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Ocular findings in lissencephaly
Ocular Findings in Lissencephaly Naeem U. Nabi, FRCSE, FRCOphth,a Eedy Mezer, MD,a Susan I. Blaser, MD, FRCP,b Alex A. Levin, MD, MHSc, FRCSC,a and J. Raymond Buncic, MD, FRCSCa Purpose: To report our retrospective study of 20 cases with lissencephaly and describe ocular and visual abnormalities associated with this disorder. Methods: Patients with lissencephaly were identified and classified into classic (type I) or cobblestone (type 2) lissencephaly on the basis of a review of clinical records and neuroimaging studies. Only patients examined by an ophthalmologist were included in the study. Results: Only 1 patient had a normal ocular examination. Ocular abnormalities included optic nerve hypoplasia and atrophy, retinal dysplasia, retinal nonattachment, macular hypoplasia, anterior segment malformation, and strabismus. Conclusions: Ocular abnormalities in classic (type 1) lissencephaly are less severe. Central, steady, and maintained fixation may be present despite the presence of optic nerve hypoplasia, optic atrophy, macular hypoplasia, strabismus, or refractive errors. Retinal and anterior segment abnormalities were observed only in cobblestone (type 2) lissencephaly. These patients often have severe visual impairment because of retinal or cortical disease. (J AAPOS 2003;3:178 –184) he term, “lissencephaly,” (derived from the Greek words. “lissos” meaning smooth and “encephalus” meaning brain), or “agyria,”1 is applied to several different disorders of neuronal migration that result in smooth brain surface.2 Lissencephaly is a rare malformation of cerebral cortex that is usually associated with epilepsy, developmental delay,3,4 and mental retardation.5,6 Infant death is common in lissencephaly.7,8 The two main pathological types of lissencephaly distinguished by radiological features are classic (type 1) and cobblestone (type 2).9,10 Magnetic resonance imaging (MRI) is the best method of distinguishing different types of lissencephaly.11,12 Table 1 summarizes the various diagnostic subcategories. There may be overlap between some of the associated syndromes. Other rarer types have been reported.13 Classic lissencephaly is the most common variety, with an estimated incidence of 11.7 cases/1 million births.14 Although thicker (Figure 1), the cerebral cortex is characterized histologically by a decrease in structure from a 6 to a 4 layers.15 The cerebral cortex and gross brain structure typically show a “figure-of-8” or “hourglass” appearance on axial neuroimaging (Figure 2). 16,17 These abnormalities in cerebral cortex result from an arrest in the migration of neurons to their appropriate destinations in the brain cortex between 10 and 14 weeks’ gestation.18 Severe malformations, such as pure agyria, seen in cobblestone
T
a From the Department of Opththalmology and the bDepartment of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, Toronto, Canada. Submitted November 25, 2002. Revisions accepted November 25, 2002. Reprint requests: J. Raymond Buncic, MD, FRCSC, The Hospital for Sick Children, Eye Clinic, 555 University Ave, Toronto, Ontario M5G 1X8. Copyright © 2003 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2003/$35.00 ⫹ 0 doi:10.1016/S1091-8531(02)42005-8
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lissencephaly may occur with migrational insults as early as 6 weeks’ gestation.19 This results in a spectrum of surface architecture changes ranging from complete agyria to a combination of pachygyria and polymicrogyria, the combinations of which determine clinical subtyping.16 The cerebellum usually appears normal except in subtypes with vermis hypoplasia.13,20 Some subtypes may exhibit agenesis of the corpus callosum.13 There is usually an inversion of the normal grey–white matter ratio.21,22 The 5-year survival rate is 54% in those patients with complete or nearly complete agyria.23 The craniofacial appearance is generally normal, although bitemporal atrophy and moderate micrognathia may occur.24 Because the clinical picture is nonspecific, the diagnosis rests on the neuroradiological findings.24 An important variant of type 1 lissencephaly, the Miller-Dieker syndrome, was described by Miller7 in 1963 and Dieker et al25 in 1969. These mentally retarded children have characteristic facial dysmorphism, ie, high forehead, bitemporal atrophy, anteverted nostrils, a long philtrum with abnormal upper lip, micrognathia, and digital anomalies.24,26 Generally, they develop seizures in the first few months of life.27 Molecular genetic testing of patients with both Miller-Dieker syndrome and nonsyndromic classic lissencephaly may show microdeletion of 17p13.3.2,9,28,30 Cobblestone lissencephaly differs pathologically from type 1 in that the cortex is severely disorganized and unlayered, with extensive neuronal and glial ectopia in the leptomeninges. These changes may also be seen in the cerebellum.31 Macroscopically, the brain surface is somewhat verrucous and often compared to Moroccan leather or a pebbled surface (Figure 3). The grey-to-white matter ratio is approximately 1:1. The border between grey and white matter is indistinct. The meninges are thickened and adherent to the cortex, resulting in obliteration of the Journal of AAPOS
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TABLE 1. Diagnostic types of lissencephaly Classical Lissencephaly (Type 1) Radiological features
Associated syndromes
Cobblestone Lissencephaly (Type 2)
● Cerebral cortex thickened ● Smooth surface with a “figure of 8” configuration ● Grey-to-white matter ratio 4:1 ● Brain stem and cerebellum usually normal
● Miller-Dieker syndrome (see text)
● Cerebral cortex thickened and severely disorganized ● Pebbled surface ● ● ● ●
Grey-to-white matter ratio 1:1 Brain stem and cerebellum involved Cerebellar vermis hypoplasia Abnormal appearance of the globes on imaging ● Walker-Warburg syndrome (see text) ● Muscle-eye-brain disease (congenital muscular dystrophy ⫹ high myopia, and retinal abnormalities) ● Fukuyama congenital muscular dystrophy (congenital muscular dystrophy and retinal abnormalities not required for diagnosis) ● Dobyns-Patton-Stratton syndrome (no congenital muscular dystrophy and “normal” eyes; see text)
FIG 1. Coronal section of the brain from patient with classical lissencephaly showing thickened cerebral cortex and smooth surface.
