Congenital Disorder of Glycosylation Due to Phosphomannomutase Deficiency

CLINICAL SCIENCES Retinal On-Pathway Deficit in Congenital Disorder of Glycosylation Due to Phosphomannomutase Deficiency

Dorothy A. Thompson, PhD; Ruth J. Lyons, PhD; Alki Liasis, PhD; Isabelle Russell-Eggitt, MD; Herbert Ja¨gle, MD, FEBO; Stephanie Gru¨newald, MD

Objective: To describe novel electroretinographic (ERG) attenuated to the fifth percentile, whereas scotopic findings associated with congenital disorder of glyco- a-wave amplitudes were at the 50th to 75th percentile, giv- sylation due to phosphomannomutase deficiency (PMM2- ing a reduced a:b ratio. The scotopic a-wave waveform was CDG) (previously known as congenital disorder of gly- well defined to bright flash luminance. The number of sco- cosylation type 1a). topic oscillatory potentials was preserved, although amplitudes were smaller than average. Scotopic 15-Hz flicker Methods: Two male siblings with genetically con- ERGs were evident to a range of flash luminances and firmed PMM2-CDG underwent full-field ERG to a range showed an expected phase cancellation between −1.5 and of scotopic and photopic flash luminances that ex- −1.0 log scotopic td (troland) • s, but phase increased only tended the International Society for Clinical Electro- for the fast rod pathway. physiology of Vision standard protocol and included scotopic 15-Hz flicker and photopic prolonged on-off Conclusions: We find, for the first time to our knowl- stimulation. edge, an association of PMM2-CDG with a selective on- pathway dysfunction in the retina. This ERG phenotype Results: Photopic prolonged ERGs were profoundly elec- localizes the site of retinal dysfunction to the on-bipolar tronegative with absent b-waves but preserved oscilla- synapse with photoreceptors. Modeling the unusual com- tory potentials. Prolonged off-responses and off- bination of ERG findings helps our understanding of the oscillatory potentials were preserved. Transient full-field role of N-glycosylation at this synapse and provides a fo- photopic ERGs revealed a broad a-wave and narrow cus for future studies of potential intervention. b-wave, and the photopic 30-Hz flicker ERG had a sawtooth waveform. The scotopic b-waves of both cases were Arch Ophthalmol. 2012;130(6):712-719

ONGENITAL DISORDERS OF vere. Infants may come to us because of a glycosylation (CDGs) failure to thrive, developmental delay, or comprise a genetically muscle hypotonia; the childhood mortal- heterogeneous group of ity rate due to infection or organ failure multisystem disorders is approximately 20%.5,6 Characteristics that result from enzymatic defects in the that may be identified in the infantile pe- C 1-3 glycosylation of proteins and lipids. Con- riod are inverted nipples, abnormal dis- genital disorder of glycosylation due to tribution of fat pads, and cerebellar hypo- phosphomannomutase deficiency (PMM2- plasia, although not all patients manifest CDG) (previously known as congenital these signs.2 Older children frequently pre- disorder of glycosylation type 1a) is by far sent with convergent squint and myopia. the most common diagnosis (Online Men- Retinitis pigmentosa (RP) has been de- delian Inheritance in Man #212065). It is scribed as another common ocular asso- associated with a deficiency of phospho- ciation.7 Our study of 2 mildly affected sib- Author Affiliations: Clinical mannomutase encoded by the PMM2 gene lings provides new insight into the and Academic Department of located on chromosome 16p13.3,4 This en- mechanism of retinal dysfunction in Ophthalmology zyme is located in the cytosol and con- PMM2-CDG. (Drs Thompson, Lyons, Liasis, verts mannose-6-phosphate to mannose- and Russell-Eggitt) and 2 1-phosphate. This enzyme has an essential METHODS Department of Metabolic role early in the N-glycosylation process2 Medicine (Dr Gru¨ newald), and in the synthesis of glycosylphosphati- Great Ormond Street Hospital 4 Two male siblings (16 years old [patient 1] and for Children, London, England; dylinositol, which is used to anchor pro- 14 years old [patient 2]) of nonconsanguine- and University Eye Clinic, teins to the cell membrane. PMM2-CDG ous white parents diagnosed as having PMM2- Regensburg, Germany is a multisystem disease with a broad clini- CDG were referred for investigation of any signs (Dr Ja¨gle). cal spectrum that ranges from mild to se- of RP. Patient 1 failed to thrive in the early new-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Full-field electroretinograms (ERGs) were recorded using DTL corneal electrodes according to International Society for Clinical Electrophysiology of Vision standards,8 which were extended to include a wider range of flash luminances and photopic prolonged on-off flashes. Pupils were dilated and the dim- mest flashes were presented after 20 minutes of dark adaptation. Patient 1 had extended dark adaptation in one eye for more than 6 hours before testing. The ERGs were elicited in response to flash stimuli of strengths 0.0001 to 200 photopic cd (can- delas) • s/m2 presented scotopically and 0.3 to 10 photopic cd • s/m2 presented photopically on a Ganzfeld background luminance of 30 cd/m2. The ERGs were acquired in a time window of 250 milliseconds, which included a 20-millisecond prestimulus interval. Oscillatory potentials (OPs) were filtered between 100 and 300 Hz. In addition, scotopic 15-Hz flicker ERGs (14.93 Hz) to 10 flash strengths were presented in as- cending order from −3.0 to 0.5 log td (troland) • s/m2 and were

