Autonomic Disorders Information for Patients and Families

  • Autoimmune Autonomic Ganglionopathy
  • Baroreflex Failure
  • Congenital Autonomic Disorders
  • Congenital Norepinephrine Deficiency due to CYB561 Mutations
  • Dopamine Beta-Hydroxylase Deficiency (DBH)
  • Familial Autonomic Ganglionopathy
  • Familial Dysautonomia (FD)
  • Hypovolemic Postural Tachycardia Syndrome (POTS)
  • Lewy Body Diseases
  • Multiple System Atrophy (MSA)
  • Neurally Mediated Syncope (NMS)
  • Norepinephrine Transporter (NET) Deficiency
  • Parkinson’s Disease with Autonomic Failure
  • Pure Autonomic Failure (PAF)
  • Takotsubo syndrome

What is autoimmune autonomic ganglionopathy?

Autoimmune autonomic ganglionopathy (AAG) 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.

Symptoms include:

  • Severe orthostatic hypotension (low blood pressure upon standing) that persists for weeks to years
  • Fainting
  • Constipation
  • Urinary retention
  • Fixed and dilated pupils
  • Dry mouth and eyes
  • Absence of sweating or anhidrosis
  • Sexual dysfunction
  • Abdominal pain and vomiting

Who gets autoimmune autonomic ganglionopathy ?

AAG can affect people of both sexes and all ages, although it typically presents in the fifth to seventh decade.

What causes autoimmune autonomic ganglionopathy?

The cause of AAG is unknown. Symptom onset can be acute or insidious and may follow a virus, surgery or an immunization.

How is autoimmune autonomic ganglionopathy diagnosed?

AAG can be diagnosed by high blood levels of antibodies to a protein called a ganglionic nicotinic acetylcholine receptor (AChR). Autonomic testing shows a decreased sweating response, absent or diminished increase in blood pressure because of decreased sympathetic vasoconstriction during the Valsalva Maneuver, and a significant fall in blood pressure during head up tilt table testing without a compensatory increase in heart rate.

Are there treatments for autoimmune autonomic ganglionopathy?

  • For mild cases, symptom management is the treatment.
  • Many patients remain unable to function normally and disorder modifying therapy (plasma exchange, immunotherapy) may help.
  • There is no established treatment.

Please see https://rarediseases.info.nih.gov/diseases/11917/autoimmune-autonomic-ganglionopathy for additional information.

What is baroreflex failure?

Baroreflex failure is a rare disorder characterized by changes in blood pressure with episodes of severe hypertension (high blood pressure). There can be increased heart rate during stress and hypotension (low blood pressure) with normal or reduced heart rate during rest. Patients may also experience orthostatic hypotension. The labile blood pressures are the result of a disruption of the afferent signals of the baroreflex, a feedback loop that modulates blood pressure.

Symptoms may include:

  • Headache
  • Excessive sweating
  • Extremely high or volatile blood pressure and heart rate with spikes in blood pressure in response to stress, with periods of normal or even low blood pressure during rest. Hypertensive crises are frequently accompanied by facial flushing.
  • Heart rate that does not respond to medications intended to improve it. Note that baroreflex failure may resemble another rare disorder called pheochromocytoma, a catecholamine-secreting tumor.

What causes baroreflex failure?

Afferent baroreflex failure is most often associated with damage to the carotid sinus nerve during neck surgery or radiation. Possible causes may include:

  • Surgery and radiation for cancer of the throat.
  • Injury to glossopharyngeal and vagus nerves (nerves involved in sensing blood pressure)
  • Cell loss on both sides in the nuclei of the solitary tract (NTS, a column of cells located in the medulla) in the setting of a degenerative neurologic disease of the brain
  • For many patients, the cause of baroreflex failure is not known.

How is baroreflex failure diagnosed?

Baroreflex failure resembles other more common disorders, so its diagnosis is challenging. In addition to asking detailed questions about the patient’s health and family history, the physician will conduct a physical examination, which will include checking blood pressure and heart rate in specific circumstances, such as during daily activity and with medication challenges.

Are there treatments for baroreflex failure?

Treatment for baroreflex failure involves medications to control blood pressure and heart rate and to reduce stress.

