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]. In addition to absence of tears (alacrima) with emotional crying, a cardinal feature of the disorder, feeding difficulties are frequent due to poor oral coordination and hypotonia. Recurrent misdirection, especially of liquids, and frequent gastroesophageal reflux put the patient at risk for aspiration and chronic lung disease. Protracted episodes of nausea and vomiting can be triggered by emotional or physical stress, and even arousal from sleep. These episodes, also termed the dysautonomic crisis, usually are associated with a constellation of signs, including agitation, tachycardia, and hypertension. Vasomotor and cardiovascular perturbations manifest as erythematous skin blotching and hyperhidrosis with excitation or even eating. Patients can exhibit both extreme hypertension and profound and rapid postural hypotension without compensatory tachycardia. Consistent with decreased autonomic neurons, patients exhibit denervation hypersensitivity to cholinergic and adrenergic agents [Bickel et al., 2002; Smith et al., 1965]. Patients have baroreflex failure and chemoreceptor dysfunction, so they are relatively insensitive to hypoxemia [Bernardi et al., 2002; Edelman et al., 1970; Filler et al., 1965; Maayan et al., 1992], which limits ability to cope with pneumonia or travel to high altitudes. Ensuing hypoxemia may lead to hypotension, bradyarrhythmia, and even syncope. Developmental milestones commonly are delayed, but intelligence usually is within normal ranges [Welton et al., 1979].

Although the gene has been identified and there are early reports of nutritional supplements that may be able to modify genetic expression in cell culture [Anderson et al., 2003a, b; Slaugenhaupt et al., 2004; Lee et al., 2009], the mainstay of treatment remains preventative and supportive. These treatments have included measures to maintain eye moisture, fundoplication with gastrostomy to provide nutrition and avoid risk of aspiration, use of central agents such as benzodiazepines and clonidine to control vomiting and the dysautonomic crisis, and fludrocortisone and midodrine to combat cardiovascular lability [Axelrod, 2005]. As a result of improved supportive measures, about half of the patients now reach adulthood [Axelrod et al., 2002a, b].

Hereditary Sensory and Autonomic Neuropathy Type IV (Congenital Insensitivity to Pain with Anhidrosis)

Congenital insensitivity to pain with anhidrosis is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 (NTRK1) gene, located on chromosome 1 (1q21–q22) [Indo et al., 1996]. As a result of loss-of-function mutations, signal transduction at the NGF receptor is impeded, and NGF-dependent neurons – the nociceptive sensory and sympathetic neurons – fail to survive. There is no particular ethnic distribution for this disorder but one-half of reported cases have occurred in consanguineous marriages [Axelrod, 2002a, b].

HSAN type IV is characterized by anhidrosis – absent or markedly decreased sweating, which probably is secondary to impaired thoracolumbar sympathetic outflow. It is the anhidrosis that causes episodic fevers and extreme hyperpyrexia, which are usually the earliest signs of the disorder. Anhidrosis also contributes to the thick and calloused appearance of the skin, with lichenification of palms, dystrophic nails, and areas of hypotrichosis on the scalp [Pinsky and DiGeorge, 1966]. As evidence of parasympathetic dysfunction, patients exhibit miosis with dilute intraocular mecholyl. Cardiovascular responses are normal in the early years but some of the adolescents and adults manifest mild postural hypotension. Severe learning problems, often associated with hyperactivity, are frequent and may be due to central autonomic involvement [Indo et al., 1996; Vassella et al., 1968]. In contrast to patients with familial dysautonomia, emotional tearing is normal, there is no acrocyanosis, and gastrointestinal dysmotility is infrequent. Cyclical crises do not occur. Insensitivity to hypoxia and hypercapnia has not been noted.

However, the insensitivity to pain is profound and can result in self-mutilation, auto-amputation, and corneal scarring. Although there is no immunological problem, ectodermal structures, skin and bone, heal poorly. Fractures are slow to heal and large weight-bearing joints appear particularly susceptible to repeated trauma and infection. Temperature sensation also is decreased or absent but deep tendon reflexes usually are intact.

Neuropathological studies have demonstrated decreased neuronal populations. Sural nerve biopsies show that myelinated nerve fibers are present but unmyelinated fibers are absent [Dyck, 1993]. Skin biopsy morphology of HSAN IV patients reveals deficient C and Aδ fibers in the epidermis, and absent or hypoplastic dermal sweat glands without innervation [Goebel et al., 1980; Langer et al., 1981; Nolano et al., 2000]. The lack of sweat gland innervation accounts for the clinical manifestation of severe anhidrosis and the objective absence of sympathetic skin responses [Hilz et al., 1999].