Patient 1 Patient 2 recorded from dark adapted eyes to test slow and fast rod pathways, respectively.9 Flicker ERGs to each of these stimuli were acquired within a 402-millisecond time window containing 6 Figure 1. Fundus photographs of the macular region of patient 1 and patient periods, and response magnitude and phase were determined ϫ 2 showing foveal and parafoveal, yellow dots (original magnification 2). by Fourier analysis. Response waveform significance was esti- mated using the method proposed by Meigen and Bach.10 Pro- born period but improved when solid foods were introduced. He longed on-off flashes (200 cd/m2) were presented under phot- was notably hypotonic by 1 year of age and was labeled as hav- opic conditions (43 cd/m2) for durations of 90 and 120 ing cerebral palsy. At 2 years of age, his developmental mile- milliseconds, and on- and off-responses were recorded within stones were delayed. Magnetic resonance imaging revealed cer- a time window of 330 milliseconds that included a 15- ebellar hypoplasia. He walked at school age with a rotator. He millisecond prestimulus interval. This study followed the te- had surgery for a convergent strabismus at 3 years of age when nets of the Declaration of Helsinki and was registered with the nystagmus was noted. Further investigations at 13 years of age local research governance committee. revealed an accessory nipple and an unusual fat distribution on his upper thighs. PMM2-CDG was suspected, but transferrin iso- RESULTS forms were thought to be normal. However, because of his typi- cal features, phosphomannomutase activity was measured in leuko- cytes, which was found to be very low at 0.17 nmol/min/mg of The scotopic ERG waveforms for each patient are shown protein (reference range,0.9-2.3 nmol/min/mg). in Figure 2. No interocular difference was found in sco- Ocular examination at 16 years of age revealed variable nys- topic ERG amplitudes in patient 1 after a longer dura- tagmus, most often fine, with leftward-moving quick phases, tion of dark adaptation of one eye (6 hours compared with but occasionally his eyes were still in the primary position of 20 minutes). Amplitudes and time to peaks were com- gaze. His saccades were poor. Visual acuity with both eyes open pared with fifth and 95th percentile normative data. The with a low hyperopic prescription (ϩ1.75 diopters [D]) was logMAR 0.2 at 4 m, and monocular visual acuity was logMAR scotopic a-waves fall within the reference range, but the 0.46 in the right eye and logMAR 0.2 in the left eye. Color vi- scotopic b-wave amplitudes fall at and below the fifth per- sion test results were normal (Ishihara Plates 13/13; Kanehara centile. This gives a reduced a:b amplitude ratio of 1 or & Co Ltd). Funduscopy revealed slightly narrow retinal ves- less, a so-called negative ERG waveform. The b-wave time sels, which were considered suggestive of early retinal dystro- to peaks are within the reference range. Fourier analysis phy, and detailed examination of fundus photographs re- of the scotopic 15-Hz flicker data revealed significant data vealed parafoveal, fine, yellow dots of varying sizes that appeared in both low- and high-range flash strength. The magni- to be at the level of the retinal pigment epithelium. Autofluo- tude profiles of both patients were similar to normal pro- rescent imaging results were normal. files, albeit with smaller amplitude in patient 2. Data for Patient 2, the younger sibling, also had failure to thrive, incomplete and incomplete congenital stationary blind- verted nipples, and unusual fat distribution on his upper thighs. He was extremely ill as an infant, with emphysema and pleurode- ness (CSNB) are shown for comparison. Although both sis. At 2 years of age, magnetic resonance imaging revealed cer- patients’ data show an expected phase cancellation at mid- ebellar hypoplasia. His phosphomannomutase level in leuko- flash strengths, an increase in phase with increasing flash cytes was undetectable. strength was noted only for the second limb, the fast path- He underwent strabismus surgery for esotropia at 6 years way (Figure 3). The scotopic OPs are present at nor- of age and had a consecutive exotropia. Ophthalmic examina- mal time to peaks but are small amplitude. tion at 14 years of age showed a low hyperopic prescription Photopic ERG waveforms have broad a-waves of nor- ϩ ( 2.25 D), and visual acuity was logMAR 0.04 (N4.5) in the mal amplitude, followed by sharply defined, narrow right eye and logMAR 0.2 (N4.5) in the left eye. Color vision b-waves. The photopic 30-Hz flicker ERGs have a saw- was normal (Ishihara plates 13/13). He had jerky pursuit in all tooth waveform (Figure 4). Photopic OPs to transient directions of gaze and a fine horizontal nystagmus that increased in the lateral gaze. Fundus photographs revealed yel- flashes are normal for patient 1 but small for patient 2 low, foveal dots (Figure 1). Autofluorescent imaging results (Figure 5). Photopic prolonged on-off ERGs show a were normal. Retinal nerve fiber layer thickness, assessed with large, well-defined off-response, but the photopic on- optical coherence tomography (Spectralis), was within nor- response b-wave is absent (Figure 6). These on-off wave- mal limits for each eye. forms were filtered, revealing preserved on- and off-

