Familial Vasovagal Syncope: Clinical Characteristics and Potential Genetic Substrates

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Potential Genetic Substrates

A. GONZÁLEZ-HERMOSILLO, M.F. MÁRQUEZ, M. VALLEJO, K.I. URIAS, M. CÁRDENAS

Introduction

Vasovagal syncope (VVS) is a common clinical problem that has been the subject of extensive research in recent years. In this type of syncope, which affects all age groups, cerebral hypoperfusion develops as a consequence of abnormal autonomic control of the circulation, leading to hypotension with or without bradycardia. Estimates are that approximately 12–48% of healthy young adults and 6% of older individuals suffer from recurrent syncopal events, and the quality of life may be compromised by the condition [1].

Syncopal events that do not reach medical attention occur much more frequently. In fact, recently published results of a survey of students averaging 20 years of age demonstrated that about 20% of males and 50% of females had experienced at least one syncopal episode [2]. While the exact aetiology and pathophysiologic processes involved in VVS have yet to be fully elucidat- ed, a basic understanding has begun to emerge. Studies have shown that the autonomic nervous system plays a fundamental role in the pathophysiology of VVS [3]. Several lines of evidence indicate the presence of central and peripheral abnormalities of sympathetic function. A better understanding of the pathophysiology of VVS could provide a more rational basis for therapy and help to optimise the resources currently used to obtain a diagnosis.

Under some circumstances, a diagnosis of VVS can be made based on the clinical history and is often confirmed by tilt testing. Therapy is aimed at preventing or reducing the recurrence of syncope.

Calkins et al. [4], in a study done at a tertiary-care centre, estimated that up to US $16 000 of unnecessary testing may be performed on patients who

Electrocardiology Department, Instituto Nacional de Cardiología ‘Ignacio Chávez’, Tlalpan, México

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ultimately receive a diagnosis of VVS, emphasising the difficulty of making the diagnosis.

Family History in Vasovagal Syncope

In VVS, especially when confirmed, there is frequently a positive family history, especially when the onset is below the age of 20. A case control study by Camfield and Camfield [5] showed that among children with VVS a significant proportion, 27/30 (90%), had a parent or sibling with syncope, an association not seen in control subjects. In this study, none of the patients’ best friends fainted, although 33% (8/24) of their friends had a first-degree relative with syncope. Mathias et al. [6] reported a familial tendency for VVS in patients with an onset before the age of 20. A family history of VVS was found in 57% (33/58) of these patients compared with 18% (11/61) with a later onset. Of the 44 with a family history, 73% had a least one parent or child with a VVS. They included four patients with a family history over three generations, and one who had a twin sister with syncope. In 9%, a sibling was the only relative with VVS; 18% had a grandparent, aunt, uncle, or cousin with VVS. Most adult-onset patients with VVS did not have a family history. In those with a family history, 73% had a parent or child with a his- tory of VVS, but only 27% (n = 12) had other relatives with syncope [6].

A study from Newcastle, UK, suggested that in at least 20% of patients with recurrent syncope, other members of the family had experienced syncopal symptoms, suggesting familial clustering of VVS and that this syndrome has a significant inheritable component [1]. From a data base of the Royal Victory Infirmary, researchers identified 603 individuals with a diagnosis of VVS. Of these, 441 (81%) answered a postal questionnaire, of whom 84 (19%) described a positive family history for faints and 75 (89%) supplied details of first-degree relatives. Overall, of the 389 first-degree relatives, 145 were affected (37.2%). The total number of siblings in affected families was 145, with 47 (32.4%) affected. The total number of offspring was 102, with 42 affected (41%) [1]. Further evidence for a genetic basis to this condition is provided by examining haemodynamic responses to head-up tilt in first- degree relatives of patients with VVS. Newton et al. [1] described a total of 11 first-degree relatives from six families who agreed to undergo the head-up tilt test with nitrates provocation. Seven were affected and four unaffected.

