.7–2.1), with a normal increase after standing up (mean of two analyses: 3.2 nmol/L). A likewise normal noradrenaline response was observed at repeated testing performed 2 years later.
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Other catecholamine analyses, dopamine, diurnal cortisol curve, serum aldosterone, urine osmolality, plasma renin, plasma troponin-I, myocardial perfusion scintigraphy, isotope angiography, continuous electrocardiogram (ECG) for 48 h, carotid massage and blood volume measurement were all within normal limits (see Electronic Supplementary Material [ESM] file 1 for details).
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Phenylephrine infusion induced a stepwise increase in BP that was clearly related to the stepwise rise in dose (Fig. 3), indicating normal noradrenergic receptor reaction to catecholamine stimulation. The phenylephrine-induced increased BP was accompanied by a likewise dose-dependent reduction in HR (Fig. 3). The patient reported no discomfort during the infusion.
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Bioinformatic analysis of exome sequencing data revealed no pathogenic gene variants. All detected gene variants are listed in ESM Table S1, file 2. Variants shortlisted by the Franklin software using the relevant HPO terms were excluded based on either the inheritance pattern (recessive genes), absence of reported pathogenicity (benign or likely benign in ClinVar) or high population frequency (ESM Table S2, file 3).
Treatment | Active rise | Lying (BP; HR) | Standing | Standing (symptoms/signsa) |
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No treatment | Rapid rise | 104/64 mm Hg; 65 bpm | 86/67 mm Hg; 125 bpm | Syncope New attempt: presyncope |
Semirapid rise | 106/60 mm Hg; 63 bpm | 91/68 mm Hg; 125 bpm | Presyncope | |
Slow rise | 109/63 mm Hg; 60 bpm | 96/74 mm Hg; 125 bpm | Dizziness | |
Rise to standing with crossed legs | 101/76 mm Hg; 63 bpm | 120/107 mm Hg | 0 | |
1.5 h after administration of midodrine 10 mg | Rapid rise | 112/67 mm Hg; 45 bpmc | 78/61 mm Hg; 110 bpm | Syncope New attempt: presyncope |
Slow rise | 116/70 mm Hg; 45 bpm | 77/54 mm Hg; 105 bpm | Dizziness | |
Rise to standing with crossed legsb | 116/70 mm Hg; 45 bpm | 108/72 mm Hg; 105 bpm | 0 |
Subjects III:1 and IV:3
Subject | Lying (BP; HR) | Standing (BP; HR) | Standing (symptoms/signs) | Sustained standing (BP; HR)a |
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III:1 | 110/61 mm Hg; 76 bpm | 61/34 mm Hg; 129 bpm | Presyncope, pale | 90/69 mm Hg; 108 bpm |
IV:3 | 94/76 mm Hg; 74 bpm | 52/44 mm Hg; 135 bpm | Presyncope, swaying, pale | 85/74 mm Hg; 125 bpm |
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Neurography, electromyography and sensory thresholds (performed due to foot configuration) were normal.
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Routine autonomic testing, performed as for subject IV:1, was normal in both subjects.
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BP reactions:
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Rapid active rise to standing position with continuous BP recording (Table 2) revealed an abnormal pattern similar to that of the index patient and with a twofold increase in HR (see Fig. 2A). The effort was associated with presyncope and paleness. Standing with crossed the legs gave a marked rise in BP and freedom from orthostatic symptoms in subject IV:3 (compare with Fig. 2A, part c); this manoeuvre was not tested for subject III:1. Recovery after return to lying was rapid in both cases.
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Routine tilt test revealed a pronounced fall in BP to unmeasurable values with a 57% increase in HR in the younger brother (subject IV:3) whereas the test was within normal limits for the father (this test not done the same day as active rise to standing).
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BP reaction to apnoea and Valsalva manoeuvre was qualitatively normal, as for the index patient (compare with Fig. 2c, D).
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Test cycling in sitting position (case IV:3) showed marked increase in HR (68–182 bpm), with a normal systolic BP increase (105–182 mmHg) and good working capacity; no light-headedness. (Not performed for case III:1.)
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Carotid massage did not evoke fall in BP.
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Occlusion plethysmography in lower arm with infusion of nitroprusside and metacholine in subject IV:3 was normal, i.e. with no sign of nitric oxide-dependent abnormal vasodilatation. (This test not done in the index patient and subject III:1).
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Serum noradrenaline level at rest and after standing up, urine excretion of catecholamines, serum adrenaline and cortisol levels (morning and afternoon) were normal in both subjects.
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An attempt to direct recording of sympathetic nerve activity in case IV:3 failed for technical reasons.
Subject IV:2
Active rise | Lying (BP; HR) | Standing (BP; HR) | Sustained standing (BP; HR)a |
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Rapid rise | 116/68 mm Hg; 72 bpm | 71/35 mm Hg; 110 bpm | 95/65 mm Hg; 104 bpm |
Further course of subject IV:1 and IV:3
Additional family members
Subject, sex | Supine (BP; HR)a | Standing, immediately (BP; HR) | Standing, steady state 1 min (BP; HR) | Symptoms | Interpretation | Body feature | Conclusion |
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III:2, male | 140/80 mm Hg; 72 bpm | 133/80 mm Hg; 90 bpm | 128/82 mm Hg; 82 bpm | – | Slightly marked sympathicotonic heart reaction | Tall | Affected? |
III:3, female | 150/95 mm Hg; 60 bpm | 137/92 mm Hg; 75 bpm | 145/90 mm Hg; 63 bpm | – | Normal reaction | Tall Pes cavus | Affected?b |
IV:4, female | 110/70 mm Hg; 65 bpm | 115/72 mm Hg; 72 bpm | 110/70 mm Hg; 72 bpm | – | Normal reaction | Tall | Normal |
IV:5, female | 115/72 mm Hg; 54 bpm | 92/65 mm Hg; 90 bpm | 110/75 mm Hg; 73 bpm | Dizziness | Marked sympathicotonic postural BP fall; persistent tachycardia at steady state | Very tall Pes cavus | Affected |
IV:6, male | 128/75 mm Hg; 55 bpm | 115/70 mm Hg; 88 bpm | 123/78 mm Hg; 78 bpm | Dizziness | Slight sympathicotonic postural BP fall; persistent tachycardia at steady state | Very tall Pes cavus | Affected |
III:4, female | 145/92 mm Hg; 71 bpm | 125/82 mm Hg; 85 bpm | 130/85 mm Hg; 83 bpm | Slight dizziness | Moderate sympathicotonic postural BP fall; mild persistent tachycardia at steady state | Pes cavus | Affectedc |
IV:7, female | 120/70 mm Hg; 70 bpm | 80/65 mm Hg; 110 bpm | 105/72 mm Hg; 93 bpm | Dizziness | Marked sympathicotonic postural BP fall; persistent tachycardia at steady state | TallPes cavus | Affected |
IV:8, male | 122/77 mm Hg; 57 bpm | 110/75 mm Hg; 72 bpm | 113/70 mm Hg; 62 bpm | – | Normal reaction | Normal |