Acoustic impairment is a distinguishable clinical feature of Asidan/SCA36

ObjectiveTo investigate acoustic function of Asidan/spinocerebellar ataxia type 36 (SCA36) in which sensorineural hearing loss may be found as one of extracerebellar symptom that can be a distinguishable feature from other degenerative ataxias.MethodsAcoustic function in the groups of normal control (n = 31), Asidan/SCA36 (n = 13), cortical cerebellar atrophy (CCA, n = 28), multiple system atrophy of cerebellar predominance (MSA-C, n = 48), SCA31 (n = 4), and other forms of SCAs (n = 14) was evaluated by pure tone average (PTA) calculated by the results of audiogram and brainstem auditory evoked potentials (BAEPs).ResultsPTA was significantly decreased in Asidan/SCA36 in comparison to normal control and other ataxic groups, but not significant within other ataxic groups and normal control. In comparison to other groups, Asidan/SCA36 showed a constant depression at 7 different frequencies in audiogram, especially at 4000 and 8000 Hz. BAEPs in 2 Asidan/SCA36 cases suggested possible involvement in the inner ear or the peripheral part of the auditory system. PTA in Asidan/SCA36 cases significantly correlated with their severity of ataxia.ConclusionsIn addition to signs for motor neuron involvement, acoustic impairment in Asidan/SCA36 is another characteristic clinical feature that is distinguishable from other forms of SCAs.     

Electrophysiological evaluation of spinocerebellar ataxias 1, 2 and 3

IntroductionSubclinical neuropathy is an important feature of spinocerebellar ataxias (SCA) but the true prevalence and electrophysiological characteristics in genetically proven patients of SCA 1, 2 and 3 are largely unknown.MethodsWe prospectively compared the electrophysiological characteristics of neuropathy in 61 genetically confirmed cases of SCA (SCA1 = 28, SCA2 = 16 and SCA3 = 17). Nerve conduction studies were performed in at least one sensory and one motor nerve, in right upper and lower limb using standard methods.ResultsThe mean age of patients and duration of illness were comparable among SCA groups (mean age (years): SCA1—34.1 ± 12.7, SCA2—35.2 ± 13.9 and SCA3—38.1 ± 11.3; mean duration (years): SCA1—5.4, SCA2—6.1, and SCA3—4.4). Electrophysiological evidence of neuropathy was highest in SCA1 (96.4%), followed by SCA3 (94.1% and SCA2 (87.5%). A mixed sensorimotor neuropathy was commonly observed in all the subgroups (SCA1—78.6%, SCA2—50%, and SCA3—41.2%). Pure sensory neuropathy was most common in SCA3 (55.9%), followed by 31.3% in SCA2 and 17.9% in SCA1. Pure motor neuropathy was uncommon (6.3% in SCA2 and none in SCA1 and SCA3).ConclusionsElectrophysiological evidence of mixed sensorimotor and pure sensory neuropathy is seen in all the three subtypes of SCAs, while pure motor neuropathy is distinctly uncommon.     

Frequency analysis and clinical characterization of different types of spinocerebellar ataxia in Serbian patients.

The relative frequencies of different spinocerebellar ataxias (SCAs) vary widely among different ethnic groups, presumably due to a founder effect. We investigated the relative prevalence of SCA1-3, 6-8, 12, 17; dentate-rubro-pallidoluysian atrophy; and Friedreich's ataxia (FRDA) in Serbian patients with adult-onset (>20 years of age) hereditary and sporadic SCAs, and compared clinical features of patients with genetically confirmed SCAs. A total of 108 patients from 54 families (38 apparently dominant [ADCA] and 16 apparently recessive) with adult-onset hereditary ataxia and 75 apparently sporadic patients were assessed. Of 38 families with ADCA, 13 (34%) were positive for an expansion in an SCA1 and 5 families (13%) for an expansion in an SCA2 allele. In 20 families (53%), no expansions have been identified in any of the analyzed genes. Gaze palsy, spasticity, and hyperreflexia were significantly more common in SCA1, whereas slow saccades, hypotonia, hyporeflexia, and dystonia prevailed in SCA2 patients. Among the 16 families with an apparently recessive mode of ataxia inheritance, 4 (25%) were identified as having the FRDA mutation. Ataxia-causing mutations were identified in 8 (10.6%) of patients with apparently sporadic adult-onset ataxia.     

