The Natural History of Familial Dysautonomia

Study Overview
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Brief Summary
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The study will collect clinical information from patients with FD and allow them to give blood to help develop biological markers of the disease to aid diagnosis and treatment. This is a non-invasive, non-interventional, observation study that poses only minimal risk for participants. The study will document the clinical features of patients with FD overtime by storing their routine clinical test results in a central database. The study will involve collaborators at other specialist clinics around the world who follow/evaluate patients with FD annually. Providing blood for future use is optional.

Detailed Description
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Define the phenotypic characteristics, severity and clinical evolution of FD on a patient-by patient basis. Investigators will enroll patients with FD in a multi-center observational natural history study to evaluate their biochemical, neurological and autonomic phenotype. Investigators will follow patients to systematically study the onset and scaled severity of all clinical problems. Investigators will define progression rates of patients outside of a clinical trial to distinguish between static and progressive features, a challenge in congenital neuropathies. Investigators will continue banking blood to look for ways to monitor the disease phenotypes. Biomarkers that quantify renal, cardiovascular, respiratory, skeletal and cognitive aspects of the disease will be evaluated. This information is relevant when monitoring toxicity to drugs in clinical trials. Detailed clinical follow-up of patients with FD will allow investigators to determine when standard of care therapies (e.g., non-invasive ventilation, gastrostomy feedings) should be initiated and how these impact survival outcomes. Specific Aim 2: Develop ways to measure progressive neurological deficits as outcome measures for future clinical trials. Investigators will test the hypothesis that worsening gait ataxia and progressive visual loss are caused by ongoing neuronal degeneration. Investigators will develop precise outcome measures based on these deficits to test the efficacy of new treatments. Investigators will prospectively evaluate longitudinal changes in the retinal structure (with optical coherence tomography) and visual function in a cohort of patients with FD. Investigators will determine the extent and severity of retinal abnormalities in all patients and how they change overtime. Investigators will establish whether structural abnormalities in the retina are correlated with disease severity and look for functional correlates as measured by visual acuity and color discrimination. Following the recent discovery that gait ataxia in patients with FD is the result of sensory deficits, investigators will perform quantitative assessments of passive joint angle matching at the knee to measure proprioceptive acuity. Investigators will determine how these measures change overtime as well as their impact on daily function and quality of life. An organized, multi-site natural history study of patients with FD will enable investigators to define disease-specific outcomes for testing new therapies, a major breakthrough for these patients. The study also offers a unique opportunity to understand better how the brain develops when devoid of crucial sensory inputs.

Official Title
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Natural History of Familial Dysautonomia

Conditions
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Familial Dysautonomia (Riley-Day Syndrome), Hereditary Sensory and Autonomic Neuropathies, Hereditary Sensory and Autonomic Neuropathy 3

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of any age with a diagnosis of familial dysautonomia (FD) with molecular confirmation of the IKBKAP mutation. Ability to provide informed consent (or assent) and comply with the study protocol Exclusion Criteria: Subjects that do not wish to be a part of the study.

Ages Eligible for Study
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Minimum Age: 4 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Familial Dysautonomia<br>Patients diagnosed with familial dysautonomia, a genetic disorder that affects the development and survival of nerve cells in the autonomic nervous system. It primarily affects neurons that control involuntary actions like regulation of blood pressure and breathing. It also affects the sensory nervous system and the perception of pain, heat and cold. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. To create a database of familial dysautonomia disorder that will serve as a phenotypic core | Investigators will create an enrollment database of patients with familial dysautonomia. All patients will have standardized phenotypic evaluations that will combine clinical, physiological and biochemical strategies to characterize complex autonomic phenotypes, both known and still undiscovered. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To define the natural history of visual function and identify predictive biomarkers of disease progression and severity. | Investigators will map the natural history of visual function including retinal structure and visual acuity and test the hypothesis that worsening visual loss is caused by ongoing neuronal degeneration. | 5 years | 
| To define the natural history of gait ataxia and identify predictive biomarkers of disease progression and severity | Investigators will map the natural history of gait ataxia and test the hypothesis that progressive ataxia is correlated with increasing loss of proprioceptive acuity caused by ongoing death of sensory neurons. | 5 years |