Axelrod et al. (1983) stated that the clinical diagnosis of familial dysautonomia is based on the presence of 5 signs: lack of axon flare after intradermal injection of histamine, absence of fungiform papillae on the tongue, miosis of ... Axelrod et al. (1983) stated that the clinical diagnosis of familial dysautonomia is based on the presence of 5 signs: lack of axon flare after intradermal injection of histamine, absence of fungiform papillae on the tongue, miosis of the pupil after conjunctival instillation of methacholine chloride (2.5%), absent deep tendon reflexes, and diminished tear flow. However, they noted that consistent neuropathologic findings in sural nerve biopsies may be the best diagnostic criterion to differentiate familial dysautonomia from other forms of congenital sensory neuropathy. Axelrod et al. (1983) reported the case of a gypsy child with congenital sensory neuropathy who had all 5 signs in addition to skeletal abnormalities, dysmorphic features, and hypohidrosis, but whose sural nerve biopsy was inconsistent with dysautonomia. The authors noted that many non-Jewish cases of 'familial dysautonomia' may be another form of congenital sensory neuropathy (e.g., 201300, 256800). Axelrod et al. (1987) suggested that the possibility of familial dysautonomia should be suspected in a child of Eastern European Jewish extraction with breech delivery, meconium staining, poor suck, hypotonia, or hypothermia. The diagnosis could be confirmed by inspection of the tongue for fungiform papillae, determination of deep tendon reflexes, and performance of intradermal histamine and intraocular pilocarpine tests. If results in either of the latter 2 tests are normal or equivocal, they should be repeated after 6 weeks of age. - Prenatal Diagnosis Eng et al. (1995) used CA-repeat polymorphisms located in the 9q31-q33 region for prenatal diagnosis of familial dysautonomia. All 7 families studied were informative for the markers, and fetal diagnoses were made in 8 pregnancies. Six fetal diagnoses were predicted with more than 98% accuracy, whereas 2 with recombinations were predicted with at least 88% and 92% accuracy. Using linkage and linkage disequilibrium analyses with highly polymorphic dinucleotide repeat markers known to flank the familial dysautonomia locus, Oddoux et al. (1995) performed prenatal diagnosis in 8 pregnancies in 7 informative families. All of the fetuses were predicted to be heterozygous unaffected; 7 had come to term and were normal.
Riley et al. (1949) first described this disorder in 5 Jewish patients with autonomic dysfunction and defective lacrimation. Other features included episodic hypertension, hyperhidrosis, cyclic vomiting, and skin blotching. Smith and Dancis (1963) noted the lack of an ... Riley et al. (1949) first described this disorder in 5 Jewish patients with autonomic dysfunction and defective lacrimation. Other features included episodic hypertension, hyperhidrosis, cyclic vomiting, and skin blotching. Smith and Dancis (1963) noted the lack of an axon flare after intradermal histamine, and Smith et al. (1965) noted the absence of fungiform papillae on the tongue. These authors also described Ashkenazi Jewish heritage and decreased deep tendon reflexes. In an extensive review of 210 children with familial dysautonomia from 172 families, Brunt and McKusick (1970) concluded that FD is an autosomal recessive disorder occurring almost exclusively in persons of Ashkenazi Jewish descent. Common features included alacrima, absence of lingual fungiform papillae with impaired taste, vasomotor instability, hypoactive or absent deep tendon reflexes, and relative indifference to pain and temperature. Patients showed incoordination, and neuropathic joints and scoliosis were often seen. Although emotional instability occurred, intellect was unimpaired. Patients also showed increased sensitivity to adrenergic and cholinergic agents, suggesting functional autonomic denervation. Axelrod et al. (1981) demonstrated clinical variability in sensory impairment among 75 patients with FD. Older patients tended to have increased dysfunction in pain sensation, joint position and Romberg sign, and vibratory sense. Testing after a 5-year interval showed significant worsening with increased age. Pearson et al. (1980) demonstrated glomerulosclerosis in 10 or 13 autopsied and biopsied patients with familial dysautonomia. Sympathetic nerve terminals could not be identified in renal vessels from the patients, whereas they were demonstrated in controls. In a review of 79 patients, elevated serum creatinine (32% of patients) and blood urea nitrogen (76% of patients) were found, and an association was found between hypotension and renal dysfunction. Pearson et al. (1980) suggested that altered renovascular responsivity to systemic hypotension in the disorder may lead to ischemia and subsequent sclerosis of glomeruli. In patients with FD, Gadoth et al. (1983) found a prolonged pupil cycle time (light response) and interpreted it as indicative of denervation hypersensitivity. Parenterally administered Mecholyl caused overflow tearing and temporary normalization of deep tendon reflexes and response to intradermal histamine, suggesting functional