Intrafamilial variability of Parkinson phenotype in SCAs: novel cases due to SCA2 and SCA3 expansions

BackgroundParkinson's disease (PD) has been related to mutations associated with spinocerebellar ataxias (SCA); the frequency of the diagnosis of these mutations is low in general late-onset PD cases. Our aim was to investigate a selected high-risk group of PD patients.MethodsPD patients with autosomal dominant inheritance or atypical neurological manifestations were enrolled, underwent a full neurological examination and had the CAG tracts of their SCA1, 2, 3, 6 and 7 genes analyzed.ResultsOf the 23 studied families, two SCA3 and one SCA2 cases were identified. All had autosomal dominant inheritance. In the SCA2 pedigree, four affected sibs had a homogeneous PD phenotype. CAG repeats varied between 35 and 44 with CAA interruptions. Intrafamilial phenotypic heterogeneity was identified in the SCA3 pedigrees; parkinsonian and ataxic phenotypes coexisted in both kindreds. CAGn varied between 69 and 71 repeats. Age of onset was lower in the SCA3 patients than in the remaining 24 cases (38 versus 46.7 ± 12 years of age, p = 0.003).ConclusionsSCA2 and SCA3 mutations were detected in 13% of the present sample: the strategy of selecting a high-risk group increased the rate of making these diagnoses. The SCA2 cases confirmed an association between PD and interrupted expansions, as well as PD intrafamilial phenotypic homogeneity. Clinical heterogeneity of SCA3 pedigrees suggests that disease-modifying agents outside the MJD1 gene may play a role in determining PD symptoms in this disorder.     

A survey of spinocerebellar ataxia in South Brazil – 66 new cases with Machado-Joseph disease, SCA7, SCA8, or unidentified disease–causing mutations

Background The autosomal dominant spinocerebellar ataxias (SCAs) are a clinical and genetically heterogeneous group of debilitating, neurodegenerative diseases, related to fourteen different loci– SCAs 1, 2, 4, 5, 6, 7, 8, 10, 11, 12, 13 and 14, Machado-Joseph disease (MJD/SCA 3), and DRPLA. Objectives (1) to verify the frequency of SCA1, SCA2, MJD, DRPLA, SCA6, SCA7 and SCA8 in a series of new SCA patients from South Brazil and (2) to compare their molecular and clinical characteristics with other patients previously described. Methods sixty-six cases were included in the present study: 52 were familial and 14 sporadic. Molecular analysis of the trinucleotide repeat loci were performed according to methods in the literature. Results 92 % of families with autosomal dominant inheritance segregated the MJD1 mutation, 2 % of families segregated the SCA7 mutation and 6 % remained undiagnosed. Among 14 isolated cases, one showed the SCA8 mutation. Clinical and molecular findings were similar to those already described in the literature, but revealed (1) one SCA7 patient with eyelid retraction, a sign usually related to MJD; and (2) one sporadic case of SCA8. Conclusions The proportion of MJD cases was very high, probably reflecting an Azorean founder effect. The estimated frequency of affected individuals with MJD, in our region, was 1.8 / 100,000, and of SCAs other than MJD, 0.2/100,000. Received: 13 February 2001, Received in revised form: 6 April 2001, Accepted: 9 April 2001     

Profile of extrapyramidal manifestations in 85 patients with spinocerebellar ataxia type 1, 2 and 3

This study aimed to determine the prevalence and type of extrapyramidal signs (EPS) in spinocerebellar ataxia (SCA) type 1, 2 and 3. Eighty-five patients with genetically confirmed SCA (SCA1 = 40, SCA2 = 28, SCA3 = 17) were evaluated for the prevalence and types of EPS. Forty-one SCA patients (48.2%) had one or more types of EPS. The prevalence of EPS was 60.7% in SCA2, 52.9% in SCA3, and 37.5% in SCA1. Among SCA2 patients, bradykinesia was the most frequent (35.3%), followed by reduced facial expression, postural tremor and dystonia (29.4% each), rest tremor, titubation and rigidity (23.5% each), and lip/jaw tremor and chorea (11.8% each). In SCA3 the common EPS were bradykinesia (44.4%), staring look, postural tremor and dystonia (33.3% each), and reduced facial expression and rigidity (22.2% each). In SCA1, staring look was the most common (53.3%), followed by dystonia and bradykinesia (33.3% each), and postural tremor (26.7%). In all three groups, there was no significant difference in the mean length of repeat of the abnormal allele between those with and without EPS. To conclude bradykinesia, staring look, dystonia and postural tremor were the most frequent EPS observed in SCA. In SCA1, these signs were seen more often in younger patients with early onset of symptoms.     

