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Familial Dysautonomia

Riley-Day Syndrome

Familial dysautonomia is a genetic disorder that affects development and survival of sensory and autonomic neurons.


Presentation

FD manifests in early childhood, but the severity of symptoms varies greatly [1] [2]. Parents report that their infants have dysphagia, excess drooling, blunted swallowing reflexes, and frequent vomiting . Recurrent infections of the respiratory tract result from repeated aspiration. While the patient's body temperature may vary considerably due to their reduced capability to react to temperature changes, many patients show prolonged periods of hypothermia. On the other hand, they may sweat profusely. These children cry without producing tears. Reduced quantities of lacrimal fluids and an overall insensitivity to pain leave them prone to corneal lesions and ulcers. Other injuries, mainly skin lesions, are also common, particularly burns. It has been repeatedly observed that pediatric FD patients hold their breath until they become cyanotic or faint. This behavior does not usually persist into puberty.

Although the majority of FD patients show a pleasant personality and normal intelligence, delayed learning and sometimes even neuropsychiatric symptoms such as concentration problems may be observed in these children. They may be highly irritable and react to physical or emotional stress with dysautonomic crises. The latter is characterized by hypertension, tachycardia, sweating and vomiting.

The overall muscle tone of FD patients is decreased. While hypotension is considered characteristic, bouts of hypertension may also be observed as has been stated above. FD may also be related to skeletal defects. Impaired bone development leaves these patients susceptible to fractures - that may not even be recognized because of lack of sensitivity to pain, spine curvature, and overall reduced height. Most adult patients have scoliosis. Ataxia is commonly observed and may be partly due to absent or blunted reflexes, reduced muscle tone and cerebellar atrophy. Ataxia often aggravates over time. Also, neurologic deterioration progresses and manifests, for instance, as loss of vision due to optic nerve atrophy. Cardiac, pulmonary and renal function may be increasingly impaired.

