Familial dysautonomia (FD) is an autosomal recessive neurodevelopmental disorder also known as Riley-Day syndrome. In 1949, Riley and Day first reported extensive sensory and autonomic abnormalities characterized by decreased tear production, excessive sweating, hypersalivation, diminished deep tendon reflexes, and blood pressure fluctuations in children of Ashkenazi Jewish descent.
Currently, FD is classified as type III of hereditary sensory and autonomic neuropathy (HSAN) 1). The prevalence among Ashkenazi Jews is approximately 1 in 3,700, with a carrier frequency estimated at 1 in 27 to 1 in 32. Other HSAN types do not show such a strong ethnic predilection.
In 2001, the causative gene was identified as IKAP (I-κB kinase-associated protein)/ELP-1 (elongator protein 1) on the long arm of chromosome 9. The most common mutation is a T→C substitution at the donor splice site of intron 20, which causes abnormal splicing of the IKAP gene and impairs sensory neuron development 1).
QWhy is it more common in Ashkenazi Jews?
A
This is because the carrier frequency of the causative IKAP gene mutation is very high in the Ashkenazi Jewish population, approximately 1/27 to 1/32. This is due to a population genetic phenomenon called the founder effect. Other HSAN types do not show this ethnic bias.
The ocular symptoms of FD are progressive, and the following subjective symptoms are observed.
Decreased tears: Basal secretion and production of emotional tears are markedly reduced. It is characteristic that tears do not flow even when crying.
Lack of eye pain: Due to decreased corneal sensation (part of systemic neuropathy), there is insensitivity to eye pain caused by foreign bodies or irritants.
Decreased visual acuity: Progressive, worsening with age. May eventually lead to legal blindness.
Color vision abnormality: Red-green color vision deficiency is observed in elderly patients.
Central visual field defect: Occurs with progression of optic atrophy.
Optic atrophy: Most pronounced on the temporal side. Accompanied by RNFL loss in the papillomacular bundle.
OCT findings: Thinning of the macular retinal ganglion cell layer and RNFL. The periphery is relatively preserved.
Ocular motor abnormalities: Slowing of saccades and optokinetic responses may be observed.
Major systemic signs
Autonomic crisis: Episodes of transient hypertension, tachycardia, diffuse sweating, vomiting, and personality changes1).
Orthostatic hypotension: Causes dizziness and syncope. Long-term, it can lead to renal failure.
Dysphagia: Oropharyngeal incoordination. High risk of aspiration pneumonia.
Loss of fungiform papillae on the tongue: Causes taste disturbance. Also a characteristic diagnostic finding.
Skeletal abnormalities: Short stature, scoliosis. Straightening of the upper lip is also characteristic.
Late-onset optic neuropathy is often recorded after the first decade of life, and with recent improvements in survival rates, this finding is becoming apparent in more patients.
QWhy does vision decrease in FD?
A
There are two pathways. First, progressive loss of retinal ganglion cells and retinal nerve fiber layer due to optic atrophy (especially the papillomacular bundle) causes decreased vision, central visual field defects, and color vision abnormalities. Second, chronic corneal epithelial damage due to alacrima, decreased corneal sensation, and lagophthalmos leads to corneal scarring.
The cause of FD is a point mutation in the IKAP/ELP-1 gene on the long arm of chromosome 9. Three mutations have been discovered, but the most common is a T→C substitution at the donor splice site of intron 20.
This mutation causes abnormal mRNA splicing, resulting in the following:
Splicing out of exon 20: A frameshift mutation occurs, leading to a premature stop codon that produces a truncated IKAP protein.
Tissue-specific abnormality: In neurons, mutant IKAP mRNA is predominantly produced, while in other cells, both normal and mutant forms are present.
Impaired innervation: IKAP deficiency during embryonic development causes failure of primary sensory innervation, resulting in loss of dorsal root ganglia and sympathetic neurons.
The mechanism of autonomic crises is thought to involve impaired afferent neurons of the arterial baroreceptors, leading to uncontrolled sympathetic outflow1).
Currently, DNA testing of the IKAP gene is the first choice for definitive diagnosis. Before genetic testing became available, diagnosis was made based on a combination of the following clinical features.
The major clinical diagnostic criteria are shown below.
Diagnostic Finding
Description
Alacrima
Marked reduction in tear production
Absence of fungiform papillae
Fungiform papillae on the tongue are absent
Loss of patellar tendon reflex
Decreased to absent deep tendon reflexes
In addition, the intradermal histamine test (failure to induce a normal flare response) was also used for diagnosis. However, other HSAN types may also fail to induce an intradermal histamine response, requiring careful evaluation of clinical findings. Sural nerve biopsy reveals a marked reduction in unmyelinated axons.
Autonomic nervous system diseases to differentiate
The following autonomic nervous system diseases should be considered in the differential diagnosis of FD.
Adie syndrome: Presents with tonic pupil and tendon reflex abnormalities. A low-concentration (0.125%) pilocarpine hydrochloride eye drop test shows miosis due to denervation supersensitivity.
Ross syndrome: In addition to Adie syndrome, it is accompanied by autonomic symptoms such as orthostatic hypotension and sweating abnormalities. It shares similarities with autonomic dysfunction in FD.
Horner syndrome: Caused by impairment of the ocular sympathetic nervous system, presenting with miosis, ptosis, and decreased lacrimation. Detection of denervation supersensitivity using 1% apraclonidine hydrochloride (Iopidine) eye drops is useful.
