Chapter 98 Disorders of the Autonomic Nervous System
Autonomic Dysfunction in Pediatric Practice
Introduction
The autonomic nervous system (ANS) is pervasive and affects every organ in the body, leading to its essential role in maintenance of homeostasis and stability (Figure 98-1). It is now appreciated that there is a wide spectrum of autonomic disorders affecting the pediatric population. The ANS is an integral part of the nervous system and acts to integrate multiple secondary functions, so that symptoms are widespread. Appreciation of the breadth of the ANS has increased since Langley originally proposed the generic term and designated its division into the sympathetic, parasympathetic, and enteric nervous systems [Langley, 1921]. Although the ANS is primarily an efferent system, it depends upon afferent information from various sources. Therefore, because development and maintenance of the autonomic and sensory systems are linked closely, many of the pediatric autonomic disorders are associated with sensory perturbations, especially those caused by genetic mutations. Furthermore, many functions of the peripheral ANS are regulated and integrated by a central autonomic network (CAN), whose extensive circuitry ranges from the forebrain to the brainstem, so that anatomical lesions, as well as emotions, can elicit autonomic symptoms.
![image](/wp-content/uploads/2015/04/B9781437704358000871_f98-01-9781437704358.jpg)
Fig. 98-1 Parasympathetic and sympathetic innervation of the major organs.
(From Janig W. Autonomic nervous system. In: Schmidt RF, Thews G, eds. Human Physiology, 2nd edn. Berlin: Springer, 1989;333.)
The scope of pediatric autonomic disorders is not well recognized [Axelrod et al., 2006]. Most texts that concern autonomic dysfunction focus on adult disorders; however, we now appreciate that there are a myriad of pediatric autonomic disorders, many of which present at birth or appear in early childhood. Although the basic anatomic, physiologic, and biochemical principles are the same for pediatric and adult autonomic disorders, there are some important differences in scope and presentation. Within the pediatric autonomic disorders there is a preponderance of genetic disorders with an intimate relationship to sensory dysfunction. Furthermore, the dynamic influence of neurologic maturation results in variations in clinical presentation and symptoms. This chapter will emphasize the breadth of pediatric disorders that feature autonomic dysfunction and highlight some of the more common disorders. The rationale and some techniques involved in evaluation and management also will be included.
Anatomic, Physiologic, and Biochemical Basis of Autonomic Nervous System Function
Embryologic Development
The ANS has its embryonic origins in the multipotential neural crest cells [Hamill and LaGamma, 2002]. The effector components of the ANS develop in the basal plate of the spinal cord and in the neural crest. By the 3rd week of human gestation, the neural plate begins to fuse and the neural crest cells start to migrate. These migrating cells eventually evolve into sensory and autonomic ganglia, as well as the adrenal chromaffin cells. The primitive sympathetic ganglia, in the thoracolumbar portion of the spinal cord, are formed from neural crest cells from the sixth somite to the posterior end of the neural crest and are recognizable by the 5th week of gestation. Preganglionic parasympathetic fibers arise from neural crest cells in the diencephalon and cranial part of the mesencephalon and rhombencephalon to form cranial nerves, and from neural crest cells in the second to fourth sacral segments to provide the parasympathetic supply to the pelvic viscera. The migrating neural crest cells also contribute to the formation of the enteric nervous system. After colonizing the gut, neural crest-derived cells within the gut wall then differentiate into glial cells plus many different types of neurons [Anderson et al., 2006]. Pupils, salivary glands, heart, gastrointestinal tract, and lungs become innervated from the 5th–7th week. In the 10th week, cardiac conducting fibers appear. Diseases due to defects in the neural crest induction, formation, or migration are referred to as neurocristopathies, and genes that cause some of these disorders, like Hirschsprung’s disease, have been cloned in mice models [Shahar and Shinawi, 2003].
