The Phenotype and Natural History of Primary Autonomic Disorders
Primary autonomic disorders are a group of diseases that usually begin in adulthood with the inability to stand because of dizziness, lightheadedness and fainting. Symptoms are the result of a dysfunction in the autonomic nerves that regulate blood pressure and heart rate, and are either related to the accumulation of abnormal protein deposits and a primary neurodegenerative process (like Parkinson's disease, pure autonomic failure, dementia with Lewy bodies and multiple system atrophy), secondary to genetic abnormalities (dopamine-beta-hydroxylase deficiency), an autoimmune process (autoimmune ganglionopathy), or because of a direct injury to the nerves involved in buffering blood pressure fluctuations (acquired baroreflex failure). Furthermore, there are a group disorders that are characterized by disabling orthostatic intolerance such as the postural tachycardia syndrome (POTS) in which the underlying cause is unclear. The purpose of this study is to characterize the clinical features and biological markers of the different types of primary autonomic disorders and better understand how these disorders evolve over time. The study will involve a series of follow-up visits to Centers participating in the Autonomic Disorders Consortium.
Neurogenic Orthostatic Hypotension
|Study Design:||Observational Model: Cohort
Time Perspective: Prospective
|Official Title:||The Phenotype and Natural History of Primary Autonomic Disorders|
- To create a database of primary autonomic disorders that will serve as a phenotyping core. [ Time Frame: 5 years ] [ Designated as safety issue: No ]We will create an enrollment database of patients with primary autonomic disorders. All patients will have standardized phenotyping evaluations that will combine clinical, physiological and biochemical strategies to characterize complex autonomic phenotypes, both known and still undiscovered.
- To define the natural history of neurogenic orthostatic hypotension and identify predictive biomarkers of autonomic disorders [ Time Frame: 5 years ] [ Designated as safety issue: No ]We will map the natural history of primary autonomic failure and test the hypothesis that pure autonomic failure (PAF) is a neurodegenerative synucleinopathy that remains confined to the autonomic nervous system. We will also identify biomarkers that can distinguish patients with PAF from those with early (i.e., "pre-motor") MSA, PD, DLB or autonomic failure as a result of another disorder.
Biospecimen Retention: Samples With DNA
Blood Sample for DNA processing
|Study Start Date:||June 2011|
|Estimated Study Completion Date:||July 2015|
|Estimated Primary Completion Date:||July 2015 (Final data collection date for primary outcome measure)|
Neurogenic othostatic hypotension
Patients that have sever fall in blood presure due to failure in increase sympathetic vasoconstriction activity appropriately when standing.
multiple system atrophy
is a neurodegenerative disorder charaterized by abnormal alpha-synuclein deposition in the cytoplasm of oligodendroglial cells in the CNS, and typically sparing peripheral autonomic nerves.
Pure Autonomic failure
A neurodegenerative disorder characterized by loss of peripheral noradrenergic fibers, with low levels of plasma norepinephine.
A degenerative disorder of the central nervous system that leads to termors, difficulty walking, movement and coordination.
Dementia with Lewy bodies
A neurodegenerative disorder similar to PAF and PD with the accumulation of Alpha-synuclein in the CNS however DLB patients develop dementia.
autoimmune autonomic ganglionopathy
is a rare disorder characterized by the presence of autonomic failure in association with specific antibodies directed against a specific receptor of the autonomic ganglia
Hide Detailed Description
Studying primary autonomic disorders poses special researches challenges, primarily because these disorders are rare and affect a small number of patients. Because the medical literature often consists of individual case reports or small case series, good clinical descriptions of the features and clinical evolution of many rare autonomic diseases are lacking. The Autonomic Disorders Consortium was established with the objective of combining the medical expertise of leading autonomic sites within the United States to develop a clearer understanding of primary autonomic disorders, with the hope of developing new treatments and providing better guidance and recommendations for patient care to the medical community.
The first purpose of this project is to create a database that will serve as a phenotyping core. We will use a comprehensive, integrated approach that will combine standardized clinical, physiological and biochemical studies to characterize the autonomic phenotypes of rare autonomic disorders, including both disorders already known and others still undiscovered. Specifically, we will screen patients with orthostatic intolerance and conduct careful autonomic, medical and neurological evaluations to characterize the features of the rare autonomic disorders. This database will also allow us to identify adequate candidates for the therapeutic trials and natural history study of the Autonomic RDCRC.
