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Congenital Disorder of Glycosylation Due to Phosphomannomutase Deficiency

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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 am- plitudes 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 sco- topic 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 saw- tooth 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- ARCH OPHTHALMOL / VOL 130 (NO. 6), JUNE 2012 WWW.ARCHOPHTHALMOL.COM 712 ©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 ex- tended to include a wider range of flash luminances and phot- opic 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 lu- minance of 30 cd/m2. The ERGs were acquired in a time win- dow of 250 milliseconds, which included a 20-millisecond pre- stimulus 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 path- ways, 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, in- complete 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.
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