Neuro-ophthalmic Manifestations of Familial Dysautonomia

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Disease Entity


In 1949, Riley and Day first described an unusual clinical entity in children of Ashkenazi Jewish descent characterized by extensive sensory and autonomic abnormalities, including diminished tear production, excessive sweating and salivation, red blotching of the skin, reduced deep tendon reflexes, and marked arterial hypo/hypertension. [1] This entity became known as Riley Day syndrome, or more commonly referred to as familial dysautonomia (FD). Over the following decades, FD is now classified as one of the neurodevelopmental disorders termed hereditary sensory and autonomic neuropathies (HSAN) and is also termed HSAN-III. [2]


FD is transmitted in an autosomal recessive manner and primarily affects individuals of Ashkenazi Jewish descent, with an estimated prevalence of 1/3700 in their population. With the identification of specific genetic mutations underlying FD, the carrier frequency of the most common mutation is estimated around 1/27 to 1/32 in the general Ashkenazi Jewish population. [2][3] Interestingly, other HSANs do not share such a strong ethnic predisposition. [4]


In 2001, the gene for autosomal recessive FD was identified on the long arm of chromosome 9 as elongator-1 protein (ELP-1), known also as I-k B kinase-associated protein (IKAP). While three mutations were discovered, the most common mutation is a single-base T-C transition in the donor splice site of intron 20. [3] This results in variable splicing out of exon 20 in the mRNA transcript, producing a frameshift mutation with a premature stop codon and a significantly truncated version of IKAP. Despite the systemic presence of this mutation, the splicing abnormality is tissue-specific for unknown reasons. Neurons tend to produce mostly mutant IKAP mRNA, while other cells produce a mix of normal and mutant mRNA in different ratios. [5]

While the function IKAP is not fully understood, it is widely expressed throughout the body, with the highest expression occurring in neural tissue and the retina. In vitro and in vivo studies have implicated IKAP in the migration, survival, and myelination of neurons during development. Particularly, it is believed that IKAP plays an important intracellular role in axonal branching and retrograde neurotrophic transport to fine-tune the innervation process. Consequently, it is thought that IKAP deficiency during human embryogenesis results in a failed primary sensory innervation of target tissues, leading to loss of the dorsal root ganglion and sympathetic neuronal cells. [2][5]


Neuro-ophthalmic Manifestations

Prior to the advent of genetic testing, FD was commonly recognized through a prominent constellation of ocular findings that led to gradual visual impairment and subsequent legal blindness with age progression. Notably, the most common ocular manifestation in FD patients is neurogenic alacrima (abnormal tear production). Furthermore, children with FD often have corneal hypesthesia, as part of the generalized neuropathy, that renders them insensitive to ocular pain caused by foreign bodies or other irritants. Lagophthalmos may also be present. Combined, these manifestations place FD patients at high risk of corneal epithelial defects that chronically progress to corneal abrasions and eventual corneal scarring. [6][7]

As well as the well-documented anterior ocular pathology related to the cornea, there have been numerous reports of neuro-ophthalmic manifestations to explain the observed visual impairment in FD patients with relatively normal corneas. Particularly, observations of decreased visual acuity, central visual field defects and red–green color vision deficiency in older FD patients, indicate a form of progressive optic neuropathy. In many cases, optic nerve involvement has been detected by optic atrophy, which is typically most prominent in the temporal portion of the optic nerve head and associated with retinal nerve fiber layer loss in the papillomacular bundle. [8] Further studies using high-definition optical coherence tomography demonstrated a form of optic neuropathy in FD patients characterized by reductions in the macular retinal ganglion cell layer and their axons in the retinal nerve fiber layer, with relative sparing of the more peripheral ganglion cells.[9] Much of the observed findings have been documented more recently and after the first decade of life in FD patients, suggesting that recent improvements in survival may reveal this late optic neuropathy in more patients.[8][10]

Abnormalities in ocular motility, including saccadic intrusions and slow optokinetic responses, have also been observed in FD. It is unknown whether these defects are due to abnormalities at the extraocular muscles or at higher supranuclear control centers [7][8]

Systemic Manifestations

FD is expressed from birth with genetic penetrance yet there is variable expressivity in the multiple systems involved. At birth, children with FD do not usually exhibit obvious dysmorphic features but a characteristic straightening of the upper lip may develop over time and is more prominent when smiling. Other common physical characteristics include short stature and kyphoscoliosis. [2][4]

Given the significant loss of unmyelinated sensory neurons in FD, deep tendon reflexes are often diminished and there is a general pain and temperature insensitivity. A cardinal sign that is often observed is the absence of lingual fungiform papillae, resulting in taste disturbances.[1][2] Emotional instability and impaired coordination are often observed. From a cognitive standpoint, intellectual ability is usually preserved but executive planning and organizational skills tend to be poor.[4]