For HSAN type IV patients, the prognosis for independent function depends on the ability to manage secondary clinical problems, especially avoidance of excessive warming and early care of orthopedic issues.

Congenital Sensory Neuropathy (Hereditary Sensory and Autonomic Neuropathy Type II)

HSAN II, also known as “Morvan’s disease,” is a recessive neuropathy typically diagnosed in the first decade [Barry et al., 1974; Hilz, 2002]. A cohort of HSAN II patients, mainly of French Canadian kinship, have loss-of-function mutations in the single-exon HSN2 gene [Lafreniere et al., 2004; Riviere et al., 2004; Roddier et al., 2005]. However, there is also a large number of patients who appear to have clinical features consistent with HSAN II, in whom these genetic mutations have not been identified, suggesting that there is at least one other cohort with similar phenotype but a different genotype [Axelrod and Gold von Simson, 2007].

HSAN II is characterized by profound sensory loss involving large- and small-fiber modalities. All peripheral sensations are affected but distribution of somatic involvement may vary. Pain, temperature, and position senses are involved. Unrecognized injuries and fractures of hands, feet, and limbs, as well as Charcot joints, are frequent. Self-mutilation may begin as early as 4 months of age and usually is associated with eruption of primary dentition [Zaenglein et al., 2002]. Tendon reflexes are diminished. Sensory nerve action potentials are absent [Dyck et al., 1983; Ohta et al., 1973]. Taste sensation is diminished and lingual fungiform papillae are hypotrophic. Corneal and gag reflexes may be diminished. Deep tendon reflexes are decreased and hypotonia is common, which delays attainment of developmental milestones and may contribute to scoliosis. Despite the marked sensory abnormalities, other aspects of the neurologic examination may be normal, including mental function and cerebellar and motor functions.

In the French Canadian HSAN II patients, autonomic dysfunction is described as minimal [Lafreniere et al., 2004; Riviere et al., 2004; Roddier et al., 2005]. However, for many other patients who are presumed to have HSAN II, the autonomic dysfunction is complex and evident from birth [Axelrod and Pearson, 1984; Dyck, 1993; Thomas, 1992]. For these latter patients, the neonatal course is characterized by severe feeding problems and frequent apnea [Axelrod, 2002b; Dyck, 1993; Thomas, 1992]. Gastroesophageal reflux occurs commonly. Episodic hyperhidrosis, as well as patchy areas of anhidrosis, can occur in the same patient. Overflow tearing frequently is delayed but eventually is normal. Pupils have an exaggerated response to parasympathomimetic agents. Blood pressure lability, including postural hypotension, has not been observed. Sural nerve biopsy reveals marked reduction in nerve size and depletion of large and small myelinated fibers, but only slightly decreased number of unmyelinated fibers [Dyck, 1993; Hilz, 2002]. No cutaneous sensory receptors or nerve fibers are seen, but catecholaminergic sympathetic fibers can be demonstrated by aldehyde-induced fluorescence [Hilz, 2002].

Since DNA diagnosis is not helpful in a large number of patients, diagnosis then is based on documenting profound peripheral sensory involvement of both peripheral and cranial nerves, which includes an absent axon flare after intradermal histamine. Management is symptomatic and preventative. If feeding problems compromise nutrition and if gastroesophageal reflux also is present, fundoplication with gastrostomy is recommended. Sleep pneumograms can determine if there is central apnea and if respiratory support is needed. Parent and patient education is required to teach them how to avoid injury and to be alert for signs of unrecognized trauma.

