Familial Dysautonomia

Synonyms: Hereditary Sensory and Autonomic Neuropathy Type III (HSAN III), Riley-Day Syndrome

Bar-Aluma BE.

Publication Details

Estimated reading time: 32 minutes

Summary

Clinical characteristics.

Familial dysautonomia, which affects the development and survival of sensory, sympathetic, and parasympathetic neurons, is a debilitating disorder present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, autonomic crises (i.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and blood pressure instability. Hypotonia contributes to delay in acquisition of motor milestones. Optic neuropathy results in progressive vision loss. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Developmental delay / intellectual disability occur in about 21% of individuals. Life expectancy is decreased.

Diagnosis/testing.

The diagnosis of familial dysautonomia is established in a proband with suggestive findings and biallelic pathogenic variants in ELP1 (formerly IKBKAP) identified by molecular genetic testing.

Management.

Treatment of manifestations: Affected individuals are often managed by multidisciplinary specialists that include neurologists, physiatrists, orthopedic surgeons, physical and occupational therapists, speech-language pathologists, pulmonologists, cardiologists, nephrologists, ophthalmologists, dentists and dental hygienists, and social workers. Feeding teams manage neurogenic dysphagia; mental health professionals treat anxiety.

Surveillance: Routine monitoring of the following: weight, nutrition, safety of oral feeding, developmental/educational progress, mental status, pulmonary function, sleep-disordered breathing, frequency and severity of dysautonomic crises, blood pressure lability, vision and low vision needs, ataxia and activities of daily living, spine for scoliosis, dental care and needs; assessment of caregiver needs.

Agents/circumstances to avoid: The following can exacerbate symptoms: hot or humid weather; full bladder.

Pregnancy management: Pregnancies in women with FD are considered high risk because of blood pressure lability. Visceral pain related to contractions during labor is perceived normally; therefore, analgesia should be provided.

Genetic counseling.

Familial dysautonomia is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ELP1 pathogenic variant, each sib of an affected individual has at conception 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 the ELP1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible. Carrier screening is available on a population basis for individuals of Ashkenazi Jewish heritage.

Diagnosis

The five cardinal clinical diagnostic criteria for familial dysautonomia are absence of fungiform papillae on the tongue, absence of flare after injection of intradermal histamine, decreased or absent deep-tendon reflexes, absence of overflow emotional tears, and Ashkenazi Jewish descent [Axelrod & Pearson 1984]. This last criterion, however, was rebutted after the discovery of three rare non-Jewish ELP1 variants [Leyne et al 2003].

Suggestive Findings

Clinical findings

  • Gastrointestinal dysfunction with vomiting crises
  • Recurrent aspiration pneumonia
  • Altered sensitivity to pain and temperature
  • Extreme blood pressure variability with postural hypotension
  • Hypotonia
  • 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) determined either by history in infants older than age three months or the Schirmer test (See Specialized testing.)

Specialized testing

  • Schirmer test. 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.

Heritage. Infant is of Ashkenazi Jewish heritage. (Absence of known Ashkenazi Jewish heritage does not exclude the diagnosis.)

Establishing the Diagnosis

The diagnosis of familial dysautonomia is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in ELP1 (formerly IKBKAP) identified by molecular genetic testing.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic ELP1 variants of uncertain significance (or identification of one known ELP1 pathogenic variant and one ELP1 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are more likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of familial dysautonomia has not been considered may be more likely to be diagnosed using genomic testing (see Option 2).

Option 1

Single-gene testing. Sequence analysis of ELP1 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. Typically, if only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; however, to date such variants have not been identified as a cause of this disorder.

In individuals of Ashkenazi Jewish heritage, targeted analysis for the ELP1 variant c.2204+6T>C (formerly IVS20+6T>C) can be performed first. This founder variant accounts for more than 99% of pathogenic variants among Ashkenazi Jewish individuals with FD.

A hereditary neuropathy multigene panel that includes ELP1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of familial dysautonomia has not been considered because an individual has atypical phenotypic features and/or is not known to have Ashkenazi Jewish heritage, comprehensive genomic testing, which does not require the clinician to determine which gene is likely involved, is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

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Table 1.

Molecular Genetic Testing Used in Familial Dysautonomia

Clinical Characteristics

Clinical Description

Familial dysautonomia (FD) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, autonomic crises (I.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and cardiovascular instability. Hypotonia contributes to delay in acquisition of motor milestones. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Developmental delay / intellectual disability occur in about 21% of individuals. Life expectancy is decreased [Welton et al 1979].

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Table 2.