Various factors promote normal progression from the embryonic to the mature autonomic and sensory nervous systems [Edlund and Jessell, 1999; Goridis and Brunet, 1999]. The process of differentiation is incumbent upon exposure of migrating neural crest cells to growth factors released by structures along the migratory route and then within the target tissue. Eventually, specificity will be determined by a neuronal cell’s ability to produce specific neurotransmitters. Several key transcription factors have been identified that play critical roles in the development of the ANS, such as the MASH1 and PHOX genes, which are necessary for differentiation of uncommitted neural crest cells to the developing ANS [Sommer et al., 1995; Tiveron et al., 1996]. Another important regulator of development and survival is nerve growth factor (NGF) [Levi-Montalcini, 1972; Thoenen and Barde, 1980]. In the embryonic neuron, NGF binding promotes migration from the neural crest and enhances maturation through neurite outgrowth. In the mature neuron, dependence on NGF decreases but it continues to enhance neurotransmitter synthesis [Thoenen and Barde, 1980].
The Peripheral Autonomic Nervous System
The peripheral ANS is a visceral and largely involuntary motor/effector (efferent) system. Its subdivisions can be defined by their anatomical locations or their function, as mediated by neurotransmitters. Traditionally, the ANS has been divided into sympathetic (thoracolumbar) and parasympathetic (craniosacral) divisions [Pick, 1970]. In addition, there is an important enteric division.
Sympathetic outflow emanates from major nuclei in the hypothalamus, midbrain, and brainstem, and descends through the cervical spinal cord, where axons synapse in the intermediolateral cell mass. From the thoracic and upper lumbar spinal segments, myelinated axons emerge in white rami and synapse in paravertebral ganglia, which are some distance from target organs. Postganglionic fibers, which are unmyelinated, rejoin the mixed nerve through the gray rami and innervate target organs, except for the adrenal medulla, which has only a preganglionic supply (see Figure 98-1). Parasympathetic outflow consists of cranial and sacral efferents. Cranial efferents accompany cranial nerves III, VII, IX, and X, and supply the eye, lacrimal and salivary glands, heart and lungs, and gastrointestinal tract, down to the level of the colon. The sacral outflow supplies the urinary tract and bladder, the large bowel, and the reproductive system. Most parasympathetic ganglia are close to target organs.
Although the traditional concept is that the sympathetic and parasympathetic systems are antagonistic, this is not always the case, as indicated in Table 98-1. Thus, when the sympathetic system is stimulated, a host of receptor systems are activated, including dilatation of the pupil, increase in glandular secretions, bronchodilatation, increase in heart rate and force of contraction, decrease in gastrointestinal tract motility, decrease in function of the reproductive organs, and mobilization of energy substrates. The parasympathetic system tends to have more focal responses, but some effects may be quite broad, particularly with the wide-ranging innervation of the vagus nerve. However, the parasympathetic system appears to have less influence on exocrine and endocrine function.
Organ | Sympathetic | Parasympathetic |
---|---|---|
Eye | ||
Pupil | Dilatation | Constriction |
Ciliary muscle | Relax (far vision) | Constrict (near vision) |
Lacrimal gland | Slight secretion | Secretion |
Salivary glands | Slight secretion | Secretion |
Heart | Increased rate | Decreased rate |
Positive inotropism | Negative inotropism | |
Lungs | Bronchodilatation | Bronchodilatation |
Gastrointestinal | Decreased motility | Increased motility |
Kidney | Decreased output | None |
Bladder | Relax detrusor | Contract detrusor |
Contract sphincter | Relax sphincter | |
Penis | Ejaculation | Erection |
Sweat glands | Secretion | Palmar sweating |
Blood vessels | ||
Arterioles | Constriction | None |
Muscles | ||
Arterioles | Constriction or dilatation | None |
Metabolism | Glycogenolysis | None |
(Adapted from Axelrod FB et al. Pediatric autonomic disorders. State of the art. Pediatrics 2006;118:309.)
