Ординатура / Офтальмология / Английские материалы / Electrodiagnosis of Retinal Disease_Miyake_2005
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2.10 Complete and Incomplete Types of CSNB 103
Fig. 2.70. Left: Map of the amplitudes and implicit times of first-order kernels of multifocal ERGs for four patients with complete CSNB. White areas, values within the 5th to 95th percentile range of normal; black areas, amplitudes and implicit times outside the 5th to 95th percentile range of normal. Note that there are regional variations for both the amplitudes and implicit times of the multifocal ERG across the retina for normal subjects. The normal ranges of the amplitude and implicit time were calculated independently for all locations. Right: Summated second-order kernels for all 61 local responses for 20 myopic controls and four patients with complete CSNB. All responses were superimposed in the top trace and averaged in the bottom trace. (From Kondo et al. [21], with permission)
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2.10.7 Carrier State of X-Linked CSNB
In 1983 we reported that the OPs of the fullfield, mixed rod–cone ERG in patients with the X-linked Schubert-Bornschein type of CSNB were significantly reduced [22]. At that time, however, we thought that the Schubert-Born- schein type was one disease entity and had not classified CSNB into complete and incomplete forms. Therefore, our analysis was of complete and incomplete CSNB combined. After we classified CSNB into the two types [2], we reanalyzed the results and found that the full-field mixed rod–cone ERGs of both complete and
incomplete CSNB have a carrier state with reduced OPs [23].
Figure 2.71 shows the full-field rod–cone ERGs recorded from female carriers of X- linked recessive complete and incomplete CSNB. A single flash ERG was recorded with a bright-white flash, 20 joules in intensity, after 30 min of dark adaptation. Two recordings were done simultaneously, using two different time constants (TC).A TC of 0.003s was used to evaluate OPs. In both types, only OPs are selectively reduced.
Fig. 2.71. Single flash rod–cone ERGs recorded with two different time constants in a normal subject (top) and in female carriers of complete (bottom left) and incomplete (bottom right). The a-wave and b- wave are normal, but the OPs show selective reduction of amplitude. The implicit time of OPs is within the normal range
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2.10.8Molecular Genetics
Evidence of genetic heterogeneity in X-linked complete and incomplete CSNB was reported by Boycott et al. in 1998 [3]. Soon thereafter, the gene for X-linked incomplete CSNB was identified by Strom et al. [6] and Bech-Hansen et al. [7] as the pore-forming subunit of an L-type voltage-gated calcium channel (CACNA1F) that is found in the retina. Loss of the functional channel impairs the calcium influx into rods and cones that is needed for sustaining the tonic release of neurotransmitters from the presynaptic terminals.
Among our Japanese patients with incomplete CSNB, all had the CACNA1F gene mutation, indicating that the phenotypic classification had provided a precise diagnosis of incomplete CSNB [10, 11]. A summary of the CACNA1F protein, showing all reported mutations including those of our studies, is presented in Fig. 2.72. The fundus photographs from all patients with incomplete CSNB who had been proven to have a mutation of the CACNA1F gene are shown in Fig. 2.53, and the full-field ERGs from all of these patients and the specific mutations are shown in Fig. 2.73. It is surprising that the shape of the ERGs was
extremely uniform, and all patients had had a correct diagnosis of incomplete CSNB before undergoing a molecular genetic examination. This indicates how the full-field ERGs provide significant information for the correct diagnosis.
In 2000 the NYX gene was cloned from the Xp11 region by Bech-Hansen et al. [4] and Pusch et al. [5] The NYX gene encodes the glycosylphosphatidyl (GTP)-anchored extracellular protein nyctalopin. Nyctalopin, a new, unique member of the small, leucine-rich proteoglycan family, may be the gene product that guides and promotes the formation and function of the on pathway in the retina.
The full-field ERGs of patients with complete CSNB caused by a mutation in the NYX gene and ERGs from individuals who do not have this mutation are shown in Fig. 2.74. The fundus photographs of these patients were shown earlier, in Fig. 2.54. The inheritance pattern of the patients with the NYX gene mutation is X-linked recessive,and that of those without the NYX gene mutation is most likely autosomal recessive. The full-field ERGs are not significantly different in the two groups, and both groups show a uniform waveform.
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Fig. 2.72. Mutated sites in the CACNA1F gene reported in the literature, including our patients. Filled circles, our patients; circle with left diagonal lines, patients of Storm et al.; circles with right diagonal lines, patients of Bech-Hansen et al. (From Nakamura et al. [11], with permission)
Fig. 2.73. Full-field ERGs recorded from a normal subject and 15 of our patients with incomplete CSNB and a CACNA1F gene mutation. The specific mutation is given in the right column. (From Nakamura et al. [11], with permission)
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Fig. 2.74. Full-field ERGs recorded from a normal subject (upper), 6 patients with complete CSNB and an NYX gene mutation (middle) and 5 patients with complete CSNB but without an NYX gene mutation (lower). The specific mutation is given in the right column of the NYX(+) patients (From Miyake [10])
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2.10.9Possible Pathogenesis
Pathophysiological studies on clinical patients and animal models as well as molecular genetic analyses suggest that patients with X-linked complete CSNB have an almost complete block of synaptic transmission from the photoreceptors to the on bipolar cells in both the rod and cone visual pathways. The off pathway, however,
appears to be intact. Patients with autosomal recessive complete CSNB appear to have similar pathophysiology. In contrast, patients with incomplete CSNB have an incomplete defect of the synapses in the on and off bipolar cells in the rod and cone visual pathways (Fig. 2.75).