Clinical Manifestations of Familial Dysautonomia

Most infants with familial dysautonomia are born after an uncomplicated term pregnancy. However, there is an increased rate of polyhydramnios and breech presentation.

Autonomic dysfunction. Neonates (i.e., infants age ≤28 days) typically have impaired oropharyngeal incoordination (i.e., neurogenic dysphagia) manifest as poor initiation of sucking and poor swallowing mechanisms. Protective airway reflexes (including cough) are decreased or lacking; the risk of aspiration and aspiration pneumonia shortly after birth is extremely high. Additional gastrointestinal problems that can interfere with eating and weight gain include esophageal dysmotility and GERD.

Infants with FD may have difficulties maintaining normal body temperature and may be indifferent to pain stimuli.

Sympathetic nervous system involvement results in orthostatic hypotension that is exacerbated by exercise and warm environments. Syncope is surprisingly infrequent, and usually indicates volume depletion, anemia, or hypoxia.

Urinary stress incontinence is common in adolescent and adult women [Saini et al 2003].

Episodic somnolence has been reported.

Autonomic crises, also described as hypertensive vomiting attacks, occur in about 40% of individuals. Attacks occur when stimuli increase sympathetic outflow causing an uncontrolled release of catecholamines (neurotransmitters such as epinephrine and dopamine) into the circulation. Common triggers include emotion, illness, abdominal discomfort, and bladder distension; however, sometimes the crises are unpredictable and without obvious cause. Dopamine, which is believed to activate receptors in the chemoreceptor trigger zone of the area postrema (located in the medulla oblongata), cause cyclic vomiting (or retching in persons who have undergone fundoplication). These dopaminergic crises can also be associated with tachycardia, hyperhidrosis, irritability, and personality changes. Crises may last several days.

Sensory disturbances are significant. Pain and temperature thresholds are greatly elevated; affected individuals report a relative indifference to pain. The risk for decubitus ulcers, burns, and other minor injuries to become infected is increased. Failure to recognize fractures has also been described.

Motor development. Infants and young children have varying degrees of hypotonia that contribute to delay in motor milestones. Although some infants may acquire motor skills in the usual timeframe, most infants demonstrate some degree of delay in acquisition of motor skills. Sitting without support is usually achieved around age 12-18 months, standing alone around age one to two years, and walking independently around age two to three years [Sheba Medical Center Familial Dysautonomia Database, unpublished data].

Older individuals often have a broad-based, ataxic gait that progressively deteriorates over time. Individuals with FD have difficulty performing rapid movements and maintaining their balance while changing direction or turning. By age 20 years 3% of affected individuals require assistance walking; this percentage increases linearly to 14% by age 30 years, 27% by age 40 years, and 49% by age 50 years [Macefield et al 2011].

Ophthalmologic. Recurrent corneal ulcers and occasionally permanent opacities result from alacrima and corneal hypoesthesia.

The major cause of visual loss in FD is optic neuropathy affecting mostly the P-type retinal ganglion cells. Beginning early in life, all individuals with FD experience progressive loss of retinal ganglion cell axons. The temporal retinal nerve fiber layer (RNFL) is the most affected. The less energy-dependent ganglion cells are relatively spared, whereas the more energy-dependent maculopapillary ganglion cells are selectively damaged [Mendoza-Santiesteban et al 2014]. The accelerated retinal damage continues until the third decade of life and then plateaus [Kfir et al 2021]. Visual impairment frequently begins at an early age and can progress to blindness usually after the third decade of life.

Eye movement disorders such as strabismus are very common.

Respiratory illness is common. According to the New York University Familial Dysautonomia Patient Registry [Kazachkov et al 2018], upper-airway obstruction is present in 83%, lower-airway disease in 85%, and restrictive lung disease in 94% [Palma et al 2019].

Although most individuals undergo gastrostomy with Nissen fundoplication upon diagnosis, recurrent lower-airway infections remain common. Most individuals with FD develop chronic lung disease secondary to recurrent aspiration. CT imaging of the lungs shows bronchiectasis in 26% of affected individuals.

Lack of input from the peripheral chemoreceptors results in almost absent ventilatory responses to hypoxemia; the chemoreceptor ventilatory responses to hypercapnia are also reduced, but to a lesser extent.

The majority of children and adults with FD have some degree of sleep-disordered breathing. Central apnea is more frequent in children; obstructive apnea is more frequent in adults.

The increased incidence of sudden death during sleep can be attributed to the following risk factors: treatment with fludrocortisone, plasma potassium concentrations <4 mEq/L, and untreated sleep apnea [Palma et al 2017].