See https://rarediseases.info.nih.gov/diseases/10664/baroreflex-failure for additional information.

Congenital Autonomic Disorders

Extremely rare autonomic disorders are characterized by a lifetime of orthostatic problems. These can take the form of orthostatic hypotension, in which blood pressure drops by at least 20 mmHg systolic or 10 mmHg diastolic with standing, without a compensatory increase in heart rate, or orthostatic tachycardia, in which heart rate increases by at least 30 beats/min with standing, in the absence of orthostatic hypotension. The cardiovascular changes are accompanied by lightheadedness and other orthostatic symptoms that are relieved by lying down. Biochemical and physiological findings during the physical examination and a suggestive family history may lead to the suspicion that the patient has a congenital disorder and provide clues about the causative gene(s). The specific mutations are then identified with genetic analyses. Five rare congenital autonomic disorders that the autonomic consortium studies are:

  • Familial Dysautonomia
  • Familial Autonomic Ganglionopathy
  • Dopamine beta-Hydroxylase Deficiency
  • Norepinephrine Transporter Deficiency
  • Norepinephrine Deficiency due to CYB561 mutations

What is Congenital Norepinephrine Deficiency due to CYB561 Mutations?

Cytochrome b561 (CYB561) is a protein that generates ascorbic acid, a cofactor required for dopamine beta-hydroxylase (DBH) to convert dopamine to norepinephrine. As a result of mutations in the CYB561 gene, these patients have a congenital absence of CYB561. With impaired production of ascorbic acid, DBH function is impaired and norepinephrine levels are deficient. Epinephrine and downstream metabolite levels are also low in urine and plasma. Only six patients with this condition have been described in the United States (3), the Netherlands (2) and India (1). These patients experience lifelong severe orthostatic hypotension and selective sympathetic noradrenergic failure.

Symptoms of Congenital Norepinephrine Deficiency due to CYB561 Mutations include:

  • Severe orthostatic hypotension without compensatory tachycardia
  • Dizziness
  • Occasional fainting
  • Impaired renal function
  • Episodes of hypoglycemia in childhood
  • Mild anemia
  • Normal dopamine and metabolites in urine and plasma

What causes Congenital Norepinephrine Deficiency due to CYB561 Mutations?

Genetic analysis revealed that the norepinephrine deficiency is caused by having the same variant in both CYB561 genes in two affected sisters in a Dutch family and a different mutation in both CYB561 genes in two affected American sisters. Three of the four patients died before the age of 60 years. An additional patient of Indian origin, a 31-year-old male, was recently found to have a missense mutation and a deletion in the same gene.

Treatment of Congenital Norepinephrine Deficiency due to CYB561 Mutations

Treatment with L-dihdroxyphenylserine (droxidopa), up to 200 mg three times daily, raised urinary norepinephrine, increased blood pressure, and improved orthostatic symptoms. Ascorbic acid cannot be restored by oral or parenteral administration because it is not taken up by the catecholamine vesicles, wherein norepinephrine is synthesized.

What is dopamine beta-hydroxylase (DBH) deficiency?

DBH deficiency is a disorder characterized by virtual absence of norepinephrine, epinephrine, and their metabolites. However, there is greatly increased dopamine in plasma, cerebrospinal fluid, and urine. These biochemical changes are caused by the absence of DBH, the protein that converts dopamine to norepinephrine, due to mutations in the gene that codes for the protein.

Symptoms of DBH deficiency include:

  • As children, DBH deficient patients have had a markedly reduced ability to exercise, perhaps because of hypotension engendered by the physical exertion.
  • Symptoms have generally worsened in late adolescence and by early adulthood, patients complain of profound orthostatic hypotension, especially early in the day and during hot weather or after alcohol ingestion.
  • In addition to drooping of the eyelids, there is a tendency for nasal stuffiness to occur, especially in the supine posture.
  • Presyncopal symptoms in these patients have included dizziness, blurred vision, dyspnea, nuchal discomfort, and occasionally chest pain.

Physical Examination

  • The physical examination usually includes a normal or low normal supine blood pressure and a normal heart rate but a standing blood pressure that is less than 80 mmHg systolic.
  • Heart rate rises on standing but appears to have an attenuated elevation given the very low blood pressure with upright posture.
  • Pupils are somewhat small but respond to light and accommodation. Parasympatholytics dilate the eye appropriately.