All eleven individuals had abnormal responses to tilt testing: five out of the 11 subjects tested became hypotensive in association with symptoms, three of these were affected subjects who had full reproduction of presyncopal symptoms and the remaining two were unaffected subjects who experienced symptoms that clinically resembled those experienced by ‘fainters.’ Neither

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of the latter two subjects could recall a prior similar experience. Of the remaining six tested subjects, five became tachycardic (four previously affected subjects experienced presyncopal symptoms and one previously unaffected subject experienced new symptoms clinically consistent with presyncope). The remaining subject who was previously unaffected developed syncope in association with bradycardia, although he had never experienced these symptoms before. This finding suggests that first-degree relatives of those with VVS, even if they do not express the syncopal phenotype, still have a vasovagal reaction tendency. Intriguingly this raises the possibility of incomplete penetrance of a genetic disorder or ‘genetic variability’ in unaffected first-degree relatives of VVS patients. One alternative explanation is that VVS is a complex trait arising from the interaction between one or more alleles and the environment. Environmental factors may include infectious agents, medication, nutrition, toxins, and stress [1]. Therefore, the inherited tendency to faint may be multifactorial but requires an environmental stim- ulus for expression. Another alternative is that the disorder represents an autosomal recessive condition, but with a relatively common frequency of the recessive allele [7].

Recently [7], the findings from a family that showed VVS inheritance in at least three generations, in absence of any cardiac or autonomic abnormalities, were reported. The proband was a 10-year-old child with an 18-month history of recurrent syncopal episodes. The proband’s sibling had developed syncopal episodes at the age of 12. Their father had suffered from occasional syncopal episodes, and the paternal uncle also had similar symptoms. A child of the proband’s uncle also developed syncope at the age of 10. The other child provided no history of syncopal events, though one possible presyncopal event was noted. The paternal grandfather, and his brother and sister had all suffered presyncopal events during their early to late teens.

Although it was not possible to ascertain whether the great-grandparents had experienced syncopal events, there was some suggestion that the great- grandfather may have experienced them, There was no evidence for syncope in the proband’s mother’s family. No family members had abnormal autonomic function or heart-rate variability when compared with age and sex controls. In the proband, the tilt test confirmed the diagnosis of VVS with hypotension and reproduction of syncope. In the seven family members originally described as affected or possibly affected, on clinical evaluation all had symptom reproduction during tilt testing. In the three unaffected family members who underwent tilt testing, two were normal (mother and mater- nal grandmother).The third (paternal grandmother) had hypotension in association with presyncope, which she had never experienced previously.

The pedigree of this family suggests that familial VVS may be an autosomal dominant disorder with incomplete penetrance in some individuals.

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Assessment of the phenotype of this common condition allows better char- acterisation of affected and unaffected family members and, using whole genome scanning and linkage analysis in suitable families, will potentially lead to identification of the responsible locus [7].

We have reported two groups of monozygotic twins, from different families, and a family with several members affected with VVS. One set of twins consisted of male patients with no history of syncope in their parents or relatives. The other set consisted of females with a history of syncopal attacks in their mother. Tilt testing was positive in all [8]. In another family, the proband was a 20-year-old woman referred to our unit with a 4-year history of recurrent syncopal episodes, the father, a brother, and two sisters were affected and all had a positive tilt test.

These data alone strongly indicate that genetic factors play a role in the aetiology of VVS. However, it is difficult, if not impossible to define whether familial syncopes have a genetic basis or are due to the high frequency of this symptom in the general population.

Mendelian Forms of Hypotension

Several genetic determinants that control blood pressure and cardiovascular responses are known, with some being possible candidates for a gene causing familial VVS.

Identification of the molecular basis of several autosomal-dominant forms of hypertension has permitted unambiguous identification of mutant gene carriers, allowing the spectrum of blood pressures in gene carriers to be assessed. Some family members who have inherited these mutations have normal or only minimally elevated blood pressures, which suggests that, just as there are alleles that raise blood pressure, there are likely to be alleles in the population that lower blood pressure [9].

One approach to this problem to determining the genetic basis of VVS is to identify mutations causing recessive forms of severe hypotension; heterozygous carriers of these same mutations, which will be much more preva- lent than their homozygous counterparts, may be protected from the development of hypertension. Once relevant mutations are identified, the hypoth- esis that the heterozygous state lowers blood pressure can be tested [8]. Most of the patients with VVS have a long history of arterial hypotension during their youth. In 1996, the molecular causes of two inherited forms of hypotension were reported. Autosomal recessive pseudohypoaldosteronism type 1 (PHA-1) is characterised by life-threatening dehydration in the neonatal period, marked hypotension, salt-wasting, a high serum potassium level, metabolic acidosis, and marked elevation in plasma rennin activity and

