- Email: [email protected]
A novel CACNA1F mutation in a french family with the incomplete type of X-linked congenital stationary night blindness
cataract extraction experience. The study design is an interventional case series examining the visual outcomes and incidence of vitreous loss of a consecutive series of phacoemulsification cataract surgeries performed by ophthalmology residents in one ophthalmology residency program. In all, 332 cases of phacoemulsification cataract surgery performed by four third-year ophthalmology residents (two consecutive cycles of two third-year residents) from July 1999 through June 2001 were evaluated. Before serving as the primary cataract surgeon, the residents assisted faculty during their first and second years of training. They also participated in numerous cataract surgery conferences and phacoemulsification wet laboratories. All phacoemulsification cataract surgeries, including combined phacoemulsification and trabeculectomies, were included in the evaluation. Procedures were performed using retrobulbar or topical anesthesia through a superior or temporal clear corneal incision, except combined procedures, which were performed through a scleral tunnel. An attending physician experienced in phacoemulsification directly supervised all cases. Data collected included preoperative and postoperative best-corrected visual acuity, preexisting ocular comorbidities, and intraoperative and postoperative complications. This represents an ongoing quality improvement project initiated by the Penn State Ophthalmology Residency Program to monitor resident performance of phacoemulsification cataract surgery. In consideration of patient rights and patient protection, the data accumulation was approved by the Institutional Review Board. A total of 332 phacoemulsification surgeries were performed by the four third-year residents; 19 of 332 (5.7%) were combined phacoemulsification/trabeculectomy procedures. Preoperative best-corrected visual acuity ranged from 20/30 to light perception, with 311 of 332 (96.6%) 20/50 or worse. Significant ocular comorbidities existed in 37 of 332 (11.1%). Ocular comorbidities included agerelated macular degeneration, diabetic retinopathy, chronic uveitis, and macular hole. Postoperative bestcorrected visual acuity ranged from 20/15 to hand motions, with 296 of 332 (89%) 20/40 or better. If those eyes with preexisting ocular comorbidities were excluded, 291 of 298 (97.7%) achieved a postoperative best-corrected visual acuity of 20/40 or better. Vitreous loss occurred in 16 of 332 (4.8%) of cases; of those, 11 of 16 (68.8%) achieved best-corrected visual acuity or 20/40 or better. Of the five eyes that did not achieve a best-corrected visual acuity of 20/40 or better, three had preexisting ocular pathology affecting vision. In the two eyes with no preexisting ocular comorbidities, vision loss was attributed to cystoid macular edema. The results of our study and other studies on resident cataract surgery outcomes confirm that the vast majority of patients recover excellent vision, particularly when those with preexisting ocular comorbidities are excluded.1–5 Factors that contribute to this level of success include resident VOL. 135, NO. 5
participation in cataract surgery conferences and phacoemulsification wet laboratories, the opportunity to serve as an assistant during the early years of residency training, and direct supervision by faculty physicians experienced in performing and teaching phacoemulsification cataract surgery. The incidence of vitreous loss (4.8%) in our study is similar to that reported in other studies of residents learning phacoemulsification cataract surgery (1.8% to 14.7%, mean 7.0%).1–5 Although vitreous loss during cataract surgery is a serious complication, most eyes achieve a final visual acuity of 20/40 or better.5 Causes of persistent vision loss in eyes with vitreous loss include cystoid macular edema and other ocular comorbidities such as diabetic retinopathy and age-related macular degeneration. Ophthalmology residents can learn to perform phacoemulsification cataract surgery safely and effectively without prior planned extracapsular cataract extraction experience. We no longer require residents to perform a prerequisite number of planned extracapsular cataract extraction before transitioning to phacoemulsification cataract surgery. REFERENCES
1. Corey RP, Olson RJ. Surgical outcomes of cataract extractions performed by residents using phacoemulsification. J Cataract Refract Surg 1998;24:66 –72. 2. Allinson RW, Metrikin DC, Fante RG. Incidence of vitreous loss among third-year residents performing phacoemulsification. Ophthalmology 1992;99:726 –730. 3. Blomquist PH, Rugwani RM. Visual outcomes after vitreous loss during cataract surgery performed by residents. J Cataract Refract Surg 2002;28:847–852. 4. Karp KO, Albanis CV, Pearlman JB, Goins KM. Outcomes of temporal clear cornea versus superior scleral tunnel phacoemulsification incisions in a university training program. Ophthalmic Surg Lasers 2001;32:228 –232. 5. Tarbet KJ, Mamalis N, Theurer J, Jones BD, Olson RJ. Complications and results of phacoemulsification performed by residents. J Cataract Refract Surg 1995;21:661–665.