Testing for DBH

  • Many specialized tests differentiate these patients from those with familial dysautonomia. Cholinergic sensitivity as assessed by conjunctival methacholine is normal, and intradermal histamine evokes a typical flare reaction in DBH deficiency, whereas this does not occur in familial dysautonomia. Atrial fibrillation occasionally occurs in adults.
  • These patients have no response even to high doses of tyramine, which normally increases blood pressure by releasing neuronal norepinephrine. Dopamine, rather than norepinephrine, levels increase when the patient stands, during sustained handgrip, and after tyramine administration, while they decrease after clonidine administration.
  • Muscle sympathetic nerve traffic, as measured by direct intraneuronal recordings, is present in excess under basal conditions but is otherwise normally modulated by baroreflex mechanisms in these patients. Therefore, primary autonomic neuronal pathways are intact and respond to appropriate stimuli, but dopamine instead of norepinephrine is present in noradrenergic nerve terminals.
  • Sympathetic cholinergic function is intact, as assessed by normal sweating.
  • Parasympathetic function is also preserved, as assessed by intact sinus arrhythmia, normal heart rate increase during Valsalva, and tachycardia after atropine.
  • A diagnosis of DBH deficiency is based on the characteristic plasma catecholamine pattern of absent norepinephrine and epinephrine and elevated dopamine.

Are there treatments for DBH deficiency?

  • Once the specific enzymatic defect was elucidated, investigators determined that an effective long-term treatment result could be achieved with L-dihydroxyphenylserine (droxidopa or L-DOPS, marketed in the USA as Northera™. Droxidopa is converted directly to norepinephrine (NE) by L-aromatic amino acid decarboxylase, thereby bypassing DBH. The administration of droxidopa to these patients results in dramatic increases in blood pressure and in the restoration of plasma and urinary levels of norepinephrine toward normal. Long-term experience with this drug indicates continued effectiveness at 100 to 600 mg droxidopa orally twice or three times daily.
  • Fludrocortisone at relatively high doses has successfully raised blood pressure with some benefit. Indomethacin has also been of modest benefit in raising blood pressure, but one patient had aggressive ideation while receiving this drug.
  • The monoamine oxidase inhibitor tranylcypromine also produced paranoid thinking in one patient.
  • There has been a reasonable response to phenylpropanolamine (25 and 50 mg), perhaps because of the hypersensitive alpha-adrenoreceptors in these patients.
  • Metyrosine significantly reduces urinary and plasma dopamine levels in DBH deficiency.

See https://ghr.nlm.nih.gov/condition/dopamine-beta-hydroxylase-deficiency and https://rarediseases.info.nih.gov/diseases/1903/dopamine-beta-hydroxylase-deficiency for additional information.

What is Familial Autonomic Ganglionopathy?

Familial Autonomic Ganglionopathy is a disorder characterized by lifelong orthostatic hypotension or significant drops in blood pressure when standing and other problems related to impairments of the sympathetic and parasympathetic branches of the autonomic nervous system. In three individuals from two unrelated families, genetic variants in the CHRNA3 gene that encodes the AChR3 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) have been determined to cause neurogenic orthostatic hypotension and autonomic failure. AChRα3 is primarily found in the autonomic ganglia.

Neurotransmission through the autonomic ganglia is critical to the ability of the sympathetic and parasympathetic neural pathways to regulate blood pressure upon standing. Orthostatic stress stimulates the release of acetylcholine at the autonomic ganglia. Acetylcholine acts on nAChR, resulting in activation of the sympathetic and inhibition of the parasympathetic function to maintain blood pressure. Abnormal AChR3 protein, due to genetic mutations, impairs ganglionic transmission, and leads to neurogenic orthostatic hypotension.

Symptoms of Familial Autonomic Ganglionopathy include:

  • Neurogenic orthostatic hypotension
  • Orthostatic symptoms with dizziness, blurred vision, weakness, nausea
  • Fixed small pupils
  • Ptosis
  • Constipation
  • Fatigue
  • Impaired sympathetic vasoconstriction
  • Low plasma levels of norepinephrine and its intraneuronal metabolite with normal plasma dopamine

What causes Familial Autonomic Ganglionopathy?