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aldosterone levels. Genetic analysis of affected offspring of consanguineous unions demonstrated linkage of this disease to segments of either chromosome 12 or 16, each of which contains genes encoding different subunits of the epithelial sodium channel (ENaC). Examination of the ENaC subunit genes in families with PHA-1 revealed mutations that result in loss of function [8]. This was previously known from familial forms of defects in renal salt handling, such as Gitelman’s syndrome, which is due to mutations and loss of function of the renal sodium-chloride cotransporter (NCCT) that increase salt clearance and lead to hypotension [10]. Gitelman’s syndrome is an autosomal recessive trait characterised by low serum potassium and high serum bicarbonate levels, renal salt wasting, low urinary calcium excretion, low serum magnesium levels, and an activated renin-angiotensin system.

Patients with this disorder have low blood pressure and neuromuscular abnormalities. The gene causing Gitelman’s syndrome has been mapped to a region of chromosome 16 that contains the gene encoding the renal thiazide- sensitive NA-Cl co transporter, which mediates reabsorption of sodium and chloride [11].

Genetic Catecholamine Disorders

Many syndromes associated with orthostatic intolerance show similarities to VVS, suggesting a potential overlap and possible common aetiology [12].

Postural orthostatic tachycardia syndrome (POTS) is a disabling chronic disorder characterised by tachycardia, symptoms of cerebral hypoperfusion, and sympathetic activation. Most attempts to explain the hyperadrenergic state in these patients have focused on an increased release of norepinephrine (NE) in response to the change from supine to upright posture. An alternative explanation is an abnormality in the clearance of the NE from the synaptic cleft. Recently, a missense mutation (converting alanine to proline) in the human NE transporter (NET) gene A457P, located on chromosome 16q12.2, was identified in an individual and her identical twin suffering from POTS [13]. This mutation renders the transporter nonfunctional. In these subjects, the release of NE into the synapse is normal, but reduced amounts are taken back up into the sympathetic nerve terminal as a result of the decreased activity of NET. Spillover of NE into the circulation is increased, and more NE is available in the synapse to interact with adrenergic recep- tors. However, the A457P mutation does not explain all cases of POTS. The mutation was not present in any of 254 unrelated persons, including normal subjects, patients with hypertension, and other patients with orthostatic intolerance. Furthermore, although family members who had the mutation also had some of the physiologic and biochemical abnormalities detected in

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the proband and her twin sister, none had the full-blown syndrome.

Dopamine-β-hydroxylase (DBH) is the enzyme responsible for intraneur- al conversion of dopamine to NE. Its deficiency results in failure of NE syn- thesis, excessive dopamine release, orthostatic hypotension, and, sometimes, ptosis of the eyelids. Subjects with DBH deficiency syndrome have worsen- ing symptoms in late adolescence, including reduced ability to exercise, nasal stuffiness, dyspnoea, nuchal discomfort, precordial pain, syncope, and fre- quent postural symptoms [15]. The DBH gene maps to chromosome 9q34, and several mutations of the DBH gene that cause this very rare syndrome have now been identified. Kim et al. [14] identified seven novel variants, including four potentially pathogenic mutations, in the human DBH gene of two unrelated DBH-deficient patients and their families. A sole finding of absent plasma DBH is insufficient, since about 4% of the population lacks DBH. Once the specific enzymatic defect for DBH deficiency had been eluci- dated, investigators were able to devise a better treatment. A favourable long- term result has been achieved with l-dihydroxyphenylserine (l-DOPS). This agent is a prodrug acted upon by endogenous dopa-decarboxylase to yield NE. The administration of DOPS to DBH-deficient patients resulted in dra- matic increases in blood pressure and in restoration of plasma and urinary levels of NE to nearly normal [15]. The successful treatment of DBH deficiency encourages us to hope that other autonomic disorders may one day also yield to genuinely effective therapeutic intervention.

Streeten et al. [16] described a familial form of postural orthostatic hypotension with marked rise in heart rate, syncope, and associated cuta- neous dilatation in the face and lower limbs. The findings have been attrib- uted to excessive bradykinin levels. Recently, DeStefano et al. [17] showed linkage in these families to a 25cM region of chromosome 18q between 18S858 and 18S541. Whilst no specific mutations in any genes have been described in this particular syndrome, the renal urea transporters HUT1 and HUT2 are located in this region and polymorphism in the latter is known to be associated with reduced diastolic blood pressure in males [18].