The Central Autonomic Nervous System
The peripheral ANS can operate independently but, to some extent, it is regulated and integrated by the CAN, whose circuitry ranges from the forebrain to the brainstem (Table 98-2) [Loewy, 1990]. The CAN maintains integral relationships with visceral sensory neurons via afferent input, primarily from cranial nerve X (vagus nerve), which is 80 percent afferent, transmitting visceral sensory information from the larynx, esophagus, trachea, and abdominal and thoracic viscera, as well as the stretch receptors of the aortic arch and chemoreceptors of the aortic bodies. This information is relayed through the nucleus tractus solitarius (NTS) to the major cerebral centers concerned with autonomic regulation, which include the amygdala, hypothalamus, midbrain, and forebrain [Loewy, 1990].
Anatomic Area | General Function | Clinical Manifestations |
---|---|---|
Insular and medial prefrontal cortices | High-order autonomic control Input from gastric mechanoreceptors, arterial chemoreceptors, baroreceptors |
Cardiac arrhythmia |
Extended amygdala | Expression of emotional states Integrates autonomic and motor responses |
Viscerosensory phenomena (e.g., unilateral hyperhidrosis) Vomiting (left temporal focus) Sexual arousal |
Hypothalamus | Homeostasis Initiates and coordinates biologic rhythms, autonomic, neuroendocrine, and behavioral responses |
Hypo- or hyperthermia Poor stress response (autonomic storm) Insomnia |
Midbrain | Coordinates autonomic, pain-controlling, and motor mechanisms for stress-related, aggressive, and reproductive behaviors | Hyper- or hypotension, arrhythmias Intractable vomiting and dysmotility Hypoventilation Urinary retention |
Pons | Relays viscerosensory information to forebrain | |
Nucleus of tractus solitarius | Relays viscerosensory information from vagus and glossopharyngeal nerves to other CAN regions | |
Medulla | Cardiovascular and respiratory control via premotor autonomic and respiratory neurons controlling input to spinal, respiratory, and preganglionic motor neurons | Sleep disorders (e.g., apnea) |
CAN, central autonomic network.
(Adapted from Axelrod FB et al. Pediatric autonomic disorders. State of the art. Pediatrics 2006;118:309.)
Disorders in the forebrain circuits, such as ischemia secondary to blood flow disturbance or seizures, can cause cardiac arrhythmia [Hilz et al., 2002]. Within this circuitry, the NTS in the medulla oblongata, which receives input from the vagus and glossopharyngeal nerves, functions as a major relay station, allowing continuous feedback and integration. The hypothalamic area appears to have major influences on thermoregulation and sleep–wake cycling. Thus, the CAN serves many critical functions and affects visceromotor and neuroendocrine function, as well as motor and pain modulation. It aids in reflex adjustments of autonomic responses, and integrates autonomic, neuroendocrine, and behavioral responses that, in turn, maintain homeostasis, emotional expression, and response to stress [Benarroch and Chang, 1993; Critchley et al., 2001].
Neurotransmitters
The peripheral ANS provides physiologic responses via multiple neurotransmitters and a chemical coding system of autonomic neurons. The neurotransmitters, which include amino acids, peptides, and monoamines, act by relaying, amplifying, and modulating signals between two neurons, or a neuron and another cell, such as the smooth muscle cell of blood vessel. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to receptors in the membrane on the postsynaptic side of the synapse (Figure 98-2). During the last two decades, it has become clear that, within a single neuron, multiple transmitter systems coexist and that, within a given ganglion, the variety and pattern of neurotransmitters is extensive. In turn, multiple organ systems then respond to the neurotransmitters released via various receptor systems.