Two members of family 1 were both compound heterozygotes for two variants in the CHRNA3 gene, meaning that their two CHRNA3 genes had different mutations. The third affected individual, from another family, was homozygous or had two genes with one of the same mutations found in the first family. These variants are predicted to damage the function of the nAChR3 subunit so that neurotransmission at the peripheral autonomic ganglia is impaired.

Treatment of Familial Autonomic Ganglionopathy

The acetylcholinesterase inhibitor, pyridostigmine, increases levels of acetylcholine and improves ganglionic neurotransmission. In a controlled single-dose trial with one patient, pyridostigmine increased standing blood pressure and improved orthostatic tolerance and symptoms. Two of the affected individuals did not require treatment despite significant neurogenic orthostatic hypotension.

What is familial dysautonomia (FD)?

Familial Dysautonomia (FD), also known as hereditary sensory and autonomic neuropathy type III or Riley-Day Syndrome, is a genetic disease primarily causing dysfunction of the autonomic and sensory nervous systems.

Symptoms displayed by a baby with FD include:

  • Hypotonia (Poor muscle tone)
  • Weak or absent suck
  • Respiratory congestion due to misdirected swallowing
  • Blotching of skin
  • Difficulty in maintaining body temperature

Symptoms in an older child with FD include:

  • Delay in developmental milestones such as walking and speech
  • Poor balance and unsteady gait
  • Scoliosis (spinal curvature)
  • Orthostatic hypotension (extreme drop in blood pressure with change in posture)
  • Breath holding in early years to the point of fainting
  • Episodic vomiting
  • Excessive drooling and sweating
  • A smooth tongue and decrease in sense of taste
  • Difficulty in maintaining body temperature
  • Poor weight gain and growth
  • Frequent lung infections
  • Decreased reaction to pain and temperature or no reaction at all
  • Cold, puffy hands and feet
  • Extremes in blood pressure
  • Corneal abrasions and dry eyes
  • Gastric dysmotility (abnormal movement through the stomach)
  • Sleep-disordered breathing
  • Dysautonomic "crisis" (severe reactions to physical and emotional stress)

Who gets familial dysautonomia (FD)?

FD occurs primarily in persons of Ashkenazi (central or eastern European) Jewish descent.

What causes familial dysautonomia (FD)?

Familial Dysautonomia is caused by mutations in the IkB kinase-associated protein gene (IKBKAP). The IKBKAP gene provides instructions for making a protein called IKK complex-associated protein (IKAP). This protein is found in a variety of cells throughout the body, including brain cells, and when functional protein is lacking, sensory and autonomic neurons do not develop normally. Nearly all individuals with familial dysautonomia have two copies of the same IKBKAP mutation in each cell.

More information on the IKBKAP gene can be found at Genetics Home Reference (https://ghr.nlm.nih.gov/).

How is familial dysautonomia (FD) diagnosed?

To diagnose FD, physicians use health and family history in addition to physical examination. A definitive diagnosis can be made with a blood test. Over 99% of affected individuals will have two copies of the most common gene mutation.

Are there treatments for familial dysautonomia (FD)?

Treatment of FD is individualized, since FD symptoms may vary greatly among patients. Treatment often involves managing the most problematic symptoms, such as:

  • Blood pressure
  • Respiration problems
  • Alacrima (dry eyes)
  • Feeding difficulties
  • Speech difficulties
  • Nausea and vomiting (improved with carbidopa)
  • Injury
  • Orthopedic problems

Please see https://rarediseases.info.nih.gov/diseases/7581/familial-dysautonomia for additional information.

What is hypovolemic postural tachycardia syndrome (POTS)?

When a patient’s heart rate speeds up 30 beats per minute or more without much change in blood pressure on standing, the patient may have orthostatic intolerance (OI). Because upright heart rate is usually greatly increased, the more common term used now is hypovolemic postural tachycardia syndrome (POTS). The increase in heart rate may be a sign that the cardiovascular system is working hard to maintain blood pressure and blood flow to the brain.