Rett’s Syndrome

Rett’s syndrome is a neurodevelopmental disorder predominantly affecting females. Mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2) on the X chromosome have been identified in 95 percent of girls with the Rett’s syndrome phenotype [Amir et al., 1999; Fang et al., 2004]. Typically, development is normal until 6–8 months of age, but then there is regression, with slowing of head circumference growth, loss of language, development of stereotypical hand movements, and gait and truncal apraxia. Some girls also develop electroencephalogram abnormalities, seizures, spasticity, and scoliosis. The autonomic features include cardiorespiratory dysregulation and abnormal blood pressure responses. Respiratory dysregulation includes hyperventilation, apnea, breath holding, and rapid shallow breathing [Cirignotta et al., 1986; Elian and Rudolf, 1991; Julu et al., 1997, 2001; Kerr, 1992; Nomura et al., 1997; Southall et al., 1988; Weese-Mayer et al., 2005]. During wakefulness, breathing dysrhythmias are associated with agitation or excitement, as well as other motor functions. During sleep, polysomnography has documented increased frequency of desaturation events and periodic breathing, and treatment is required to protect the child from the sequelae of acute and chronic intermittent hypoxemia and hypercarbia. The abnormal blood pressure responses include episodic extreme hypertension and tachycardia due to decreased cardiac vagal tone and subsequent unopposed sympathetic activity [Julu et al., 2001; Nomura et al., 1997]. Further support for autonomic dysregulation comes from observations of decreased heart rate variability, prolongation of corrected QT intervals, and sinus bradycardia [Ellaway et al., 1999; Guideri et al., 1999, 2001; Sekul et al., 1994]. Despite survival into adulthood, 26 percent of all deaths from Rett’s syndrome are sudden and unexpected, and cardiac causes for sudden death have been suggested due to autonomic dysregulation [Guideri et al., 1999; Sekul et al., 1994].

Prader–Willi Syndrome

Prader–Willi syndrome is a multisystem genetic disorder caused by deletion or suppressed expression of genes on chromosome 15q. Due to imprinting, the maternally inherited copies of these genes are virtually silent; only the paternal copies of the genes are expressed. Prader–Willi syndrome results from the loss of paternal copies of this region. Necdin, one of the several proteins genetically inactivated in individuals with Prader–Willi syndrome, has a role in promoting cellular migration and axon outgrowth, and is important for the differentiation of central and sensory neurons [Tennese et al., 2008]. In addition to hypotonia, short stature, polyphagia, obesity, small hands and feet, hypogonadism, and mild mental retardation, there are clinical features suggesting central and peripheral ANS involvement. Hypothalamic dysfunction is suggested by abnormalities in appetite regulation and pubertal development, and growth hormone serum levels are depressed. Patients with Prader–Willi syndrome appear to have diminished parasympathetic nervous system activity, based on studies demonstrating lower resting diastolic blood pressures and significantly less change in diastolic blood pressure with head-up tilt [DiMario et al., 1994].

Fragile X Syndrome

Fragile X syndrome is the most common cause of inherited mental retardation and is associated with cognitive, behavioral, and neuropsychological difficulties. Problems include autistic-like behavior, sensory integration difficulties, impulsivity, anxiety, and mood disturbances. In addition, there are physical signs associated with fragile X syndrome that are more obvious during adolescence or after puberty, and most frequently involve the craniofacial, genital, and musculoskeletal systems. These include elongated face, large or protruding ears, flat feet, hypotonia, and larger testicles in men.

Fragile X syndrome is caused by a change in the FMR1 gene, located on the X chromosome. The expansion of a single trinucleotide gene sequence (CGG) results in methylation of that portion of the DNA and silencing of the FMR1 protein that is required for normal neural development. Normally, the FMR1 gene contains between 6 and 55 repeats of the CGG codon. In people with fragile X syndrome, the FMR1 allele has more than 200 CGG repeats of this codon [Nolin et al., 2003; Sherman, 2002]. The degree of severity correlates with the number of repeats.

Fragile X-Associated Tremor/Ataxia Syndrome

Fragile X-associated tremor/ataxia syndrome has been reported in carriers of permutation alleles (55–200 CGG repeats). Clinical features include cerebellar ataxia, neuropathy, autonomic dysfunction, severe intention tremor, and other signs of neurodegeneration, such as brain atrophy, memory loss and dementia, anxiety, and irritability. Premature ovarian failure is reported in 25 percent of women with permutations. Women with permutations have been noted to have increased prevalence of autoimmune diseases, such as hypothyroidism and fibromyalgia [Coffey et al., 2008]. Here, the clinical problems are thought due to toxic gain of function of the elevated levels of the expanded repeat FMR1 messenger RNA [Hessl et al., 2007]. Affected individuals have been shown to have diminished amygdala and autonomic responsiveness to social-emotional stimuli, as measured by functional MRI; lack of eye blink potentiation; and reduced sympathetic outflow, as measured by skin conductance [Hessl et al., 2007].