Quantitative evaluation of balance in patients with spinocerebellar ataxia type 1: A case control study

ObjectiveQuantitative assessment of balance in spinocerebellar ataxia type 1 (SCA1).BackgroundEvaluation of balance in degenerative ataxias is often clinical and subject to bias. Quantification of balance is crucial for evaluating the efficacy of therapeutic and rehabilitative interventions.MethodsThe subjects were 20 patients (males: 14, females: 6) with genetically positive SCA1 and 20 age and gender matched healthy subjects. Ataxia was rated using the International Cooperative Ataxia Rating Scale (ICARS). Balance was assessed by dynamic posturography (Biodex, USA) which included: (a) ability to control balance in all directions (overall balance index, OBI), front to back (anterior–posterior index, API) and side-to-side (medio–lateral index, MLI); and (b) the limits of stability (LOS) in all directions. Balance index was considered abnormal if the actual value exceeded the predictive value.ResultsImpaired balance was found in 80% of patients (all indices in 35%, OBI + API in 25%, only OBI in 15%, and OBI + MLI in 5%). Compared to controls, SCA1 patients had significantly higher balance indices and lower LOS scores. Unlike in controls, the mean value of API was significantly higher than MLI in SCA1. LOS was found to the best predictor of balance abnormality. In patients, all balance indices had significant positive correlations with ICARS, static score of ICARS, body weight, severity and duration of illness, but not with the CAG repeat length.ConclusionsPatients with SCA1 had global impairment of balance, with greater instability in anterior–posterior than medio–lateral directions. Apart from severity and duration of illness, body weight was detriment to maintenance of balance in SCA1. This information may be useful in planning balance rehabilitation in SCA.     

Uses of the postural stability test for differential diagnosis of hereditary ataxias

Friedreich's ataxia (FRDA) and spinocerebellar ataxia type 2 (SCA 2) are among the most commonly diagnosed hereditary ataxias in Czech Republic. Although criteria differentiate the ataxias, disorder onset symptoms may be similar. Our goal was to determine whether and to what degree of validity posturographic examination may be utilized, with the aim of differential diagnosis; which specific posturographic parametres are suitable for differential diagnosis; and which differences in FRDA and SCA 2 patient posturographic findings may be established. 17 SCA 2 and 12 FRDA patients were examined with ten healthy controls. A multi-sensor tenzometric platform was used for posturographic examination. Toe standing position was added to basic tests, including standing position with and without visual control. There was no difference between patients in standing position with visual control but there were distinct differences between FRDA and SCA 2 patients, based on upright stance without visual control and medio-lateral deviation. There were no differences between patients in toe standing position, suggesting not only the cerebellum, but also deep sensation, helps to create the so-called adaptive controller. Posturography is attested to as a useful method for differential diagnosis of hereditary ataxias and provides neurophysiological findings in cerebellar and sensoric ataxias.     

The clinical diagnosis of autosomal dominant spinocerebellar ataxias

The spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal dominantly inherited progressive ataxia diseases. Up to now, almost 30 different gene loci have been found. In 14 of them, the underlying mutations have been identified. The more common SCAs, SCA1, 2, 3 and 6 are due to translated CAG repeat expansions that code for an elongated polyglutamine tract within the respective proteins. These diseases belong to a larger group of polyglutamine disorders that also includes Huntington’s disease. Epidemiological studies conducted in different European regions found prevalence rates of SCAs ranging from 0.9 to 3.0:100,000. In all SCAs, ataxia is the prominent symptom. However, the majority have a complex phenotype in which ataxia is accompanied by varying non-ataxia symptoms. In all ataxia patients with proven or suspected autosomal dominant mode of inheritance, the available molecular genetic tests for SCA mutations should be performed. Depending on the geographical origin of the family, these tests will lead to positive diagnostic results in at least half of the families.     