Under normal circumstances, the concentration of NE in a noradrenergic synapse is determined by the level of sympathetic activity. A steady state is maintained as a result of a careful balance among catecholamine synthesis, storage, release, and reuptake (see Fiugre 98-2) [Vincent and Robertson, 2002]. DA is the first catecholamine to be synthesized, with NE and epinephrine, in turn, being derived from further modifications of DA. Catecholamine synthesis also requires important co-factors; the enzyme dopamine β-hydroxylase (DβH) requires copper as a co-factor, and DOPA decarboxylase requires pyridoxal-phosphate. Approximately 70–90 percent of released NE is removed from the synaptic cleft through reuptake into the presynaptic neuron by the NE transporter. The remaining 10–30 percent is subject to extraneuronal uptake or spills over into the circulation [Eisenhofer et al., 2004].
The catecholamines also are vital neurotransmitters in the CAN, where they mediate such functions as attention, arousal, learning, memory, and mood. Dopamine is produced largely in neuronal cell bodies in two areas of the brainstem, the substantia nigra and the ventral tegmental area. Neurons containing NE and epinephrine also reside within several brainstem nuclei, including the locus ceruleus [Vincent and Robertson, 2002]. These efferent sympathetic neuronal pathways control autonomic reflexes at the level of the brainstem and spinal cord. They regulate postganglionic sympathetic synapses in the peripheral nervous system.
Genetic errors involved in synthesis, transport, storage, or metabolism of the neurotransmitters can result in a variety of autonomic disorders, such as DβH deficiency, in which lack of this essential enzyme results in inability to convert DA to NE, leading to symptoms consistent with sympathetic insufficiency [Robertson et al., 1986].
Clinical Features of Autonomic Dysfunction
As the ANS and its CAN component have pervasive effects affecting multiple other systems secondarily, there can be a myriad of clinical manifestations, depending upon which organ systems are perturbed. Rather than use an anatomic approach, one can use a functional or system approach, as listed in Table 98-3. Occasionally, there is autonomic dysfunction in a single system, with one or more isolated dysfunctions, such as children who have prominent enteric or gastrointestinal dysfunction or isolated gastroesophageal reflux disease. In such cases, the symptoms are limited to the particular system and investigations also should be restricted accordingly.
Table 98-3 Functional Organization of Symptoms Associated with Autonomic Disorders
System | Dysfunction | Symptom |
---|---|---|
Vasomotor/cardiovascular | Hypertension Hypotension Arrhythmia Vascular changes |
Headache Dizziness, lightheadedness, blurred vision, loss of consciousness/syncope Palpitations, loss of consciousness/syncope Purple feet, mottled skin, acrocyanosis, blotching |
Gastrointestinal | Oropharyngeal dysmotility Esophageal dysmotility Gastroesophageal reflux Bowel dysmotility |
Feeding problems (poor suck, drooling, aspiration pneumonia) Dysphagia (difficulty swallowing) Nausea, recurrent vomiting Bloating, profound constipation or diarrhea |
Ophthalmologic | Alacrima Nonreactive/sluggish pupil Eyelid weakness |
Dry eye Dark/light intolerance Ptosis |
Respiratory | Alveolar hypoventilation Apnea Insensitivity to hypoxia Insensitivity to hypercarbia |
Cyanosis with sleep Breath-holding spells Syncope at high altitudes/plane travel |
Sudomotor | Altered sweating | Hypo- or hyperhidrosis, excessively dry skin, clammy hands and feet, unexplained fevers, heat intolerance |
Urinary | Nocturia | Frequent awakenings to urinate or nocturnal enuresis >5 yrs of age |
Central dysfunction | Thermoregulatory abnormalities Sleep–wake disturbance Altered affect and emotions Learning disability |
Decreased basal body temperature, unexplained high fevers Fractured sleep, insomnia, nocturnal enuresis >5 yrs of age Poor socialization skills, increased anxiety, emotional lability, tics/phobias Poor school performance, poor executive planning, attention problems, hyperactivity |
Associated sensory dysfunction | Altered perception of pain | Decreased response to injury, injections, and dental procedures, self-mutilation, tactile defensiveness |
(Adapted from Axelrod FB et al. Pediatric autonomic disorders. State of the art. Pediatrics 2006;118:309.)