Congenital Central Hypoventilation Syndrome

Disorders with cardiorespiratory dysregulation as their prominent feature affect breathing control. Thus, their consequences can be fatal. One of these disorders, congenital central hypoventilation syndrome, is now recognized as a specific genetic entity. First described in 1970 and often referred to as “Ondine’s curse” [Mellins et al., 1970; Weese-Mayer et al., 1999], it typically presents in the newborn period with cyanosis during sleep. More severely affected cases hypoventilate when awake and asleep, with resultant hypercarbia and hypoxemia [Weese-Mayer et al., 1999]. With compromised ventilatory and arousal responses to hypercarbia and hypoxemia, patients do not increase their minute ventilation nor perceive the physiologic compromise from breath holding or exercise. In addition to its prominent effect on cardiorespiratory regulation, children with congenital central hypoventilation syndrome often have diffuse ANS dysfunction, affecting heart rate and blood pressure responses, gastrointestinal motility, and other homeostatic functions, including sweating and body temperature regulation [Faure et al., 2002; Trang et al., 2005; Weese-Mayer et al., 2001]. Altered perceptions of pain and anxiety, and ophthalmologic abnormalities, including strabismus, altered pupillary responses, and accommodation, also have been described [Goldberg and Ludwig, 1996; Pine et al., 1994; Weese-Mayer et al., 1992, 2001]. Hirschsprung’s disease occurs in about 20 percent of cases and various tumors of neural crest origin in about 5 percent of cases [Bower and Adkins, 1980; Haddad et al., 1978; Weese-Mayer et al., 1992]. For children with congenital central hypoventilation syndrome, neurodevelopmental outcome depends on the ability to compensate for ANS dysregulation and the impact of chronic/intermittent hypoxemia [Weese-Mayer et al., 2001]. The mainstay of treatment is mechanical ventilation, with or without tracheostomy. Diaphragm pacing, mask ventilation, and negative pressure ventilation are other options.

Individuals with the congenital central hypoventilation syndrome phenotype are heterozygous for a PHOX2B gene mutation, located on chromosome 4p12 [Amiel et al., 2003; Matera et al., 2004; Sasaki et al., 2003; Weese-Mayer et al., 2003]. In 90–95 percent of congenital central hypoventilation syndrome cases, there is a polyalanine expansion mutation in exon 3, and in 5–10 percent of cases there is a unique mutation. A relationship has been noted between polyalanine repeat length and the severity of autonomic dysfunction, as indicated by number of associated autonomic symptoms [Berry-Kravis et al., 2005; Matera et al., 2004; Trochet et al., 2005; Weese-Mayer et al., 2003]. Subjects with unique mutations in PHOX2B have a higher rate of Hirschsprung’s disease, higher frequency of 24-hour/day ventilation, and more frequent neural crest tumors than the polyalanine expansion mutation group.

Reflex Anoxic Seizures

When vasovagal episodes begin in the very young (ages 6 months to 2 years) and are recurrent, they may induce reflex anoxic seizures [Appleton, 1993; Stephenson, 1978]. Like seizures, the attacks can occur in clusters. However, the episodes are not true seizures, as they are induced by vagal stimulation with the neurologic manifestation secondary to cerebral anoxia. Children who exhibit reflex anoxic seizures are believed to have vagal hypersensitivity or increased vagotonia that results in cardioinhibition. The vagal stimulus causes a period of asystole, which is brief, usually lasting less than 15 seconds. During an asystolic phase, the child is limp and pale. Frequently, following the limp period, there is stiffening of the body or opisthotonus, and there even may be urinary incontinence. Use of anticholinergic agents and pacemakers has been beneficial for some patients with extremely frequent episodes.

Dopamine-β-Hydroxylase Deficiency

DβH deficiency is a mendelian recessive disorder that demonstrates the critical role of catecholamines in controlling central and peripheral autonomic functions [Robertson et al., 1986]. The enzyme DβH is required for conversion of DA to NE, so that loss of DβH leads to an inability of the neuron to synthesize NE, resulting in accumulation of DOPA and DA and its metabolites. As DβH is located almost exclusively in the chromaffin granules of the adrenal medulla and the large dense-core synaptic vesicles of noradrenergic neurons, clinical features of DβH deficiency are consistent with normal parasympathetic and sympathetic cholinergic function, but there is a lack of sympathetic noradrenergic function and adrenomedullary failure. Affected individuals experience orthostatic hypotension, exercise intolerance, fatigue, episodes of fainting, and syncope. Ptosis, hyperextensible joints, sluggish deep-tendon reflexes, mild facial weakness, and hypotonic skeletal muscles occur in some patients [Man in’t Veld et al., 1987; Robertson et al., 1986, 1991; Timmers et al., 2004]. Although DβH deficiency is present from birth, the diagnosis may not be recognized until adulthood, despite ptosis of eyelids being a frequent occurrence. In some patients, the perinatal period can be complicated as a result of episodic vomiting, dehydration, hypotension, hypothermia, and profound hypoglycemia. Children have markedly reduced exercise capacity and, by adulthood, orthostatic hypotension can be debilitating.

