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

Gene. 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. 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. Summary of Molecular Genetic Testing Used in Familial Dysautonomia

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
IKBKAP	Targeted mutation analysis	c.2204+6T>C, p.Arg696Pro 2	>99% (Ashkenazi Jewish population) 3	Clinical
	Sequence analysis	Sequence variants 4	Unknown

Test Availability refers to availability in the GeneTests Laboratory Directory. 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.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Targeted mutations may vary by laboratory.

3. Dong et al [2002]

4. Small intragenic deletions/insertions, missense, nonsense, and splice site mutations

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming/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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

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

Natural History

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].

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].

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).

Evaluations 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 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, 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 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

Regular 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].

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, 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.

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 IKBKAP.

• 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 IKBKAP 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 to 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 IKBKAP to the Ashkenazi Jewish partner and to evaluate the offspring of an individual with FD with molecular genetic testing of IKBKAP.

• 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 possible if the IKBKAP mutations have been identified in the family.

Carrier testing is possible for 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, are carriers, or are at risk of being carriers.

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. 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 to 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 .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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 (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.

Normal 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.

Literature Cited

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Suggested Reading

1. Axelrod FB. A world without pain or tears. Clin Auton Res. 2006;16:90–7. [PubMed: 16683067]

Revision History

• 1 June 2010 (me) Comprehensive update posted live

• 22 October 2007 (me) Comprehensive update posted live

• 10 January 2005 (me) Comprehensive update posted live

• 21 January 2003 (me) Review posted live

• 6 November 1999 (bp) Original submission