Symptoms & Signs (for at least 6 months):

  • Lightheadedness, palpitations and tremulousness during standing
  • Other upright posture symptoms may include:
    • Visual changes
    • Discomfort in the head and neck
    • Throbbing of the head
    • Poor concentration
    • Tiredness
    • Weakness
    • Occasionally fainting
    • Nausea
    • Chest discomfort
    • Shortness of breath

The Role of Hypovolemia in POTS

Hypovolemia is an abnormal decrease in blood volume, or more specifically an abnormal decrease in the volume of blood plasma. This sometimes occurs in POTS patients. It may occur due to blood pooling in the abdomen and legs.

Long-Term Outlook for Patients with POTS

The majority of patients with POTS have a relatively mild disorder which improves over weeks or months. Most patients will eventually be free of symptoms. However, in some patients, the symptoms are more severe, the duration of the illness may be longer, and the expected recovery may not occur.

Who gets POTS?

POTS is most frequently seen in young women, often less than 35 years of age. Orthostatic intolerance affects an estimated 500,000 Americans and causes a wide range of disabilities.

What causes POTS?

The cause of POTS is unknown. Sometimes, a recent viral infection happens soon before symptoms occur. Many patients remain undiagnosed because the severity changes and the disorder can be called many different names. Another problem in the diagnosis of OI is its overlap with other conditions such as Chronic Fatigue Syndrome (CFS), Neurally Mediated Syncope (NMS), or physical deconditioning.

Patients may also experience hypovolemia, or a decrease in blood plasma volume due to blood pooling in the abdomen and legs.

How is POTS diagnosed?

Treatments for POTS aim to relieve low blood pressure or regulate circulatory problems. These include:

  • Orthostatic “exercise”
  • Medication therapy, including beta blockers, alpha-2 agonists (such as Clonidine), alpha-1 agonists (such as Midodrine), or Alpha-Methyldopa (Aldomet)
  • Drinking water may help to temporarily raise blood pressure
  • Salt and /or fludrocortisones

No single treatment has been found to be effective for every patient. Some treatments are more successful than others and are often used together for best results.

Lewy body diseases

A group of neurodegenerative diseases, including Parkinson’s disease (PD) with autonomic impairment (PD+), dementia with Lewy bodies (DLB), pure autonomic failure (PAF), and multiple system atrophy (MSA), are characterized by a common underlying pathology of abnormal intracellular deposits and clumping of the protein alpha-synuclein within the nervous system. These diseases are referred to as synucleinopathies. The clinical features of the different synucleinopathies depend on the location of alpha-synuclein deposits and the associated neurodegeneration, and can involve motor, autonomic, and cognitive pathways. PD, DLB and PAF affect peripheral sympathetic neurons and are included in the synucleinopathy subset of Lewy body diseases. However, there is also a degree of central autonomic involvement in these disorders. Our consortium focuses on PAF and PD+.

What is multiple system atrophy (MSA)?

Multiple system atrophy (MSA) is a rare neurodegenerative disease marked by a combination of symptoms affecting movement, blood pressure, and other body functions; hence the label "multiple system" atrophy. It was formerly known as Shy Drager syndrome. According to the American Autonomic Society, MSA is a sporadic, progressive, adult-onset disorder characterized by autonomic dysfunction, parkinsonism and ataxia (a failure of muscular coordination) in any combination.

Symptoms of MSA include:

  • Orthostatic hypotension, or a significant fall in blood pressure when standing, causing dizziness, lightheadedness, fainting, or blurred vision
  • Urinary difficulties or constipation
  • Motor control symptoms, including tremor, rigidity, and loss of muscle coordination, loss of balance
  • Male impotence (inability to achieve or maintain an erection)
  • Speech or swallowing difficulties

Who gets MSA?

MSA affects both men and women primarily in their 50s.

What causes multiple system atrophy (MSA)?

MSA is associated with deterioration and shrinkage (atrophy) of portions of the brain (cerebellum, basal ganglia and brainstem) that regulate internal body functions, digestion and motor control.

There is no known cause for brain changes in MSA.

How is multiple system atrophy (MSA) diagnosed?