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Patient 2

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Figure 2. Scotopic electroretinogram waveforms for patients 1 and 2. The b-wave amplitudes are reduced compared with the normal profile, and an a:b ratio of 1 is seen to scotopic 3 flashes. Gray area shows the control data.

pathway OPs. These responses are displayed with tionary night blindness genes: RHO, GNAT1, PDE6B, SAG, comparison data from a control participant and a pa- NYX, CACNAF1, GRM6, CABP4, and CACNA2DA (Asper tient with CSNB type 1 (CSNB1). To 4-millisecond single Biotech). flashes, a single photopic OP is seen in CSNB1, but the prolonged on-response b-wave and prolonged on- pathway OPs are absent. COMMENT Mutational analysis of the PMM2 gene revealed that each case was a compound heterozygote for 2 point mu- To our knowledge, our data are the first description of a tations: P69S c.205CϾG and R141H c.422GϾA. Muta- negative ERG caused by an on-pathway deficit in PMM2- tional screening of the parents revealed that the father CDG, a congenital disorder of N-glycosylation. carried P69S and the mother carried R141H. No muta- N-linked glycans are present in all layers of the retina,11 tions were found in the tested array of 9 congenital sta- but the lack of photopic on-response b-wave in our pa-

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Figure 3. Scotopic 15-Hz flicker magnitude and phase for patients 1 and 2 compared with 2 healthy controls and patients with incomplete congenital stationary blindness (iCSNB) and complete congenital stationary blindness (cCSNB). The magnitudes show the normal profile and lower amplitude in patient 2. The phase data show a lack of phase change to low flash strength in patients 1 and 2 compared with control data. Connecting lines to phase data are drawn starting with the first significant data point. Open circles indicate not significant; closed circles, P Ͻ .05.

cCSNB

+ 100 µV Patient 1

Patient 2

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Figure 4. Photopic electroretinograms for patients 1 and 2 compared with control data and complete congenital stationary blindness (cCSNB) traces. The broad a-wave and narrow b-wave are emphasized to photopic 10 flashes.

tients places the site of retinal dysfunction in PMM2- directly, must prevent depolarization of cone on- CDG at the cone photoreceptor synapse with the on- bipolar cells, yet must allow signal transfer to spiking neu- bipolar cell. The ERG b-wave is generated from rons to preserve the photopic on-oscillatory potentials. depolarizing rod and cone on-bipolar cells. To model our Depolarization of rod on-bipolar cells has to occur to ac- ERG findings, the N-glycosylation defect, directly or in- count for the preserved rod-driven b-waves.

