Dominant Transmission Observed in Adolescents and Families with Orthostatic Intolerance

Abstract

Objective

Orthostatic intolerance is typically thought to be sporadic and attributed to cerebral autonomic dysfunction; we sought to identify families with inherited autonomic dysfunction manifest as symptomatic orthostatic intolerance to characterize mode of inheritance and clinical features.

Methods

Sixteen families with two or more first- or second-degree relatives with autonomic dysfunction and orthostatic intolerance were enrolled. A clinical diagnosis of autonomic dysfunction defined by symptomatic orthostatic intolerance diagnosed by head-up tilt table testing was confirmed for each proband. Clinical features and history were obtained from each proband using a standardized intake questionnaire, and family history information was obtained from probands and available relatives.

Results

Comprehensive pedigree analysis of 16 families (39 individuals with orthostatic intolerance, and 40 individuals suspected of having orthostatic intolerance), demonstrated dominant transmission of autonomic dysfunction with incomplete penetrance. Affected individuals were predominantly female (71.8%, 28/39; F:M::2.5:1). Male-to-male transmission, though less common, was observed and demonstrated to transmit through unaffected males with an affected parent. Similar to sporadic orthostatic intolerance, probands report a range of symptoms across multiple organ systems, with headaches and neuromuscular features being most common.

Conclusions

Familial occurrence and vertical transmission of autonomic dysfunction in 16 families suggests a novel genetic syndrome with dominant transmission, incomplete penetrance, and skewing of the sex ratio. Elucidation of potential genetic contributions to orthostatic intolerance may inform therapeutic management and identification of individuals at risk. Adolescent evaluation should include identification and treatment of potential at-risk relatives.

INTRODUCTION

Orthostatic intolerance typically presents as lightheadedness or dizziness in young adults and teenagers, but may also be manifest by symptoms of migraine, tachycardia, hypotension, fatigue, weakness, and nausea.^{1, 2} These symptoms have been attributed to the inability to maintain adequate venous return to the heart due to venous pooling, mostly in the lower body during upright position.³ Orthostatic intolerance can result from autonomic nervous system dysfunction, and is clinically characterized as neurally-mediated (vasovagal) syncope, orthostatic hypotension, or postural orthostatic tachycardia syndrome (POTS).^{1, 4-7} Many individuals with orthostatic intolerance experience symptoms suggestive of multi-organ involvement, such as headaches, fatigue, lightheadedness, palpitations, joint pain, temperature intolerance, and nausea. This constellation of symptoms is consistent with a role for the autonomic nervous system throughout the body.^{1, 7} The head-up tilt table (HUTT) test, which enables measurements of blood pressure and heart rate during and after a change from supine to upright positioning, can be useful in both diagnosis of and distinction among different types of orthostatic intolerance.⁵ The HUTT is also a useful tool for recapitulating the lightheadedness, fatigue, and nausea reported by many patients with orthostatic intolerance; significant hypotension, tachycardia, and/or syncope can be observed in severely affected individuals during testing. Somewhat paradoxically, patients can display a bradycardic response to HUTT, and cardiac asystole has been reported.^8-11

Orthostatic intolerance is common, and estimates suggest that there are at least 500,000 individuals within the United States alone.⁷ While orthostatic intolerance can occur as an adverse medication effect or a manifestation of another disease, such as Parkinson disease or amyloidosis,⁷ there are increasing reports of individuals with autonomic dysfunction for which there is no identifiable cause. Most patients represent isolated orthostatic intolerance cases and are thus thought to be sporadic, but there have been a few case reports for which multiple family members are affected,^12-14 with phenotypes ranging from orthostatic hypotension,^{15, 16} POTS together with functional gastrointestinal disease,¹⁷ or vasovagal syncope.^18-23

We describe 16 families for which at least two first- or second-degree relatives are affected with autonomic dysfunction defined by symptomatic orthostatic intolerance in the absence of any identifiable etiology or syndromic features. Clinical characteristics including detailed objective laboratory investigations and observed familial aggregation and segregation are described.

PATIENTS AND METHODS

Enrollment

Approximately 1000 sequential patients referred to the Dysautonomia Clinic at The University of Texas Health Science Center at Houston, McGovern Medical School between 2010 and 2015 were considered for inclusion in this study, which was approved by the Institutional Review Boards at The University of Texas Health Science Center and Baylor College of Medicine. During the time of the study, candidate index patients with a clinical diagnosis of autonomic nervous system dysfunction were chosen based on the presence of a positive family history and exclusion of a primary motor or sensory neuropathy, neurodegenerative disease, cerebral palsy, spinal trauma, autoimmune disease, mitochondrial disease, thyroid dysregulation, and diabetes mellitus. A total of 16 unrelated families were enrolled and available clinical information was collected for an additional 228 relatives. Each proband provided clinical symptom and family history information and underwent a clinical evaluation, including objective laboratory investigations as described below. Criteria for a clinical diagnosis of autonomic dysfunction were (1) evidence of orthostatic intolerance on HUTT evaluation performed and interpreted as previously described,²⁴ and (2) patient-reported symptoms of autonomic dysfunction. Patients with an abnormal HUTT evaluation but absence of symptoms during HUTT evaluation were excluded.