The biochemical hallmark of this syndrome consists of minimal or undetectable plasma NE and epinephrine levels, in conjunction with a 5- to 10-fold elevation of plasma DA level. Diagnosis can be made based on this unique catecholamine profile, as DβH molecular genetic testing is available on a research basis only. The only effective treatment is l-threo-3,4-dihydroxyphenylserine (DOPS), which is converted peripherally directly into NE. Treatment with DOPS results in a sustained relief of orthostatic symptoms [Timmers et al., 2004].

Norepinephrine Transporter Deficiency

The norepinephrine transporter (NET) is a sodium-dependent 12-transmembrane-spanning protein that is located presynaptically on noradrenergic axons and varicosities, and serves to inactivate NE following release in the central and peripheral nervous system. The gene encoding NET is located on chromosome 16q12.2 [Robertson et al., 2001; Shannon et al., 2000]. Shannon et al. found that a missense mutation in exon 9 in one family resulted in nonfunctional NET and clinical symptoms of orthostatic intolerance, with postural tachycardia. Consistent with the inability to inactivate NE, the probands had elevated plasma NE and diminished conversion to the intraneuronal metabolite, dihydroxyphenylglycol (DHPG) [Shannon et al., 2000]. Treatment of NET deficiency is directed at attenuating the postural tachycardia.

Menkes’ Disease

Menkes’ disease, also known as kinky hair disease, is an infantile-onset, X-linked recessive neurodegenerative disorder caused by deficiency or dysfunction of a copper-transporting ATPase, ATP7A [Kaler et al., 2008; Menkes et al., 1962; Vulpe et al., 1993]. It was Danks et al. who noted the similarity of kinky hair to the brittle wool of Australian sheep raised in areas with copper-deficient soil, and demonstrated abnormal levels of copper and ceruloplasmin in these patients [Danks et al., 1973]. As the result of a mutation in the ATP7A gene, copper is distributed poorly to cells in the body. Copper accumulates in some tissues, such as the small intestine and kidneys, while the brain and other tissues have unusually low levels. The decreased supply of copper can reduce the activity of numerous copper-containing enzymes that are necessary for the structure and function of bone, skin, hair, blood vessels, and the nervous system. Children with the classic form of Menkes’ disease are fair-complexioned and usually present at 2–3 months of age with loss of developmental milestones, profound truncal hypotonia, and seizures; death usually occurs by 3 years of age. People with milder variants may have minimal neurologic symptoms, with normal intelligence or only mild mental retardation and autonomic dysfunction.

The clinical and pathologic features of this condition reflect decreased activities of enzymes that require copper as a co-factor, including DβH, cytochrome c oxidase, and lysyl oxidase. Deficient cytochrome c oxidase probably accounts for most of the neurologic symptoms, similar to patients with Leigh’s disease (subacute necrotizing encephalomyelopathy) who have reduced or absent cytochrome c oxidase activity and similar neuropathologic changes. Decreased lysyl oxidase activity accounts for the connective-tissue fragility and vascular abnormalities in Menkes’ disease, since lysyl oxidase deaminates lysine and hydroxylysine in the first step of collagen cross-linkage. Lysyl oxidase localizes to the trans-Golgi network, so subcutaneous injections of copper-histidine do not improve the activity of lysyl oxidase, as the copper is not delivered into the Golgi apparatus. Tyrosinase deficiency (involved in melanin biosynthesis) most likely accounts for the hypopigmentation of the hair and skin seen in Menkes’ disease. Due to the partial deficiency of DβH, patients with Menkes’ disease have a unique catecholamine profile; the ratio of dihydroxyphenylacetic acid to dihydroxyphenylglycol is distinctively elevated and there is a high ratio of dopamine to norepinephrine [Kaler et al., 1993]. These findings can be detected in the neonatal period, allowing treatment with daily copper injections to commence within days after birth. Although survival appears to be improved, clinical outcomes are variable; it has been suggested that the response to early copper treatment depends on the ATP7A genotype and that optimal outcomes occur only in patients with mutations that permit some residual copper transport [Kaler et al., 2008].