rather than structural denervation. Axelrod and Abularrage (1982) reported on survival in dysautonomia. From 1969 to 1982, 227 patients had been referred to the Dysautonomia Center at New York University. At the time of report, 59 patients were 20 years of age or older and accounted for 33% of the living patients. The oldest was 38 years old. Axelrod (1998) provided an update of the patients at the Dysautonomia Center. In 1998, 40% of the active population of 307 patients were over the age of 20 years. In addition to worsening peripheral sensory dysfunction, the adults complained of poor balance, unsteady gait, and difficulty concentrating. They were prone to depression, anxieties, and even phobias. Sympathovagal balance became more precarious with worsening of orthostatic hypotension, development of supine hypertension, and even occasional bradyarrhythmias. Fishbein and Grossman (1986) described the pulmonary complications in a 29-year-old man with familial dysautonomia. In an extensive review of HSAN3, Axelrod and Hilz (2003) noted that autonomic disturbances are very prominent, including alacrima, episodic hyperhidrosis, and vasomotor and cardiovascular perturbations. Patients can exhibit both extreme hypertension and profound and rapid postural hypotension without compensatory tachycardia. There is also a relative insensitivity to hypoxemia. Patients often experience episodes termed 'dysautonomic crises,' which are characterized by nausea and vomiting, agitation, tachycardia, and hypertension, and are often triggered by emotional or physical stress. Somatic growth is poor, and by 10 years of age, 85% of patients have scoliosis. Seizures with decerebrate posturing can follow breath-holding episodes. - Pathologic Findings Brown et al. (1964) described autopsy findings in 2 Jewish sibs with HSAN3, which included demyelination in the medulla, pontine reticular formation, and dorsolongitudinal tracts, and degeneration, pigmentation, and loss of cells in autonomic ganglia. Pearson et al. (1975) reported that sural nerve biopsy from patients with HSAN3 showed reduced transverse fascicular area, diminished numbers of myelinated axons, especially those of small diameter, and very few nonmyelinated axons. In addition, catecholamine-containing nerve endings were not identified in accompanying arteries. The authors noted that the changes were compatible with the clinical phenotype. Pearson et al. (1978) stated that intrauterine development and postnatal maintenance of dorsal root ganglion neurons are abnormal in FD. They found that neurons in dorsal root ganglia were markedly diminished in young patients and continued to deplete with increasing age. Quantitative studies on C8 dorsal root ganglia showed that FD patients had as little as 10% the number of neurons as controls, with the smallest number being in the oldest patient. Lateral spinal root entry zones and loss of dorsal column myelinated axons were also found. The findings correlated with clinical features of diminished sensation and coordination of limb movements. In adult patients with FD, Pearson and Pytel (1978) found that the mean volume of superior cervical sympathetic ganglia was reduced to 34% of normal. The mean totals of preganglionic neurons in the first 3 thoracic cord segments were reduced by about 50%. The authors noted that defects in sympathetic neurons account for many of the autonomic manifestations of the disorder.
Slaugenhaupt et al. (2001) and Anderson et al. (2001) demonstrated that the major haplotype of familial dysautonomia is associated with a mutation in the IKBKAP gene (603722.0001). A minor haplotype was found to be associated with a different ... Slaugenhaupt et al. (2001) and Anderson et al. (2001) demonstrated that the major haplotype of familial dysautonomia is associated with a mutation in the IKBKAP gene (603722.0001). A minor haplotype was found to be associated with a different mutation (R696P; 603722.0002).
In the United States, HSAN3 is a disorder almost completely limited to persons of Ashkenazi Jewish extraction (Brunt and McKusick, 1970). In Israel, as in the United States, most cases were Ashkenazim from Poland, according to Goldstein-Nieviazhski and ... In the United States, HSAN3 is a disorder almost completely limited to persons of Ashkenazi Jewish extraction (Brunt and McKusick, 1970). In Israel, as in the United States, most cases were Ashkenazim from Poland, according to Goldstein-Nieviazhski and Wallis (1966). Maayan et al. (1987) calculated an incidence of 1 in 3,703 for familial dysautonomia among Ashkenazi Jews in Israel. Rare non-Jewish cases of presumed familial dysautonomia have been reported (e.g., Burke, 1966), but the diagnosis is usually in question. For example, the patient of Burke (1966) was later seen by Rogers (1993) who concluded that although the patient had a hereditary sensory neuropathy, the disorder was not familial dysautonomia. However, Leyne et al. (2003) identified a patient, previously described by Blumenfeld et al. (1999), who fulfilled all diagnostic criteria other than pure Ashkenazi Jewish ancestry (the patient's mother was of Irish-German/Sicilian heritage) and identified a novel mutation in the IKBKAP gene (603722.0003).
