Familial Dysautonomia

Clinical characteristics.

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, vomiting crises, recurrent pneumonia, altered sensitivity to pain and temperature perception, and cardiovascular instability. About 40% of individuals have autonomic crises. Hypotonia contributes to delay in acquisition of motor milestones. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Life expectancy is decreased.

Diagnosis/testing.

The diagnosis of FD is established by molecular genetic testing of ELP1 (IKBKAP). Two pathogenic variants account for more than 99% of mutated alleles in individuals with FD of Ashkenazi Jewish descent. The major founder variant c.2204+6T>C (formerly IVS20+6T>C) is responsible for virtually all occurrences of FD among the Ashkenazim.

Management.

Treatment of manifestations: Maintenance of adequate nutrition; measures to avoid aspiration; standard treatment of gastroesophageal reflux (i.e., intravenous or rectal diazepam, rectal chloral hydrate, IV fluids for vomiting crises); daily chest physiotherapy; possible high-frequency chest-wall oscillation; hydration, elastic stockings, leg exercises, counter-maneuvers (e.g., squatting, bending forward, abdominal compression) to treat orthostatic hypotension; pacemaker for bradyarrhythmia and/or syncope; artificial tear solutions for corneal healing; spinal fusion as needed.

Prevention of secondary complications: Adequate hydration during general anesthesia; attention to pressure points when fitting orthopedic devices; exercise to correct/prevent secondary contractures.

Surveillance: Annual spine examination for scoliosis.

Genetic counseling.

Familial dysautonomia is inherited in an autosomal recessive manner. 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. Carrier testing and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

Suggestive Findings

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.
  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].
• It was necessary for the following six cardinal features to be present in each affected individual.

With the specificity and wide availability of molecular genetic testing, the following are now considered suggestive findings on clinical evaluation and specialized testing.

Clinical findings

• 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.

Specialized testing results

• 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.

Establishing the Diagnosis

The diagnosis of familial dysautonomia is established in a proband with biallelic pathogenic variants identified in ELP1 (IKBKAP) on molecular genetic testing (see Table 1).

Approaches to molecular genetic testing include the following:

• Targeted analysis for the two pathogenic variants that account for more than 99% of pathogenic variants in individuals with FD of Ashkenazi Jewish descent [Dong et al 2002]. The major founder variant c.2204+6T>C, formerly IVS20+6T>C, is responsible for virtually all occurrences of FD among the Ashkenazim. The p.Arg696Pro pathogenic variant is rarely identified.
• Sequence analysis of the entire coding region which identifies the two common pathogenic variants as well as rare variants, such as a proline-to-leucine pathogenic missense variant in exon 26, p.Pro914Leu, which was identified in an individual with FD who is not of Ashkenazi Jewish heritage [Leyne et al 2003]. If only one pathogenic variant is identified and the clinical findings are suggestive, deletion/duplication analysis should be considered.
• Use of a multigene panel that includes ELP1 and other genes of interest (see Differential Diagnosis). 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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.

Clinical Description

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 pathogenic variant 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; may 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.
• Assessment of chronic respiratory disease including spirometry (possible from age 6 years onwards), arterial blood gases, polysomnography, and a swallow study
• Clinical genetics consultation

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. Aversion to feeding and failure to thrive are managed frequently by percutaneous endoscopic gastrostomy (PEG) placement.

Gastroesophageal reflux. Upright positioning with feeds, prokinetic agents, H2 antagonists, proton pump inhibitors, 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.

Other treatments used include [Palma et al 2014]:

• Alpha2 adrenergic agonist clonidine (transdermal clonidine patch): 0.1-0.3 mg/24h provides stable blood levels and is preferable to oral dosages. 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]. Although no controlled trials have been conducted, clonidine is frequently used in autonomic crisis. Slow tapering is recommended when discontinuing clonidine treatment [Palma et al 2014].
• In some patients admitted to an ICU, dexmedetomidine (a selective agonist of alpha2 adrenoreceptors in the brain and spinal cord that inhibit sympathetic outflow) was effective.