A Novel CACNA1F Mutation in a French Family With the Incomplete Type of X-linked Congenital Stationary Night Blindness Felix Karl Jacobi, MD, Christian P. Hamel, MD, PhD, Bernard Arnaud, MD, Nikolaus Blin, Martina Broghammer, Philipp C. Jacobi, MD, Eckart Apfelstedt-Sylla, MD, and Carsten M. Pusch, PhD
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FIGURE 1. (Top) The pedigree is compatible with an X-linked recessive mode of inheritance. The patients whose DNA were clinically examined in this study are marked with an asterisk. (Bottom) Fundus photographs of two male siblings with CSNB2 displaying a slightly titled disk with temporal rim pallor.
To describe a French family with the incomplete type of X-linked congenital stationary night blindness (CSNB2) associated with a novel mutation in the retina-specific calcium channel ␣1 subunit gene (CACNA1F). DESIGN: Interventional case report. METHODS: Two family members with a history of nonprogressive night blindness and subnormal visual acuity were clinically examined and the genotype determined by molecular genetic analysis. RESULT: Both patients had clinical manifestations characteristic of CSNB2. Electrophysiologically, we found a predominant reduction of the ERG B-wave in the maximal response. Both rod and cone function were subnor-
mal, with the latter tending to be more attenuated. We identified a C deletion at nucleotide position 4548, resulting in a frameshift with a predicted premature termination at codon 1524. CONCLUSIONS: The clinical and genetic study of a novel mutation in the CACNA1F gene adds further support to the contention that CSNB2 represents a genetically distinct retinal disorder of a calcium channel. (Am J Ophthalmol 2003;135:733–736. © 2003 by Elsevier Inc. All rights reserved.)
PURPOSE:
X
(XLCSNB) defines a distinct subgroup of nonprogressive eye disorders. Its cardinal features are a defective night vision from birth and an inner retinal transmission defect as indicated by the so-called negative or Schubert-Bornschein type of electroretinogram (ERG) in response to maximal light stimulus under scotopic conditions. Clinically and genetically, two subtypes of XLCSNB, namely the complete (CSNB1; MIM310500) and incomplete (CSNB2; MIM300071) type have been defined.1 The basic distinction between both types of XLCSNB in electroretinographical testing is a mildly abnormal cone function
Accepted for publication Nov 4, 2002. From the Zentrum fu¨ r Augenheilkunde (F.K.J.), Universita¨ tsklinikum Giessen, Giessen, Germany; Department of Ophthalmology (C.P.H., B.A.), Hoˆ pital Gui de Chauliac, Montpellier, France; Institut fu¨ r Anthropologie und Humangenetik (N.B., M.B., C.M.P.), Abteilung fu¨ r Molekulare Genetik, Tu¨ bingen, Germany; Zentrum fu¨ r Augenheilkunde der Universita¨ t zu Ko¨ ln (P.C.J.), Ko¨ ln, Germany; and Katharinenhospital Stuttgart (E.A.-S.), Stuttgart, Germany. Inquiries to Felix Karl Jacobi, MD, Zentrum fu¨ r Augenheilkunde, Universita¨ tsklinikum Giessen, Friedrichstr. 18, 35392 Giessen, Germany; fax: (⫹49) 641-9943809; e-mail: [email protected]
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OPHTHALMOLOGY
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FIGURE 2. (Top) Electroretinogram of two male siblings with CSNB2 (II:2, II:3) recorded under light-adapted conditions with white and colored stimuli to enhance the separation of the rod (blue light) and cone (red light) responses. The B-wave amplitude is calculated from the difference of amplitudes of the A-wave and B-wave markers. Normal B-wave amplitudes for the white, blue, and red flash light are 20 to 30 V, >20 V, and > 15 V, respectively. (Bottom) Automated sequencing data of a normal subject and male sibling with CSNB2 displaying a CACNA1F single nucleotide deletion. Amino acid sequence given in single letter code above the nucleotide sequence; the asterisk indicates a premature stop codon.