Prior to the introduction of clinical molecular genetic testing, the diagnosis of familial dysautonomia (FD) relied on the clinical recognition of both sensory and autonomic dysfunction and the presence of at least one parent of Ashkenazi Jewish ancestry. It was necessary for the following six cardinal features to be present in each affected individual: ...
DiagnosisClinical DiagnosisPrior to the introduction of clinical molecular genetic testing, the diagnosis of familial dysautonomia (FD) relied on the clinical recognition of both sensory and autonomic dysfunction and the presence of at least one parent of Ashkenazi Jewish ancestry. It was necessary for the following six cardinal features to be present in each affected individual: Hypotonia in infancy Decreased or absent deep tendon reflexes Decreased taste and absence of fungiform papillae of the tongue, giving it a smooth, pale appearance Absence of overflow tears with emotional crying (alacrima). Either history or the Schirmer test is used to establish this finding. As newborns do not cry tears, the Schirmer test must be performed after age six months. In the Schirmer test, the end of a filter paper, 5 mm wide and 35 mm long, is placed in the lateral portion of a lower eyelid. Less than 10 mm of wetting of the filter paper after five minutes indicates diminished baseline and reflex tear secretion. Absence of axon flare response after intradermal histamine injection Pupillary hypersensitivity to parasympathomimetic agents. Topical administration of methacholine 2.5% or pilocarpine 0.0625% has no observable effect on the normal pupil but causes miosis after approximately 20 minutes in almost all individuals with FD. Note: (1) Some non-Jewish individuals reported to have FD have hereditary sensory and autonomic neuropathies (HSANs) other than FD. (2) At least one non-Jewish individual has had molecularly confirmed FD [Leyne et al 2003].Molecular Genetic TestingGene. IKBKAP is the only gene in which mutation is known to cause FD. Clinical testing Targeted mutation analysis. Two mutations account for more than 99% of mutant alleles in individuals with FD of Ashkenazi Jewish descent [Dong et al 2002]. The major founder mutation c.2204+6T>C, formerly IVS20+6T>C, is responsible for virtually all occurrences of FD among the Ashkenazim. The p.Arg696Pro mutation is rarely identified. Sequence analysis of the entire coding region identifies rare mutations. A proline-to-leucine missense mutation in exon 26, p.Pro914Leu, was identified in an individual with FD who is not of Ashkenazi Jewish heritage [Leyne et al 2003]. Table 1. Summary of Molecular Genetic Testing Used in Familial DysautonomiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1 Test AvailabilityIKBKAPTargeted mutation analysis c.2204+6T>C, p.Arg696Pro 2>99% (Ashkenazi Jewish population) 3 Clinical Sequence analysisSequence variants 4Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Targeted mutations may vary by laboratory.3. Dong et al [2002]4. Small intragenic deletions/insertions, missense, nonsense, and splice site mutationsInterpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyConfirming/establishing the diagnosis in a proband. For patients with clinical findings suggestive of familial dysautonomia, especially those of Ashkenazi Jewish ancestry, clinical suspicion alone is sufficient to proceed to molecular genetic testing to confirm the diagnosis.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in IKBKAP.
Familial dysautonomia (FD) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease that is present from birth. Progressive neuronal degeneration continues throughout life. Affected individuals have gastrointestinal dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain and temperature, and cardiovascular instability (Table 2) [Axelrod 1996, Axelrod 1999, Axelrod 2002]. ...