subarachnoid space with secondary hydrocephalus.22,32 The current diagnostic imaging criteria for cobblestone lissencephaly, seen in the congenital muscular dystrophies consist of mixed agyria; pachygyria and polymicrogyria with pebbled surface; abnormal white matter caused by dysmyelination; enlarged ventricles; and brain stem and cerebellar hypoplasia, particularly involving vermis (Figure 4). 22,31,32 Cobblestone lissencephaly may be associated with a variety of anterior and posterior segment ophthalmic abnormalities such as coloboma, Peter’s anomaly, persistent fetal vasculature, retinal dysplasia, retinal detachment, optic nerve coloboma, and optic nerve hypoplasia.33 Several
FIG 2. Classical lissencephaly. Axial cranial magnetic resonance imaging scan (TI ⫽ weighted) at the level of third ventricle showing “figure-of-8” configuration caused by underoperculization of the Sylvian fissures (arrow shows primitive fissure), smooth cortical surface, thick cortex and thin white matter.
syndromic associations, in particular the congenital muscular dystrophies, are described in Table 1. Walker-Warburg syndrome is the most common, with an estimated incidence of 0.21 case/10,000 live births.34 In the older literature it is also described as HARD⫹/⫺E: hydroceph-
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and 1998. Neuroimaging reports and inpatient diagnostic codes initially identified the cases for study. By way of review of computed tomography and MRI reports, 111 patients with severe cortical underdevelopment were identified according to brain phenotypes described in the literature.13,17,20,21,31 Of these, 83 films were available for review by our pediatric neuroradiologist (SIB). All but 1 of the reviewed patients underwent MRI. After the films were reviewed, 36 patients with lissencephaly were identified. Patients not examined by an ophthalmologist were excluded from study.
RESULTS
FIG 3. Cobblestone lissencephaly. Magnetic resonance imaging scan (T2-weighted) of brain showing pebbled cortical surface and typical ventricular dilatation in a patient with Walker-Warburg syndrome.
FIG 4. Magnetic resonance imaging (T1-weighted) scan showing vermis hypoplasia (arrow) in a patient with cobblestone lissencephaly. Increased signal of both globes may represents fluid accumulation secondary to retinal nonattachment.
alus, agyria, retinal dysplasia ⫾ encephalocele.35 Following is a review of our experience examining the eyes of patients with lissencephaly.
METHODS We conducted a retrospective study of clinical and neuroimaging records of all patients with lissencephaly diagnosed at The Hospital for Sick Children between 1968
Of the 36 patients, 31 (86%) had classic lissencephaly. Twelve of 25 (48%) with isolated lissencephaly and 3 of 6 (50%) with Miller-Dieker syndrome had been examined by an ophthalmologist. Five of the 36 patients (14%) had cobblestone lissencephaly. All 5 had Walker-Warburg syndrome and had been examined by an ophthalmologist. One case included in this study has been previously reported.2 The clinical data is summarized in Table 2. Patient age at the time of eye examination ranged from 2 days to 10.5 years (average, 1.64 years). Seven patients were male. Vision Because of young patient age and mental incapacity, it was not possible to carry out quantitative acuity tests, including Teller acuity. Vision was assessed in 10 of 12 patients with isolated classic lissencephaly. Visual evoked potentials (VEP) under monocular conditions—when tolerated— or binocularly conditions—when patients would not tolerate occlusion of one eye—were done in 7 of the 8 patients who could fix and follow and were present to flash and/or pattern stimuli in all. Two patients with responses to 120-minute and 480-minute check sizes had both optic nerve atrophy and hypoplasia (diagnosis based on the presence of small optic nerve head size with or without double ring). One patient (10%) showed responses only to flash stimuli despite ability to fix and follow and a normal fundus. This child had severe developmental delay, and we believe the poor result of VEP testing was related to cortical visual impairment. Of the 2 patients who could not fix and follow, 1 showed a positive response to optokinetic nystagmus–inducing stimuli. One had optic nerve atrophy, and the other had normal discs and maculae. Two patients (a 2-day-old and a 5-month-old) with isolated classic lissencephaly did not have a documented vision assessment. Of 3 patients with Miller-Dieker syndrome, 2 could fix and follow. Both had rotary nystagmus. During testing of the patient with no central, steady, maintained fixation, a seizure occurred, and further testing was abandoned. Only 1 of the 5 patients with cobblestone lissencephaly was able to fix and follow. His examination showed bilateral retinal colobomas. This child had severe developmen-
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TABLE 2. Ocular abnormalities Classical Lissencephaly (n ⴝ 12) Vision
VEP
Anterior segment
Fundus
Miller-Dieker Syndrome (n ⴝ 3)
CSM: 8 cases (80%)
CSM: 2 cases
CSM: 1 case
No CSM: 2 cases (20%)
No CSM: 1 case
Light perception: 1 case
CSM: Responses present up to check size stimulus of 60 minutes: 1 case
No CSM: 3 cases CSM: Responses present up to check size stimulus of 15 minutes: 1 case