Carbidopa (a reversible dopa-decarboxylase inhibitor) 200 mg three times daily was assessed in a recent double-blind, randomized, placebo-controlled clinical trial that provided level II-b evidence that treatment with carbidopa can reduce the frequency and severity of hypertensive vomiting [Norcliffe-Kaufmann et al 2013].

Lung disease. Chronic lung disease is treated with daily chest physiotherapy (nebulization, bronchodilators, cough augmentation, incentive spirometry, 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.

Early diagnosis of pneumonia and infectious agents is important due to the common involvement of gastric flora (secondary to aspirations).

Individuals with FD are prone to viral respiratory infections and, in some cases, concomitant bacterial infections. Treatment with oseltamivir is indicated for influenza virus infections [Palma et al 2014].

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.

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.

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 persons treated with fludrocortisone with untreated persons and found that cumulative survival was significantly higher during the first decade in treated versus untreated individuals. In subsequent decades, the addition of midodrine improved cumulative survival. Of note, treatment of orthostatic hypotension with high doses of fludrocortisone (>0.2 mg/day) was shown to accelerate the progression of renal damage in persons with FD [Norcliffe-Kaufmann et al 2013].

Hypertension. Attention to factors precipitating hypertension rather than use of antihypertensive agents is appropriate because blood pressure is labile.

Sleeping with the head of the bed raised (20°-40°) helps to reduce orthostatic hypotension by lowering supine hypertension, reducing nocturnal pressure-diuresis, and raising intravascular volume in the morning.

The guidelines for hypertension treatment in patients with FD and chronic kidney disease are the same as for the general population.

Kidney and bladder. Chronic renal failure, resulting from ischemic glomerulosclerosis, is common.

Adequate control of blood pressure is an important factor in delaying the appearance of kidney disease.

Renal tubular acidosis, which occurs frequently in FD, often requires treatment with bicarbonate.

Hyperkalemia, which is also common, is treated with low potassium diet.

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.

If sleep-disordered breathing is confirmed, treatment with continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BiPAP) must be initiated.

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.

Chronic blepharitis is common and requires treatment with combined topical antibiotic/corticosteroid ointment.

Strabismus is almost always present (93%), and early surgical correction may help.

Spine. Spinal fusion may be necessary.

Other

• Many adults use walkers or wheelchairs when outside the home.
• Sialorrhea is a common. Surgical and anti-cholinergic drugs were used in the past. Recently the use of botulinium toxin injected to major salivary glands has been suggested [Daniel & Cardona 2014].

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

The following are appropriate:

• Routine assessment of growth in children
• Periodic evaluation of chronic respiratory disease: spirometry (possible from age 6 years onwards), arterial blood gases, polysomnography, and a swallow study. Follow-up frequency depends on findings.
• Regular monitoring of blood pressure and optimal management of blood pressure lability to help prevent some of the neurologic progression with age, which can be associated with compromised cerebral perfusion
• Routine monitoring of 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) [Axelrod & Gold-von Simson 2007]
• Monitoring for adequate hydration by measurement of blood urea nitrogen levels
• Screening for sleep-disordered breathing with polysomnography
• Periodic eye examination for strabismus, corneal opacities, or abnormal eye movements
• Annual examination of the spine for early evidence of scoliosis to permit timely institution of bracing and exercise therapy
• Periodic assessment of psychomotor development and behavior in children

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 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 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].

Environmental situations associated with hypobaric hypoxia (e.g., aircraft flight or ascent to high altitude) pose a potential risk to patients 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; therefor, 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

Kinetin. FD results from an intron 20 pathogenic variant that causes a unique pattern of tissue-specific exon skipping. Accurate splicing of the mutated allele is particularly inefficient in the nervous system. Slaugenhaupt et al [2004] showed that treatment with the plant cytokinin kinetin alters splicing of ELP1 (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 ELP1 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 ELP1 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 ELP1 splicing in vivo. They administered kinetin to 29 healthy carriers of the major ELP1 pathogenic variant associated with FD and monitored adverse effects, as well as kinetin and ELP1 mRNA levels. After eight days they found that ELP1 mRNA expression in leukocytes increased as kinetin levels increased and noted that these findings strongly suggest a therapeutic role for kinetin in FD.