Natural HistoryFamilial dysautonomia (FD) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease that is present from birth. Progressive neuronal degeneration continues throughout life. Affected individuals have gastrointestinal dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain and temperature, and cardiovascular instability (Table 2) [Axelrod 1996, Axelrod 1999, Axelrod 2002]. Infants and young children have varying degrees of hypotonia, contributing to delay in motor milestones. Episodic somnolence has been reported [Casella et al 2005]. In older individuals, the gait is often broad-based and ataxic. Progressive deterioration in gait occurs over time. Individuals with FD have difficulty performing rapid movements and maintaining their balance while changing direction or turning.Pain insensitivity may result in failure to recognize fractures or inadvertent trauma to joints.FD has always been recognized as a potentially life-threatening disorder with a high mortality rate and is associated with a high incidence of sudden death. Causes of death are primarily pulmonary (26%) and unexplained (38%); the latter may result from unopposed vagal stimulation. Sepsis is also a significant cause of death (11%). Axelrod [2002] showed that improved supportive treatment has extended survival and the probability of an individual with FD reaching age 20 years has now increased to 60%. Renal function tends to deteriorate with advancing age, possibly secondary to renal hypoperfusion from recurrent dehydration, postural hypotension, or vasoconstriction from sympathetic supersensitivity during autonomic crises. Persons with FD are far more likely than the general population to develop end-stage renal disease (ESRD). Elkayam et al [2006] reported that of individuals with FD alive at age 25 years, 19% eventually required dialysis, as compared with the national average of approximately 0.1%. Almost all persons with FD who reach their fourth decade have a markedly decreased glomerular filtration rate. The absence of feeding gastrostomy tube placement early in life and a greater extent of orthostatic hypotension appear to be risk factors for ESRD [Elkayam et al 2006].Table 2: Clinical Manifestations of Familial DysautonomiaView in own windowSystem Involved Clinical Manifestations Sensory system • Insensitivity to pain (sparing hands, soles of feet, neck, and genital areas) 1• Abnormal temperature appreciation on the trunk and lower extremities 1 • Depressed patellar reflexes Autonomic system• Oropharyngeal incoordination (60% of neonates) • Esophageal dysmotility, gastroesophageal reflux 1• Insensitivity to hypercapnea and hypoxia 2• Breath holding • Orthostatic hypotension without compensatory tachycardia 1, 3• Supine hypertension 1 Motor system • Hypotonia • Mild/moderate developmental delay • Broad-based or mildly ataxic gait 1 • Spinal curvature (95%, especially kyphosis) 1 Cranial nerves • Absence of overflow tears • Depressed corneal reflexes • Optic nerve atrophy 1 • Strabismus • Deficient taste, especially sweet • Dysarthric, nasal speech Intelligence/personality• Usually normal intelligence (verbal skills better than motor) • Concrete or literal thinking • Skin picking (especially fingers and nose) • Resistance to change (phobias) 1 Adapted from Axelrod [1996] 1. Progressive neurologic abnormalities 2. Bernardi et al [2003] 3. Brown et al [2003]Oropharyngeal incoordination is manifest as poor sucking or discoordinated swallowing. It often persists and predisposes to aspiration pneumonia. Autonomic crises occur in about 40% of individuals and are characterized by the following [Axelrod 1996]: Excessive sweating of the head and trunk Erythematous blotching of the face and trunk Mottling (cutis marmorata) of distal extremities Hypertension and tachycardia Nausea/vomiting Severe dysphagia/drooling Irritability Insomnia Worsening of muscle tone Clinical manifestations of orthostatic hypotension worsen with age and include light-headedness or dizzy spells. Urinary incontinence is common in adolescent and adult women [Saini et al 2003]. Sexual maturation is frequently delayed, but sexual development is normal in both sexes. Women with FD have delivered normal infants following uncomplicated pregnancies. Fertility in males has been reported; one male has fathered six children. Using a questionnaire to evaluate the quality of life in persons with FD, Sands et al [2006] determined that FD imposed a greater physical than psychosocial burden on children, whereas young adults reported both mental and physical quality of life within the average range. Self-esteem was problematic and improved with age. Both age groups reported decreasing physical quality of life with age, with worsening general health that limited their role at school or work [Sands et al 2006].Neuropathology Sensory nervous system. The dorsal root ganglia are progressively reduced in size and number with time. Loss of dorsal column myelinated axons occurs over time. The transverse fascicular area of the sural nerve in affected individuals of all ages is decreased because of reduction in the number of nonmyelinated axons and small-diameter myelinated axons. These characteristic findings allow differentiation from other sensory neuropathies. Sympathetic nervous system. The number of neurons is decreased in sympathetic ganglia. Autonomic nerve terminals are absent in peripheral blood vessels. Parasympathetic nervous system. The size and number of parasympathetic ganglia are decreased, but not as consistently as in the sympathetic nervous system.
None has been observed [Blumenfeld et al 1999]. ...
Genotype-Phenotype CorrelationsNone has been observed [Blumenfeld et al 1999]. The p.Arg696Pro mutation is extremely rare in the Ashkenazi Jewish population and has never been detected in a homozygous state; therefore, the phenotype associated with p.Arg696Pro homozygosity is unknown.