Not documented: 2 cases CSM: Responses present up to check size stimulus of 15 minutes: 4 cases 120 minutes: 1 case 480 minutes: 1 case Response present only to flash: 1 case
Response present only to flash: 1 case
Not recorded: 4 case
Not recorded: 1 case
No CSM: Response present only to flash: 1 case
No CSM: Response present only to flash: 1 case
Normal
Peter’s anomaly OU: 1 case PFV OU: 1 case
Normal
Iris hypoplasia OU: 1 case Retinal nonattachment OU: 1 case Retinal nonattachment in one eye and retinal dysplasia in fellow eye: 1 case Retinal dysplasia with nonattached retina: 1 case Retinal dysplasia with nonattached retina and ON atrophy: 1 case Retinal coloboma in one eye and retinal colobome involving the disk in other: 1 case No strabismus: 5 cases
No CSM: Response present only to flash: 2 cases Normal
Optic nerve and macular hypoplasia: 4 cases (33%) optic atrophy: 2 cases (17%) normal: 6 cases
Strabismus
Cobblestone lissencephaly (WWS) (n ⴝ 5)
Exotropia (range 30 to 50 prism diopters): 6 cases (50%)
No strabismus: 3 cases
Esotropia (20 prism diopters): 1 case (8.3%) No strabismus: 5 cases Refraction
Average spherical error ⫹2.75 (range ⫹0.75 to ⫹4.25 D): 7 cases (58.3%)
hyperopia (OU ⫹ 1.50 D): 1 case
Average astigmatic error ⫹1.53 (range ⫹ 1.00 to ⫹2.50 D): 5 cases (41.6%) Anisometropia or myopia: none
Not done: 2 cases
Hyperopia ⫹ astigmatism (OD ⫹4.00⫹2.00 ⫻ 115° OS ⫹4.00⫹2.00 ⫻ 80°): 1 case
Not recorded: 4 cases Anisometropia or myopia: none
Abbrevation: WWS, Walker–Warburg syndrome; CSM, central, steady, maintained fixation for patients with strabismus refers to fixing eye; PFV, persistent fetal vasculature; ON, optic nerve; D, diopter; *Only 10 of 12 children with type 1 malformation had their vision assessed.
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tal delay and was unresponsive and lethargic. On his first visit at 2.5 months of age, he could not fix and follow but had recognizable, repeatable VEP with small amplitudes to bright flash stimuli under monocular viewing. Under binocular viewing, a repeatable response was found for the 240-minute check sizes, suggesting gross form perception. On subsequent visits he could fix and follow. VEP showed improvement at 1 year, and responses were present to 15-minute stimulus at 1.5 years of age. In another patient with retinal dysplasia in 1 eye and retinal nonattachment in the other, there was an avoidance response to bright light, indicating light perception, which was confirmed by flash VEP response. No patients showed substantial visual improvement on serial examinations. Anterior Segment Three of 5 patients with cobblestone lissencephaly had anterior segment anomalies. One patient had bilateral Peter’s anomaly, with corneal diameters of 8.75 mm. The second patient had bilateral persistent fetal vasculature with corneal diameters of 7.75 and 8.25 mm and bilateral cataracts. The third patient had iris hypoplasia with iris transillumination. The ocular abnormalities seen in our patients are summarized in Table 2.
DISCUSSION Ophthalmologic abnormalities have not been consistently recognized in patients with classic lissencephaly.22,24 Therefore, it is not surprising that only 15 of 31 patients (48.4%) identified in our study were referred to an ophthalmologist, whereas all patients with cobblestone lissencephaly had been referred for ophthalmic assessment. A review of the literature concerning patients with classic lissencephaly showed ocular abnormalities in 6 of 31 patients (19.3%), including no ocular fixation or tracking,23 poor visual tracking, nystagmus, variable esotropia, corneal clouding, oculomotor apraxia,36 abnormal irides, and tortuous fundal vessels,10 and delayed visual maturation.37 In our study, classic lissencephaly was associated with milder ocular abnormalities than was cobblestone lissencephaly. We found a higher incidence of ocular and visual abnormalities, however, in patients with classical lissencephaly than was previously reported.22 These included optic nerve and macular hypoplasia, optic nerve atrophy, refractive errors, and cortical visual impairment. Neither retinal nonattachment, retinal dysplasia, nor anterior segment anomalies were observed. The relatively high incidence of exotropia most likely reflects the more common occurrence of exotropia in developmentally delayed children. The rotary nystagmus found in both cases of MillerDieker syndrome was most likely either of central vestibular origin, or it may have been a type of congenital nystagmus. To some extent, our higher incidence figures might be explained by referral bias. Patients are often referred only if the primary care physician suspects or notes an ocular problem; both in the subjects we reviewed
