The hereditary eye diseases associated with the negative-type ERG (a-wave larger than b-wave) with normal a-wave amplitude are congenital stationary night blindness, X-linked congenital
retinoschisis, and Batten disease. Two addi- tional conditions whose etiology is still uncer- tain are described in this section.
2.18 Association of Negative ERG
with Diseases of Unknown
Etiology
148 2 Hereditary Retinal and Allied Diseases
In 1989 we reported four male patients [1] who had bull’s-eye maculopathy and an otherwise normal fundus except for a dark choroid seen on fluorescein angiography in one patient (Fig.
2.123). The bright flash, mixed rod–cone ERG in the dark was made up of a normal a-wave but the b-wave that was reduced and smaller than the a-wave (Fig. 2.124). The full-field rod ERGs were moderately reduced, and the cone and 30- Hz flicker ERGs were relatively well preserved (Fig. 2.125). Other findings common to all four patients were moderately low visual acuity (normal visual acuity initially), mild to moder- ate color vision deficiency, normal peripheral visual fields, normal EOGs, near-emmetropia, and appearance predominantly in men.
Recently, molecular genetic examinations were performed in all patients, and one patient (case 2) had a novel missense mutation, Ala101Pro (c.301G to C) in the XLRS1 gene, which was identified from his genomic DNA.
He was thus diagnosed as having X-linked retinoschisis. Although bull’s-eye maculopathy is rarely associated with X-linked retinoschisis, we should consider the possibility of this dis- order when bull’s-eye maculopathy is associ- ated with negative ERGs. We could not find any mutation in the other patients. Case 1 showed a dark choroid, which is often seen with Stargardt disease, but no mutation of the gene associated with Stargardt disease was detected.
2.18.1 Bull’s-eye Maculopathy
Fig. 2.125. Full-field ERGs recorded from the four patients whose mixed rod–cone ERGs are shown in Fig. 2.124. The ages of patients are 12 (case 1), 36 (case 2), 22 (case 3) and 40 years old (case 4). (From Miyake et al. [1], with permission)
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Fig. 2.123. Fluorescein angiograms of four patients with bull’s-eye maculopathy and negative ERGs. Case 1 shows a dark choroid. Case 4 was diagnosed as having X-linked congenital retinoschisis by molecular genetic examinations. (From Miyake et al. [1], with permission)
Fig. 2.124. Mixed rod–cone ERGs elicited by a bright flash recorded from a normal control and the four patients whose fluorescein angiograms are shown in Fig. 2.123. (From Miyake et al. [1], with permission)
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2.18.2 Familial Optic Atrophy with Negative ERG
Earlier investigators reported that negative ERGs were rarely associated with optic nerve atrophy because patients with the inherited forms of optic atrophy had been reported to have normal ERG findings [2]. The optic atrophy was assumed to occur from transsy- naptic degeneration of the bipolar cells.
In 1992, in collaboration with Richard Weleber of Portland, Oregon, we found that the affected members of two families with presum- ably autosomal dominant optic atrophy also had negative-type ERGs (Fig. 2.126) [3]. They had poor central vision, and the decrease occurred during the second to third decade of life. Ophthalmological examinations showed that the affected members had visual acuities of 1.0–0.4, defective color vision, mild to moder- ate myopia, and pericentral or centrocecal sco- tomas. Optic atrophy was found in four of the five patients (Fig. 2.127). The age of the affected members ranged from 21 to 56 years (mean 42 years).
The amplitude of the a-wave of the full-field ERGs (Fig. 2.128) and the scotopic rod–cone ERGs were normal, but the amplitude of the b- wave was markedly reduced. The amplitudes of the rod responses were moderately reduced but with normal implicit times. The amplitudes of the b-wave of the photopic ERGs varied from normal to mildly reduced, and the implicit times were normal. The amplitudes of 30-Hz flicker ERGs were normal.
The moderately low visual acuity of these patients may be caused by optic atrophy or some macular problem. The essentially normal focal macular ERGs suggest that the low visual acuity is caused by optic nerve dysfunction.
Because negative ERGs are not seen with other familial optic atrophies, we concluded that this disease, with an association of optic atrophy and abnormal negative ERGs, represented a new genetic disorder.
Fig. 2.126. Two pedigrees showing the family members with optic atrophy and negative ERGs. The black dot at the side of the symbols identifies individuals who were examined ophthalmoscopically. Males III-1 and III-2 of Family 2 were fraternal twins, one of whom died. Patients 4 and 6 of Family 2 also had McArdle’s (Mc) disease, but this is an autosomal recessive trait unassociated with either optic atrophy or ERG abnormalities. (From Weleber and Miyake [2]) RDI2(104%) 9/9/05 8:22 PM Page 150
Fig. 2.127. Fundi of case 1 (top left), case 2 (top right), case 3 (center left), case 4 (center right), and case 5 (bottom).
(From Weleber and Miyake [2])
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References
1. Miyake Y, Shiroyama N, Horiguchi M, Saito A, Yagasaki K (1989) Bull’s eye maculopathy and negative ERG. Retina 9:210–215
2. Yagasaki K, Miyake Y, Awaya S, Ichikawa H (1986) ERG (electroretinogram) in hereditary optic atrophy. Acta Soc Ophthalmol Jpn 90:124–130
3. Weleber RG, Miyake Y (1992) Familial optic atrophy with negative electroretinograms. Arch Ophthal- mol 110:640–645
Fig. 2.128. Full-field ERGs recorded from a normal control and three patients (cases 1, 2, and 3) exam- ined in Nagoya, Japan (A); and two patients (cases 4 and 5), a patient with complete CSNB, and a normal control examined in Portland, Oregon, USA (B). A Rod ERGs are subnormal, and mixed rod–cone (bright white) ERGs have the shape of the negative- type ERG. The OPs are reduced. The cone and 30-Hz flicker ERGs are normal. B The blue light was sco- topically balanced with the red light for production of equal-amplitude rod responses. Note that the rod b-waves responses to dim white light and dim blue light were subnormal for both patients and nearly undetectable for the patient with complete CSNB. The cone-mediated ERGs were normal. (From Weleber and Miyake [2])
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