Kyphoscoliosis, a common finding, develops during the first two decades. By age 20 years, 80% of affected individuals have some degree of spinal deformity, possibly due to abnormal posture of the trunk as needed to maintain balance.

Renal. Chronic kidney disease is common. Renal function tends to deteriorate with advancing age. Almost all persons with FD who reach their fourth decade have a markedly decreased estimated glomerular filtration rate (eGFR) [Elkayam et al 2006].

Baroreflex failure, manifest as excessive increases or decreases in blood pressure with wide fluctuations, is associated with a faster progression of renal disease. Some individuals progress to end-stage renal disease and may require dialysis. A few renal transplants have been performed.

Renal tubular acidosis, requiring treatment, is common. Hyperkalemia, which is also common, is not always explained by the degree of renal insufficiency.

There is also an increased incidence of congenital renal defects, including a single kidney, horseshoe kidney, and crossed renal ectopia (i.e., a kidney that has crossed from its side to the other side such that the kidneys are both located on one side of the body) [Norcliffe-Kaufmann et al 2013a].

Cognitive function differs widely among affected individuals. Both learning difficulties and poor concentration are common. Although acquisition of verbal skills is delayed during the first nine years, verbal skills subsequently improve to within the normal range for age [Palma et al 2014].

Personality issues. Anxiety is the most common psychiatric problem. Skin or nail picking and trichotillomania occur in around 10% of individuals [Palma et al 2014].

Other

  • Craniofacial findings include small jaw, mandibular retrognathia, malocclusion, dental crowding, and smaller tooth size [Mass 2016].
  • Dental trauma occurs in 60% of individuals (often from frequent falling due to ataxia and balance issues); 32% have orodental self-mutilation (i.e., chewing the gums without noticing).
  • Sexual maturation is frequently delayed; however, 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.
  • Growth. Neonates with FD are usually born appropriate for gestational age with head circumference within the normal range. Individuals with FD often fall severely below their projected midparental adjusted height; the reported average adult height for males is 158 centimeters and for females is 150 centimeters.
    Although poor linear growth velocity, low-to-normal insulin-like growth factor-I (IGFI) levels, and delayed skeletal age are reported in FD, challenge tests for growth hormone deficiency have been inconclusive. Growth hormone treatment in individuals in an open-label study resulted in growth velocity that exceeded pre-treatment rates in 12 of the 13 treated individuals [Kamboj et al 2004].

Quality of life. 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 roles at school or work.

Prognosis. FD has always been recognized as a potentially life-threatening disorder with a high mortality rate and 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].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed [Blumenfeld et al 1999].

The p.Arg696Pro pathogenic variant is extremely rare in the Ashkenazi Jewish population and has never been detected in the 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 of the 298 of full non-Polish background (1:99).

Differential Diagnosis

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Table 3.

Genes and Disorders of Interest in the Differential Diagnosis

HSAN1B (OMIM 608088), a disorder of unknown genetic cause, can also be considered in the differential diagnosis. HSAN1B is characterized by cough and gastroesophageal reflux; loss of pain & temperature sensation; osteomyelitis; lancinating pain; distal motor involvement (variable); and facultative deafness. There are no visceral signs of autonomic involvement.

Management

Clinical practice guidelines have been published [Kazachkov et al 2018] (full text).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with familial dysautonomia, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

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Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Familial Dysautonomia

Treatment of Manifestations

There is no curative therapy for familial dysautonomia. Treatment is supportive.

Affected individuals are often managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, physical and occupational therapists, speech-language pathologists, pulmonologists, and social workers (see Table 5).

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Table 5.

Treatment of Manifestations in Individuals with Familial Dysautonomia

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • Individualized education plan (IEP) services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Surveillance

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Table 6.

Recommended Surveillance for Individuals with Familial Dysautonomia

Agents/Circumstances to Avoid

Symptoms tend to be worse in hot or humid weather; affected individuals should try to avoid being outdoors in such conditions as much 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 as much as possible [Axelrod & Gold-von Simson 2007].

Episodic hypertension can occur in response to emotional stress or visceral pain, and therefore should be avoided when possible [Axelrod & Gold-von Simson 2007].

Environmental situations associated with hypobaric hypoxia (e.g., aircraft flight or ascent to high altitude) pose a potential risk to individuals with daytime hypercapnia [Palma et al 2014].

Evaluation of Relatives at Risk

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

Pregnancy Management

Pregnancies in women with FD are considered high risk because of abrupt changes in blood pressure.

High blood pressure secondary to FD is difficult to differentiate from toxemia or other causes of pregnancy-related high blood pressure.