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Figure 5. Oscillatory potentials (OPs) for patients 1 and 2 for transient flashes compared with control data. The scotopic OPs are small but when enlarged (shown for patient 1) have normal configuration and number. OnOff On Off Photopic OPs for patient 1 are normal. 0 100 200 300 0 100 200 300 Time, ms Time, ms Only a few clinical reports of patients with PMM2- CDG display ERG waveforms, but most describe re- Figure 6. Prolonged on-off electroretinograms (ERGs) for patients 1 and 2 duced scotopic ERG amplitudes, indicating a general- compared with control data and complete congenital stationary blindness ized rod system defect. Cone involvement has been (cCSNB) traces. The on-response is profoundly electronegative, but oscillatory reported in patients as young as 18 months12 and more potentials (OPs) are preserved. Asterisk indicates absence of a response. frequently as patients get older, providing evidence that PMM2-CDG is associated with a progressive rod cone dys- a-wave amplitude is normal, and we did not observe any trophy.7,12-16 A postmortem study17 found degeneration schitic areas. and loss of photoreceptors in the outer nuclear layer, and To look for candidate N-linked glycoproteins respon- Andre´asson et al18 hypothesized that RP in PMM2-CDG sible for the ERG features in our cases of PMM2-CDG, we could be due to a glycosylation defect that involved the reviewed the photoreceptor-bipolar signaling cascades using photoreceptor glycoprotein opsin and interreceptor bind- the UniProt database (www.uniprot.org). Our current ing protein. Few conditions to date have been associ- knowledge of the bipolar synapse derives mostly from re- ated with interreceptor binding protein, although re- cent gene knockout and ERG studies on animal mod- cently autosomal recessive RP was described with els.26-28 It is known that depolarization of the on-bipolar mutations of IMPG2, which encodes the interphotore- cells involves metabotropic synapses with photorecep- ceptor matrix proteoglycan.19 Negative ERGs with tors, whereas off-bipolar cells use ionotropic synapses. All a:b-wave amplitude ratios of 1 or less have been re- of the rod and half of the cone bipolar cells are on-bipolar ported in RP, but both the b-wave and the a-wave am- cells that receive direct glutamatergic input from photo- plitudes are subnormal.20,21 In addition, both the on- and receptor cells in the dark.29 The mGluR6 receptor is the off-responses of the photopic prolonged-flash ERG are primary postsynaptic glutamate receptor on the invaginat- affected in RP.21 In contrast, our patients have normal ing on-bipolar synapse. The N-glycosylated proteins nyc- rod photoreceptor function, evidenced by normal a- talopin and mGluR6 work together at this synapse to trig- wave amplitudes after standard dark adaptation times, ger a second messenger cascade involving G␣o.30 Nyctalopin and the cone off-response is normal. is tethered to the cell membrane via a glycosylphosphati- Retinal arteries were slightly narrowed in patient 1, dylinositol anchor, but it is the presence of nyctalopin at but pigmentary changes, typically seen in RP, were not the cell membrane that is essential for function rather than evident. A closer examination of magnified fundus pho- its anchor.31 Other G proteins and regulators of G-protein tographs revealed subtle, fine, yellow dots at the macu- signaling (RGS) colocalize with G␣o. These G␣o- lae of each case, although autofluorescent imaging find- interacting proteins, G␤5-RGS7 and G␤5-RGS11 com- ings were unremarkable. A combination of reduced a:b plexes, determine bipolar cell kinetics.32 All these pro- ratio and white dots has been reported in retinoschi- teins are located in the dendritic tips of rod and cone sis.22,23 Also, a predominant on-pathway deficit has been on-bipolar cells. described,22,24 but the cone photoreceptor a-wave is re- The decrease in glutamate released by photorecep- duced in retinoschisis.24,25 In our patients, the cone tors in response to light rapidly inactivates the mGluR6-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 coupled G␣o. This process removes a negative signal from notype because the cone pathway is affected more than its downstream target, the transient receptor potential cat- the rod pathway, but in contrast to CSNB2, our patients ion channel subfamily M member 1 (TRPM1), also known have profound electronegative, photopic, prolonged- as melastatin 1, and opens the channels to a cation cur- flash on-responses; preserved off-responses and OPs are rent that depolarizes the on-bipolar cells.32-34 Knockout not delayed. The possibility that our patients had dual mice models show negative ERGs when any part of this conditions is unlikely because no known mutations were cascade is disrupted (eg, there is a complete absence of found in 9 genes associated with X-linked, autosomal re- scotopic b-wave and absent scotopic and photopic OPs cessive, and autosomal dominant CSNB.41,45 if there are defects in proteins mGluR6, G␣o, G␤5, or The ERGs of mouse models of presynaptic no b-wave Trpm1).32,35,36 In humans, mutations in the NYX (nycta- mutants share some characteristics with other mutants lopin), GRM6 (mGluR6), or TRPM1 (TRPM1) genes are that show disrupted control of glutamate release, includ- associated with on-pathway dysfunction, which