Vasovagal Syncope
The most frequent noncardiac cause of unexplained transient loss of consciousness, or faint, is vasovagal syncope. It also is known as neurally mediated syncope and neurocardiogenic syncope, common or emotional fainting, or reflex syncope. During vasovagal syncope, vasodilatation and bradycardia occur simultaneously (Figure 98-3). The bradycardia is due to increased parasympathetic (vagal) outflow to the sinus node of the heart. The decrease in blood pressure is due to vasodilatation but the mechanism is not clear. Both reduction in sympathetic vasoconstrictor traffic (i.e., “passive” vasodilatation) and activation of a vasodilator system (i.e.,“active” vasodilatation) have been postulated [Kaufmann and Hainsworth, 2001]. Among the various postulated causes for active vasodilatation is activation of β2-adrenergic receptors secondary to epinephrine release from the adrenal medulla [Glover et al., 1962], and increased nitric oxide, a powerful vasodilator released by endothelial and other cells [Kaufmann et al., 1993].
Orthostatic Hypotension
Orthostatic hypotension, also called postural hypotension, is a temporary lowering of blood pressure (hypotension), usually due to standing up suddenly (orthostatic). The change in position causes a temporary reduction in blood flow and oxygen to the brain. When an individual stands up, gravity promotes the pooling of blood in the lower extremities, which decreases venous return of blood circulating back to the heart. Normally, cardiac and carotid sinus baroreceptors sense the decrease in blood volume and initiate increased heart rate and peripheral vasoconstriction. The latter increases resistance to blood flow and increases blood pressure. The underlying pathophysiology in individuals with orthostatic hypotension is an impaired efferent sympathetic signal to the arterioles, a failure to release norepinephrine appropriately upon standing, and consequent vasoconstrictive insufficiency resulting in blood pooling in the lower extremities, with subsequent decreased venous return to the heart and brain [Freeman, 2003]. Thus, orthostatic hypotension also is a common feature of a number of central autonomic neurodegenerative disorders, such as multiple system atrophy and Parkinson’s disease, and peripheral autonomic disorders, such as the autonomic peripheral neuropathies, in which there are decreased peripheral noradrenergic neurons or enzyme deficiencies resulting in low levels of NE – for example, in familial dysautonomia and dopamine β-hydroxylase deficiency, respectively. Furthermore, when blood volume is lowered by dehydration or shifted by food ingestion, orthostatic hypotension can be unmasked in physiologically intact individuals, especially older people.
Orthostatic hypotension can be confirmed by measuring blood pressures and heart rate in supine and upright positions. Orthostatic hypotension is defined as a sustained drop in blood pressure of greater than 20 mmHg systolic or 10 mmHg diastolic within 3 minutes of being upright, associated with symptoms. The heart rate response to changes in blood pressure is minimal, although there may be a mild compensatory increase, i.e., below 30 beats per minute. (Figure 98-4). Presyncopal symptoms can appear, and include dizziness, lightheadedness, headache, and tunnel vision. Occasionally, individuals will faint and have syncope. The symptoms typically improve on lying down.
In a physiologically intact individual with no underlying condition, no medical treatment usually is needed for orthostatic hypotension. The most important treatments are assuring adequate fluids and avoiding potential triggers, such as prolonged sitting, quiet standing, warm environments, or vasodilating medications. Other measures that have been found helpful are use of postural maneuvers and physical therapy and exercise [van Lieshout et al., 1992]. When there is a coexisting underlying medical condition, then the orthostatic hypotension can be very debilitating and these supportive measures may not suffice [Freeman, 2003]. In such cases, various medications may be used, i.e., medications that increase blood volume (fludrocortisone, erythropoietin), medications that interfere with the release or action of epinephrine and NE (beta blockers, angiotensin-converting enzyme inhibitors), and medications that improve vasoconstriction (midodrine).