Feeding Difficulties
  • This results in feeding difficulties, excessive sweating, absence of tears, indifference to pain, reduced corneal sensitivity, emotional lability and red blotching of the skin. Riley, Conrad Milton, U.S. pediatrician, 1913–.[medical-dictionary.thefreedictionary.com]
  • Thus, the earliest sign of autonomic dysfunction usually is feeding difficulties due to gastrointestinal dysmotility (oropharyngeal incoordination, abnormal esophageal peristalsis, erratic gastric emptying, gastroesophageal reflux and episodes of protracted[orpha.net]
  • Symptoms of FD include: hypotonia (poor muscle tone) feeding difficulties poor growth lack of tears attacks of nausea with vomiting frequent lung infections difficulty maintaining body temperature erratic swings in blood pressure.[contact.org.uk]
Hypothermia
  • While the patient's body temperature may vary considerably due to their reduced capability to react to temperature changes, many patients show prolonged periods of hypothermia. On the other hand, they may sweat profusely.[symptoma.com]
  • Newborns have absent or weak suck reflex, hypotonia and hypothermia. Retarded physical development, poor temperature and motor in coordination are seen in early childhood.[web.archive.org]
  • Signs & Symptoms An infant born with familial dysautonomia typically has poor sucking ability, impaired swallowing reflexes, poor muscle tone (hypotonia), and/or abnormally low body temperature (hypothermia).[rarediseases.org]
Intermittent Fever
  • Ira Shah M.D, DNB, DCH(Gold Medalist), FCPS Case Report : A 5 year old female child, 3rd of 3 siblings born of third degree consanguineous marriage presented with intermittent fever since birth, self mutilation since 2½ years of age and ulcer over left[web.archive.org]
  • The remainder of the hospital course was notable for intermittent fevers beginning on day 4 posttransplantation; vancomycin, piperacillin/tazobactam, and fluconazole were started empirically.[cjasn.asnjournals.org]
  • fevers, impaired sensory perception, hypotonia, and apnea.[ncbi.nlm.nih.gov]
Recurrent Infection
  • Recurrent infections of the respiratory tract result from repeated aspiration.[symptoma.com]
  • These include failure to thrive, fevers (sometimes with no obvious cause), recurrent infections (especially due to aspirations), and insomnia.[dermatologyadvisor.com]
Pediatric Disorder
  • In addition, expertise has been developed in assessment of other sensory and autonomic disorders so that the Center is now a referral center for other hereditary sensory and autonomic neuropathies (HSAN) and for other pediatric disorders with autonomic[web.archive.org]
  • disorders with induced pluripotent stem cells Matthew D.[nature.com]
Failure to Thrive
  • The typical clinical features consist of somatic abnormalities: failure to thrive, characteristic facies, excessive sweating, labile blood pressure, recurrent aspiration pneumonias, lack of tears, and diminished and later absent deep tendon reflexes with[ncbi.nlm.nih.gov]
  • Mapped to human chromosome 9q31-q33. familial dysautonomia familial dysautonomia An autosomal recessive disorder (OMIM:223900) characterised by failure to thrive and progressive degeneration of sensory, sympathetic and parasympathetic neurons.[medical-dictionary.thefreedictionary.com]
  • Some of the symptoms associated with familial dysautonomia include: A failure to grow despite normal growth hormone Difficulty in feeding, choking, and defective swallowing coupled with a failure to thrive Severe episodes of vomiting Anorexia The absence[hormonesmatter.com]
  • These include failure to thrive, fevers (sometimes with no obvious cause), recurrent infections (especially due to aspirations), and insomnia.[dermatologyadvisor.com]
Hypertension
  • Abstract Familial dysautonomia (FD) is an inherited, fatal, neurodegenerative disorder manifested by autonomic/hypertensive crises and cardiac instability.[ncbi.nlm.nih.gov]
  • This was felt to represent chronic hypertensive nephrosclerosis with periods of accelerated hypertension.[cjasn.asnjournals.org]
Orthostatic Hypotension
  • hypotension as well as labile blood pressure that increases markedly during emotional excitement.[ncbi.nlm.nih.gov]
  • Results: HUT showed orthostatic hypotension without compensatory tachycardia in FD patients but not in controls. LF-NS increased LF power of RRI and BP and HF-NS increased HF power of RRI in controls, but not in FD patients.[neurology.org]
  • Fludrocortisone 0.1 mg daily has been continued for orthostatic hypotension.[cjasn.asnjournals.org]
Hypersalivation
  • Symptoms include speech and movement problems, anterior sialorrhea (drooling) due to hypersalivation as a consequence of poor oropharyngeal coordination; dysphagia and aspiration pneumonia secondary to recurrent posterior sialorrhea.[ncbi.nlm.nih.gov]
  • […] system and aberrations in autonomic nervous system function such as indifference to pain, diminished lacrimation, poor vasomotor homeostasis, motor incoordination, labile cardiovascular reactions, hyporeflexia, frequent attacks of bronchial pneumonia, hypersalivation[medical-dictionary.thefreedictionary.com]
  • […] is compromised intravascular volume due to both dysphagia impeding optimal fluid intake and acute episodes of dehydration during dysautonomic vomiting crises, which are often accompanied by increased insensible losses from excessive diaphoresis and hypersalivation[cjasn.asnjournals.org]
Increased Sweating
  • The features of familial dysautonomia include lack of tears, emotional lability, relative indifference to pain, increased sweating, cold hands and feet, red blotching of the skin, corneal anesthesia and corneal ulcers, paroxysmal hypertension, taste deficiency[medicinenet.com]
  • The increased sweating rate at baseline seen in our QSART results might also be explained by such a mechanism.[jnnp.bmj.com]
  • In addition, they may experience increased sweating and an accelerated heart rate. A decreased awareness of pain makes it difficult for children with this disorder to be aware of injuries; bone fractures may go unrecognized.[rarediseases.org]