clini- ing mutations of the glycoprotein dystrophin.26 Dystro- cally manifest as X-linked and autosomal recessive CSNB1 phin and b-dystroglycan, a member of the dystrophin- (complete CSNB).37,38 The CSNB1 phenotype shows com- associated glycoprotein complex, colocalize at the plete absence of photopic on-response b-wave, preser- invaginated synaptic complex of photoreceptors.47 Mu- vation of the off-response, a sawtooth waveform 30-Hz tations in dystrophin affecting the retinal isoform are flicker ERG, and absence of scotopic b-waves.39 The OPs known to cause negative scotopic ERGs in Duchenne mus- in the transient flash ERG are reduced in number in cular dystrophy, and there is a concomitant loss of OPs CSNB1 and GRM6.40 Zeitz et al41 describe a remnant OP with increasing severity of on-pathway dysfunction.48 Dys- at 33 milliseconds that has been attributed to the off- glycosylation of dystroglycan to date has been associ- pathway.42 This finding concurs with the prolonged on- ated only with defects in O-linked glycosylation, re- off OP data shown in CSNB1 in Figure 5. Therefore, the cently referred to as dystroglycanopathies. Five conditions ERGs associated with dysfunction of N-linked proteins belonging to that group have mutations in proven or pu- mGluR6 and nyctalopin share a number of features with tative glycosyltransferases, leading to a disruption of the our patients, but there are some distinct differences. Our heavily O-glycosylated part of the dystroglycan com- patients have a full complement of photopic OPs to both plex. Examples are POMT1/POMT2-CDG, transient and prolonged on-off stimulation, have scoto- POMTGNT1-CDG, FKTN-CDG, FKRP-CDG, and pic OPs, and retain scotopic ERG b-waves. LARGE-CDG.49 Scotopic 15-Hz flicker is thought to distinguish 2 of To explain the greater photopic ERG alteration in our 5 rod pathways: a slow pathway at low flash strengths cases, it may be necessary to postulate a glycoprotein re- and a fast pathway at higher flash strengths. The slow ceptor or subunit with greater expression in the cone, pathway reflects a network connecting rods via rod bi- rather than rod, pathway. For example, the Na/Ca-K ex- polars and AII amacrines to cone on-bipolar cells, whereas changer (N-linked NCKX) plays a critical role in Ca2ϩ the fast rod pathway uses gap junctions between rod and homeostasis in retinal rod and cone photoreceptors. The cone pedicles to reach the cone on-bipolar cells.9 Our NCKX1 isoform is found in rods, whereas the NCKX2 15-Hz magnitude data suggest both fast and slow path- isoform is found in cones.50 ways are functioning in a similar proportion to normal Although we have considered direct influences of pathways (Figure 3), which can explain why scotopic OPs N-glycosylation at the on-bipolar synapse, it is possible are preserved; however, the slow pathway phase distinc- that glycosylation defects influence other proteins and tion does not increase in the same way as normal path- indirectly affect the ERG. For example, at gap junc- ways, which suggests that, although still active, it is com- tions, connexin 43 itself is not glycosylated, yet inhibi- promised more than the fast pathway. tion of glycosylation causes connexin 43 cell-to-cell chan- A closer link between our ERG findings in PMM2- nels to open.51,52 Deletion of the amacrine AII localized CDG and the reported RP phenotype might be made if connexin 36 and the on-bipolar localized connexin 45 the PMM2 mutation has greater effect at the presynaptic can reduce scotopic b-wave amplitude by 40% to 50%.53,54 photoreceptor terminals that control glutamate release. More recently, N-glycosylated pannexins have been de- Slowing calcium influx reduces glutamate release. scribed that colocalize with connexins. They are plenti- L-voltage–dependent calcium channel heteromulti- ful in the retina and could alter gap junction cell-to-cell meric protein subunits are essential for Ca2ϩ channel as- communication.55-57 Gap junctions between cone bipo- sembly and function.43 Mutations in CACNA1F, the volt- lars to AII and AII-to-AII are bidirectional over a wide 58 age-dependent L-type channel subunit 1F (Cav1.4), which range of light intensities. is expressed presynaptically, causes X-linked CSNB2 (in- The sporadic evidence that some retinal diseases have complete CSNB). Patients with this mutation have some a greater effect on the on-pathway of cones rather than preservation of scotopic rod-driven ERG b-waves. rods has intrigued observers for some time.59 Sieving60 CACNA1F has a potential N-linked site, and interest- described a hyperpolarizing pattern of ERG in which the ingly, patients with CSNB2 have preserved but delayed photopic on-response was affected, but the scotopic OPs.40 Subunit ␣1F occurs in rods and cones and ␣1D b-wave was near normal. In these cases, the photopic, only in cones.44 This explains why both cone- and rod- prolonged-flash off-responses were preserved, even en- driven ERGs are affected in CSNB2 and why both on- and hanced.60 He advanced 2 hypotheses. The first was that off-responses of the photopic ERGs are reduced.45 No hu- the 2-amino-4-phosphonbutyrate–sensitive glutamate re- man disease has been described yet with mutations in ceptors on the rod on-bipolar and cone on-bipolar cells CACNA1D.46 Our patients are similar to the CSNB2 phe- have some unknown subtle differences. The second drew