Genetic Evaluation

Detailed 3- or 4-generation family histories were obtained by interview of the proband (or parent of proband if minor) and additional family members when available. Pedigrees were constructed using available information, and used to assess potential inheritance patterns and penetrance of the autonomic dysfunction phenotype. For these analyses, probands and relatives meeting strict criteria for a clinical diagnosis of autonomic dysfunction (abnormal tilt table test and patient-reported symptoms of orthostatic intolerance in the absence of secondary causes) were classified and considered as affected (Figure 1, black symbols). Individuals with symptoms suggestive of autonomic dysfunction who have not undergone tilt table testing were also recorded (Figure 1, grey symbols).

Figure 1.

Familial autonomic dysfunction in 16 pedigrees demonstrates autosomal dominant inheritance with incomplete penetrance. Females and males are indicated by circles and squares, respectively; spontaneous pregnancy loss is represented by small triangles. Red arrows indicate proband. Numbers inside white shapes indicate the number of unaffected females (circles) or males (squares) within the indicated section of the pedigree. Black shapes indicate formal diagnosis of autonomic dysfunction. Grey shapes indicate suspected diagnosis of autonomic dysfunction in individuals unavailable for formal evaluation. Shapes with hatch marks indicate individuals for whom HUTT or symptom assessment was negative.

Symptom Assessment

For each proband, symptoms of autonomic dysfunction were assessed using a structured 4-page symptom and history questionnaire organized by organ system (Supplemental Information). The questionnaire requires patients to record the presence and severity of 55 symptoms related to neurologic, cardiologic, genitourinary, immunologic, gastrointestinal, musculoskeletal, and dermatologic organ systems. Severity of each symptom is rated by the patient on a scale of 0-4 with zero representing absence of the symptom and ‘4’ representing that the symptom occurs frequently and is severe. The questionnaire includes a detailed headache assessment that records duration and frequency of headaches, as well as severity assessed using the universal 10-point scale,^{25, 26} with a score of ‘0’ indicating no pain, and ‘10’ indicating the most severe pain the patient has experienced. Genitourinary symptoms, not captured by the earliest version of the structured questionnaire, were not included in this study. For individuals under the age of 18 years, a parent or guardian completed the questionnaire (Supplemental Information). For relatives not locally available, telephone interviews were used to capture clinical features based on the components of the structured questionnaire.

RESULTS

Demographics

A total of 16 index patients and their available relatives were enrolled in the study. Of these 16 families, 39 individuals had a clinical diagnosis of autonomic dysfunction based on the presence of symptoms of autonomic dysfunction and abnormal HUTT testing. Females were more frequently affected (71.8%, 28/39; F:M::2.5:1). An additional 40 individuals were suspected of having autonomic dysfunction based on reported symptoms, but were unavailable for HUTT during the time frame of the study; this group was also predominantly female (70.0%, 28/40; F:M::2.3:1). Ethnic or racial background was self-reported by each family and included mixed European Caucasian descent in 100% (16/16); one family additionally reported Hispanic descent. Index patients were between 13 and 16 years of age at the time of initial evaluation.

Pedigree analysis

Detailed pedigree analysis demonstrated 16 probands diagnosed with autonomic dysfunction for whom one or more first-, second- or third-degree relatives were also diagnosed with autonomic dysfunction or suspected to have autonomic dysfunction based on symptom profile and available clinical history (Figure 1). All recorded unions were reported as nonconsanguineous. Individuals with a diagnosis of autonomic dysfunction or symptoms suggestive of autonomic dysfunction were mostly female (70.9%, 56/79; F:M::2.43:1). Of 16 probands, 11 (68.8%) were demonstrated to inherit autonomic dysfunction from an affected mother with abnormal HUTT, and the other 5 (31.3%) had a mother or maternal relative for whom a diagnosis of autonomic dysfunction was suspected but not yet confirmed by HUTT. Considering only those individuals (probands and relatives) formally diagnosed with autonomic dysfunction (symptoms and documented abnormal HUTT), 23 individuals shared this diagnosis with a maternal relative, and for 16 the suspected parent-of-origin for the phenotype could not be determined. Of these 16, in 8 cases both parents were asymptomatic (this may reflect either incomplete penetrance or a de novo mutational event), in 7 cases one parent was symptomatic but HUTT not yet performed, and in 1 case parental information was not available. Considering all individuals with autonomic dysfunction or suspected autonomic dysfunction, 46 shared the reported phenotype with a maternal relative consistent with potential X-linked dominant transmission, 4 with a paternal relative, and for 29 the parent-of-origin could not be determined. Paternal transmission was observed in families 2, 4, and 6, including male-to-male transmission in families 2 and 6 consistent with potential autosomal dominant transmission. However, no familial male-to-male transmission was observed wherein there were two generations of affected males diagnosed by objective laboratory investigations. No families reported a history of recurrent pregnancy loss.