Hyperhidrosis
  • However, such a reorganisation of sweat gland innervation could not explain the excessive hyperhidrosis occurring during autonomic crises.[jnnp.bmj.com]
  • Episodic hypertension alternating with hypotension, hyperhidrosis, cyclic vomiting, and skin blotching are common. Deep tendon reflexes are often diminished or absent and there is a general indifference to pain and temperature.[disorders.eyes.arizona.edu]
  • This might also explain excessive episodic hyperhidrosis in situations with increased central sympathetic outflow.[dermatologyadvisor.com]
  • You have headaches, dizziness (vertigo), fatigue, excessive thirst (polydipsia), intestinal issues (reflux, nausea, constipation, diarrhea), slow or rapid heartbeat (tachycardia), excessive sweating (hyperhidrosis), perspiration depletion (anhidrosis)[clinicalposters.com]
Flushing
  • Signs and symptoms include nausea, which is usually accompanied by vomiting, and signs of sympathetic storm such as hypertension, hypersecretion of respiratory mucus, diaphoresis, drooling, tachycardia, flushed skin, irritability, and personality changes[journals.lww.com]
  • Patients with FD suffer recurrent uncontrollable nausea and vomiting crises accompanied by skin flushing, tachycardia and arterial hypertension. Current treatments of nausea are ineffective or have intolerable side sides.[clinicaltrials.gov]
  • Usually, when an AD attack occurs, there is an irritant impacting the person below the level of their spinal cord injury, and because their autonomic nervous system cannot process messages properly, this results in a severe spike in blood pressure, flushing[dysautonomiainternational.org]
Dry Eyes
  • eyes and lack of tears when crying Poor coordination and unsteady walk Seizures Unusually smooth, pale tongue surface and lack of taste buds and decrease in sense of taste After 3 years old, most children develop autonomic crises.[nlm.nih.gov]
  • Severe eye problems are common because of the resulting dry eye and the absence of corneal response to foreign objects in the eye.[childlifesociety.org]
Absent Lacrimation
  • Pathology Familial dysautonomia was originally reported as "central autonomic dysfunction with absent lacrimation" [ 4 ], yet consistent neuropathological findings all have been restricted to the periphery [ 43 ] and the information derived suggests that[doi.org]
Neuropathic Arthropathy
  • Neuropathic arthropathy (Charcot joints) occurs. Except for decreased or absent tendon reflexes, general neurologic examination is normal. HSAN2, which includes HSAN2A, HSAN2B, and HSAN2C, is inherited in an autosomal recessive manner.[ncbi.nlm.nih.gov]
Muscle Hypotonia
  • The appearance of the tongue together with severe muscle hypotonia, absent or very sluggish tendon reflexes and swallowing difficulties in an infant born to one or both parents of AJ extraction, is highly suggestive of FD.[rarediseasesjournal.com]
Emotional Lability
  • During the ensuing months, familial dysautonomia was suggested by recurrent pulmonary infections, dysphagia, alacrima, hyperhydrosis, emotional lability, and unexplained episodes of hyperthermia and breath-holding spells.[ncbi.nlm.nih.gov]
  • The features of familial dysautonomia include lack of tears, emotional lability, relative indifference to pain, increased sweating, cold hands and feet, red blotching of the skin, corneal anesthesia and corneal ulcers, paroxysmal hypertension, taste deficiency[medicinenet.com]
  • This results in feeding difficulties, excessive sweating, absence of tears, indifference to pain, reduced corneal sensitivity, emotional lability and red blotching of the skin. Riley, Conrad Milton, U.S. pediatrician, 1913–.[medical-dictionary.thefreedictionary.com]
Dysautonomia
  • OBJECTIVE: We have investigated the dysautonomia crisis by evaluating the expression of the familial dysautonomia gene - IKBKAP, in patients during different crisis stages.[ncbi.nlm.nih.gov]
  • The decreased amount of functional IKAP protein in cells causes familial dysautonomia.[en.wikipedia.org]
  • The major haplotype accounts for more than 99.5% of the familial dysautonomia chromosomes, corresponding to a founder defect.[emedicine.com]
Hyporeflexia
  • […] congenital syndrome with specific disturbances of the nervous system and aberrations in autonomic nervous system function such as indifference to pain, diminished lacrimation, poor vasomotor homeostasis, motor incoordination, labile cardiovascular reactions, hyporeflexia[medical-dictionary.thefreedictionary.com]
  • Dysfunction in the remainder of the central nervous system is indicated by such symptoms and signs as relative indifference to pain, hyporeflexia, poor motor coordination, and retarded motor development.[pubs.rsna.org]
  • Esterly, et al46 reported on a patient with Pupillotonie, hyporeflexia and segmental hypohodrosis.[healio.com]
Hyperactivity
  • Irritability, hyperactivity, and susceptibility to rages are seen in about 50% of patients. Chlorpromazine has been helpful as well as behavior modification.[doi.org]
Decreased Pain and Temperature Perception
  • Overview Familial dysautonomia is an HSAN disorder characterized by both sensory and autonomic dysfunction, resulting in decreased pain and temperature perception as well aspervasive manifestations of autonomic dysregulation.[medlink.com]
  • Sensory: decreased pain and temperature perception, decreased pain in bones and reduced or absent taste buds at the edge of the tongue.[jnetics.org]
  • Among the criteria used to establish the diagnosis of familial dysautonomia were Jewish Ashkenazi extraction, delayed development, failure to thrive, episodic fevers, decreased pain and temperature perception, absent deep tendon reflexes, absence of overflow[jnnp.bmj.com]
Neonatal Hypotonia
  • HSAN VI (OMIM 614653 ) is a lethal autonomic sensory neuropathy characterized by severe neonatal hypotonia, contractures, respiratory and feeding difficulties, and lack of psychomotor development.[ncbi.nlm.nih.gov]