Fabry’s Disease

Fabry’s disease, or angiokeratoma corporis diffusum, is an X-linked, recessively inherited disorder that is associated with deficiency of the enzyme α-galactosidase A (ceramide trihexosidase). The enzyme deficiency results in the accumulation of ceramide trihexoside and other neutral glycosphingolipids. The condition affects hemizygous males, as well as both heterozygous and homozygous females; males tend to experience the most severe clinical symptoms, while females vary from virtually no symptoms to those as serious as in males. This variability is thought to be due to X-inactivation patterns during embryonic development of the female. There is extensive lipid deposition in various tissues that include the skin, nervous system, vascular endothelium, kidney, cardiovascular system, and eye [Brady, 1993]. There is preferential involvement of small nerve fibres and the accumulation of storage product in the central ANS and autonomic ganglia. Sural nerve biopsies have demonstrated degeneration and loss of unmyelinated fibres [Toyooka and Said, 1997], and skin biopsies show decreased intraepidermal small nerve fibers [Cable et al., 1982]. Fabry’s disease can be diagnosed by assaying the enzyme α-galactosidase A in leukocytes or skin fibroblasts.

Young males with this disorder typically present with severe episodes of lancinating pain and burning paraesthesias in the extremities, often triggered by changes in temperature. Vascular deposition result in truncal, reddish-purple, macular-papular rash and angiectases of the skin, conjunctiva, nailbed, and oral mucosa. These corpora angiokeratoma result from deposition of the glycolipid in skin; together with painful distal peripheral neuropathy, progressive renal disease, corneal opacities, and cerebrovascular accidents in adult life, they constitute the typical clinical manifestations of this disorder.

The autonomic manifestations include hypohidrosis or anhidrosis, reduced saliva and tear formation, impaired cutaneous flare response to scratch and intradermal histamine, and disordered intestinal motility. Patients’ gastrointestinal symptoms may be as severe as their sensory complaints. Pupillary constriction to dilute pilocarpine has been documented, suggesting denervation supersensitivity, although the cardiovascular autonomic reflexes in one series were normal [Cable et al., 1982].

Until recently, treatment of Fabry’s disease targeted the symptomatic effects. Currently, however, it is being treated at the cellular level through costly enzyme replacement therapy using agalsidase alpha and agalsidase beta [Hilz, 2007]. Unfortunately, enzyme replacement therapy is not a cure, and must be infused recurrently for maximum benefit.

Familial Amyloid Polyneuropathy

There are multiple types of amyloidosis but familial amyloidosis is the only one that is inherited. Symptoms do not appear until adulthood but, because the disorder is transmitted as an autosomal-dominant trait, there are strong implications for the pediatric population. Sensory, motor, and autonomic abnormalities result from deposition in peripheral nerves of a mutated amyloid protein – transthyretin, or TTR protein, which is manufactured in the liver. This typically causes numbness and tingling in the arms and legs, dizziness upon standing, and diarrhea.

Diagnosis is made by family history and DNA technology. In addition, amyloid deposits can often be identified using biopsy specimens obtained from the rectum or the abdominal fat. The major therapy is liver transplantation; it appears to prevent progression and may reverse some neuropathic features.

Thyroid Disorders

Thyroid disorders illustrate this interrelationship between the autonomic and endocrine systems. Many of the early signs of hypothyroidism, such as fatigue, dry skin, sleep disturbances, and constipation, might be interpreted as central and peripheral autonomic dysfunction. Conversely, hyperthyroidism and its extreme manifestation, thyroid storm or thyrotoxic crisis, look like excessive sympathetic activity, as fever, tachycardia, hypertension, and neurologic and gastrointestinal abnormalities are features. In fact, adrenergic receptor activation has been hypothesized as one possible mechanism. The dramatic response of thyroid storm to beta blockers and the precipitation of thyroid storm after accidental ingestion of adrenergic drugs, such as pseudoephedrine, support this theory.

Diabetes Mellitus

Diabetes mellitus is associated with autonomic neuropathy in adults. However, this association is less well recognized in the pediatric population. In one study that utilized cardiovascular reflex tests to assess autonomic involvement in children newly diagnosed with insulin-dependent diabetes mellitus, almost one-fifth of the diabetic children had cardiovascular autonomic dysfunction [Verrotti et al., 1995]. Thus, the probability of autonomic involvement in pediatric patients may be higher than previously considered. In the adult with diabetic autonomic neuropathy, morbidity and mortality are considerably higher than in those without neuropathy, and it has been implicated in the increased risk of ischemic heart disease and sudden death from cardiac arrhythmias. Other clinical features of diabetic neuropathy seen in adult patients include hypertension, as well as postural hypotension, gastrointestinal dysmotility (gastroparesis and diarrhea), and sudomotor abnormalities such as gustatory sweating. These areas need better evaluation in the pediatric population.