with an undetectable rod activity in CSNB1, whereas CSNB2 has residual rod activity and a more significantly abnormal cone ERG. The elucidation of the molecular basis has identified the matrix protein nyctalopin in CSNB1 and the ␣1 subunit of a retina-specific calcium channel in CSNB2, which are both predicted to function at various levels of retinal signal transduction.2,3 The characteristic clinical findings in XLCSNB that are variably associated with a range of other ocular abnormalities predict an unusual molecular defect in this disorder. Two male siblings (II:2, II:3) of a three-generation French pedigree with a history nonprogressive decreased VOL. 135, NO. 5
visual acuity and myopia from birth, and moderately impaired night vision were ophthalmologically examined (Figure 1, top). The family history was compatible with an X-linked recessive mode of inheritance and indicated a third affected male family member (II:5). Both patients had reduced visual acuities with mildly to highly myopic refractive errors (II:2, 61 years old: 20/63 in both eyes with ⫺2.75/⫺0.50/175 degrees in the right eye and ⫺2.50/ ⫺0.50/180 degrees in the left eye; II:3, 55 years old: 20/100 in the right eye and 20/250 in the left eye with ⫺10.00/ ⫺2.00/45 degrees and ⫺1.00/⫺1.00/90 degrees [pseudophakia], respectively). Fundus examination disclosed
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tion 1524 (TGA codon) with a loss of 450 residues (counting starts at the mutated leucine residue) at the C terminus (Figure 2, bottom). No polymorphism or other sequence variants were found. Our study adds support to the contention that CSNB2 represents a genetically distinct disorder of a retinal calcium channel. The similarities (impaired visual acuity, fundus appearance, and ERG traces) and variation (refractive error, ocular motility) in the clinical expression in two related patients suggests the presence of other genetic or environmental factors to determine the phenotype in CSNB2.
the appearance of titled disk with pallor of the temporal disk rim (Figure 1, bottom). The visual fields were normal by standard Goldmann kinetic perimetry. Color vision was tested only in patient II:2 and revealed lines of confusion from blue and yellow color caps consistent with a mild tritan defect. Nystagmus and exotropia were seen in the patient II:3, whereas patient II:2 revealed no abnormality of ocular motility. The mixed cone-rod ERG demonstrated a reduction of the B-wave amplitude with a relative preservation of the A-wave, causing the typical negative type of ERG. The responses with red flash light were more attenuated compared with responses elicited with the blue flash light in patient II:2, while being similar in patient II:3 (Figure 2, top). After informed consent, blood was obtained from one affected individual (II:2), and genomic DNA was extracted by a standard procedure. On the basis of the clinical diagnosis of CSNB2 the analysis of the CACNA1F gene was done by direct sequencing of each of the 48 exons. This revealed a deletion of a cytosine at position 4548 (amino acid residue 1516 encoded by CTC, leucine) in CACNA1F exon 39, resulting in a frame shift (LPWSGHP*) and premature protein truncation at posi-
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REFERENCES
1. Miyake Y, Yagasaki K, Horiguchi M, et al. Congenital stationary night blindness with negative electroretinogram. A new classification. Arch Ophthalmol 1986;104:1013–1020. 2. Bech-Hansen NT, Naylor MJ, Maybaum TA, et al. Loss-offunction mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nat Genet 1998;19:264 –267. 3. Pusch CM, Zeitz C, Brandau O, et al. The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein. Nat Genet 2000;26:324 –327.