Hereditary sensory and autonomic neuropathies (HSANs). Familial dysautonomia (FD) belongs to the family of HSANs [Hilz 2002]. Five HSANs are recognized: ...
Differential DiagnosisHereditary sensory and autonomic neuropathies (HSANs). Familial dysautonomia (FD) belongs to the family of HSANs [Hilz 2002]. Five HSANs are recognized: HSAN I. Hereditary sensory neuropathy type I (HSN1) is an axonal form of hereditary motor and sensory neuropathy distinguished by prominent early sensory loss and later positive sensory phenomena including dysesthesia and characteristic "lightning" or "shooting" pains. Loss of sensation can lead to painless injuries, which, if unrecognized, result in slow wound healing and subsequent osteomyelitis requiring distal amputations. HSN1 is often associated with progressive sensorineural deafness. Motor involvement is present in all advanced cases and can be severe. After age 20 years, the distal wasting and weakness may involve proximal muscles so that in later life a wheelchair may be required for mobility. Drenching sweating of the hands and feet is sometimes reported and rare individuals have pupillary abnormalities; visceral signs of autonomic involvement are not present. Inheritance is autosomal dominant. Mutations in SPTLC1 are identified in about 90% of individuals with a positive family history and about 10% of simplex cases (i.e., a single occurrence in a family). HSAN II (Morvan disease; acrodystrophic neuropathy). Symptoms occur in infancy or early childhood. Affected individuals have acral anhidrosis; ulcers, paronychia, whitlows, or other trophic changes of the fingers and toes; and other autonomic dysfunction including tonic pupils, oromotor incoordination, constipation from gastrointestinal dysmotility, bladder dysfunction, intermittent fevers, impaired sensory perception, hypotonia, and apnea. Unrecognized injuries and neuropathic arthropathy (Charcot joint) occur. Except for decreased or absent tendon reflexes, general neurologic examination is normal. Inheritance is autosomal recessive. HSAN III is familial dysautonomia. HSAN IV (congenital insensitivity to pain with anhidrosis [CIPA]). Affected individuals have impaired autonomic, sensory, and motor function. CIPA closely resembles FD. Anhidrosis predisposes to high fevers if not managed properly. Insensitivity to superficial and deep pain results in mutilation (e.g., of tongue and cheek), neuropathic joints, risk for unrecognized injuries (burns, fractures), and corneal ulceration. Intellectual disability occurs. Inheritance is autosomal recessive. CIPA is caused by a mutation in NTRK1 [Indo 2002]. HSAN V. Individuals have a selective loss of pain perception but normal response to tactile, vibratory, and thermal stimuli. Neurologic examination is otherwise normal. The finding that a boy diagnosed with HSAN V was homozygous for a mutation in NTRK1 suggested that HSAN IV and HSAN V may be allelic [Houlden et al 2001]. However, the report of a child with HSAN V with no mutations in NTRK1 suggested that another gene or genes were causative in some individuals [Toscano et al 2002]. More recently, three severely affected individuals with HSAN V born to consanguineous parents in a large Swedish family were homozygous for a mutation in NGFB [Einarsdottir et al 2004]. Stüve-Wiedemann syndrome. Affected individuals have a combination of autonomic nervous system symptoms resembling FD and characteristic bony changes (bowing of long bones, camptodactyly) [Di Rocco et al 2003].
To establish the extent of neurologic and intellectual impairment in an individual diagnosed with familial dysautonomia, the following evaluations are recommended: ...
