Familial dysautonomia (FD), also known as the Riley-Day syndrome or hereditary sensory and autonomic neuropathy type III, is an autosomal recessive disorder that impairs the development of specific sensory and autonomic neurons during embryogenesis (1–5). The most common mutation, located on the long arm of chromosome 9 (9q31) (6,7), results in a splicing abnormality and a deficiency of the IkB kinase complex–associated protein (IKAP or Elp1) (8–12). The splicing abnormality is tissue specific: neurons produce mostly mutant IKAP messenger RNA (mRNA) and little protein product, whereas other cells produce both normal and mutant mRNAs in different ratios (13). IKAP is widely expressed throughout the body, with its expression being highest in neural tissue and the retina (14).
Patients with FD have a complex neurological phenotype with decreased pain and temperature perception, impaired sense of taste, abnormal swallowing, gait ataxia, decreased/absent myotatic reflexes, and extremely labile blood pressure. Vision deteriorates with age in patients with FD, and by adulthood, most patients have severe visual loss (15–18). Visual impairment has dramatic consequences for these patients as they lack proprioceptive afferents and thus rely heavily on vision for activities of daily living. Dry eye secondary to lacrimal deficiency, myopia, corneal anesthesia, corneal abrasions, and ulcerations were believed to be the main cause of visual deterioration (15,17). However, based on clinical observations, the degree of visual impairment cannot be explained by corneal complications alone, and visual loss occurs in patients without severe corneal damage. Early case reports describe exotropia, pupillary dysfunction, and optic nerve atrophy, but it is not known whether these neuro-ophthalmic features occur in all patients (18–24). Our aim was to define the neuro-ophthalmic phenotype of patients with FD.
We evaluated 32 eyes in 16 patients with FD, 6 men and 10 women with a mean age of 26.8 years (range, 12–61 years). All patients had typical clinical features, and the diagnosis was confirmed by genetic testing. All patients signed an informed consent and the NYU Institutional Review Board approved the study.
Best-corrected visual acuity (BCVA) was assessed independently for each eye using Snellen optotypes with optimum refractive correction, and the results were presented as decimal units. Color vision was estimated using Ishihara plates (Ishihara 16 plates, Tokyo, Japan), and Hardy-Rand-Rittler color vision test (American Optics, Richmond, VA). Pupillary reflexes were assessed using a standard bright light (Halogen illuminator lamp HPX 3.5 V; Welch Allyn, Skaneateles Falls, NY). Ductions, fixation, saccades, pursuit, convergence, vestibulo-ocular reflexes, and optokinetic responses were assessed. Visual fields were obtained using a Humphrey Field Analyzer (HFA 750i; Carl Zeiss, Dublin, CA), with the 30-2 program and SITA Fast strategy using optimal refractive correction. Anterior segments were examined by slit-lamp biomicroscopy. Ocular fundus examination was performed with a binocular indirect ophthalmoscopy (Keeler Vantage, London, United Kingdom) and slit-lamp biomicroscopy (Haag Streit BQ 900; Haag Streit, Koeniz, Switzerland) to evaluate the posterior pole using a noncontact lens of +78 diopters and red-free light with particular attention of the retinal nerve fiber layer. In some patients, mydriatic color and red-free fundus photographs (TRC 50 IX; Topcon, Tokyo, Japan) were acquired.
The main neuro-ophthalmic findings are summarized in Table 1. Myopic refractive defects were present in 27 of 32 eyes. Most patients had a history of corneal lesions. We classified the corneal opacities as absent or mild (17 eyes), moderate (13 eyes), and severe (2 eyes). In none of the eyes was the opacity severe enough to preclude fundus examination through indirect ophthalmoscopy or non–contact lens biomicroscopy, even in the 2 severely affected eyes. Band keratopathy was present in 1 eye.
BCVA ranged from 0.05 to 1.0 decimal units. Most of the patients had acuity less than 0.5 decimal units, which did not appear to be due to corneal opacities or other surface abnormalities except in 2 eyes.