Genetic etiology of a Chinese ataxia cohort: Expanding the mutational spectrum of hereditary ataxias

IntroductionHereditary ataxias demonstrate a high degree of clinical and genetic heterogeneity. Understanding the genetic etiology of hereditary ataxias is crucial for genetic counseling and clinical management.MethodsThe clinical and genetic data of patients with familial or sporadic ataxias who referred to our tertiary medical center were retrospectively analyzed. Probands in this study underwent SCA repeat expansion panel firstly to screen for repeat expansion SCAs; those with negative results had NGS-targeted panels or WES testing to detect conventional mutations.ResultsA total of 223 patients were enrolled from 206 families. 5 kinds of coexisting SCA repeat expansions were observed (SCA3/SCA17, SCA3/SCA8, SCA2/SCA8, SCA3/SCA12 and SCA8/SCA12) in 12 patients from 8 families, among which SCA2/SCA8, SCA8/SCA12 and SCA3/SCA12 were reported for the first time. The coexistence of expanded SCA3 with SCA17 alleles was the most common in our study. NGS identified pathogenic/likely pathogenic variants in 12 ataxia causative genes in 13 probands. Spastic paraplegia ataxia was the most common diagnosis. Six novel mutations were detected in five ataxia-related genes.ConclusionCoexistence may not specific to a certain SCA subtype and the frequency might have been underestimated before. SCA repeat expansion panel should be considered in patients with overlapping SCA features. In addition, our study broadened the conventional mutation spectrum in ataxia-related genes. These results facilitate a better understanding of the genetic basis for hereditary ataxias.     

Analysis of spinocerebellar ataxias due to expanded triplet repeats in Greek patients with cerebellar ataxia

The relative frequency of different autosomal dominant cerebellar ataxias, commonly referred to as spinocerebellar ataxias (SCAs), varies considerably among populations of different ethnic origin. No data exist at present on the frequency of different SCAs in the Greek population. In the present study we investigated the presence of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in a cohort of 83 Greek patients with slowly progressive cerebellar ataxia. Twenty patients came from autosomal dominant (AD) pedigrees, seven displayed recessive or unclear inheritance and 56 were sporadic. We found four patients with pathological SCA expansions, all from AD pedigrees. Two patients had SCA1, one SCA2 and one SCA7 (10.0, 5.0 and 5.0% of the AD group, respectively). The clinical features of these patients were within the expected spectrum. In total, a pathological expansion was detected in 20% of patients from AD pedigrees. Interestingly, no cases of SCA3 or SCA6 were detected in the AD group. No expansions were found in other familial cases or in sporadic patients. Overall, no cases of SCA3, SCA6, SCA12, SCA17 or DRPLA were identified in the Greek population. In conclusion, SCA1, SCA2 and SCA7 are present in Greek patients with AD cerebellar ataxia in frequencies similar to those observed in other populations. SCA3 and SCA6 appear however to be rare in Greece. The genetic cause for the majority of AD ataxias remains to be identified.     

Other causes of ataxia in patients with SCA mutations

Autosomal dominant spinocerebellar ataxias (SCAs) are slowly progressive and have a variable clinical presentation. Overlapping clinical features among the SCAs make the clinical diagnosis of these ataxias difficult. Even when genetic testing identifies an SCA mutation, clinicians should be vigilant for other causes of neurological dysfunction in these patients. We report two patients who developed other causes of ataxia in the setting of SCA-3 and SCA-8 mutations, respectively.     

Intraoperative brain mapping during awake surgery in symptomatic supratentorial cavernomas

BackgroundComplete resection of symptomatic supratentorial cavernoma (SCA) and removal of the surrounding gliotic area is recommended to minimize the risk of persistent seizures or (re)bleeding. Surgery of SCA located in an eloquent area, can carry out severe postoperative neurological morbidity. We report a study aimed to assess feasibility, extent of resection and outcome after surgical removal of CA by cortico-subcortical intraoperative brain stimulation (ioBS) in the awake patient.MethodsSix patients diagnosed of symptomatic SCA located on an eloquent area and operated on while awake under local anaesthesia ioBS, were included. Preoperative planning included neuropsychologic assessment of language-related functions, sociocognitive functions and executive functions. Intraoperatively, we recorded the results achieved in the planned neuropsychological tasks when stimulation was applied (cortical and subcortical). Postoperative control 3D MRI was scheduled at 1 month after surgery to calculate extent of resection. Neuropsychological assessment at 6 months after surgery was performed in all cases.ResultsSix patients (5 females, 1 male) aged 24–48 years were included in our study. Locations of the lesions were right insular (n = 1), left insular (n = 1), left temporo-insular (n = 1), left temporal (n = 2) and left frontal (n = 1). In all patients, positive findings were obtained during ioBS. In 5 patients, complete surgical resection was achieved. Two patients had postoperative transient neurological deficits, one case of hemiparesis, one case of dysnomia, both cleared over a 6-month period. Clinical follow-up revealed that all patients experienced complete recovery from preoperative symptoms within a year and five patients with seizures showed marked improvement and eventually quit antiepileptic drugs. Neuropsychological assessment at 6 months provided normal results compared to preoperative baseline in all domains.ConclusionsOur study suggests that ioBS in the awake surgery of symptomatic SCA located in eloquent areas, allows to increase the rate of complete resection, minimizing postoperative neurological and neuropsychological deficit, and improving postoperative seizures control.     

