Familial Dysautonomia

[Hereditary Sensory and Autonomic Neuropathy, Type III; Riley-Day Syndrome; HSAN III]

Clinical Diagnosis

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:

• 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 Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene.   IKBKAP is the only gene known to be associated with 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, previously designated IVS20(+6T>C), is responsible for virtually all occurrences of FD among the Ashkenazim.

  • The p.Arg696Pro mutation is rarely identified.

• Sequence analysis.  Sequence analysis of the entire coding region is available on a clinical basis for identification of 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. Molecular Genetic Testing in Familial Dysautonomia

Test Method	Mutations Detected  1	Mutation Detection Frequency  2	Test Availability
Targeted mutation analysis	c.2204+6T>C; p.Arg696Pro in IKBKAP	>99% (Ashkenazi Jewish population)  3	Clinical
Sequence analysis	IKBKAP sequence variants	Unknown

1.  When possible, standardized nomenclature is used for mutations (www.hgvs.org).
2.  Proportion of affected individuals with a mutation(s) as classified by test method
3. Dong et al 2002

Testing Strategy

To confirm the diagnosis in a proband, molecular genetic testing for the major mutation is performed.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for an 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 mutation in the family.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in IKBKAP.

Natural History

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 et al (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].

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].

Genotype-Phenotype Correlations

None 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.

Prevalence

The incidence of FD among the Ashkenazim is 1:3,700 live births, which corresponds to a carrier frequency of 1:36 [Slaugenhaupt et al 2001]. A study by Lehavi et al (2003) from Israel identified 34 carriers among 1100 individuals of full Ashkenazi Jewish parentage (carrier rate 1:32). Further analysis revealed different carrier frequencies among a subset of Polish Ashkenazi Jews: Among the 195 individuals of full Polish background, 11 carriers were detected (1:18), in contrast to only three out of the 298 of full non-Polish background (1:99).

Treatment of Manifestations

Feeding 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, and 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 if fludrocortisone is effective in treating postural hypotension and if 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.

Countermaneuvers (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 countermaneuver 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 Complications

Use 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.

Surveillance

Annual examination of the spine for early evidence of scoliosis allows timely institution of bracing and exercise therapy.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Growth 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) protein 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 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 2003]. Anderson & Rubin (2005) found that individuals with FD have reduced MAO A mRNA levels, and that FD-derived cells, stimulated with tocotrienols or EGCG 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.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Familial dysautonomia (FD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore each carries a single copy of a disease-causing mutation in the IKBKAP gene.

• Heterozygotes are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.

Offspring of a proband

• All offspring of an individual with FD inherit a disease-causing mutation in the IKBKAP gene from their affected parent.

• The risk that the Ashkenazi Jewish reproductive partner of an individual with FD is heterozygous for an IKBKAP disease-causing allele is 1:32. Thus, the risk for the offspring of an affected individual and an Ashkenazi Jewish partner of having FD is approximately 1.5%. It is appropriate to offer molecular genetic testing of the IKBKAP gene to the Ashkenazi Jewish partner and to evaluate the offspring of an individual with FD with molecular genetic testing of the IKBKAP gene.

• The risk that a person of non-Ashkenazi Jewish ancestry is a carrier of FD is less than 1:150. For offspring of an individual with FD and a non-Ashkenazi Jewish reproductive partner, the risk of having FD is less than 1:300.

Other family members.  Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing is available to at-risk family members once the IKBKAP mutations have been identified in the family.

Carrier testing is also available to the Ashkenazi Jewish reproductive partners of known carriers.

Related Genetic Counseling Issues

Population Screening.   Because of the increased IKBKAP mutation frequency in Ashkenazi Jews and the availability of genetic counseling and prenatal diagnosis, targeted mutation analysis of IKBKAP is often included in the panel of "Ashkenazi Jewish mutations" offered to individuals interested in preconception or prenatal risk assessment modification. Through this type of screening, couples in which both partners are carriers can be made aware of their status and risks before having affected children. Then, through genetic counseling and the option of prenatal testing, such families can, if they choose, bring to term only those pregnancies in which the fetus is unaffected [ACOG Committee on Genetics 2004].

Family planning.  The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, to carriers, and to those at risk of being carriers.

DNA banking.  DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling at approximately ten to 12 weeks' gestation. Both disease-causing alleles must be identified in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Molecular 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, previously designated 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: The IKBKAP gene 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; both are predicted to encode an identical 150-kd protein.

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 at amino acid residue 699. Indeed, Elp1 carrying the p.Arg696Pro mutation displays reduced phosphorylation as determined by immunoprecipitation from labeled cells. The IKBKAP reference sequence for the mutation designations is NM_0003640.2. (For more information, see Table A: locus-specific databases and HGMD.)

Normal gene product: Elongator complex protein 1 is homologous to the Elp1 protein of Saccharomyces cerevisiae, a member of the six-subunit Elongator complex, which is 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 utilizing allele-specific primers demonstrated that every FD cell type examined expressed variable ratios of both wild-type and mutant IKBKAP mRNA.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Readings

Revision History

• 22 October 2007 (me) Comprehensive update posted to live Web site

• 10 January 2005 (me) Comprehensive update posted to live Web site

• 21 January 2003 (me) Review posted to live Web site

• 6 November 1999 (bp) Original submission