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 on the demonstration that a timing delay at the on- 11. Wu WC, Lai CC, Liu JH, et al. Differential binding to glycotopes among the lay- synapse of as little as 2.5 milliseconds could mimic the ers of three mammalian retinal neurons by man-containing N-linked glycan, T␣ (Gal␤1-3GalNAc␣1-), Tn (GalNAc␣1-Ser/Thr) and I␤/II␤ (Gal␤1-3/4GlcNAc␤-) negative on-response waveform recorded in CSNB1 (this reactive lectins. Neurochem Res. 2006;31(5):619-628. assumed the b-wave is the result of subtractive interfer- 12. Voegtle´ R, Laplace O, Nordmann JP. Carbohydrate-deficient-glycoprotein syn- ence of depolarizing and hyperpolarizing bipolar cells). drome and ophthalmological manifestations. J Fr Ophtalmol. 2002;25(4):404- Changes in membrane resting potential and reduced dy- 408. namic range have been described in presynaptic no 13. Casteels I, Spileers W, Leys A, Lagae L, Jaeken J. Evolution of ophthalmic and electrophysiological findings in identical twin sisters with the carbohydrate de- b-wave models, which could potentially manifest such a ficient glycoprotein syndrome type 1 over a period of 14 years. Br J Ophthalmol. 46 timing effect. In this instance, on-pathway signaling may 1996;80(10):900-902. proceed to the inner retina, but the slight delay would 14. Fiumara A, Barone R, Buttitta P, et al. Carbohydrate deficient glycoprotein syn- alter the epiphenomenon of the ERG b-wave (ie, mark- drome type I: ophthalmic aspects in four Sicilian patients. Br J Ophthalmol. 1994; 78(11):845-846. edly attenuate amplitude). This explanation requires the 15. Morava E, Wosik HN, Sykut-Cegielska J, et al. Ophthalmological abnormalities OP latencies to be unaffected by this delay because tim- in children with congenital disorders of glycosylation type I. Br J Ophthalmol. ing in our patients was normal. A dissociation of OPs 2009;93(3):350-354. from a- and b-wave amplitudes has been noted recently 16. de Lonlay P, Seta N, Barrot S, et al. A broad spectrum of clinical presentations in in a rabbit model of retinal degeneration caused by a congenital disorders of glycosylation I: a series of 26 cases. J Med Genet. 2001; 38(1):14-19. rhodopsin mutation. This finding opens the possibility 17. Strømme P, Maehlen J, Strøm EH, Torvik A. The carbohydrate deficient glyco- that changes in inner retinal neuronal networks, sec- protein syndrome. Tidsskr Nor Laegeforen. 1991;111(10):1236-1237. ondary to photoreceptor dysfunction, can be associated 18. Andre´asson S, Blennow G, Ehinger B, Stro¨mland K. Full-field electroretino- with diminished b-wave but preserved, even enhanced, grams in patients with the carbohydrate-deficient glycoprotein syndrome. Am J OPs.61 Ophthalmol. 1991;112(1):83-86. 19. Bandah-Rozenfeld D, Collin RW, Banin E, et al. Mutations in IMPG2, encoding We have shown, for the first time to our knowledge, interphotoreceptor matrix proteoglycan 2, cause autosomal-recessive retinitis a negative ERG waveform in association with PMM2- pigmentosa. Am J Hum Genet. 2010;87(2):199-208. CDG. This places the site of dysfunction predominantly 20. Cideciyan AV, Jacobson SG. Negative electroretinograms in retinitis pigmentosa. at the cone on-bipolar synapse with the photoreceptors. Invest Ophthalmol Vis Sci. 1993;34(12):3253-3263. Studies of N-glycosylation disruption at this site may help 21. Renner AB, Kellner U, Cropp E, Foerster MH. Dysfunction of transmission in the inner retina: incidence and clinical causes of negative electroretinogram. Graefes identify a potential therapeutic intervention to prevent Arch Clin Exp Ophthalmol. 2006;244(11):1467-1473. progressive retinal dysfunction. Our findings also pro- 22. Alexander KR, Fishman GA, Barnes CS, Grover S. On-response deficit in the elec- vide a clinical example of differential resilience of OPs troretinogram of the cone system in X-linked retinoschisis. Invest Ophthalmol and an insight of retinal networks in disease. Vis Sci. 2001;42(2):453-459. 23. Tsang SH, Vaclavik V, Bird AC, Robson AG, Holder GE. Novel phenotypic and genotypic findings in X-linked retinoschisis. Arch Ophthalmol. 2007;125(2): Submitted for Publication: October 14, 2011; accepted 259-267. November 15, 2011. 