Orthostatic Intolerance/Postural Tachycardia Syndrome
Orthostatic intolerance (OI) is considered as a type of autonomic dysfunction that occurs as part of many autonomic disorders. As upright heart rate usually is increased greatly, the term postural tachycardia syndrome (POTS) also is used [Low et al., 2001].
Investigations demonstrate that, during postural challenge, the blood pressure does not fall, but the heart rate increases by more than 30 beats per minute or rises above 120 beats per minute (Figure 98-5). The supine heart rate usually is normal or slightly raised. Additional findings include a standing plasma NE level of at least 600 pg/mL, and blood volume usually is reduced. In the hyperadrenergic subgroup of OI patients, plasma renin activity and aldosterone are attenuated.
![image](/wp-content/uploads/2015/04/B9781437704358000871_f98-05-9781437704358.jpg)
Fig. 98-5 Blood pressure and heart rate measured continuously before, during and after 60-degree head-up tilt.
(From Mathias CJ. To stand on one’s own legs. Clin Med 2002;2:237.)
The etiology of OI is unknown. It has been observed predominantly in young postpubertal females (female to male ratio at least 4:1) and the onset often is predated by a recent viral infection. Further supporting the hypothesis that OI is an immunologically mediated phenomenon is the fact that it often is a prominent feature of other secondary autonomic disorders that are believed to have an autoimmune etiology, such as idiopathic autonomic neuropathy and chronic fatigue syndrome. Increased propensity to venous pooling [Streeten et al., 1998] and a strong association with the joint hypermobility syndrome have been reported [Gazit et al., 2003].
Autonomic Disorders in Children and Adolescents
Pediatric autonomic disorders can be thought of as either primary (inherited) or secondary (acquired or associated with other systemic disorders). Within the primary or inherited disorders are many genetic disorders that result in incomplete development of the ANS or biochemical errors that affect neurotransmitter production or efficiency; for some of these disorders, the specific genetic mutations have been identified (Table 98-4). Clinical manifestations of the developmental disorders are noted early, usually within the first year of life. Those disorders that occur as a result of a biochemical error leading to inefficient mitochondrial metabolism or to storage of deleterious material within the neuron can be more insidious and later in their presentation.
Disorders | Category | Disorders |
---|---|---|
PRIMARY | ||
Developmental disorders | Hereditary sensory and autonomic disorders (HSAN) | Familial dysautonomia (HSAN III) Congenital sensory neuropathy with anhidrosis (HSAN IV) Congenital sensory neuropathy (HSAN II) |
Allgrove’s syndrome | ||
Chromosomal disorders | Rett’s syndrome Prader–Willi syndrome Fragile X/fragile X-associated tremor/ataxia syndrome |
|
Prematurity | ||
Dysregulation disorders | Cardiorespiratory and cardiac | Congenital central hypoventilation syndrome (CCHS) Reflex anoxic seizures |
Biochemical errors | Myopathies | Mitochondrial myopathies Leber’s hereditary optic neuropathy Leigh’s syndrome Kearns–Sayre syndrome Myoneurogastrointestinal disorder with encephalopathy |
Neurotransmitter deficiencies | Dopamine β-hydroxylase deficiency Norepinephrine transporter deficiency Menkes’ disease |
|
Storage disorders | Fabry’s disease Familial amyloid polyneuropathy (FAP) |
|
SECONDARY | ||
Metabolic | Endocrine disorders | Diabetes Addison’s/Cushing’s disease Thyroid disorders |
Autoimmune | Postinfectious? | Idiopathic autonomic neuropathy Paraneoplastic disorders Chronic fatigue syndrome |
Neoplasia | Secreting tumors | Pheochromocytoma Carcinoid tumors |
Intoxications | Drugs that modify sympathetic or parasympathetic activity | |
Psychosocial/unknown | Functional gastrointestinal disorders | Cyclic vomiting syndrome Functional abdominal pain |
Autism |
The secondary autonomic disorders include a number of broad and heterogeneous categories. For some of the secondary autonomic disorders, autoimmune mechanisms have been postulated [Etienne and Weimer, 2006; Low et al., 2003]. Other autonomic disorders are associated secondarily with metabolic diseases, such as diabetes; others are secondary to deleterious effects of drugs or toxins; and still others are idiopathic or unknown. Table 98-4 lists some of these disorders, but the number of primary and secondary disorders continues to expand. A few representative disorders that are present in childhood will be described.