Assessment of swallowing in motor neuron disease and Asidan/SCA36 patients with new methods

BackgroundWe report on a unique complication of cerebellar ataxia and motor neuron disease named Asidan/SCA36 with a high frequency of tongue atrophy. We aimed to elucidate dysphagia in amyotrophic lateral sclerosis (ALS) and spinal, bulbar muscular atrophy (SBMA), and Asidan/SCA36 patients with new methods.MethodsPatients diagnosed with ALS (n = 20), SBMA (n = 6), and Asidan (n = 12) were included. A videofluoroscopic swallow study (VFS), an assessment of maximal tongue pressure (MTP), and impedance pharyngography (IPG) were applied.ResultsThe frequencies of VFS abnormalities were 70%, 50%, and 33% in ALS, SBMA, and Asidan/SCA36, respectively. Compared with control subjects (31.6 ± 6.3 kPa, mean ± SD), MTP was significantly decreased in ALS patients and SBMA patients, but was relatively preserved in Asidan patients. ALS patients performed more swallowing actions (Ns) detected by IPG than did control subjects, but SBMA and Asidan/SCA36 patients performed similar Ns to control subjects.ConclusionsVFS showed a higher frequency of swallowing abnormalities in ALS patients. MTP and IPG measurements showed the most severe involvement in ALS patients and a relatively preserved swallowing function in SBMA and Asidan/SCA36 patients.     

Gastrocnemius and soleus spasticity and muscle length in Friedreich’s ataxia

Lower limb spasticity compromises the independence of people with Friedreich’s ataxia (FRDA). This study sought to examine lower limb spasticity in FRDA in order to offer new insight as to the best approach and timing of spasticity management. Gastrocnemius and soleus spasticity and muscle length were measured by the Modified Tardieu Scale (MTS) in 31 participants with typical and late-onset FRDA. Relationships between the MTS and the Friedreich Ataxia Rating Scale (FARS), Functional Independence Measure (FIM), and disease duration were analysed. Differences between ambulant (n = 18) and non-ambulant (n = 13) participants were also examined. All participants had spasticity in at least one muscle, and 38.9% of ambulant and 69.2% of non-ambulant participants had contracture in one or both of their gastrocnemius muscles. Significant negative correlations were found between both gastrocnemius and soleus angle of catch and the FARS score. The FIM score also demonstrated significant correlations with gastrocnemius muscle length and angle of catch. Gastrocnemius and soleus spasticity and contracture is apparent in people with FRDA. Spasticity is evident early in the disease and in ambulant participants. Management of spasticity and reduced muscle length should be considered in people with FRDA at disease onset to optimise function.     

Altered neocortical tactile but preserved auditory early change detection responses in Friedreich ataxia

ObjectiveTo study using magnetoencephalography (MEG) the spatio-temporal dynamics of neocortical responses involved in sensory processing and early change detection in Friedreich ataxia (FRDA).MethodsTactile (TERs) and auditory (AERs) evoked responses, and early neocortical change detection responses indexed by the mismatch negativity (MMN) were recorded using tactile and auditory oddballs in sixteen FRDA patients and matched healthy subjects. Correlations between the maximal amplitude of each response, genotype and clinical parameters were investigated.ResultsEvoked responses were detectable in all FRDA patients but one. In patients, TERs were delayed and reduced in amplitude, while AERs were only delayed. Only tactile MMN responses at the contralateral secondary somatosensory cortex were altered in FRDA patients. Maximal amplitudes of TERs, AERs and tactile MMN correlated with genotype, but did not correlate with clinical parameters.ConclusionsIn FRDA, the amplitude of tactile MMN responses at SII cortex are reduced and correlate with the genotype, while auditory MMN responses are not altered.SignificanceSomatosensory pathways and tactile early change detection are selectively impaired in FRDA.     