There are other hereditary autonomic disorders associated with orthostatic hypotension. In the majority there are associated neurological deficits. It is far beyond the scope of this chapter to review every autonomic disorder.

Interested readers are referred to an excellent text on the subject [19].

Conclusions

Disturbances in autonomic function can result in a wide variety of condi- tions that may ultimately culminate in the loss of consciousness. Success in identification of genes conferring susceptibility to hypotension and its clini-

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cal sequelae is expected to provide new insights into the pathophysiology of this condition and lead to development of highly accurate genetic tests, per- mitting identification of subjects with specific inherited susceptibility. These insights may permit intervention at preclinical stages with therapies tailored to underlying primary abnormalities, improving efficacy of treatment (nowadays, mostly empirical), and reducing morbidity from these diseases.

References

1. Newton JL (2003) Prevalence of family history in vasovagal syncope and haemodynamic response to head up tilt in first degree relatives. Preliminary data for the Newcastle cohort. Clin Auton Res 13:22–26

2. Wieling W, Ganzeboom KS, Philip SJ (2004) Reflex syncope in children and adole- scents. Heart 90:1094–1100

3. Kochiadakis GE, Papadimitriou EA, Marketou ME et al (2004) Autonomic nervous system changes in vasovagal syncope: Is there any difference between young and older patients? PACE 27:1371–1377

4. Calkins H, Byrne M, el-Atassi R et al (1993) The economic burden of unrecognized vasodepressor syncope. Am J Med 95:473–479

5. Camfield PR, Camfield CS (1990) Syncope in childhood: A case control clinical study of the familial tendency to faint. Can J Neurol Sci 17:306–308

6. Mathias C, Deguchi K, Bleasdale-Barr K, Smith S (1998) Frequency of family history in vasovagal syncope. Lancet 352:33–34

7. Newton JL, Kerr S, Pairman J et al (2005) Familial neurocardiogenic (vasovagal) syncope. Am J of Med Genetics 133A:176–179

8. Márquez MF, Urias KI, Hermosillo AG et al (2005) Familial vasovagal syncope.

Europace (in press)

9. Lifton RP (1996) Molecular genetics of human blood pressure variation. Science 272:676–680

10. Cruz DN, Simon DB, Nelson-Williams C et al (2001) Mutations in the Na-Cl co transporter reduce blood pressure in humans. Hypertension 37:1458–1464 11. Cruz DN, Shaer AJ, Bia MJ et al (2001) Yale Gitelman’s and Bartter syndrome

Collaborative Study Group. Gitelman’s syndrome revisited: A reevaluation of the symptoms and health related quality of life. Kidney Int 59:710–717

12. Gonzalez-Hermosillo A, Márquez MF, Kostine A et al (2004) Vasovagal syncope, orthostatic hypotension and postural orthostatic tachycardia syndrome: Is there a connection? In: Raviele A (ed) Cardiac Arrhythmias 2003. Springer, Milan, pp 615–624

13. Shannon JR, Flattem NL, Jordan J (2000) Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med 342:541–549 14. Kim CH, Zabetian CP, Cubells JF (2001) Mutations in the dopamine ß-hydroxylase

gene are associated with human norepinephrine deficiency. Am J Med Genet 108:140–147

15. Robertson D, Haile V, Perry SE et al (1991) Dopamine beta-hydroxylase deficiency.

A genetic disorder of cardiovascular regulation. Hypertension 18:1–8

16. Streeten DHP, Kerr LP, Kerr CB et al (1972) Hyperbradykinism: A new orthostatic syndrome. Lancet II:1048–1053

17. DeStefano AL, Baldwin CT, Burzstyn M et al (1998) Autosomal dominant hypoten-

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sive disorder maps to chromosome 18q. Am J Hum Genet 163:1425–1430

18. Ranade K, Wu KD, Hwu CM et al (2001) Genetic variation in the human urea transporter is associated w ith variation in blood pressure. Hum Mol Genet 10:2157–2164

19. Mathias CJ, Bannister R (1999) Dopamine ß-hydroxylase deficiency with a note on other genetically determined causes of autonomic failure. In: Mathias CJ, Bannister R (eds) Autonomic Failure. A Textbook of Clinical Disorders of the Autonomic Nervous System. Fourth edition. Oxford University Press, Oxford-New York, pp 387–401