Beyond the sensory deficits, autonomic abnormalities are often observed in FD patients and progress with age. Starting at a young age, autonomic dysfunction in FD patients most commonly manifests as oropharyngeal incoordination with poor sucking reflexes, gastroesophageal reflux and nausea and vomiting. In some cases, a dysautonomic crisis can occur, manifesting as episodic vomiting with transient hypertension, tachycardia, diffuse sweating and sometimes personality changes. The combination of these gastrointestinal manifestations predisposes to aspiration, leading to early lung infections and failure to thrive. Furthermore, central hypopneas and apneas can occur during sleep causing nocturnal hypoxia. These autonomic abnormalities place FD patients at high risk of sudden death.[2]

Vasomotor instability is common in FD and patients often exhibit episodes of severe orthostatic declines in blood pressure. These episodes often manifest acutely as spells of lightheadedness or syncope while the hypoperfusion gradually precipitates renal failure. Older patients may also exhibit supine hypertension.[1][2]


Prior to the identification of its underlying genetic mutation, the diagnosis of FD was based upon clinical recognition of symptoms underlying sensory and autonomic neuropathies. A characteristic combination of five cardinal features including alacrima, absent fungiform papillae, depressed patellar reflexes, and abnormal histamine test in an individual of Ashkenazi Jewish descent were sufficient enough to meet a high index of suspicion for FD. Since individuals affected with the other HSANs may also fail to trigger a response to intradermal histamine, careful evaluation of clinical findings is necessary in order to distinguish between these disorders. Furthermore, a sural biopsy is often performed to demonstrate markedly diminished numbers of unmyelinated axon, a characteristic finding in FD. However, since the genetic mutations for FD are now available, DNA testing is the modality of choice for definitive diagnosis.[2][4]


Management of Systemic Manifestations

Although there is no cure for FD, the goal of medical intervention is to improve quality of life through targeted symptomatic management. An important goal of early treatment is to provide adequate nutrition and avoid aspiration to maintain growth potential. For infants, thickened formula and the use of alternative feeding techniques are useful in managing oropharyngeal incoordination. While the long-term effects of FD on survival are unclear, fundoplication with gastrostomy can prevent aspiration pneumonia and reduce reflux symptoms in FD patients with recurrent symptoms. Orthostatic hypotension can be managed through midodrine, which has been shown to increase survival in FD patients. Clonidine and diazepam can be utilized for supine hypertension and to reduce the length of dysautonomic crisis.[2][11]

With the discovery of the genetic mutation underlying FD, interest in splicing modification therapy for FD patients has gained traction. Particularly, two available agents, kinetin and phosphatidylserine, have been shown to overcome the splicing defect and increase the expression of wild-type IKAP. Nevertheless, long-term trials are underway to determine whether raising IKAP levels can prevent or delay further deterioration of neurological features like optic atrophy.[11][12]

Management of Ophthalmic Manifestations

Decreased basal and emotional tear production remains one of the well-documented features in FD, yet therapy remains symptomatic and has changed very little over the past few decades. Corneal lubrication through regular use of artificial tear solutions, moisture chamber goggles during sleep and adequate body hydration remain the mainstay of therapy to prevent corneal abrasions and ulcerations. Furthermore, the use of soft contact lenses or occlusion of the lacrimal puncta can also be of therapeutic value.[8] In refractory and chronic cases unresponsive to these measures, tarsorrhaphy can be performed but has undesirable cosmetic and vision-limiting effects. Corneal transplantation has had limited success due to poor healing and epithelial defects.[11]

Given the predisposing dry eye environment, symptoms of an apparent red eye should be promptly evaluated for potential chronic blepharitis, bacterial conjunctivitis, or fungal keratitis. Chronic blepharitis is commonly seen and is treated with combined topical antibiotic and corticosteroid ointment. Finally, in cases of significant strabismus, early correction surgery has been shown to be of benefit in preserving visual function. [7][11]


Despite the primarily supportive treatment approach for FD patients, the use of pharmaceutical interventions and various surgical measures has yielded substantial gains in quality of life and concurrent reductions in morbidity and mortality. In fact, these interventions have improved survival such that FD can no longer be considered a strictly childhood illness, with greater than 50% of the FD population being 15 years of age or older. [13]

Interestingly, while there has been a decline in causes of death from aspiration-related complications, there has been an unexplained rise in sudden deaths perhaps due to altered sleep structure or cardiac arrhythmias.[2][4] Therefore, until definitive genetic treatment is available, greater understanding of sleep physiology and cardiac arrhythmias may prevent sudden death and further prolong survival.

In summary, FD is characterized by corneal epithelial defects from alacrima which can lead to long term corneal scarring. Other neuro-ophthalmic complications including optic atrophy and ophthalmoplegia have been described in FD. Although there is no cure for FD supportive measures might be helpful to improve quality of life.


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