OF
OPHTHALMOLOGY
MAY 2003
participation in cataract surgery conferences and phacoemulsification wet laboratories, the opportunity to serve as an assistant during the early years of residency training, and direct supervision by faculty physicians experienced in performing and teaching phacoemulsification cataract surgery. The incidence of vitreous loss (4.8%) in our study is similar to that reported in other studies of residents learning phacoemulsification cataract surgery (1.8% to 14.7%, mean 7.0%).1–5 Although vitreous loss during cataract surgery is a serious complication, most eyes achieve a final visual acuity of 20/40 or better.5 Causes of persistent vision loss in eyes with vitreous loss include cystoid macular edema and other ocular comorbidities such as diabetic retinopathy and age-related macular degeneration. Ophthalmology residents can learn to perform phacoemulsification cataract surgery safely and effectively without prior planned extracapsular cataract extraction experience. We no longer require residents to perform a prerequisite number of planned extracapsular cataract extraction before transitioning to phacoemulsification cataract surgery. REFERENCES
1. Corey RP, Olson RJ. Surgical outcomes of cataract extractions performed by residents using phacoemulsification. J Cataract Refract Surg 1998;24:66 –72. 2. Allinson RW, Metrikin DC, Fante RG. Incidence of vitreous loss among third-year residents performing phacoemulsification. Ophthalmology 1992;99:726 –730. 3. Blomquist PH, Rugwani RM. Visual outcomes after vitreous loss during cataract surgery performed by residents. J Cataract Refract Surg 2002;28:847–852. 4. Karp KO, Albanis CV, Pearlman JB, Goins KM. Outcomes of temporal clear cornea versus superior scleral tunnel phacoemulsification incisions in a university training program. Ophthalmic Surg Lasers 2001;32:228 –232. 5. Tarbet KJ, Mamalis N, Theurer J, Jones BD, Olson RJ. Complications and results of phacoemulsification performed by residents. J Cataract Refract Surg 1995;21:661–665.
A Novel CACNA1F Mutation in a French Family With the Incomplete Type of X-linked Congenital Stationary Night Blindness Felix Karl Jacobi, MD, Christian P. Hamel, MD, PhD, Bernard Arnaud, MD, Nikolaus Blin, Martina Broghammer, Philipp C. Jacobi, MD, Eckart Apfelstedt-Sylla, MD, and Carsten M. Pusch, PhD
BRIEF REPORTS
733
FIGURE 1. (Top) The pedigree is compatible with an X-linked recessive mode of inheritance. The patients whose DNA were clinically examined in this study are marked with an asterisk. (Bottom) Fundus photographs of two male siblings with CSNB2 displaying a slightly titled disk with temporal rim pallor.
To describe a French family with the incomplete type of X-linked congenital stationary night blindness (CSNB2) associated with a novel mutation in the retina-specific calcium channel ␣1 subunit gene (CACNA1F). DESIGN: Interventional case report. METHODS: Two family members with a history of nonprogressive night blindness and subnormal visual acuity were clinically examined and the genotype determined by molecular genetic analysis. RESULT: Both patients had clinical manifestations characteristic of CSNB2. Electrophysiologically, we found a predominant reduction of the ERG B-wave in the maximal response. Both rod and cone function were subnor-
mal, with the latter tending to be more attenuated. We identified a C deletion at nucleotide position 4548, resulting in a frameshift with a predicted premature termination at codon 1524. CONCLUSIONS: The clinical and genetic study of a novel mutation in the CACNA1F gene adds further support to the contention that CSNB2 represents a genetically distinct retinal disorder of a calcium channel. (Am J Ophthalmol 2003;135:733–736. © 2003 by Elsevier Inc. All rights reserved.)
PURPOSE:
X
(XLCSNB) defines a distinct subgroup of nonprogressive eye disorders. Its cardinal features are a defective night vision from birth and an inner retinal transmission defect as indicated by the so-called negative or Schubert-Bornschein type of electroretinogram (ERG) in response to maximal light stimulus under scotopic conditions. Clinically and genetically, two subtypes of XLCSNB, namely the complete (CSNB1; MIM310500) and incomplete (CSNB2; MIM300071) type have been defined.1 The basic distinction between both types of XLCSNB in electroretinographical testing is a mildly abnormal cone function
Accepted for publication Nov 4, 2002. From the Zentrum fu¨ r Augenheilkunde (F.K.J.), Universita¨ tsklinikum Giessen, Giessen, Germany; Department of Ophthalmology (C.P.H., B.A.), Hoˆ pital Gui de Chauliac, Montpellier, France; Institut fu¨ r Anthropologie und Humangenetik (N.B., M.B., C.M.P.), Abteilung fu¨ r Molekulare Genetik, Tu¨ bingen, Germany; Zentrum fu¨ r Augenheilkunde der Universita¨ t zu Ko¨ ln (P.C.J.), Ko¨ ln, Germany; and Katharinenhospital Stuttgart (E.A.-S.), Stuttgart, Germany. Inquiries to Felix Karl Jacobi, MD, Zentrum fu¨ r Augenheilkunde, Universita¨ tsklinikum Giessen, Friedrichstr. 18, 35392 Giessen, Germany; fax: (⫹49) 641-9943809; e-mail: [email protected]
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AMERICAN JOURNAL
-LINKED CONGENITAL STATIONARY NIGHT BLINDNESS
OF
OPHTHALMOLOGY
MAY 2003
FIGURE 2. (Top) Electroretinogram of two male siblings with CSNB2 (II:2, II:3) recorded under light-adapted conditions with white and colored stimuli to enhance the separation of the rod (blue light) and cone (red light) responses. The B-wave amplitude is calculated from the difference of amplitudes of the A-wave and B-wave markers. Normal B-wave amplitudes for the white, blue, and red flash light are 20 to 30 V, >20 V, and > 15 V, respectively. (Bottom) Automated sequencing data of a normal subject and male sibling with CSNB2 displaying a CACNA1F single nucleotide deletion. Amino acid sequence given in single letter code above the nucleotide sequence; the asterisk indicates a premature stop codon.