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as well as subjects in other studies, no specific effort was made to conduct a full ocular examination in every patient. Many series in the literature have described syndromes that include both cobblestone lissencephaly and ocular abnormalities (Table 1).3,8,38 – 40 Many of the syndromes require retinal dysplasia as a diagnostic criterion. Dobyns and Truwit2 reported 40 patients with Walker-Warburg syndrome. They found microphthalmia in 15 of 16 patients (93.7%), retinal dysplasia in 10 of 23 (43.4%), optic nerve hypoplasia in 20 of 21 (95%), coloboma in 3 of 28 (10.7%) and anterior chamber abnormalities such as glaucoma in 13 of 26 (50%), angle abnormalities in 14 of 24 (58.3%), cataract in 16 of 28 (57.1%), pupil abnormalities in 14 of 24 (58.3%), and persistent hyperplastic primary vitreous in 12 of 15 (80%). Micropthalmos (n ⫽ 2), cataracts (n ⫽ 3) and retinal malformation (n ⫽ 3) were reported in 3 patients with Walker-Warburg syndrome. Nystagmus (n ⫽ 2), strabismus (n ⫽ 3), and mild myopia (n ⫽ 2) were reported in 3 patients with Dobyns-PattonStratton syndrome, often defined as cobblestone lissencephaly with “normal eyes.” All children with Walker-Warburg syndrome in our series of 5 patients had retinal abnormalities and 3 had anterior segment malformation. Given the small number of patients, we cannot compare our data with that of Dobyns and Truwitt.2 It is apparent from both studies, however, that anterior and posterior segment abnormalities are commonly found, and vision is often poor. Lissencephaly is a neuronal migration disorder.41 The gene implicated in type I lissencephaly with profound cerebellar hypoplasia is RELN mapped to 17q22,42 which manufactures the protein, reelin.43 This protein is believed to be involved in extracellular matrix signalling by involving the very–low-density lipoprotein and apolipoprotein E receptor-2 cell surface receptors and, in turn, the intracellular adaptor protein distabled-1 (Dab1) pathway, which activates tyrosine phosphorylation of Dab1.44 Phosphorylation of the microtubule-associated protein, Tau, is necessary for neuronal migration.45,46 Likewise, the LIS1 gene mapped to 17p13.3, which is mutated or deleted in 65% of classic type I lissencephaly47 and deleted in 93% of Miller-Dieker syndrome,9,29 is also believed to be involved with microtubule function via its role as a subunit in the brain lipid messenger platelet-activating factor acetylhydrolase 1B,48 its interaction with the microtubule motor cytoplasmic dynein in mice,49,50 and its association with the nuclear distribution gene F (NudF) because Nud proteins are known to be involved with microtubules. Xlinked dominant lissencephaly in male patients as well as and 20% of classic lissencephaly are caused by mutations in the DCX gene mapped to Xq22.3-q23,51 which manufactures doublecortin and is yet another protein that affects microtubule function.52,53 Dab1 was found to be normally expressed in a specific type of retinal amacrine cells and is expressed during the first postnatal week during the time at which amacrine
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cells extend neurites and form synaptic connections in the inner plexiform layer in the mouse retina. This raises the possibility that the reelin–Dab1 signaling pathway contributes to formation of intraretinal circuitry in the neural retina.54 This might explain the macular hypoplasia seen in 2 of our patients with classic lissencephaly. The genes for Walker-Warburg syndrome, muscleeye-brain disease (MEB), and Fukayama-type muscular dystrophy (FCMD) are unknown, although the latter two have been mapped to 1p32 and 9q31, respectively.55–57 There is some evidence to suggest that Walker-Warburg syndrome and FCMD might be genetically identical.58 An ancient retrotransposal insertion, 3 kb long, was reported to cause FCMD.59 Mutations in the POMGnT1 gene, which catalyzes the second glycosyl transfer step in the biosynthesis of mammalian O-mannosyl glycans, were recently shown to be the primary genetic defect in MEB.60 It is more difficult to explain the ocular abnormalities seen in cobblestone lissencephaly until the genes have been characterized.
CONCLUSION Of 20 patients with lissencephaly seen by an ophthalmologist, only 1 had an normal ocular examination. Sixty seven percent of patients with type 1 lissencephaly had ocular abnormalities, contrasting with the 100% anomaly rate in type 2 disease. These children have a spectrum of visual ability ranging from light perception to moderate form vision. Cobblestone lissencephaly is more commonly associated with severe anomalies of the anterior and posterior segment. Anterior segment disease occurred only in type 2 lissencephaly. We recommend full eye examination of all children with lissencephaly. Nota bene: While the present article was in press, a paper was published that is relevant to the pathogenesis of WWS, MEB, and FCMD61. The article illustrates that mutations in the POMT1 gene cause some cases of WWS. The gene encodes the enzyme O-mannosyltransferase 1, which catalyzes the addition of the first of 4 residues of O-mannosyl glycan. Loss-of-function on target proteins in the eye may be secondary to defective glycosylation of proteins yet unknown. POMGnT1, the MEB gene product,60 adds the second residue, an N-acetylglucosamine. The function of the Fukutin is unknown, but it has been hypothesized also to be a glyucosyltransferase.62,63 Hypoglycosylated ␣-dystroglycan, an extracellular matrix O-glycan, crucial for the correct contraction of muscle, causes muscular dystrophy. The observation in muscle tissue from patients with mutations in POMGnT1, and FCMD of hypoglycosylation of ␣-dystroglycan indicates the implication of a common glycan synthesis disorder. Other possible O-mannosylation targets may include diffusible brain development factors, reelin, a glycoprotein, mentioned earlier in our discussion, and tenascin-J1, which shows repellent activity on neurite extension in neuroblast culture.64 These observations suggest an important role of glycosylation in neural migration. The authors thank Dr Venita Jay for providing the photograph of smooth brain with lissencephaly and Dr Carol Westall for her contri-