The second purpose of this project is to identify patients with neurogenic orthostatic hypotension that will be followed in a longitudinal observational study with yearly visits to map the natural history of the different types of primary autonomic failure and better characterize how these diseases evolve over time. As part of the natural history study, we will determine whether the neurodegenerative process always damages neurons in the brain (resulting in a movement disorder and/or signs of dementia) or can, in certain cases, remain confined to the autonomic neurons outside the brain. We will also develop biological markers that can distinguish between the different disorders that cause chronic autonomic failure.
Study Hypothesis: There are a number of unclassified autonomic disorders yet to be discovered. There is a group of patients with a neurodegenerative disorder who have autonomic failure but do not develop a movement disorder or cognitive problems. These patients may have some genetic "advantage" that protects their brain from progressive neuronal damage.
Comparison(s): Based on the final diagnosis established after 5 years, we will compare disease biomarkers in patients with various different types of autonomic disorders in order to determine their predictive value.
2. Objective and Research Questions
SPECIFIC AIM 1. THE FIRST SPECIFIC AIM IS TO CREATE A PHENOTYPING DATABASE TO DEFINE THE CLINICAL CHARACTERISTICS OF PRIMARY AUTONOMIC DISORDERS. The overall goal of specific aim 1 is to conduct detailed standardized autonomic, clinical and neurological evaluations to create a phenotyping database that will define the clinical characteristics of the different autonomic disorders that are associated with orthostatic intolerance. We also hope to discover novel types of rare autonomic disorders, as we have done in the past with dopamine-beta-hydroxylase deficiency, norepinephrine transporter deficiency and autoimmune autonomic ganglionopathy. To avoid duplication of efforts, the phenotyping database will also function as an enrollment database that will identify patients who are eligible for inclusion in the natural history study of neurogenic orthostatic hypotension and therapeutic clinical trials that will be conducted in collaboration with other members of our Autonomic RDCRC.
SPECIFIC AIM 2. THE SECOND SPECIFIC AIM IS TO DETERMINE THE NATURAL HISTORY OF NEUROGENIC ORTHOSTATIC HYPOTENSION AND IDENTIFY PREDICTIVE BIOMARKERS OF AUTONOMIC DISORDERS. The second specific aim will focus exclusively on patients with neurogenic orthostatic hypotension using a longitudinal observational study that will define the natural history of chronic autonomic failure. To determine whether autonomic function progressively worsens over time in patients with isolated autonomic failure, we will measure blood pressure and heart rate responses to a battery of standardized autonomic function tests at yearly office visits. To determine which patients with primary autonomic failure develop end-organ target damage we will monitor organ function with a series of routine clinical tests, including creatinine clearance. We will also define the prevalence of sleep disorders such as REM behavior disorder, restless leg syndrome and sleep apnea (obstructive or central) using questionnaires and sleep studies in selected patients. In addition, the natural history study will test the hypothesis that there is a group of patients with primary autonomic failure in whom the accumulation of alpha synuclein and the neurodegenerative process remains confined to the peripheral autonomic nervous system and does not develop into a motor or cognitive disorder. By banking DNA and looking at the genes that may promote neuronal sprouting or impede alpha synuclein aggregation, we will ascertain whether patients with the pure autonomic failure (PAF) phenotype have some genetic "neuro-protective" advantage that prevents the disorder from spreading to the striatal or other cortical structures. Within the natural history project we will also develop predictive biomarkers that can distinguish between the different types of autonomic failure. After baseline phenotyping, selected patients with neurogenic orthostatic hypotension will undergo a series of biomarker measurements. At the end of the 5-year follow-up a final diagnosis will be established and based on this diagnosis, we will determine which biomarkers have the best predictive value and are the most useful in the differential diagnosis of patients with PAF from those with early (i.e., "pre-motor") MSA, PD or autonomic failure as a result of another disorder.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01799915
|United States, New York|
|NYU Medical Center||Recruiting|
|New York, New York, United States, 10016|
|Contact: Jose Martinez, MA 212-263-7225 firstname.lastname@example.org|
|Principal Investigator: Horacio Kaufmann, MD|
|Principal Investigator:||Horacio C Kaufmann, MD||NYU MEDICAL CENTER|