with an undetectable rod activity in CSNB1, whereas CSNB2 has residual rod activity and a more significantly abnormal cone ERG. The elucidation of the molecular basis has identified the matrix protein nyctalopin in CSNB1 and the ␣1 subunit of a retina-specific calcium channel in CSNB2, which are both predicted to function at various levels of retinal signal transduction.2,3 The characteristic clinical findings in XLCSNB that are variably associated with a range of other ocular abnormalities predict an unusual molecular defect in this disorder. Two male siblings (II:2, II:3) of a three-generation French pedigree with a history nonprogressive decreased VOL. 135, NO. 5
visual acuity and myopia from birth, and moderately impaired night vision were ophthalmologically examined (Figure 1, top). The family history was compatible with an X-linked recessive mode of inheritance and indicated a third affected male family member (II:5). Both patients had reduced visual acuities with mildly to highly myopic refractive errors (II:2, 61 years old: 20/63 in both eyes with ⫺2.75/⫺0.50/175 degrees in the right eye and ⫺2.50/ ⫺0.50/180 degrees in the left eye; II:3, 55 years old: 20/100 in the right eye and 20/250 in the left eye with ⫺10.00/ ⫺2.00/45 degrees and ⫺1.00/⫺1.00/90 degrees [pseudophakia], respectively). Fundus examination disclosed
BRIEF REPORTS
735
tion 1524 (TGA codon) with a loss of 450 residues (counting starts at the mutated leucine residue) at the C terminus (Figure 2, bottom). No polymorphism or other sequence variants were found. Our study adds support to the contention that CSNB2 represents a genetically distinct disorder of a retinal calcium channel. The similarities (impaired visual acuity, fundus appearance, and ERG traces) and variation (refractive error, ocular motility) in the clinical expression in two related patients suggests the presence of other genetic or environmental factors to determine the phenotype in CSNB2.
the appearance of titled disk with pallor of the temporal disk rim (Figure 1, bottom). The visual fields were normal by standard Goldmann kinetic perimetry. Color vision was tested only in patient II:2 and revealed lines of confusion from blue and yellow color caps consistent with a mild tritan defect. Nystagmus and exotropia were seen in the patient II:3, whereas patient II:2 revealed no abnormality of ocular motility. The mixed cone-rod ERG demonstrated a reduction of the B-wave amplitude with a relative preservation of the A-wave, causing the typical negative type of ERG. The responses with red flash light were more attenuated compared with responses elicited with the blue flash light in patient II:2, while being similar in patient II:3 (Figure 2, top). After informed consent, blood was obtained from one affected individual (II:2), and genomic DNA was extracted by a standard procedure. On the basis of the clinical diagnosis of CSNB2 the analysis of the CACNA1F gene was done by direct sequencing of each of the 48 exons. This revealed a deletion of a cytosine at position 4548 (amino acid residue 1516 encoded by CTC, leucine) in CACNA1F exon 39, resulting in a frame shift (LPWSGHP*) and premature protein truncation at posi-
736
AMERICAN JOURNAL
REFERENCES
1. Miyake Y, Yagasaki K, Horiguchi M, et al. Congenital stationary night blindness with negative electroretinogram. A new classification. Arch Ophthalmol 1986;104:1013–1020. 2. Bech-Hansen NT, Naylor MJ, Maybaum TA, et al. Loss-offunction mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nat Genet 1998;19:264 –267. 3. Pusch CM, Zeitz C, Brandau O, et al. The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein. Nat Genet 2000;26:324 –327.
OF
OPHTHALMOLOGY
MAY 2003