Diagnosis of MSA can be challenging because there is no test that can make or confirm the diagnosis in a living patient. Certain signs and symptoms of MSA also occur with other disorders, such as Parkinson's disease, making the diagnosis more difficult.

If your doctor suspects MSA, he or she will obtain a medical history and perform a physical examination. You may receive a referral to a neurologist or other specialist for specific evaluations that can help in making the diagnosis.

Tests that may be helpful in making a diagnosis include:

  • Tilt table test - In this procedure, your blood pressure is monitored while you are on a special table that will tilt you to an almost upright position. This allows the physician to record blood pressure irregularities, and information about whether they occur with a change in physical position.
  • Blood tests
  • A sweat test to evaluate perspiration
  • Tests to assess your bladder and bowel function
  • Electrocardiogram to track the electrical signals of your heart
  • Brain-imaging tests, particularly a magnetic resonance imaging (MRI) scan, to determine if another condition might be triggering symptoms
  • Pharmacological challenge tests (administering certain medications and observing the patient’s body’s reaction to them, in controlled clinical settings)

For patients with sleep irregularities, particularly if they involve interrupted breathing or snoring, physicians may recommend an evaluation in a sleep laboratory to determine if there is an underlying and treatable sleep disorder, such as sleep apnea.

What is the treatment for multiple system atrophy (MSA)?

There is no known cure for MSA, so management of the disease focuses on treating the more disabling symptoms listed above.

Frequently Asked Questions about MSA

How common is MSA?

Between 25,000 and 100,000 Americans are believed to have MSA. The incidence (new cases per 100,000 person years) for ages 50-99 years is 3-5.

What is the progression of MSA?

Disease progression in MSA is quicker than in Parkinsonism. About 80% of patients are disabled within 5 years of onset of the motor symptoms, and only 20% survive past 12 years. The mean survival after diagnosis is roughly 6 years. The rate of progression differs in every case and speed of decline may vary widely in individual patients.

What is the prognosis of MSA / Shy-Drager Syndrome?

The probable outcome is poor. There is a progressive loss of physical functions until general debilitation develops. Early death is likely. Most people who are diagnosed with MSA die within seven to 10 years after symptoms begin.

Pneumonia is the most common cause of death, although irregularities in heartbeat or breathing may be responsible for death in some patients. Breathing problems such as aspiration, stridor (high-pitched breathing sounds due to airway obstruction), or cardiopulmonary arrest can occur.

See https://ghr.nlm.nih.gov/condition/multiple-system-atrophy for additional information.

What is Neurally Mediated Syncope (NMS)?

Syncope (described as “fainting” or “passing out”) is a common problem, accounting for approximately 3% of emergency room visits. Neurally mediated syncope (NMS) is also called neurocardiogenic, vasovagal, vasodepressor or reflex mediated syncope.

Repeated episodes of NMS may be caused by a wide variety of medical problems, and require diagnosis and treatment. It is important to distinguish syncope from “dizziness”, which generally refers to an alteration in balance, vision, or perception of the environment, without the loss of consciousness.

What causes NMS?

NMS occurs when the part of the nervous system that regulates heart rate and blood pressure malfunctions, often in response to a trigger. The heart rate slows, and the blood vessels in the legs widen. This allows blood to pool in the legs, which lowers blood pressure. The drop in blood pressure and slowed heart rate quickly cause diminished blood flow to the brain, causing fainting.

How is NMS diagnosed?

The diagnosis of NMS often focuses on ruling out other potential causes of fainting - particularly heart-related problems. Tests may include:

  • Electrocardiogram
  • Echocardiogram
  • Exercise stress test
  • Blood tests
  • Tilt table tests to measure your blood pressure with changes in posture

What is the treatment for NMS?

In many cases, education about ways to avoid “triggers” may be enough to control NMS.

Treatment may require medications, therapies to increase blood pressure or decrease pooling of blood in the legs or the use of an electrical pace maker to regulate heartbeat. Other therapies include using compression stockings, sleeping with the head of the bed slightly elevated, and mild aerobic conditioning (especially in the water).

What is NET Deficiency?