Awareness of volume loss and low blood pressure is important because of the absence of reflex tachycardia to low blood pressure.

Visceral pain related to contractions during labor is perceived normally; therefore, analgesia should be provided. Epidural anesthesia is preferable due to blood pressure lability during general anesthesia or spinal block [Maayan et al 2000].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

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 (i.e., presumed to be carriers of one ELP1 [IKBKAP] pathogenic variant based on family history).
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an ELP1 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
    • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
    • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
  • Heterozygotes are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for an ELP1 pathogenic variant, each sib of an affected individual has at conception 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

  • All offspring of an individual with FD inherit a pathogenic variant in ELP1 from their affected parent.
  • The risk that the Ashkenazi Jewish reproductive partner of an individual with FD is heterozygous for an ELP1 disease-causing allele is 1:32 (see Prevalence). Thus, the risk to the offspring of an affected individual and an Ashkenazi Jewish partner of having FD is approximately 1.5%. (The risk that a person of non-Ashkenazi Jewish ancestry is a carrier of FD is <1:150. For offspring of an individual with FD and a non-Ashkenazi Jewish reproductive partner, the risk of having FD is <1:300.)
  • It is appropriate to offer molecular genetic testing of ELP1 to the reproductive partner of an individual with FD (see Related Genetic Counseling Issues, Population screening).

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ELP1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ELP1 pathogenic variants in the family.

See Related Genetic Counseling Issues, Population screening for information about carrier testing in individuals who do not have a family history of FD.

Related Genetic Counseling Issues

Population screening

  • Because of the increased carrier rate for FD in individuals of Ashkenazi Jewish heritage (see Prevalence), the American College of Obstetricians and Gynecologists recommends offering carrier screening for FD to individuals of Jewish descent [ACOG 2017] (full text). Targeted analysis for pathogenic variants in ELP1 is often included in panels of "Ashkenazi Jewish pathogenic variants" offered to individuals interested in preconception or prenatal risk assessment modification.
  • If an individual has FD or is known to be a carrier of an ELP1 pathogenic variant, it is appropriate to offer molecular genetic testing of ELP1 to the individual's reproductive partner regardless of the reproductive partner’s heritage.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the ELP1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for FD are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

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Table A.

Familial Dysautonomia: Genes and Databases

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Table B.

OMIM Entries for Familial Dysautonomia (View All in OMIM)

Molecular Pathogenesis

ELP1 protein is one of the six subunits of the Elongator complex, which facilitates transcriptional elongation, and is required for efficient translation of proteins. During embryogenesis, ELP1 is expressed first in the central and peripheral nervous systems and in the gastrointestinal tract. It is then expressed in secretory tissues and cartilage, and finally in muscle. Once the organs are formed, ELP1 expression appears in the skin and mucosal tissue. Overall, expression is more prominent in the nervous system and retina, and to a lesser extent in other organs. The complete absence of ELP1 leads to embryonic lethality with failure of vasculogenesis and neurulation [Norcliffe-Kaufmann et al 2017]. Individuals with biallelic ELP1 pathogenic variants have at birth multiple lesions affecting mostly sensory (afferent) nerve fibers.

Mechanism of disease causation. The c.2204+6T>C founder variant affects the intronic splice donor site in ELP1 exon 20. The skipping of exon 20 leads to a frameshift and generation of a premature termination codon in exon 21 of ELP1 mRNA. The aberrant skipping of exon 20 is tissue specific, mostly in neurons.

ELP1-specific laboratory technical considerations. Information on two other rare variants that have not yet been published is available in the NYU Center for Dysautonomia's 2020-2021 Year in Review (pdf).

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Table 7.

Notable ELP1 Pathogenic Variants

Chapter Notes

Acknowledgments

I would like to thank my supervisor, Professor Ori Efrati, Head of the Pediatric Pulmonary Unit at Sheba Medical Center, for establishing the National Center for Familial Dysautonomia as a part of our unit.

I would also like to thank Professor Horacio Kaufmann, Head of the Dysautonomia Center, New York University School of Medicine, for his support and guidance during my training at the Dysautonomia Center.

Author History

Bat-El Bar-Aluma, MD (2021-present)
Gabrielle J Halpern, MB, ChB; Beilinson Hospital, Petah Tikva (1999-2014)
Mordechai Shohat, MD; Sheba Medical Center at Tel HaShomer (1999-2021)
Monika Weisz Hubshman, MD, PhD; Rabin Medical Center, Beilinson Hospital (2014-2021)

Revision History

  • 4 November 2021 (bp) Comprehensive update posted live
  • 18 December 2014 (me) Comprehensive update posted live
  • 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

References

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