Addison’s Disease

Addison’s disease, or primary adrenal insufficiency, occurs when the adrenal glands are damaged and cannot produce enough of the hormone cortisol and, often, the hormone aldosterone. About 70 percent of cases in the United States are due to idiopathic atrophy of the adrenal cortex, probably caused by autoimmune processes. The remainder results from destruction of the adrenal gland by granuloma, tumor, amyloidosis, hemorrhage, or inflammatory necrosis. Other causes of hypoadrenocorticism include administration of drugs that block corticosteroid synthesis, or coexistence with another endocrine disorder, such as diabetes mellitus or hypothyroidism in polyglandular deficiency syndrome or as part of Allgrove’s syndrome, an inherited postganglionic cholinergic disorder that was described above under inherited autonomic disorders. In children, the most common cause of primary adrenal insufficiency is congenital adrenal hyperplasia.

Primary adrenal failure produces various symptoms, including hypotension and hyperpigmentation, and can lead to adrenal crisis with cardiovascular collapse. The hypotension is due to mineralocorticoid deficiency, which results in increased excretion of sodium and decreased excretion of potassium, with subsequent low serum concentration of sodium and high concentration of potassium. Inability to concentrate the urine, combined with changes in electrolyte balance, produce severe dehydration, plasma hypertonicity, acidosis, decreased circulatory volume, hypotension, and, eventually, circulatory collapse.

Among the early symptoms are weakness, fatigue, and orthostatic hypotension. Hyperpigmentation usually is noted on pressure points (bony prominences), skin folds, scars, and extensor surfaces. Anorexia, nausea, vomiting, and diarrhea also occur and there may be complaints of dizziness and syncope. The postural hypotension can become extremely problematic. Diagnosis is made by assessment of electrolytes, and by noting low cortisol and aldosterone levels with elevated ACTH levels. Imaging tests can be used to determine adrenal gland size and to rule out a mass.

Treatment consists of synthetic cortisol preparations, such as cortisone or hydrocortisone, and synthetic preparations of fludrocortisone in patients with reduced aldosterone levels. Correct dosing of cortisol is accomplished by monitoring urine cortisol levels, and mineral status due to low aldosterone is measured with serum potassium levels and plasma renin concentrations. Doses may need to be increased during times of stress or infection.

Idiopathic Autonomic Neuropathy and Paraneoplastic Disorders

These two disorders are more likely to occur in the adult population but are worth noting as a model of how an autoimmune process can be associated with autonomic failure. Idiopathic autonomic neuropathy and the paraneoplastic disorders are characterized by seropositivity for antibodies that bind to or block ganglionic acetylcholine receptors [Vernino et al., 2000]. In patients with idiopathic autonomic neuropathy, severe panautonomic failure develops in a subacute manner (over a period of days or weeks). Recovery is slow and usually incomplete. Sympathetic failure is manifested as severe orthostatic hypotension and anhidrosis, and parasympathetic failure as dry mouth, sexual dysfunction, an impaired pupillary response to light and accommodation, and a fixed heart rate [Suarez et al., 1994]. Many patients have gastrointestinal dysmotility and present with anorexia, early satiety, abdominal pain and vomiting after eating, constipation, or diarrhea. Motor-nerve and sensory-nerve abnormalities are minimal or absent. Similarly, with some types of cancer, especially small-cell carcinoma of the lung, a syndrome of subacute autonomic failure can occur, which is an indirect immunologic effect of the cancer [Khurana, 1997]. Vernino et al. were able to demonstrate a significant correlation between the serum level of ganglionic-receptor-binding antibody and the severity of autonomic dysfunction in both disorders [Vernino et al., 2000]. In addition, they noted that decreases in antibody levels were accompanied by improvement in clinical and laboratory measures of autonomic function.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is characterized by chronic or relapsing fatigue, lasting for at least 6 months, causing impaired overall physical and mental functioning [Fukuda et al., 1994]. As physical findings are limited, chronic fatigue syndrome often is a diagnosis of exclusion. Self-reported symptoms can include cognitive difficulties, muscle pain, joint pain, headache, sleep disturbance, poor sleep, and post-exercise malaise, as well as a variety of gastrointestinal symptoms [Carter et al., 1995; Fukuda et al., 1994; Rowe et al., 1995]. As the onset of symptoms often follows an infectious disease, an autoimmune mechanism has been postulated [Buchwald et al., 1997; Clements et al., 1995]. According to a report generated from a Centers for Disease Control and Prevention workshop [Fukuda et al., 1994], pediatric chronic fatigue syndrome patients mostly are teenage females who report a preceding inflammatory condition. As in the adult experience, adolescents with chronic fatigue syndrome frequently exhibit orthostatic intolerance with POTS [Rowe et al., 1995; Stewart et al., 1999]. Stewart et al. have demonstrated loss of heart rate variability consistent with vagal withdrawal, increased blood pressure variability consistent with enhanced modulation of sympathetic tone, and impaired baroreflex [Stewart et al., 1999].