Workup

The above-described symptoms justify diagnosis of FD if the following criteria are fulfilled:

  • Ashkenazi Jewish origin.
  • Closer inspection of the mouth reveals a smooth, glossy tongue that results from the absence of fungiform papillae.
  • A Schirmer tear test confirms the lack of lacrimal fluid.
  • Reflex tests show reduced or absent reflexes. Patellar reflexes cannot be provoked in about 95% of FD patients.
  • Blunted reflexes may be further confirmed by intradermal histamine injection and evaluation of the axon flare response. Healthy individuals rapidly develop a wheal at the site of injection, FD patients do not.

Genetic testing for IKBKAP gene mutations may further confirm the diagnosis. This can be done with a blood sample.

Upon diagnosis of FD, patients should undergo further tests to assess the extent of neuronal damage. Magnetic resonance imaging of the brain is used to evaluate cerebral atrophy and an intelligence test may reveal mental retardation. A swallow study, spirometry, and measurement of arterial blood gases are obtained to evaluate for sequelae and the risk of aspiration pneumonia.

Treatment

Treatment is symptomatic and preventive.

Parents should be educated to prevent aspiration of food, gastroesophageal reflux, and autonomic crises. To this end, special thickened formula is administered in an upright position. If these conservative measures are not sufficient to guarantee adequate nutrition of the infant, prokinetic and antacid drugs may be administered. Intravenous hydration and/or percutaneous endoscopic gastrostomy may become necessary in severe cases. Autonomic crises and profuse vomiting are treated with rectal application of diazepam. Carbidopa may also be effective.

Artificial tear solutions help to protect the cornea of the eye.

Blood pressure can be maintained in its physiological range with transdermal clonidine patches. Such treatment is of superior efficacy compared to oral drugs used to stabilize the cardiovascular system. It is important to note that clonidine treatment should not be stopped abruptly. Instead, it should be tapered. Low-dose fludrocortisone, potentially supplemented with midodrine, has recently been proposed as a therapeutic option for hypotensive FD patients [11]. Additionally, patients benefit from sleeping in an elevated position. In this way, morning orthostatic hypotension can be reduced significantly. Compression stockings and exercises to increase muscle tone may help to keep blood pressure up during the day. Of note, antihypertensive agents are usually not administered, not even in autonomic crises. The latter should be avoided or treated with benzodiazepines, as stated above. The maintenance of adequate blood pressure significantly contributes to preventing kidney failure.

In general, FD patients are very sensitive to drugs modulating the autonomic nerve system. Thus, in order to treat anomalies like bradycardia, which has been related to sudden death, alternative options need to be found. The use of a pacemaker was recommended to treat bradycardia [12]. Botulinum neurotoxin may help to treat sialorrhea.

Prognosis

Prognosis for FD patients has significantly improved over the past decades. Today, most patients reach adulthood and in fact, about 40% of them are now older than 20 years. Some FD patients will even celebrate their 50th birthday.

Many FD patients are able to live independently. Affected men and women are able to procreate, although blood pressure needs to be monitored during pregnancy and particularly at the time of delivery [10].

Etiology

FD is a genetic disorder inherited as an autosomal recessive trait. Distinct mutations affecting the IKBKAP gene, which is located on chromosome 9, have been identified as possible triggers of FD [4] [6]. The IKBKAP gene encodes the IKK complex-associated protein IKAP that fulfills important roles regarding regulation of transcription, presumably of proteins required for the cytoskeleton and cellular motility. In individuals with a homozygote genotype, penetrance is complete, but expression varies.