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butions to the presentation of the VEP data. We are also grateful for the assistance of our research assistant, Ms Enza Perruzza. References 1. Dorland WAN. Dorland’s illustrated medical dictionary. 29th ed. Philadelphia: Saunders; 2000. 2. Dobyns WB, Truwit CL. Lissencephaly and other malformations of cortical development: 1995 update. Neuropediatrics 1995;26:132-47. 3. Kurlemann G, Schuierer G, Kuchelmeister K, Kleine M, Weglage J, Palm DG. Lissencephaly syndromes: clinical aspects. Childs Nerv Syst 1993;9:380-6. 4. Gastaut H, Pinsard N, Raybaud C, Aicardi J, Zifkin B. Lissencephaly (agyria-pachygyria): clinical findings and serial EEG studies. Dev Med Child Neurol 1987;29:167-80. 5. Gleeson JG. Classical lissencephaly and double cortex (subcortical band heterotopia): LIS1 and doublecortin. Curr Opin Neurol 2000; 13:121-5. 6. Pilz DT, Quarrell OW. Syndromes with lissencephaly. J Med Genet 1996;33:319-23. 7. Miller JQ. Lissencephaly in 2 siblings. Neurology 1963;13:841-50. 8. Williams RS, Swisher CN, Jennings M, Ambler M, Caviness VS, Jr. Cerebro-ocular dysgenesis (Walker-Warburg syndrome): neuropathologic and etiologic analysis. Neurology 1984;34:1531-41. 9. Ledbetter SA, Kuwano A, Dobyns WB, Ledbetter DH. Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly. Am J Hum Genet 1992;50:182-9. 10. Dobyns WB, Stratton RF, Greenberg F. Syndromes with lissencephaly. I: Miller-Dieker and Norman-Roberts syndromes and isolated lissencephaly. Am J Med Genet 1984;18:509-26. 11. Barkovich AJ, Koch TK, Carrol CL. The spectrum of lissencephaly: report of ten patients analyzed by magnetic resonance imaging. Ann Neurol 1991;30:139-46. 12. Landrieu P, Husson B, Pariente D, Lacroix C. MRI-neuropathological correlations in type 1 lissencephaly. Neuroradiology 1998;40: 173-6. 13. Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB. Classification system for malformations of cortical development: update 2001. Neurology 2001;57:2168-78. 14. de Rijk-van Andel JF, Arts WF, Hofman A, Staal A, Niermeijer MF. Epidemiology of lissencephaly type I. Neuroepidemiology 1991;10: 200-4. 15. Crome L. Pachygyria. J Pathol Bacteriol 1956;71:335-52. 16. Banna M, Malabarey T. Lissencephaly and pachygyria. Can Assoc Radiol J 1989;40:156-8. 17. Dobyns WB, McCluggage CW. Computed tomographic appearance of lissencephaly syndromes. Am J Neuroradiol 1985;6:545-50. 18. Dobyns WB. Developmental aspects of lissencephaly and the lissencephaly syndromes. In: Gilbert EF, Opitz JM, editors. Genetic aspects of developmental pathology. New York: Liss; 1987. p. 225 Vol 23.. 19. Dobyns WB. The neurogenetics of lissencephaly. Neurol Clin 1989; 7:89-105. 20. Dobyns WB, Truwit CL, Ross ME, Matsumoto N, Pliz DT, Ledbetter DH, et al. Differences in the gyral pattern distinguish chromosome 17-linked and X-linked lissencephaly. Neurology 1999;53: 270-7. 21. Byrd SE, Osborn RE, Bohan TP, Naidich TP. The CT and MR evaluation of migrational disorders of the brain. Part I. Lissencephaly and pachygyria. Pediatr Radiol 1989;19:151-6. 22. Kuchelmeister K, Bergmann M, Gullotta F. Neuropathology of lissencephalies. Childs Nerv Syst 1993;9:394-9. 23. de Rijk-van Andel JF, Arts WF, Barth PG, Loonen MC. Diagnostic features and clinical signs of 21 patients with lissencephaly type 1. Dev Med Child Neurol 1990;32:707-17. 24. Dobyns WB, Curry CJ, Hoyme HE, Turlington L, Ledbetter DH. Clinical and molecular diagnosis of Miller-Dieker syndrome. Am J Hum Genet 1991;48:584-94.
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25. Dieker H, Edwards RH, ZuRhein G, Chou SM, Hartman HA, Opitz JM. The lissencephaly syndrome. In: Bergsma D, editor. The clinical delineation of birth defects: malformation syndromes. New York: National Foundation-March of Dimes; 1969. p. 53-64. 26. Selypes A, Laszlo A. Miller-Dieker syndrome and monosomy 17p13: a new case. Hum Genet 988;80:103-4. 27. Van Allen M, Clarren SK. A spectrum of gyral anomalies in MillerDieker (lissencephaly) syndrome. J Pediatr 1983;102:559-64. 28. Lo Nigro C, Chong CS, Smith AC, Dobyns WB, Carrozzo R, Ledbetter DH. Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. Hum Mol Genet 1997;6:157-64. 29. Dobyns WB, Reiner O, Carrozzo R, Ledbetter DH. Lissencephaly. A human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13. JAMA 1993;270:2838-42. 30. Chong SS, Pack SD, Roschke AV, Tanigami A, Carrozzo R, Smith AC, et al. A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3. Hum Mol Genet 1997;6:147-55. 31. Cormand B, Pihko H, Bayes M, Valanne L, Santavuori P, Talim B, et al. Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease. Neurology 2001;56:105969. 32. Dobyns WB, Pagon RA, Armstrong D, Curry CJ, Greenberg F, Grix A et al. Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet 1989;32:195-210. 