Determinants of depression among patients with epilepsy in Athens,Greece

ObjectiveDepression is common among patients with epilepsy. The aim of our study was twofold: to estimate the prevalence of a major depressive episode and to identify its determinants among patients with epilepsy treated in the largest Greek hospital in Athens.MethodsAll consecutive patients with epilepsy that visited the epilepsy outpatient clinic of Evangelismos General Hospital were invited to participate in the study. Ninety-four patients met our inclusion criteria.ResultsA diagnosis of a current major depressive episode was established in 21 out of 94 eligible to participate (22.3%) patients. Being a female was associated with a 19.68-fold increase in the odds of having a major depressive episode (95% CI 3.39–114.14, p = 0.001); being unemployed was associated with a 6.46-fold increase in the odds of having a major depressive episode (95% CI 1.23–34.07, p = 0.028), and each extra seizure experienced per month was associated with a 1.38-fold increase in the odds of having a major depressive episode (95% CI 1.03–1.85, p = 0.031).ConclusionUnemployment, female gender, and seizure control are important determinants of a major depression episode among patients with epilepsy.     

Autosomal dominant spinocerebellar ataxias: an Asian perspective

Autosomal dominant cerebellar ataxias, frequently referred to as spinocerebellar ataxias (SCAs) have been under intense scientific research limelight since expansions of coded CAG trinucleotide repeats were demonstrated to cause several dominantly inherited SCAs. The number of new SCA loci has expanded dramatically in recent years. At least ten genes have been identified for SCAs 1, 2, 3, 6, 7, 8, 10, 12, 17, dentatorubral-pallidoluysian atrophy (DRPLA), and six loci responsible for SCAs 4, 5, 11,13, 14, and 16 have been mapped. Genetic testing is essential for diagnosis due to the overlapping and varied phenotypic features of the different SCAs. While there is no effective treatment available, genetic counseling is important for addressing the many ethical, social, legal, and psychological issues facing SCA patients. Researchers have recently provided valuable information on the pathogenesis of the disease and hopefully a cure will be available in the near future.     

Prevalence of family history in patients with reflex syncope

Reflex syncope is defined by a rapid transient loss of consciousness caused by global cerebral hypoperfusion resulting from vasodilatation and/or bradycardia attributable to inappropriate cardiovascular reflexes. A hereditary component has been suggested, but prevalence of family history may differ among subtypes of reflex syncope, as these have different autonomic responses and pathogeneses may be diverse. The present study aimed to assess the prevalence of a positive family history of syncope and cardiovascular characteristics in patients with cardioinhibitory and vasodepressor reflex syncope. Patients (n = 74) were classified into subtypes of reflex syncope – cardioinhibition/asystole (Vasovagal Syncope International Study subtypes II-B [VASIS II-B], n = 38) or vasodepressor (VASIS III, n = 36) – using the head-up tilt test. Family history was obtained by questionnaires supplemented by interview. Patients with cardioinhibitory syncope had a mean onset of disease 8 years earlier than vasodepressor patients (mean ± standard deviation 14.5 years ± 12.6 for cardioinhibitory patients compared to 22.4 years ± 11.9 for vasodepressor patients, p < 0.001). Thirty-seven (50%) of 74 probands had a positive family history with at least one relative affected with syncope, arrhythmias, known sudden unexpected death, and/or heart disease. The prevalence of a positive family history was higher in patients with cardioinhibitory syncope compared to vasodepressor syncope (24 (63%) compared to 13 (36%); p = 0.02). Overall, 40 first-degree relatives (26%) and 27 second- or third-degree relatives (25%) were affected. The most frequent events in families of patients with cardioinhibitory or vasodepressor reflex syncope were severe syncope and/or arrhythmias, known sudden unexpected deaths, and heart disease. In conclusion, prevalence of familial occurrence of syncope is in agreement with previous studies. However, a high occurrence of all-cardiovascular disorders in cardioinhibitory patients may reflect shared genetic susceptibility to these diseases.