A red-green color vision defect was found bilaterally in all patients examined with variable degrees of severity, and in 4 eyes of 2 patients, blue-yellow color deficiency also was detected.
Central or cecocentral visual field defects were predominant and found in 26 eyes. Four eyes had generalized, deep field depression, and this was associated with poor visual acuity (Table 1). Two eyes had normal visual fields.
Retinal nerve fiber layer loss was detected in all eyes, accompanied by temporal pallor of the optic disc. Twenty-five eyes showed only pallor in the temporal region of the optic nerve together with a wedge-shaped loss of fibers in the papillomacular bundle (Table 1). In 7 eyes, there was also generalized optic nerve pallor, but this was always more evident in the temporal portion of the disc (Fig. 1). Retinal vascular tortuosity was present in 6 eyes.
Ocular motility was impaired in various ways (Table 1). While ductions and versions were full in all patients, exophoria was seen in almost all cases (30 eyes). This was associated with limited convergence. There were no limitations of excursions. Saccades tended to be dysmetric; more often they were hypermetric with corrective refixation saccades. In some cases, there was adduction slowing, which was confirmed by testing with the optokinetic drum. Pursuit movements were interrupted by repeated saccadic intrusions in almost all cases.
The main neuro-ophthalmic finding in patients with FD was a characteristic optic neuropathy. Visual acuity was reduced in most patients and appeared to be worse in the older patients. Corneal opacities were present in many eyes, but, in almost all eyes, the central corneas appeared clear enough by slit-lamp biomicroscopy to allow for good vision. The predominant red-green color deficiency that was almost always detected is consistent with optic neuropathy, although some blue color deficits in some eyes may suggest additional retinal dysfunction. The central and cecocentral visual field defects seen in most patients are very similar to those seen in patients with hereditary, toxic, and nutritional deficiency optic neuropathies. In some cases, the central and cecocentral visual field defects were profound and associated with poor visual acuity and color perception. Also, in almost all cases, there was optic nerve head pallor, which was confined to or most prominent in the temporal portion of the optic nerve head and associated with a wedge-shaped area of retinal nerve fiber loss in the papillomacular bundle.
The abnormalities in ocular motility suggest that the disease process in FD can affect ocular motor control mechanisms. The dysmetric saccades, saccadic intrusions, and disrupted pursuit eye movements that we observed might indicate loss of the fine-tuning control of eye movements. Whether these defects are due to abnormalities at the level of the extraocular muscle or due to a supranuclear control deficit cannot be determined by our studies.
There were few retinal findings in our patients. The macular area was always normal with no pigment epithelial changes. In some patients, the fundi showed myopic changes associated with myopic refractive errors greater than −7.00 diopters. Retinal vascular tortuosity was seen in 8 eyes, as previously reported (16,21).
Few authors have described optic neuropathy in FD patients. Rizzo et al (19) studied 3 patients with FD and found optic neuropathy, which they believed was “a rare manifestation of this rare disease.” They did suspect that it appeared later in the lives of affected patients (19). Diamond et al (20) described a group of FD patients who had abnormal visual evoked potentials and optic nerve pallor. Other case reports describing the optic neuropathy in patients with FD have also been published without additional details (21–24). We detected optic nerve damage in all patients, some as young as 11 years old and all with loss of retinal nerve fibers in the papillomacular bundle.
Involvement of central visual field, deficient color perception, and the temporal optic disc pallor that we have observed in patients with FD is strikingly similar to the findings in other hereditary optic neuropathies, such as Leber hereditary optic neuropathy, dominant optic atrophy, and some recessive optic neuropathies. All these optic neuropathies have in common mitochondrial protein dysfunction caused by mutations either in nuclear or mitochondrial DNA (25,26). This suggests that the primary mutation in FD may affect mitochondrial protein synthesis in the nervous system.
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