33. Rodgers BL, Vanner LV, Pai GS, Sens MA. Walker-Warburg syndrome: report of three affected sibs. Am J Med Genet 1994;49:198201. 34. Martinez-Lage JF, Garcia Santos JM, Poza M, Puche A, Casas C, Rodriguez Costa T. Neurosurgical management of Walker-Warburg syndrome. Childs Nerv Syst 1995;11:145-53. 35. Ayme S, Mattei JF. Brief clinical report: HARD (⫹/⫺ E) syndrome: report of a sixth family with support for autosomal-recessive inheritance. Am J Med Genet 1983;14:759-66. 36. Pavone L, Gullotta F, Incorpora G, Grasso S, Dobyns WB. Isolated lissencephaly: report of four patients from two unrelated families. J Child Neurol 1990;5:52-9. 37. Hodgkins PR, Kriss A, Boyd S, et al. A study of EEG, electroretinogram,visual evoked potential, and eye movements in classical lissencephaly. Dev Med Child Neurol 2000;42:48-52. 38. Bordarier C, Aicardi J, Goutieres F. Congenital hydrocephalus and eye abnormalities with severe developmental brain defects: Warburg’s syndrome. Ann Neurol 1984;16:60-5. 39. Chitayat D, Toi A, Babul R, Levin A, Michael J, Summers A et al. Prenatal diagnosis of retinal nonattachment in the Walker-Warburg syndrome. Am J Med Genet 1995;56:351-8. 40. Santavuori P, Somer H, Sainio K, Rapola J, Krauus S, Nikitin T et al. Muscle-eye-brain disease (MEB). Brain Dev 1989;11:147-53. 41. Barkovich AJ, Kuzniecky RI, Dobyns WB, Jackson GD, Becker LE, Evrard P. A classification scheme for malformations of cortical development. Neuropediatrics 1996;27:59-63. 42. Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 2000;26:93-6. 43. DeSilva U, D’Arcangelo G, Braden VV, Chen J, Miao GG, Curran T et al. The human reelin gene: isolation, sequencing, and mapping on chromosome 7. Genome Res 1997;7:157-64. 44. D’Arcangelo G, Homayouni R, Keshvara L, Rice DS, Sheldon M, Curran T. Reelin is a ligand for lipoprotein receptors. Neuron 1999;24:471-9. 45. Hiesberger T, Trommsdorff M, Howell BW, Goffinet A, Mumby MC, Cooper A, et al. Direct binding of reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron 1999;24:481-9.
Journal of AAPOS Volume 3 Number 3 June 2003 46. Takei Y, Teng J, Harada A, Hirokawa N. Defects in axonal elongation and neuronal migration in mice with disrupted tau and map1b genes. J Cell Biol 2000;150:989-1000. 47. Cardoso C, Leventer RJ, Matsumoto N, Kuc JA, Ramocki MB, Menborn SK et al. The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene. Hum Mol Genet 2000;9:3019-28. 48. Hattori M, Adachi H, Tsujimoto M, Arai H, Inoue K. Miller-Dieker lissencephaly gene encodes a subunit of brain platelet-activating factor acetylhydrolase. Nature 1994;370:216-8 [corrected]. 49. Faulkner NE, Dujardin DL, Tai CY. A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function. Nat Cell Biol 2000;2:784-91. 50. Smith DS, Niethammer M, Ayala R, Zhou Y, Gambello MJ, Wynshaw-Boris A et al. Regulation of cytoplasmic dynein behaviour and microtubule organization by mammalian Lis1. Nat Cell Biol 2000; 2:767-75. 51. Pilz DT, Matsumoto N, Minnerath S, Mills P, Gleeson JG, Allen KM et al. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Hum Mol Genet 1998;7:2029-37. 52. Gleeson JG, Lin PT, Flanagan LA, Walsh CA. Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 1999;23:257-71. 53. Gleeson JG, Allen KM, Fox JW, Lamperti ED, Berkovic S, Scheffer I, et al. Doublecortin, a brain-specific gene mutated in human Xlinked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 1998;92:63-72. 54. Rice DS, Curran T. Disabled-1 is expressed in type AII amacrine cells in the mouse retina. J Comp Neurol 2000;424:327-8. 55. Cormand B, Avela K, Pihko H, Santavuori P, Talim B, Topaloglu H et al. Assignment of the muscle-eye-brain disease gene to 1p32-p34 by linkage analysis and homozygosity mapping. Am J Hum Genet 1999;64:126-35. 56. Toda T, Segawa M, Nomura Y, et al. Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q31–33. Nat Genet 1993;5:283-6. 57. Toda T, Miyake M, Kobayashi K, Mizuno K, Saito K, Osawa M, et al. Linkage-disequilibrium mapping narrows the Fukuyama-type congential muscular dystrophy (FCMD) candidate region to ⬍100 kb. Am J Hum Genet 1996;59:1313-20. 58. Toda T, Yoshioka M, Nakahori Y, Kanazawa I, Nakamura Y, Nakagome Y. Genetic identity of Fukuyama-type congenital muscular dystrophy and Walker-Warburg syndrome. Ann Neurol 1995;37:99101. 59. Kobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura T et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 1998;394: 388-92. 60. Yoshida A, Kobayashi K, Manya H. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell 2001;1:717-24. 61. Beltran-Valero De Bernabe D, Currier S. Mutations in the OMannosyltransferase Gene POMT1 give rise to the severe neuronal migration disorder Walker-Warbug syndrome. Am J Hum Genet 2002;71(5):1033– 43. 62. Aravind L, Koonin EV. The fukutin protein family predicted enzymes modifying cell-surface molecules. Curr Biol 1999; 9(22)R836 –7. 63. Brockington M, Blake DJ. Mutations in the fukutin related protein gene (FKRD) cause a form of congenital muscular dystrophy with secondary laminin alpha 2-defining and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet 2001;69(6):1198 –209. 64. Wing DR, Rademacher TW. Comparative glycosylation in neural adhesion molecules. Biochem Soc Trans 1992;20(2):363–90.