24. Renner AB, Kellner U, Fiebig B, Cropp E, Foerster MH, Weber BH. ERG variability Correspondence: Dorothy A. Thompson, PhD, Clinical in X-linked congenital retinoschisis patients with mutations in the RS1 gene and and Academic Department of Ophthalmology, Great Or- the diagnostic importance of fundus autofluorescence and OCT. Doc Ophthalmol. 2008;116(2):97-109. mond Street Hospital for Children, Great Ormond Street, 25. Bradshaw K, George N, Moore A, Trump D. Mutations of the XLRS1 gene cause London WC1N 3JH, England (dorothy.thompson@gosh abnormalities of photoreceptor as well as inner retinal responses of the ERG. .nhs.uk). Doc Ophthalmol. 1999;98(2):153-173. Financial Disclosure: None reported. 26. McCall MA, Gregg RG. Comparisons of structural and functional abnormalities in mouse b-wave mutants. J Physiol. 2008;586(pt 18):4385-4392. 27. Baehr W, Frederick JM. Naturally occurring animal models with outer retina REFERENCES phenotypes. Vision Res. 2009;49(22):2636-2652. 28. Abd-El-Barr MM, Pennesi ME, Saszik SM, et al. Genetic dissection of rod and 1. Jaeken J, Carchon H. Congenital disorders of glycosylation: a booming chapter cone pathways in the dark-adapted mouse retina. J Neurophysiol. 2009;102(3): of pediatrics. Curr Opin Pediatr. 2004;16(4):434-439. 1945-1955. 2. Jaeken J. Komrower Lecture: congenital disorders of glycosylation (CDG): it’s 29. Strettoi E, Masland RH. The organization of the inner nuclear layer of the rabbit all in it! J Inherit Metab Dis. 2003;26(2-3):99-118. retina. J Neurosci. 1995;15(1 pt 2):875-888. 3. Matthijs G, Schollen E, Pardon E, et al. Mutations in PMM2, a phosphomanno- 30. Dhingra A, Jiang M, Wang TL, et al. Light response of retinal ON bipolar cells mutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type requires a specific splice variant of Galpha(o). J Neurosci. 2002;22(12):4878- I syndrome (Jaeken syndrome). Nat Genet. 1997;16(1):88-92. 4884. 4. Heykants L, Schollen E, Gru¨newald S, Matthijs G. Identification and localization 31. O’Connor E, Eisenhaber B, Dalley J, et al. Species specific membrane anchoring of two mouse phosphomannomutase genes, Pmm1 and Pmm2. Gene. 2001; of nyctalopin, a small leucine-rich repeat protein. Hum Mol Genet. 2005;14 270(1-2):53-59. (13):1877-1887. 5. Grunewald S, Matthijs G, Jaeken J. Congenital disorders of glycosylation: a review. 32. Morgans CW, Wensel TG, Brown RL, et al. G␤5-RGS complexes co-localize with Pediatr Res. 2002;52(5):618-624. mGluR6 in retinal ON-bipolar cells. Eur J Neurosci. 2007;26(10):2899-2905. 6. Grunewald S. The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). 33. Dhingra A, Lyubarsky A, Jiang M, et al. The light response of ON bipolar neu- Biochim Biophys Acta. 2009;1792(9):827-834. rons requires G␣o. J Neurosci. 2000;20(24):9053-9058. 7. Jensen H, Kjaergaard S, Klie F, Moller HU. Ophthalmic manifestations of congen- 34. Vardi N, Dhingra A, Zhang L, Lyubarsky A, Wang TL, Morigiwa K. Neurochemi- ital disorder of glycosylation type 1a. Ophthalmic Genet. 2003;24(2):81-88. cal organization of the first visual synapse. Keio J Med. 2002;51(3):154-164. 8. Marmor MF, Fulton AB, Holder GE, Miyake Y, Brigell M, Bach M; International 35. Rao A, Dallman R, Henderson S, Chen CK. G␤5 is required for normal light re- Society for Clinical Electrophysiology of Vision. ISCEV Standard for full-field clini- sponses and morphology of retinal ON-bipolar cells. J Neurosci. 2007;27(51): cal electroretinography (2008 update). Doc Ophthalmol. 2009;118(1):69-77. 14199-14204. 9. Stockman A, Sharpe LT, Ru¨ther K, Nordby K. Two signals in the human rod vi- 36. Chen F, Shim H, Morhardt D, et al. Functional redundancy of R7 RGS proteins in sual system: a model based on electrophysiological data. Vis Neurosci. 1995; ON-bipolar cell dendrites. Invest Ophthalmol Vis Sci. 2010;51(2):686-693. 12(5):951-970. 37. Audo I, Sahel JA, Bhattacharya S, Zeitz C. TRPM1, a new gene implicated in con- 10. Meigen T, Bach M. On the statistical significance of electrophysiological steady- genital stationary night blindness. Med Sci (Paris). 2010;26(3):241-244. state responses. Doc Ophthalmol. 1999;98(3):207-232. 38. van Genderen MM, Bijveld MM, Claassen YB, et al. Mutations in TRPM1 are a