Autonomic crisis is an important acute complication in FD patients, caused by uncontrolled sympathetic outflow due to impaired baroreceptor feedback 1).
First-line: Benzodiazepine (enhances inhibitory neurotransmission via GABA receptors) + Clonidine (central alpha-adrenergic agonist that suppresses peripheral norepinephrine release) 1)
Beta-blocker (Labetalol): Reduces blood pressure and heart rate by competitive antagonism of catecholamines 1)
Carbidopa: Dopamine synthesis inhibitor. Effective for vomiting, but its effect on blood pressure is unclear 1)
If ocular hyperemia is present, chronic blepharitis, bacterial conjunctivitis, and fungal keratitis should be promptly evaluated. Chronic blepharitis is treated with a combination of topical antibiotics and corticosteroid ointments. If significant strabismus is present, early corrective surgery is beneficial for maintaining visual function.
QWhy does vomiting occur in autonomic crises?
A
During a crisis, along with the catecholamine surge, dopamine is also released into the bloodstream. This dopamine activates D2/D3 receptors in the chemoreceptor trigger zone of the area postrema, inducing vomiting1).
6. Pathophysiology and detailed mechanisms of onset
IKAP is a protein that shows the highest expression in neural tissues and the retina, and is widely expressed throughout the body. In vitro and in vivo studies suggest the following functions.
Neuronal migration, survival, and myelination: Plays an important role in developmental processes
Axonal branching: Contributes to the formation of appropriate branching patterns of peripheral nerves
Retrograde neurotrophic factor transport: Transmits signals from target tissues to the neuronal cell body
The most common IKAP gene mutation (T→C substitution in intron 20) causes variable splicing out of exon 20. This results in a frameshift, producing a significantly shortened IKAP protein due to a premature stop codon.
This splicing abnormality is tissue-specific. In neurons, mutant IKAP mRNA tends to be predominantly produced, whereas in other cells, normal and mutant mRNAs coexist in varying ratios. The cause of this tissue specificity is unknown.
IKAP deficiency during embryonic development leads to failure of primary sensory innervation of target tissues. As a result, dorsal root ganglion and sympathetic neurons are lost. A marked loss of unmyelinated sensory neurons is characteristic, leading to diminished deep tendon reflexes and generalized impairment of pain and temperature sensation.
OCT studies have shown that optic neuropathy in FD is characterized by a reduction in the macular retinal ganglion cell layer and its axons, the RNFL, while more peripheral ganglion cells are relatively spared. Optic atrophy is usually most pronounced on the temporal side of the optic disc, reflecting selective damage to the papillomacular bundle.
The fundamental cause is damage to sensory neurons that transmit afferent information from arterial baroreceptors. This damage leads to loss of feedback to the central nervous system, resulting in uncontrolled sympathetic outflow 1).
During a crisis, a surge of catecholamines (epinephrine and norepinephrine) occurs. At the same time, dopamine is released into the blood, activating D2/D3 receptors in the chemoreceptor trigger zone of the area postrema, thereby inducing vomiting 1).
7. Latest Research and Future Perspectives (Reports at Research Stage)
Since FD is caused by splicing abnormalities, there is growing interest in treatment through splicing modification. Two drugs in particular are attracting attention.
Kinetin: Shown to overcome splicing defects and increase expression of wild-type IKAP
Phosphatidylserine: Reported to restore IKAP expression similarly to kinetin
However, long-term trials are currently underway to determine whether increasing IKAP levels can prevent or delay further deterioration of neurological features such as optic atrophy.
Dexmedetomidine (a central alpha-2 adrenergic agonist) has been reported to be effective for refractory autonomic crises that do not respond to conventional treatment.
Subedi et al. (2022) reported a case of refractory autonomic crisis in a 19-year-old male patient with FD. The patient did not respond to labetalol, diazepam, or clonidine. Dexmedetomidine was started at 0.4 μg/kg/hr and increased by 0.1 μg/kg/hr every 30 minutes. Within 3 hours, blood pressure normalized and symptoms resolved1).
In a retrospective study of 9 FD patients, a decrease in blood pressure and heart rate was observed after dexmedetomidine use in 10 out of 14 hospitalizations1).
However, no prospective studies on dexmedetomidine have been conducted, and the rarity of FD makes it difficult to conduct studies with sufficient statistical power1).
Rand et al. (2023) discussed the future of research on rare autonomic disorders, proposing the collection of real-world data using wearable devices, advances in gene therapy and gene editing technologies, and international collaborative data collection using patient registries. More than 80% of rare diseases have a genetic component, and successful examples of treatment or cure through gene therapy are accumulating2).
QCan splicing modification therapy cure FD?
A
Although kinetin and phosphatidylserine have been shown to increase IKAP protein expression, it remains uncertain whether this can prevent or delay the progression of neurological disorders such as optic atrophy. Long-term trials are ongoing, and this is currently an investigational treatment.
Subedi A, Sharma R, Lalani I. Experience With Dexmedetomidine Use in the Treatment of Dysautonomic Crisis in Familial Dysautonomia: An Off-Label Use. Cureus. 2022;14(10):e29988.
Rand CM, Weese-Mayer DE. The future of rare autonomic disease research. Clin Auton Res. 2023. doi:10.1007/s10286-023-00957-7.
Pereira S, Vieira B, Maio T, Moreira J, Sampaio F. Susac’s Syndrome: An Updated Review. Neuroophthalmology. 2020;44(6):355-360. PMID: 33408428.
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