NET Deficiency is an extremely rare disorder of orthostatic intolerance caused by a loss-of-function mutation in the gene (SLC6A2) coding for the NET protein. NET plays a major role in the removal of norepinephrine from the synapses in the heart. A defect in transporter function caused by this mutation leads to decreased norepinephrine clearance, elevated plasma norepinephrine levels and postural tachycardia. This type of orthostatic intolerance is also known as Postural Tachycardia Syndrome (POTS) and is characterized by at least a 30 beats/min increase in heart rate with standing in the absence of orthostatic hypotension. Orthostatic symptoms occur with standing and are resolved by lying down.

The mutation was initially discovered in a patient and her twin sister. In the initial patient and her twin, the plasma concentrations of dihydroxyphenylglycol (DHPG), an intraneuronal metabolite of norepinephrine, were low in relation to the plasma norepinephrine concentrations. The proband’s mother and three additional siblings were subsequently found to have 1 copy of this mutant allele. Family members with the mutation had higher upright heart rates and plasma norepinephrine levels, compared with family members who did not have the mutation. Screening of over 150 unrelated patients with POTS in the US and Austria for this NET mutation was negative.

Symptoms of NET Deficiency include:

  • High heart rate in the supine position
  • High plasma norepinephrine with relatively low levels of the intraneuronal norepinephrine metabolite, DHPG
  • Orthostatic symptoms resolved by lying down (lightheadedness, fatigue, palpitations, tremulousness, altered mentation, presyncope or syncope)

What causes NET Deficiency?

The combination of low plasma DHPG relative to norepinephrine, decreased plasma norepinephrine clearance and an impaired response to tyramine, a drug that must be taken up into the neuron by NET before it can release norepinephrine, suggested a defect in NET function in the initial patient and her twin sister. Studies of NET gene structure in the patient revealed a coding mutation on a part of the gene where changes are likely to have consequences on function. Analysis of the protein produced by the mutant in cultured cells demonstrated greater than 98% reduction in activity relative to normal.

Treatment of NET Deficiency

As in other patients with a type of POTS associated with high norepinephrine levels, the patients with NET deficiency benefit from non-pharmacological treatment in addition to successful symptomatic pharmacotherapy. Patients are encouraged to drink 8 to 10 cups of water daily and to increase their sodium intake to 8 to 10 grams/day to maintain an adequate plasma volume. Waist-high compression panty hose can increase venous return. Acute blood volume expansion with intravenous normal saline improves orthostatic tachycardia but is not recommended. Exercise is recommended. It is important for patients to avoid medications that block the norepinephrine transporter. Fludrocortisone may increase sodium retention and increase blood volume. Low-dose short-acting propranolol is effective at lowering standing heart rate and improving symptoms. Central sympatholytic agents, like clonidine or methyldopa, can stabilize heart rate and blood pressure.

See https://rarediseases.info.nih.gov/diseases/13591/familial-orthostatic-tachycardia-due-to-norepinephrine-transporter-deficiency for additional information.

What is Parkinson’s disease with autonomic failure (PD+)?

Parkinson’s disease is a movement disorder, typically with resting tremor affecting one side of the body, rigidity or stiffness, bradykinesia or slow voluntary movement, and inability to properly balance. It is associated with intracellular aggregates, or Lewy bodies, containing the protein alpha-synuclein. Parkinson’s disease itself is not a rare disease. However, the Lewy bodies are present in the peripheral autonomic neurons, and perhaps up to 30% of PD cases may be accompanied by autonomic features.

Autonomic symptoms of PD+ include:

  • Orthostatic hypotension (fall in blood pressure with standing). Orthostatic hypotension may be described as unsteadiness, dizziness, or faintness upon standing.
  • Chronic constipation
  • Urinary dysfunction, including nocturia, urgency and frequency
  • Occasionally decreased ability to sweat although some patients note increased sweating

Who gets PD+?

Most patients with PD have no related family history and are diagnosed when around 60 years old. Of patients with PD, those with symptomatic orthostatic hypotension tend to be older, and to have longer-lasting and more severe disease.

What causes PD+?

Parkinson’s disease occurs when the nerve cells in the brain that make dopamine are slowly destroyed. Patients might also experience damage to the nerve endings that produce the neurotransmitter norepinephrine, the main chemical messenger of the sympathetic nervous system. The loss of the dopamine-containing cells leads to the typical motor problems of PD, whereas the damage to the sympathetic neurons impairs blood pressure regulation and causes other autonomic problems.