The most common mutation can be found in >99% of all FD patients. It affects pre-mRNA splicing and results in mRNA lacking exon 20. Most likely, it corresponds to a founder defect that subsequently spread throughout the Ashkenazi Jew population.

Heterozygous carriers do not develop phenotypic alterations unless additional mutations are present. This has been the case in four individuals heterozygous for the above described, most common mutation of the IKBKAP gene. These patients also presented a second mutation that impaired IKAP phosphorylation.

A third gene defect triggering FD has been described in one single patient [5]. This patient inherited a missense mutation in exon 26 of the IKBKAP gene from a non-Ashkenazi Jew parent and was heterozygous for the common mutation.

Epidemiology

Since the first description of FD was published in 1949 [3], several hundred patients have been reported. With the exception of one single case [5], all FD patients and carriers are Ashkenazi Jews. This facilitates epidemiological investigations and institution of preventive measures. Prenatal carrier tests have been utilized to screen this population, offer genetic counseling and decrease the incidence of FD.

It has been estimated that one out of 30 Ashkenazi Jews carries a mutated IKBKAP gene. Men are affected as often as women. Because of the recessive behavior of the muted allele, only one of four children whose parents are both carriers of the mutation will eventually develop FD. This results in a theoretical incidence of 1 in 3,600 births in this population. Due to the above mentioned preventive measures, the actual incidence is lower.

Thanks to a better understanding of the genetic and molecular background of the disease, therapeutic options have improved and life expectancy for FD patients has markedly increased. The vast majority of FD patients live into adulthood now compared to 50 years ago when more than 50% of FD patients died before reaching the age of 5. This same percentage of patients will reach the age of 40 years today [7] [8]. Decades ago, the most common cause of death among FD patients was aspiration pneumonia. This is no longer the case and today, renal failure or sudden, unexplained death are more frequently observed. It has been speculated that the latter results from excess vagal stimulation and lack of sympathetic compensation.

Sex distribution
Age distribution

Pathophysiology

Defective IKAP has been shown to trigger a developmental disorder that is associated with a reduced population of non-myelinated neurons and certain myelinated axons [1] [9]. Neurons pertaining to the sensory and autonomic nervous system are affected, wherein sympathetic fibers suffer more severe damage than parasympathetic ones. With regards to the sympathetic nervous system, neuronal cell counts are reduced to as little as 10% of physiological values. In FD patients, sympathetic ganglia are significantly smaller than in healthy individuals. Presumably, assembly of the cytoskeleton and cellular motility are impaired in FD, but there are still considerable knowledge gaps regarding the causes for the above-mentioned observations.

Prevention

Genetic testing is available to individuals of Ashkenazi Jewish community. If a couple is planning to conceive, prenatal diagnostics for determination of the genotype of the fetus can be carried out after as little as ten weeks.

Summary

Familial dysautonomia (FD) is a hereditary disease affecting the sensory and autonomic nervous system [1] [2]. In honor of those scientists that first described the disease, it is also called Riley-Day syndrome [3]. It pertains to the greater group of sensory and autonomic neuropathies and is listed here as sensory and autonomic neuropathy type III. FD is inherited as an autosomal recessive trait and all cases reported belong to the Ashkenazi Jewish community [4] [5] [6].

FD patients present developmental disorders that manifest in early childhood in the form of feeding problems, frequent vomiting, recurrent infections of the respiratory tract due to aspiration and an overall reduced muscle tone. The latter leads to severe hypotension and may later trigger syncopes due to orthostatic hypotension. The patient's ability to sense and react to temperature changes and pain is significantly diminished, which results in difficulty to maintain body temperature and to avoid injuries. Another prominent symptom is their reduced ability to produce tears. Individuals suffering from FD have an increased risk of fractures because osseous development is also impaired. In this context, lateral deviation of the spine is often observed. These symptoms contribute to growth retardation and delayed motor milestones especially delay in learning to walk and talk. About one out of three pediatric FD patients present with neuropsychiatric problems such as difficulty in concentration and learning. Adult FD patients frequently require walking aids to compensate for poor stature and balance.

Deterioration of sensory and autonomic neurons continues in adulthood [1] [2]. Atrophy of the optic nerves contributes to visual impairment. Also, cardiac, pulmonary and renal function may be increasingly restricted in later years.