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 common cause of complete congenital stationary night blindness. Am J Hum 50. Kinjo TG, Szerencsei RT, Winkfein RJ, Kang K, Schnetkamp PP. Topology of the Genet. 2009;85(5):730-736. retinal cone NCKX2 Na/Ca-K exchanger. Biochemistry. 2003;42(8):2485-2491. 39. Allen LE, Zito I, Bradshaw K, et al. Genotype-phenotype correlation in British fami- 51. Wang Y, Mehta PP, Rose B. Inhibition of glycosylation induces formation of open lies with X linked congenital stationary night blindness. Br J Ophthalmol. 2003; connexin-43 cell-to-cell channels and phosphorylation and Triton X-100 insolu- 87(11):1413-1420. bility of connexin-43. J Biol Chem. 1995;270(44):26581-26585. 40. Tremblay F, Laroche RG, De Becker I. The electroretinographic diagnosis of the 52. Segretain D, Falk MM. Regulation of connexin biosynthesis, assembly, gap junc- incomplete form of congenital stationary night blindness. Vision Res. 1995; tion formation, and removal. Biochim Biophys Acta. 2004;1662(1-2):3-21. 35(16):2383-2393. 53. Feigenspan A, Teubner B, Willecke K, Weiler R. Expression of neuronal con- 41. Zeitz C, Kloeckener-Gruissem B, Forster U, et al. Mutations in CABP4, the gene nexin36 in AII amacrine cells of the mammalian retina. J Neurosci. 2001;21 encoding the Ca2ϩ-binding protein 4, cause autosomal recessive night blindness. (1):230-239. Am J Hum Genet. 2006;79(4):657-667. 54. Maxeiner S, Dedek K, Janssen-Bienhold U, et al. Deletion of connexin45 in mouse 42. Schuster A, Pusch CM, Gamer D, Apfelstedt-Sylla E, Zrenner E, Kurtenbach A. retinal neurons disrupts the rod/cone signaling pathway between AII amacrine Multifocal oscillatory potentials in CSNB1 and CSNB2 type congenital stationary and ON cone bipolar cells and leads to impaired visual transmission. J Neurosci. night blindness. Int J Mol Med. 2005;15(1):159-167. 2005;25(3):566-576. 43. Catterall WA. Structure and regulation of voltage-gated Ca2ϩ channels. Annu Rev 55. Dvoriantchikova G, Ivanov D, Panchin Y, Shestopalov VI. Expression of pan- Cell Dev Biol. 2000;16:521-555. nexin family of proteins in the retina. FEBS Lett. 2006;580(9):2178-2182. 44. Morgans CW, Bayley PR, Oesch NW, Ren G, Akileswaran L, Taylor WR. Photo- 56. Boassa D, Ambrosi C, Qiu F, Dahl G, Gaietta G, Sosinsky G. Pannexin1 channels con- receptor calcium channels: insight from night blindness. Vis Neurosci. 2005; tain a glycosylation site that targets the hexamer to the plasma membrane. J Biol 22(5):561-568. Chem. 2007;282(43):31733-31743. 45. Miyake Y, Yagasaki K, Horiguchi M, Kawase Y, Kanda T. Congenital stationary 57. D’hondt C, Ponsaerts R, De Smedt H, Bultynck G, Himpens B. Pannexins, dis- night blindness with negative electroretinogram: a new classification. Arch tant relatives of the connexin family with specific cellular functions? Bioessays. Ophthalmol. 1986;104(7):1013-1020. 2009;31(9):953-974. 46. Striessnig J, Bolz HJ, Koschak A. Channelopathies in Cav1.1, Cav1.3, and Cav1.4 58. Trexler EB, Li W, Massey SC. Simultaneous contribution of two rod pathways to voltage-gated L-type Ca2ϩ channels. Pflugers Arch. 2010;460(2):361-374. AII amacrine and cone bipolar cell light responses. J Neurophysiol. 2005;93 47. Schmitz F, Drenckhahn D. Dystrophin in the retina. Prog Neurobiol. 1997;53(5): (3):1476-1485. 547-560. 59. Cibis GW, Fitzgerald KM. The negative ERG is not synonymous with nightblindness. 48. Pillers DA, Weleber RG, Green DG, et al. Effects of dystrophin isoforms on sig- Trans Am Ophthalmol Soc. 2001;99:171-176. nal transduction through neural retina: genotype-phenotype analysis of Duch- 60. Sieving PA. Photopic ON- and OFF-pathway abnormalities in retinal dystrophies. enne muscular dystrophy mouse mutants. Mol Genet Metab. 1999;66(2):100- Trans Am Ophthalmol Soc. 1993;91:701-773. 110. 61. Sakai T, Kondo M, Ueno S, Koyasu T, Komeima K, Terasaki H. Supernormal ERG 49. Muntoni F, Brockington M, Blake DJ, Torelli S, Brown SC. Defective glycosyla- oscillatory potentials in transgenic rabbit with rhodopsin P347L mutation and tion in muscular dystrophy. Lancet. 2002;360(9343):1419-1421. retinal degeneration. Invest Ophthalmol Vis Sci. 2009;50(9):4402-4409.

Correction

Error in Data. In the article titled “Final Visual Acuity Results in the Early Treatment for Retinopathy of Pre- maturity Study” by The Early Treatment for Retinopa- thy of Prematurity Cooperative Group published in the June 2010 issue of the Archives (2010;128[6]:663-671), 1 child was mistakenly coded as having poor visual acuity outcome in both eyes when, in fact, the visual acuity outcome was favorable for both eyes. The percentage of high-risk prethreshold eyes with unfavorable visual acuity outcomes reported in 2010 was 24.6% for early- treated and 29.0% for conventionally managed eyes. Af- ter making the correction, the correct percentages are 24.3% and 28.6%, respectively. The incorrect percentages were reported in the “Results” section of the Ab- stract on page 663, the second paragraph of the “Re- sults” section on page 666, and in the Total row of Table 1 on page 666. Both the absolute difference in the percentages (4.3%) and the corresponding P value (.15) re- main unchanged. The error does not change the results of the study.

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