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a From the Department of Opththalmology and the bDepartment of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, Toronto, Canada. Submitted November 25, 2002. Revisions accepted November 25, 2002. Reprint requests: J. Raymond Buncic, MD, FRCSC, The Hospital for Sick Children, Eye Clinic, 555 University Ave, Toronto, Ontario M5G 1X8. Copyright © 2003 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2003/$35.00 ⫹ 0 doi:10.1016/S1091-8531(02)42005-8
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lissencephaly may occur with migrational insults as early as 6 weeks’ gestation.19 This results in a spectrum of surface architecture changes ranging from complete agyria to a combination of pachygyria and polymicrogyria, the combinations of which determine clinical subtyping.16 The cerebellum usually appears normal except in subtypes with vermis hypoplasia.13,20 Some subtypes may exhibit agenesis of the corpus callosum.13 There is usually an inversion of the normal grey–white matter ratio.21,22 The 5-year survival rate is 54% in those patients with complete or nearly complete agyria.23 The craniofacial appearance is generally normal, although bitemporal atrophy and moderate micrognathia may occur.24 Because the clinical picture is nonspecific, the diagnosis rests on the neuroradiological findings.24 An important variant of type 1 lissencephaly, the Miller-Dieker syndrome, was described by Miller7 in 1963 and Dieker et al25 in 1969. These mentally retarded children have characteristic facial dysmorphism, ie, high forehead, bitemporal atrophy, anteverted nostrils, a long philtrum with abnormal upper lip, micrognathia, and digital anomalies.24,26 Generally, they develop seizures in the first few months of life.27 Molecular genetic testing of patients with both Miller-Dieker syndrome and nonsyndromic classic lissencephaly may show microdeletion of 17p13.3.2,9,28,30 Cobblestone lissencephaly differs pathologically from type 1 in that the cortex is severely disorganized and unlayered, with extensive neuronal and glial ectopia in the leptomeninges. These changes may also be seen in the cerebellum.31 Macroscopically, the brain surface is somewhat verrucous and often compared to Moroccan leather or a pebbled surface (Figure 3). The grey-to-white matter ratio is approximately 1:1. The border between grey and white matter is indistinct. The meninges are thickened and adherent to the cortex, resulting in obliteration of the Journal of AAPOS
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TABLE 1. Diagnostic types of lissencephaly Classical Lissencephaly (Type 1) Radiological features
Associated syndromes
Cobblestone Lissencephaly (Type 2)
● Cerebral cortex thickened ● Smooth surface with a “figure of 8” configuration ● Grey-to-white matter ratio 4:1 ● Brain stem and cerebellum usually normal
● Miller-Dieker syndrome (see text)
● Cerebral cortex thickened and severely disorganized ● Pebbled surface ● ● ● ●
Grey-to-white matter ratio 1:1 Brain stem and cerebellum involved Cerebellar vermis hypoplasia Abnormal appearance of the globes on imaging ● Walker-Warburg syndrome (see text) ● Muscle-eye-brain disease (congenital muscular dystrophy ⫹ high myopia, and retinal abnormalities) ● Fukuyama congenital muscular dystrophy (congenital muscular dystrophy and retinal abnormalities not required for diagnosis) ● Dobyns-Patton-Stratton syndrome (no congenital muscular dystrophy and “normal” eyes; see text)
FIG 1. Coronal section of the brain from patient with classical lissencephaly showing thickened cerebral cortex and smooth surface.
subarachnoid space with secondary hydrocephalus.22,32 The current diagnostic imaging criteria for cobblestone lissencephaly, seen in the congenital muscular dystrophies consist of mixed agyria; pachygyria and polymicrogyria with pebbled surface; abnormal white matter caused by dysmyelination; enlarged ventricles; and brain stem and cerebellar hypoplasia, particularly involving vermis (Figure 4). 22,31,32 Cobblestone lissencephaly may be associated with a variety of anterior and posterior segment ophthalmic abnormalities such as coloboma, Peter’s anomaly, persistent fetal vasculature, retinal dysplasia, retinal detachment, optic nerve coloboma, and optic nerve hypoplasia.33 Several
FIG 2. Classical lissencephaly. Axial cranial magnetic resonance imaging scan (TI ⫽ weighted) at the level of third ventricle showing “figure-of-8” configuration caused by underoperculization of the Sylvian fissures (arrow shows primitive fissure), smooth cortical surface, thick cortex and thin white matter.
syndromic associations, in particular the congenital muscular dystrophies, are described in Table 1. Walker-Warburg syndrome is the most common, with an estimated incidence of 0.21 case/10,000 live births.34 In the older literature it is also described as HARD⫹/⫺E: hydroceph-
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and 1998. Neuroimaging reports and inpatient diagnostic codes initially identified the cases for study. By way of review of computed tomography and MRI reports, 111 patients with severe cortical underdevelopment were identified according to brain phenotypes described in the literature.13,17,20,21,31 Of these, 83 films were available for review by our pediatric neuroradiologist (SIB). All but 1 of the reviewed patients underwent MRI. After the films were reviewed, 36 patients with lissencephaly were identified. Patients not examined by an ophthalmologist were excluded from study.
RESULTS
FIG 3. Cobblestone lissencephaly. Magnetic resonance imaging scan (T2-weighted) of brain showing pebbled cortical surface and typical ventricular dilatation in a patient with Walker-Warburg syndrome.
FIG 4. Magnetic resonance imaging (T1-weighted) scan showing vermis hypoplasia (arrow) in a patient with cobblestone lissencephaly. Increased signal of both globes may represents fluid accumulation secondary to retinal nonattachment.
alus, agyria, retinal dysplasia ⫾ encephalocele.35 Following is a review of our experience examining the eyes of patients with lissencephaly.