Patient Information

Familial dysautonomia (FD) is a genetic disorder associated with problems in sensory and autonomic nerve cell development and survival.

Causes

FD is a genetic disorder that may be inherited and transmitted from parents to their children. The gene affected is called IKBKAP and the respective mutation is only present in the Ashkenazi Jewish population. For a child to develop FD, both parents need to have a defective gene, i.e., both parents need to be either carriers or FD patients themselves. Individuals pertaining to the Ashkenazi Jewish ethnicity may be genetically tested to evaluate the risk of their child inheriting or suffering from FD.

Symptoms

Feeding difficulties, excess drooling, a blunted swallowing reflex and frequent vomiting are often the first symptoms of FD. Aspiration of food particles may cause recurrent infections of the respiratory tract. Patients suffering from FD have reduced abilities to react to temperature changes and painful stimuli. Their body temperature may be unstable, hand and feet are often cold. Skin lesions are commonly observed because they do not avoid otherwise painful situations. One of the most striking symptoms, although not detectable until the child is seven months old, is crying without tears.

Diagnosis

FD may be diagnosed when the following criteria are fulfilled:

  • Patient is of Ashkenazi Jewish ethnicity.
  • Smooth, glossy tongue.
  • Tear test confirms reduced production of lacrimal fluid.
  • Blunted reflexes, e.g., knee jerks cannot be provoked.
  • Intradermal histamine injection does not provoke the development of a wheal.

A final confirmation may be attained after genetic testing of a blood sample.

Treatment

Treatment is symptomatic and preventive. It is of utmost importance that parents understand the disease and take adequate measures to avoid aspiration pneumonia, gastroesophageal reflux, dysregulation of blood pressure and autonomic crises. In order to do so, special thickened formula is administered to the child in an upright position. Additional drug therapy may be necessary to prevent heart burn and to promote the passage of food through the child's gastrointestinal tract. Autonomic crises, i.e., accelerated heart rate, hypertension, profuse vomiting and sweating, may be treated by rectal application of sedatives.

In severe cases, more aggressive measures may be necessary to ensure adequate nutrition of the child.

References

Article

  1. Axelrod FB. Familial dysautonomia. Muscle Nerve. 2004; 29(3):352-363.
  2. Axelrod FB. A world without pain or tears. Clin Auton Res. 2006; 16(2):90-97.
  3. Riley CM, Day RL, et al. Central autonomic dysfunction with defective lacrimation; report of five cases. Pediatrics. 1949; 3(4):468-478.
  4. Anderson SL, Coli R, Daly IW, et al. Familial dysautonomia is caused by mutations of the IKAP gene. Am J Hum Genet. 2001; 68(3):753-758.
  5. Leyne M, Mull J, Gill SP, et al. Identification of the first non-Jewish mutation in familial Dysautonomia. Am J Med Genet A. 2003; 118A(4):305-308.
  6. Slaugenhaupt SA, Blumenfeld A, Gill SP, et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet. 2001; 68(3):598-605.
  7. Axelrod FB, Goldberg JD, Ye XY, Maayan C. Survival in familial dysautonomia: Impact of early intervention. J Pediatr. 2002; 141(4):518-523.
  8. Brunt PW, McKusick VA. Familial dysautonomia. A report of genetic and clinical studies, with a review of the literature. Medicine (Baltimore). 1970; 49(5):343-374.
  9. Pearson J, Pytel BA, Grover-Johnson N, Axelrod F, Dancis J. Quantitative studies of dorsal root ganglia and neuropathologic observations on spinal cords in familial dysautonomia. J Neurol Sci. 1978; 35(1):77-92.
  10. Porges RF, Axelrod FB, Richards M. Pregnancy in familial dysautonomia. Am J Obstet Gynecol. 1978; 132(5):485-488.
  11. Axelrod FB, Goldberg JD, Rolnitzky L, et al. Fludrocortisone in patients with familial dysautonomia--assessing effect on clinical parameters and gene expression. Clin Auton Res. 2005; 15(4):284-291.
  12. Gold-von Simson G, Rutkowski M, Berlin D, Axelrod FB. Pacemakers in patients with familial dysautonomia--a review of experience with 20 patients. Clin Auton Res. 2005; 15(1):15-20.

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Last updated: 2019-07-11 20:56