In a study conducted by Axelrod et al [2011], kinetin was administered to eight individuals with FD at a dose of 23.5 mg/kg/d for 28 days. An increase in wild type ELP1 mRNA expression in leukocytes was noted after eight days in six of the eight; after 28 days, the mean increase compared with baseline was significant (p = 0.002). Long-term clinical trials are warranted.

Induced pluripotent stem cells (iPSCs). The isolation of human iPSCs offers a novel strategy for modeling human disease. 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 mutated ELP1 splice form. In contrast, no significant improvements in ELP1 splicing were observed after ECGC or tocotrienol exposure. The kinetin-mediated decrease in mutated ELP1 was associated with an increase in normal ELP1 levels and the ratio of normal:mutated transcript. No significant increase in normal ELP1 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 ELP1 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.

More recently Lee et al [2012] performed large scale screening using FD-induced pluripotent stem cells to identify compounds that rescue IKBKAP expression. They screened 6,912 small-molecule compounds and characterized eight that rescued expression of IKBKAP. One of the compounds, SKF-86466, was found to induce IKBKAP transcription through modulation of intracellular cAMP levels and PKA-dependent CREB phosphorylation. SKF-86466 also rescued IKAP protein expression and the disease-specific loss of autonomic neuronal marker expression. SKF or other compounds including kinetin do not rescue the migratory defect of FD-iPSC derived neural crest cells. Because it is not clear whether any of the compounds will affect degenerative aspects of the disease such as the survival of postmitotic sensory or autonomic neurons, more pre-clinical studies are required.

Tocotrienols. Anderson & Rubin [2005] found that individuals with FD have reduced MAO A mRNA levels, and that FD-derived cells, stimulated with tocotrienols (members of the vitamin E family) or (-)-epigallocatechin gallate (EGCG, a major polyphenolic antioxidant present in green tea 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.

Subsequently, 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 study by Anderson et al [2012] the simultaneous exposure of FD-derived cells to genistein and epigallocatechin gallate (EGCG) resulted in the almost exclusive production of the exon-20-containing transcript and the production of wild type amounts of IKAP protein. The authors suggest clinical evaluation of combined administration of these commonly used nutraceuticals.

Pregabalin. 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 experienced 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.

Phosphatidylserine (PS). Another study performed by Keren et al [2010] showed that PS, a phospholipidic component of cell membranes and FDA-approved food supplement, elevates the levels of IKAP (ELP-1) in FD cell lines. While kinetin increases the levels of correctly spliced IKAP transcripts (thus altering the ratio between exon 20 inclusion and skipping), phosphatidylserine appears to increase levels of transcription without altering the ratio. PS treatment of FD cells elevated wild type IKAP mRNA and protein levels and resulted in a cell cycle distribution similar to that of the control cells. A significant number of genes up-regulated following PS treatment are also involved in DNA metabolic processes and in DNA repair mechanisms. On increases in cellular metabolism and synthesis of nucleotides, transcription by RNA polymerase II increases; thus, the increase in mRNA levels is not specific to IKAP.

Recently, Bochner et al [2013] showed an increase of IKBAKP mRNA and IKAP protein levels following PS administration in various tissues of FD humanized mice (homozygous humanized mouse strain carrying human exon 20 and its two flanking introns) without affecting exon 20 inclusion levels. The authors of the studies suggest PS as a potential therapeutic agent.

Digoxin. The cardiac glycoside digoxin was shown by Liu et al [2013] to alter and increase the production of the wild type, exon 20-containing, I ELP1-encoded transcript and the full-length IκB-kinase-complex-associated protein in FD-derived cells. The digoxin-mediated effect on splicing was SRSF3-binding site dependent; the site is located in the intron 5' of the alternatively spliced exon and digoxin was shown to mediate its effect by suppressing the level of the SRSF3 protein. These experiments were conducted in cells transfected with an ELP1 minigene construct bearing the IVS20+6T>C pathogenic variant. The author suggests further investigation of the possible use of digoxin as a therapeutic modality for FD.

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