How is PD+ diagnosed?

The diagnosis of PD+ is generally made after careful evaluation of medical history, current symptoms, and exclusion of other conditions. Autonomic testing will determine the extent of the autonomic failure. Although tremor, rigidity, and bradykinesia are highly suggestive of Parkinson’s disease, it may be difficult to distinguish PD+ from multiple system atrophy (MSA). Imaging studies of the heart reveal a loss of functional cardiac sympathetic neurons in PD+ which contrasts with imaging studies in MSA.

What is the treatment for PD+?

The primary treatments for the motor symptoms of PD+ are a combination of levodopa with carbidopa or dopamine agonists that can act like dopamine in the damaged dopamine-containing areas of the brain. These agents, however, act on the symptoms and do not affect disease progression. They may actually produce abnormal movements called dyskinesias and may cause and exacerbate orthostatic hypotension. Other treatments focus on improving blood pressure and other autonomic symptoms.

See https://rarediseases.info.nih.gov/diseases/10251/parkinson-disease for additional information

What is Pure Autonomic Failure (PAF)?

Pure autonomic failure (PAF) is initially characterized by peripheral neurodegeneration in the autonomic nervous system with severe neurogenic orthostatic hypotension. Many patients eventually develop motor/cognitive deficits and phenoconvert to Parkinson’s disease, Lewy Body Dementia or Multiple System Atrophy. Others remain as PAF for decades.

Symptoms include:

  • In men, a common feature is impotence (inability to have or maintain an erection).
  • Orthostatic hypotension (fall in blood pressure with standing). Orthostatic hypotension may be described as unsteadiness, dizziness, or faintness upon standing. It is worse in the morning, after meals or exercise, or in hot weather. The orthostatic hypotension may also be accompanied by supine hypertension (increased blood pressure while lying down).
  • Pain in the neck or back of the head, which is relieved by lying down..
  • Loss of ability to sweat as much as the body did in the past.
  • Changes in urination including nocturia (the need to urinate during the night), urinary hesitancy (difficulty starting or maintaining a urinary stream), urgency, dribbling, and occasional incontinence.
  • Chronic constipation

Who gets PAF?

PAF is most frequently seen in men, in middle to late life.

What causes PAF?

The cause of PAF is not completely known. It is associated with peripheral deposits of alpha-synuclein protein and is a Lewy body disease.

How is PAF diagnosed?

In addition to asking detailed questions about the patient’s health, the physician will conduct a physical examination, which will include checking blood pressure and heart rate while the patient is lying, sitting and after three minutes of being upright.

What is the treatment for PAF?

Treatments for PAF focus on managing symptoms:

  • Medication options focus on raising blood pressure (vasopressor agents) and include droxidopa, midodrine and fludrocortisone. Short-acting anti-hypertensives may be used for supine hypertension.
  • Non-drug treatment options include squatting, abdominal compression, bending forward and using compression stockings.
  • To maintain upright posture, some patients find that crossing their legs helps.
  • Drinking water may help to temporarily raise blood pressure.

See https://rarediseases.info.nih.gov/diseases/10428/pure-autonomic-failure for additional information

What is takotsubo?

An abnormal stunning of the heart muscle in response to an intense period of autonomic activity. It is usually associated with or after a large physical or emotional stress. Symptoms mimic a heart attack.

Who gets takotsubo?

Nearly all cases are post-menopausal women and most recover.

What causes takotsubo?

The causes are unclear. The autonomic nervous system becomes over stimulated, causing the heart muscle to balloon into an abnormal shape. Patients can sometimes link the episodes to times of intense autonomic arousal (bad news, shock, illness, fear, exercise).

How is takotsubo diagnosed?

By ruling out a blockage of the heart circulation and finding the heart muscle is beating in an abnormal way on echocardiogram scan.

What is the treatment for takotsubo?

Patients with takotsubo are best treated during a medical admission during the acute episode. Treatments are empirical and supportive.

Frequently Asked Questions about takotsubo

What causes it? Will it reoccur? How will this affect me long-term?