Without a definitive etiology for CFS and definitive pathophysiology, treatment only can be supportive. Nonpharmacologic therapies include light exercise and patient education, as well as increased salt and water intake. Pharmacologic therapy includes fludrocortisone for severe orthostatic symptoms and beta blockers to control the tachycardia.

Cyclic Vomiting Syndrome

Cyclic vomiting syndrome (CVS) is characterized by severe, discrete episodes of nausea, vomiting, and lethargy of unclear etiology, with baseline return to health between episodes [Stein et al., 2001; Stickler, 2005]. Although CVS occurs in all age groups, it predominantly affects children with symptoms appearing between 3 and 7 years, and frequently evolves into migraine headaches in adulthood [Stickler, 2005]. Common triggers are emotional or physical stress, including exercise, menstruation, motion, and even particular foods, such as chocolate. CVS has been described as having four phases. The symptom-free interval phase is the period between episodes. The prodrome phase precedes the onset of vomiting and is characterized by nausea, usually with abdominal pain and occasionally with headache, photophobia, or vertigo. The length of the prodrome phase varies from moments to several hours. The vomiting phase consists of nausea and vomiting, and patients may require hospitalization for rehydration. In addition, autonomic symptoms usually are exhibited, including pallor, increased salivation, diaphoresis, increased blood pressure, diarrhea, dizziness, and lethargy. The final phase is the recovery phase, which begins when the nausea and vomiting stop and there is a return of appetite and energy.

The terms CVS and abdominal migraine often have been used interchangeably because of overlap in clinical criteria. As 80 percent of children with CVS have abdominal pain, and 50 percent of those with abdominal migraine vomit, many children can be diagnosed with either CVS or abdominal migraine. Both CVS and abdominal migraine feature recurrent, stereotypical, and severe episodes of abdominal pain, intervals of well periods, autonomic symptoms, and a family history of migraine headaches.

Autonomic testing in patients with CVS has demonstrated increased sympathetic modulation, as reflected in heart-rate variability and postural intolerance [Rashed et al., 1999; To et al., 1999], but the diagnosis of CVS is made by history rather than by specific tests. Criteria include five vomiting episodes, or a minimum of three episodes over a 6-month period, and stereotypical pattern and symptoms in the individual patient, with a return to baseline health between episodes and no other existing condition. The cause of CVS is unknown, but genetic factors have been suggested, as a subset of children with CVS has maternal inheritance and an associated mitochondrial DNA variation [Wang et al., 2004]. Furthermore, children with mitochondrial myopathy frequently have both severe migraines and episodic vomiting.

In the absence of known pathophysiology, treatment of CVS remains empiric. In addition to avoidance of triggers, pharmacologic therapy may be used in patients with more than a single episode of CVS per month. The preventative treatments that have been tried include cyproheptadine, amitriptyline, propranolol, phenobarbital, and erythromycin [Li and Balint, 2000]. If abortive therapy fails, supportive combinations, such as ondansetron plus lorazepam, or chlorpromazine plus diphenhydramine, may attenuate a cyclic vomiting attack. If psychological stressors trigger episodes, stress management techniques or benzodiazepine anxiolytics may help to abort attacks in the early stages. A family history positive for migraines predicts a high response rate (80 percent) to antimigraine medications [Li and Balint, 2000].

Functional Abdominal Pain

The association of functional abdominal pain and autonomic dysfunction in children still is poorly understood. It is not uncommon for children with functional gastrointestinal disorders to report various autonomic symptoms, including dizziness, headaches, flushing, sweating, Raynaud’s phenomenon, and severe fatigue [Chelimsky et al., 2001]. In addition, a subset of children with functional abdominal pain has been noted to have POTS and mild peripheral neuropathy. Patients with functional abdominal pain often respond favorably to treatments directed towards the ANS dysfunction, such as relaxation and guided imagery, and medical treatment, such as increasing dietary salt, fludrocortisone, and beta blockers [Sandroni et al., 1999].