Fig. 2.75. Possible pathogenesis of complete and incomplete CSNB. Patients with complete CSNB have complete blockage of the on synapses (solid cross lines), whereas those with incomplete CSNB have an incomplete defect of the on and off synapses in both rod and cone visual pathways (dashed cross lines)
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2.10.10Are Complete and Incomplete Cases of CSNB Really Nonprogressive?
Long-term follow-up of the corrected visual acuity in patients with complete and incomplete CSNB [24] is shown in Fig. 2.76. For both types of CSNB, most patients do not show significant changes or even slight improvement in their visual acuity during the long follow-up period. This strongly indicates that both types of CSNB are nonprogressive, at least when assessed by visual acuity.
The full-field ERGs also show little decrease in amplitude during long-term follow-up; an example is shown in Fig. 2.77. The single flash ERG (rod–cone mixed) was recorded from a patient with incomplete CSNB in 1970 and repeated again under similar conditions in 2002. After 32 years, the ERG did not decrease in amplitude, but the b-wave amplitude had increased [10]. This patient was found to have the mutated CACNA1F gene, as in most patients with incomplete CSNB [11]. In addition to these findings, families with X-linked complete and incomplete CSNB sometimes have a grandfather and grandson who, despite the large difference in age, have essentially the same clinical findings. These observations suggest that these two disorders are essentially stationary.
However, among the patients with a CACNA1F gene mutation, we have found that some had a progressive clinical course and severely deteriorated visual function [25, 26]. The full-field ERGs of a 31-year-old man showed typical findings of incomplete CSNB (Fig. 2.78A). This patient had a hemizygous Arg913 stop mutation in the CACNA1F gene [25] (Fig. 2.78B). The fundus, fluorescein
angiograms, and visual fields are shown in Fig. 2.79. The patient had atrophic retinal lesions around the inferior vascular arcades in both eyes that resembled that of pigmented paravenous retinochoroidal atrophy or sectorial retinitis pigmentosa. Fluorescein angiography revealed window defects in the areas corresponding to the atrophy, and Goldmann kinetic perimetry detected relative scotomas in the same areas.
Fundus photographs of another two brothers [26] are shown in Fig. 2.80. The younger, 56-year-old brother (Fig. 2.80A,B) had optic atrophy, attenuated retinal vessels, and slightly diffuse pigmentary atrophy in both eyes. The older, 64-year-old brother (Fig. 2.80C,D) had optic atrophy and severe chorioretinal degeneration in both eyes. Both patients had progressive decline of visual functions and had an in-frame mutation with deletion and insertion in exon 4 of the CACNA1F gene. In both patients, the mixed rod–cone ERG had a negative configuration, which is characteristic of incomplete CSNB. However, OPs were absent, and the rod and cone ERGs, which are not usually seen in patients with incomplete CSNB, were unrecordable (Fig. 2.81, cases 1, 2).
These findings of three patients in two pedigrees indicated that mutations of the CACNA1F gene often lead to ERG findings that correspond to those for incomplete CSNB, but the mutations also occasionally lead to ERG changes associated with other retinal dystrophies that have retinal and optic disk atrophy with progressively decreasing visual function.
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Fig. 2.77. Mixed rod–cone ERGs recorded in 1970 and 2002 from a patient with incomplete CSNB. (From Miyake [10])
Fig. 2.76. Changes in visual acuity in patients with complete and incomplete CSNB during long-term follow-up periods. (From Miyake et al. [24])
Fig. 2.78. A Full-field ERGs recorded from a normal subject and a patient with a CACNA1F gene mutation. B Nucleotide sequence of CACNA1F using a sense primer in this patient. A hemizygous nonsense mutation of C to T in axon 24 (Arg913stop) is shown. The arrow indicates the position of the mutation. (From Nakamura et al. [25], with permission)
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Fig. 2.79. Fundus photographs (A, B), fluorescein angiograms (C, D), and Goldmann kinetic visual fields (E) of the patient with a CACNA1F gene mutation shown in Fig. 2 78. Right eye (A, C) and left eye (B, D) show an atrophic retinal region around the inferior vascular arcade with hyperfluorescence due to RPE alterations. Visual fields show a relative scotoma in the area corresponding to retinal atrophy (E). (From Nakamura et al. [25], with permission)
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Fig. 2.80. Fundi of two patients with CACNA1F mutations (cases 1 and 2). Case 1 shows optic atrophy, attenuated retinal vessels, and diffuse RPE atrophy in both eyes. Case 2 shows optic atrophy, attenuated retinal vessels in both eyes, and severe chorioretinal degeneration in the left eye. (From Nakamura et al. [26], with permission)
Fig. 2.81. Full-field ERGs recorded from a normal subject, a patient with typical incomplete CSNB, and two patients with optic atrophy and CACNA1F gene mutations (cases 1 and 2). (From Nakamura et al. [26], with permission)