Symptom Assessment

Detailed symptom assessment prior to initiation of treatment was performed in 12 of 16 probands. Four probands were ascertained prior to the implementation of a structured clinical questionnaire. Patients were asked to rank the severity of each symptom using a 4-point scale (0-4) or, for headaches, a 10-point scale (0-10)^{25, 26} (Table 1, Supplemental Table 1). Severity and nature of symptoms varied by patient, and headaches were the most common feature, reported in 100% (12/12) individuals. Neurologic (including dizziness and syncope), musculoskeletal, and energy-related symptoms were also common and each reported as moderate or severe in 75% (9/12). Moderate or severe dermatologic or gastrointestinal features were observed in half (6/12) of patients. Cardiovascular features were less common, but also reported as moderate in severity by 25% (4/12).

Table 1.

Overview of patient-reported symptoms scored as high (∎), medium (), or low (◆) severity based on average score for each organ system as detailed in Supplemental Table 1. Proband number correlates with family number as indicated in Figure 1. Empty spaces represent no reported symptoms.

DISCUSSION

In the present report, we describe a cohort of 16 patients with non-syndromic autonomic dysfunction manifesting as symptomatic, chronic orthostatic intolerance in adolescent patients and their 63 affected relatives. Although this study is limited by small sample size and the availability of HUTT evaluation in only a proportion of studied relatives, we do observe clinically confirmed autonomic dysfunction as a familial trait in 12 of 16 reported families, for which the proband and at least one relative have both an abnormal HUTT evaluation and symptoms of autonomic dysfunction. Detailed pedigree analysis is most consistent with dominant transmission with reduced penetrance. Importantly, the observations of male transmission (family 2, 6) and non-penetrant transmitting males (family 4) suggests some families may segregate autonomic dysfunction as an autosomal dominant trait – no evidence was obtained for X-linked recessive or mitochondrial inheritance models. Adolescent onset, female preponderance, and evidence for dominant transmission distinguishes this cohort from families with the autosomal recessive form of familial autonomic dysfunction, a form of hereditary sensory and autonomic neuropathy known as Riley-Day syndrome (MIM #223900) caused by pathogenic variants in IKBKAP that result in a neuropathy further characterized by absent lingual fungiform papillae, decreased corneal reflex, and decreased pain and temperature sensation and ‘histamine flare’ by diagnostic testing.^{27, 28}

We observed a predominance of affected females in this cohort, although affected males are also observed. The basis for this gender difference is not understood, but similar observations have been reported in other patients with autonomic dysfunction due to orthostatic intolerance,^{1, 7} as well as other autosomal dominant syndromes, such as hypermobility type Ehlers-Danlos syndrome.²⁹ Skewing of phenotypic expression has been described in hereditary autoimmune-mediated lung disease and arthritis caused by pathogenic variants in COPA, for which some male individuals with the disease-causing variant are asymptomatic despite abnormal functional studies.³⁰ The sex skewing observed in familial orthostatic intolerance, taken together with the observation of transmission from both affected and unaffected males and undetermined parent-of-origin for 29/79 affected individuals suggests that male and female transmission might occur at near-equal frequencies, but ascertainment of male transmission may be masked by the relatively high frequency of non-penetrance or reduced expression in males.

Reported symptoms in this cohort varied between individuals, but headache and neuromuscular features were most commonly reported, and all patients reported at least mild neurologic symptoms such as syncope or dizziness (Supplemental File), similar to what is observed in sporadic cases. Orthostatic intolerance has previously been attributed to a pooling of blood in dependent vessels during upright positioning, leading to reduced venous return to the heart. Some have suggested that these altered hemodynamics may ultimately be responsible for the associated symptoms of autonomic dysfunction, which can affect essentially all organ systems. However, at least one recent study comparing patients referred to an autonomic dysfunction clinic for autonomic symptoms found no difference in the severity of symptoms between those with and without HUTT-confirmed orthostatic intolerance,³¹ suggesting that these symptoms may be a manifestation of the underlying disease process rather than a direct result of the orthostatic intolerance itself.

We provide evidence for a familial form of autonomic dysfunction that is distinct from the well-described, autosomal recessive Riley Day syndrome (MIM #223900). Although this study is limited by small sample size and the availability of HUTT evaluation in only a proportion of studied relatives, we do observe clinically confirmed autonomic dysfunction as a familial trait.

CONCLUSIONS

We find that autonomic dysfunction presenting as symptomatic orthostatic intolerance in adolescents can show familial aggregation and vertical transmission, demonstrating a dominant mode of inheritance with incomplete penetrance. Females are more often affected, and many affected males may remain clinically unrecognized. Familial orthostatic intolerance should be considered in the differential diagnoses for any adolescent or young adult presenting with autonomic dysfunction, and symptomatic relatives should be referred for evaluation, as treatment can often lead to significant improvement in functioning and quality of life. Future studies of the genetic etiology of the autonomic dysfunction in such families will inform our understanding of the mechanism of disease and may suggest development of new, targeted treatment strategies.