ManagementEvaluations Following Initial Diagnosis To establish the extent of neurologic and intellectual impairment in an individual diagnosed with familial dysautonomia, the following evaluations are recommended: Standardized intelligence tests frequently demonstrate better verbal than motor performance.Electroencephalography can identify epileptic activity, although seizures with decerebrate posturing can follow breath holding even in children with normal EEG findings. Magnetic resonance imaging (MRI) frequently shows generalized atrophy, including in the cerebellum, which may contribute worsening of the ataxic gait and greater balance problems. Treatment of ManifestationsFeeding problems. Maintain adequate nutrition and avoid aspiration. For infants, thickened formula and different-shaped nipples are useful in managing orophyaryngeal incoordination. Gastroesophageal reflux. Upright positioning with feeds, prokinetic agents, H2 antagonists, and gastrostomy with or without fundoplication are appropriate. Vomiting crises are treated with intravenous or rectal diazepam (0.2 mg/kg q3h) and rectal chloral hydrate (30 mg/kg q6h), and IV administration of fluids to prevent dehydration. Chronic lung disease from recurrent aspiration pneumonia is treated with daily chest physiotherapy (nebulization, bronchodilators, and postural drainage). Giarraffa et al [2005] determined that the use of high-frequency chest-wall oscillation improved all measured health outcomes significantly, including pneumonias, hospitalizations, antibiotic courses, antibiotic days, doctor visits, absenteeism, and oxygen saturation. Orthostatic hypotension. Therapeutic measures include hydration, elastic stockings, and leg exercises to increase muscle tone and reduce pooling of blood in the veins of the legs. To determine whether fludrocortisone is effective in treating postural hypotension and whether it has an effect on survival and secondary long-term FD problems, Axelrod et al [2005] compared fludrocortisone-treated patients with untreated patients and found that cumulative survival was significantly higher during the first decade in treated versus untreated patients. In subsequent decades, the addition of midodrine improved cumulative survival. Fludrocortisone significantly increased mean blood pressure and decreased dizziness and leg cramping, but not headaches or syncope. Fludrocortisone was associated with more long-term problems, which may reflect that longer survival is associated with more symptoms.Counter-maneuvers (e.g., squatting, bending forward, and abdominal compression) improve orthostatic blood pressure in persons with FD mainly by increasing cardiac output [Tutaj et al 2006]. Squatting had the greatest effect. However, the suitability and effectiveness of a specific counter-maneuver depend on the orthopedic and/or neurologic complications identified in each individual.Hypertension. Attention to factors precipitating hypertension rather than use of antihypertensive agents is appropriate because blood pressure is labile. Bradyarrhythmia. Speculating that fatal bradyarrhythmia is an etiologic factor in sudden death associated with FD, Gold-von Simson et al [2005] studied 20 persons with FD with a history of syncope and cardiac arrest and concluded that a pacemaker may protect from fatal bradyarrhythmia and may decrease the incidence of syncope. Eyes. Decreased corneal sensation and absence of tearing predispose to corneal ulcerations, which can be managed with artificial tear solutions containing methylcellulose administered three to six times daily, maintenance of normal body hydration, and moisture chamber spectacle attachments. Soft contact lenses can promote corneal healing. Tarsorrhaphy is reserved for treatment of corneal injury that is unresponsive to these measures. Corneal transplantation has had limited success. Spine. Spinal fusion may be necessary. Other. Many adults use walkers or wheelchairs when outside the home. Prevention of Secondary ComplicationsUse of general anesthetics requires adequate hydration.Fitting of braces requires care as reduced sensitivity to pain may cause decubitus ulcers to develop at pressure points.Exercise can help correct or prevent secondary contractures. SurveillanceRegular monitoring of blood pressure and optimal management of blood pressure lability could prevent some of the neurologic progression with age since this can be associated with compromised cerebral perfusion. Adequate hydration can be monitored by blood urea nitrogen levels. Other cardiovascular problems that can worsen with age (e.g., a greater degree of postural hypotension, worsening of supine hypertension, development of ischemic glomerulosclerosis and cardiac arrhythmias) warrant routine monitoring [Axelrod & Gold-von Simson 2007].Annual examination of the spine for early evidence of scoliosis allows timely institution of bracing and exercise therapy.Agents/Circumstances to Avoid Symptoms tend to be worse in hot or humid weather; patients should try to avoid being outdoors in such conditions as far as possible. Other situations that can exacerbate disease manifestations include a full bladder; frequent visits to the lavatory are recommended [Axelrod & Gold-von Simson 2007]. Since long car rides, coming out of a movie theater, or fatigue can also worsen symptoms, such situations should be avoided to the extent that this is possible [Axelrod & Gold-von Simson 2007]. Episodic hypertension can occur in response to emotional stress or visceral pain, and therefore patients should also try to avoid these [Axelrod & Gold-von Simson 2007].Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationGrowth hormone treatment improved growth velocity during the first year of treatment (from 5-6 cm/y to >7 cm/y) in 13 individuals studied by Kamboj et al [2004]. The long-term effect is still undetermined. Clonidine, which augments baroreflex sensitivity and parasympathetic modulation in familial dysautonomia, stabilizes the cardiovascular system and may attenuate feeding-induced crises [Marthol et al 2003].FD results from an intron 20 mutation that causes a unique pattern of tissue-specific exon skipping. Accurate splicing of the mutant allele is particularly inefficient in the nervous system. Slaugenhaupt et al [2004] showed that treatment with the plant cytokinin kinetin alters splicing of IKBKAP and significantly increases inclusion of exon 20 from the endogenous gene. Hims et al [2007] demonstrated that treatment of FD lymphoblast cell lines with kinetin increases IKBKAP mRNA and Elongator complex protein 1 (Elp1, also known as IKBKAP or IKAP) to normal levels and that deletion of a region at the end of IKBKAP exon 20 disrupts the ability of kinetin to improve exon inclusion. In a later study, Gold-von Simson et al [2009] investigated whether oral kinetin altered IKBKAP splicing in vivo. They administered kinetin to 29 healthy carriers of the major IKBKAP mutation associated with FD and monitored adverse effects, as well as kinetin and IKBKAP mRNA levels. After eight days they found that IKBKAP mRNA expression in leukocytes increased as kinetin levels increased and noted that these findings strongly suggest a therapeutic role for kinetin in FD. The isolation of human induced pluripotent stem cells (iPSCs) offers a novel strategy for modeling human disease. In a recent study, Lee et al [2009] derived patient-specific FD-iPSCs from three persons with familial dysautonomia and performed directed differentiation into cells of all three germ layers including peripheral neurons. They exposed FD-iPSC-derived neural crest precursors to kinetin, which resulted in a dramatic reduction of the mutant IKBKAP splice form. In contrast, no significant improvements in IKBKAP splicing were observed after ECGC or tocotrienol exposure. The kinetin-mediated decrease in mutant IKBKAP was associated with an increase in normal IKBKAP levels and the ratio of normal:mutant transcript. No significant increase in normal IKBKAP transcript levels was observed after kinetin treatment of neural crest precursors derived from control iPSCs. Although short-term (1-day or 5-day) kinetin treatment of FD-iPSC-derived neural crest precursors had considerable effects on IKBKAP splicing, it did not result in a significant increase in the expression of neurogenic markers or improve migration behavior. They next tested the effect of continuous (28-day) kinetin treatment of FD-iPSCs starting at the pluripotent stage one day before differentiation. Notably, continuous kinetin treatment induced a significant increase in the percentage of differentiating neurons and in the expression of key peripheral neuron markers such as ASCL1 and SCG10 at the neural crest precursor stage. No significant increase was observed in FD-iPSC neural crest precursor cell migration, suggesting incomplete restoration of disease phenotype. The authors note that while future studies will be required to define the developmental windows of kinetin action in greater detail, these data indicate that long-term treatment beginning in the early stage may be particularly beneficial in persons with FD.In vitro studies have shown that tocotrienols (members of the vitamin E family) can increase the amount of induced functional Elp1 protein in individuals with FD. Since the most common mutation in FD interferes with the splicing of the mRNA, thus allowing production of both the normal and abnormal transcripts, this type of change induced by tocotrienols may offer a possible therapy relevant to most individuals [Anderson et al 2003a]. Anderson & Rubin [2005] found that individuals with FD have reduced MAO A mRNA levels, and that FD-derived cells, stimulated with tocotrienols or (-)-epigallocatechin gallate (EGCG, a major polyphenolic antioxidant present in green tea that has been reported to block carcinogenesis, inhibit the growth, and induce apoptosis of cancer cells, modulate gene expression, and possess anti-microbial activity against bacteria, fungi, and viruses) to produce increased levels of functional Elp1, expressed increased amounts of MAO A mRNA transcript and protein. They found that administration of tocotrienol to individuals with FD resulted in increased expression of both functional Elp1 and MAO A transcripts in peripheral blood cells and suggested that this demonstrates the value of therapeutic approaches designed to elevate cellular levels of functional Elp1 and MAO A. In another study, Anderson et al [2003b] investigated the possible role of EGCG, which is known to reduce the levels of hnRNP A2/B1 protein and hnRNP A2/B1 gene promoter activity in FD-derived cells and increase the amount of the wild-type IKBKAP-encoded transcript and functional protein. The known ability of tocotrienols to elevate the level of transcription of IKBKAP prompted the authors to investigate the combined impact of EGCG and tocotrienols on the amount of exon 20-containing IKAP transcript and IKAP protein produced in FD-derived cells; they found that the combination of these agents — which by themselves failed to substantially increase the level of the exon 20-containing IKAP transcript and IKAP protein — resulted in a significantly increased level of transcript and protein. The authors noted that these findings suggest the possible use of EGCG as a therapeutic modality for patients with FD. In a later study, Rubin et al [2008] examined the impact of tocotrienols on the frequency of hypertensive crises and cardiac function. After three to four months of tocotrienol ingestion, 80% of the patients reported a significant (50%) decrease in the number of crises. In a smaller group of patients, most exhibited a post-exercise increase in heart rate and a decrease in the QT interval. Based on these findings, the authors hypothesized that tocotrienol therapy would improve the long-term clinical outlook and survival of patients with FD. In a new study, Axelrod & Berlin [2009] investigated the use of pregabalin, a 3-isobutyl derivative of GABA known to have anticonvulsant, antiepileptic, anxiolytic, and analgesic activities, in the treatment of nausea and dysautonomic crises. They treated a cohort of 15 patients with FD who suffered frequent dysautonomic crises with pregabalin and found that nausea and overt crises markedly decreased in 13 (87%). The overall assessments of benefit were extremely favorable, prompting the authors to suggest that pregabalin may be a potentially useful therapeutic agent in FD. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Familial Dysautonomia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDIKBKAP9q31.3Elongator complex protein 1IPN Mutations, IKBKAP IKBKAP homepage - Leiden Muscular Dystrophy pagesIKBKAPData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Familial Dysautonomia (View All in OMIM) View in own window 223900NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE III; HSAN3 603722INHIBITOR OF KAPPA LIGHT POLYPEPTIDE GENE ENHANCER IN B CELLS, KINASE COMPLEX-ASSOCIATED PROTEIN; IKBKAPMolecular Genetic Pathogenesis The molecular pathogenesis of familial dysautonomia (FD) was reviewed by Slaugenhaupt & Gusella [2002]. In summary, the Elongator complex protein 1 (Elp1) is part of the human Elongator complex, which is thought to be involved in creating a permissive chromatin structure for efficient mRNA elongation during transcription. Importantly, despite the presence of a homozygous IKBKAP mutation, cells from individuals with FD are capable of producing wild-type IKBKAP message and Elp1 protein. The predominant splice donor site mutation c.2204+6T>C (formerly IVS20+6T>C) results in variable expression of the gene in a tissue-specific manner. In individuals with FD the brain expresses primarily mutant IKBKAP mRNA, whereas lymphoblast and fibroblast cell lines from affected individuals express primarily wild-type IKBKAP mRNA. Although the molecular basis for this tissue specificity is unknown, it raises the possibility that manipulation of Elp1 protein expression may offer new therapeutic approaches [Ibrahim et al 2007]. Normal allelic variants. IKBKAP contains 37 exons and encodes a 1332-amino acid protein, Elongator complex protein 1 (Elp1; formerly IKAP) [Anderson et al 2001, Slaugenhaupt et al 2001]. Northern blot analysis of IKBKAP reveals two mRNA transcripts of 4.8 and 5.9 kb. The transcripts differ only in the length of the 3' untranslated region; they are predicted to encode identical 150-kd proteins. Pathologic allelic variants. Only two IKBKAP mutations exist in the Ashkenazi Jewish population. The first, c.2204+6T>C, a single T>C change at nucleotide 6 of intron 20, occurs with an unusually high frequency (>99.5%). The second pathologic variant is the missense mutation p.Arg696Pro, which is predicted to disrupt a potential phosphorylation site. Indeed, Elp1 carrying the p.Arg696Pro mutation displays reduced phosphorylation as determined by immunoprecipitation from labeled cells. Table 3. Selected IKBKAP Pathologic Allelic VariantsView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid Change Reference Sequencesc.2087G>Cp.Arg696ProNM_003640.3 NP_003631.2c.2204+6T>C (IVS20+6T>C )--c.2741C>Tp.Pro914LeuSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. Elongator complex protein 1 is a 1332-amino acid protein that is homologous to the Elp1 protein of Saccharomyces cerevisiae, a member of the six-subunit Elongator complex associated with hyperphosphorylated RNA polymerase II during transcriptional elongation. One member of the complex, Elp3, is a highly conserved histone acetyltransferase, which suggests that Elongator is involved in creating a chromatin structure that permits efficient elongation of mRNA during transcription. Recently, the human Elongator complex was purified and shown to contain Elp1, along with other proteins. Interestingly, although Elp1 was predictably found primarily in the nucleus, it was also detected in the nucleoli and cytoplasm by immunostaining. Moreover, Elp1 could be isolated from cellular fractions that lacked detectable hELP3 (human elongation protein 3), suggesting that perhaps the proteins in the functional Elongator complex have multiple roles in the cell. Abnormal gene product. It was recently shown that the common splicing mutation c.2204+6T>C is deleterious because it exacerbates the inherently weak splicing nucleotide motifs around exon 20 [Ibrahim et al 2007]. Recent results using allele-specific primers demonstrated that every FD cell type examined expressed variable ratios of both wild-type and mutant IKBKAP mRNA.