Primary (Inherited) Autonomic Disorders
Autonomic Disorders Associated with Developmental Arrest
Hereditary sensory and autonomic neuropathies
The complexities of the ANS and its intimate relationship with sensory function are illustrated especially well in the group of genetic disorders known as hereditary sensory and autonomic neuropathies (HSAN) [Axelrod, 2002a, b; Dyck, 1993; Minde et al., 2004] (see also Chapter 89 for further description of these neuropathies). Each HSAN disorder is caused by a different genetic error affecting a specific aspect of small-fiber neurodevelopment and resulting in variable phenotypic expression. With the exception of hereditary sensory radicular neuropathy (HSAN type I), which is a dominant disorder presenting in the second decade, the other HSANs are autosomal-recessive disorders presenting at birth. For each HSAN type, penetrance is complete but there can be marked variability in expression. Characteristic to all HSANs is the fact that intradermal injection of histamine phosphate fails to elicit a normal axon flare response. Of the five HSAN subtypes, autonomic dysfunction is associated with II, III, and IV only.
Familial Dysautonomia
Of all the HSAN disorders, familial dysautonomia is the most extensively studied and described, and often is used as the prototype with which to compare other HSAN disorders [Axelrod 2002b]. In familial dysautonomia, the gene is IKBKAP, and over 99 percent of individuals with familial dysautonomia are homozygous for a mutation in intron 20, suggesting that there was a founder effect and explaining why the disorder occurs almost exclusively in individuals of Ashkenazi Jewish extraction [Anderson et al., 2001; Slaugenhaupt et al., 2001]. The IKBKAP gene codes for the IKAP/hELP1 protein, which is associated with the human elongator complex that aids in transcriptional elongation [Hawkes et al., 2002]. Studies suggest that familial dysautonomia mutations lead to misspliced messenger RNA and tissue-specific reductions in normal IKAP/hELP1 protein, with subsequent downregulation of genes involved in neuronal migration and function. Downregulation of these critical target genes results in aberrant neurogenic differentiation and migration behavior of neural crest cells, which eventually impacts the sympathetic and sensory systems [Close et al., 2006; Chariot et al., 2007; Lee et al., 2009; Slaugenhaupt et al., 2001]. In familial dysautonomia, there is inadequate development, as well as limited survival, of sensory and autonomic neurons, with the sympathetic population affected more widely than the parasympathetic. Pathologic studies have demonstrated decreased unmyelinated and small myelinated neuronal populations in the peripheral sensory nervous system and the ANS [Grover-Johnson and Pearson, 1976; Pearson et al., 1974]. Although central autonomic symptoms are present, no consistent central neuropathology has been described yet.
Although patients with familial dysautonomia have decreased pain and temperature perception, the sensory perturbations are not as profound as in the other HSAN disorders [Hilz and Axelrod, 2000]. Bone and skin pain is diminished but not absent; sensitivity to visceral pain is intact. Corneal and tendon reflexes are hypoactive, and taste appreciation is diminished, consistent with absence of lingual fungiform papillae. With age, vibratory sensory loss and impaired coordination appear [Axelrod et al., 1981].
The autonomic disturbances, however, are pervasive and impose the greatest impediments to function and survival [Axelrod, 2002a; Axelrod et al., 2002