METHODS We conducted a retrospective study of clinical and neuroimaging records of all patients with lissencephaly diagnosed at The Hospital for Sick Children between 1968
Of the 36 patients, 31 (86%) had classic lissencephaly. Twelve of 25 (48%) with isolated lissencephaly and 3 of 6 (50%) with Miller-Dieker syndrome had been examined by an ophthalmologist. Five of the 36 patients (14%) had cobblestone lissencephaly. All 5 had Walker-Warburg syndrome and had been examined by an ophthalmologist. One case included in this study has been previously reported.2 The clinical data is summarized in Table 2. Patient age at the time of eye examination ranged from 2 days to 10.5 years (average, 1.64 years). Seven patients were male. Vision Because of young patient age and mental incapacity, it was not possible to carry out quantitative acuity tests, including Teller acuity. Vision was assessed in 10 of 12 patients with isolated classic lissencephaly. Visual evoked potentials (VEP) under monocular conditions—when tolerated— or binocularly conditions—when patients would not tolerate occlusion of one eye—were done in 7 of the 8 patients who could fix and follow and were present to flash and/or pattern stimuli in all. Two patients with responses to 120-minute and 480-minute check sizes had both optic nerve atrophy and hypoplasia (diagnosis based on the presence of small optic nerve head size with or without double ring). One patient (10%) showed responses only to flash stimuli despite ability to fix and follow and a normal fundus. This child had severe developmental delay, and we believe the poor result of VEP testing was related to cortical visual impairment. Of the 2 patients who could not fix and follow, 1 showed a positive response to optokinetic nystagmus–inducing stimuli. One had optic nerve atrophy, and the other had normal discs and maculae. Two patients (a 2-day-old and a 5-month-old) with isolated classic lissencephaly did not have a documented vision assessment. Of 3 patients with Miller-Dieker syndrome, 2 could fix and follow. Both had rotary nystagmus. During testing of the patient with no central, steady, maintained fixation, a seizure occurred, and further testing was abandoned. Only 1 of the 5 patients with cobblestone lissencephaly was able to fix and follow. His examination showed bilateral retinal colobomas. This child had severe developmen-
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TABLE 2. Ocular abnormalities Classical Lissencephaly (n ⴝ 12) Vision
VEP
Anterior segment
Fundus
Miller-Dieker Syndrome (n ⴝ 3)
CSM: 8 cases (80%)
CSM: 2 cases
CSM: 1 case
No CSM: 2 cases (20%)
No CSM: 1 case
Light perception: 1 case
CSM: Responses present up to check size stimulus of 60 minutes: 1 case
No CSM: 3 cases CSM: Responses present up to check size stimulus of 15 minutes: 1 case
Not documented: 2 cases CSM: Responses present up to check size stimulus of 15 minutes: 4 cases 120 minutes: 1 case 480 minutes: 1 case Response present only to flash: 1 case
Response present only to flash: 1 case
Not recorded: 4 case
Not recorded: 1 case
No CSM: Response present only to flash: 1 case
No CSM: Response present only to flash: 1 case
Normal
Peter’s anomaly OU: 1 case PFV OU: 1 case
Normal
Iris hypoplasia OU: 1 case Retinal nonattachment OU: 1 case Retinal nonattachment in one eye and retinal dysplasia in fellow eye: 1 case Retinal dysplasia with nonattached retina: 1 case Retinal dysplasia with nonattached retina and ON atrophy: 1 case Retinal coloboma in one eye and retinal colobome involving the disk in other: 1 case No strabismus: 5 cases
No CSM: Response present only to flash: 2 cases Normal
Optic nerve and macular hypoplasia: 4 cases (33%) optic atrophy: 2 cases (17%) normal: 6 cases
Strabismus
Cobblestone lissencephaly (WWS) (n ⴝ 5)
Exotropia (range 30 to 50 prism diopters): 6 cases (50%)
No strabismus: 3 cases
Esotropia (20 prism diopters): 1 case (8.3%) No strabismus: 5 cases Refraction
Average spherical error ⫹2.75 (range ⫹0.75 to ⫹4.25 D): 7 cases (58.3%)
hyperopia (OU ⫹ 1.50 D): 1 case
Average astigmatic error ⫹1.53 (range ⫹ 1.00 to ⫹2.50 D): 5 cases (41.6%) Anisometropia or myopia: none
Not done: 2 cases
Hyperopia ⫹ astigmatism (OD ⫹4.00⫹2.00 ⫻ 115° OS ⫹4.00⫹2.00 ⫻ 80°): 1 case
Not recorded: 4 cases Anisometropia or myopia: none
Abbrevation: WWS, Walker–Warburg syndrome; CSM, central, steady, maintained fixation for patients with strabismus refers to fixing eye; PFV, persistent fetal vasculature; ON, optic nerve; D, diopter; *Only 10 of 12 children with type 1 malformation had their vision assessed.
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tal delay and was unresponsive and lethargic. On his first visit at 2.5 months of age, he could not fix and follow but had recognizable, repeatable VEP with small amplitudes to bright flash stimuli under monocular viewing. Under binocular viewing, a repeatable response was found for the 240-minute check sizes, suggesting gross form perception. On subsequent visits he could fix and follow. VEP showed improvement at 1 year, and responses were present to 15-minute stimulus at 1.5 years of age. In another patient with retinal dysplasia in 1 eye and retinal nonattachment in the other, there was an avoidance response to bright light, indicating light perception, which was confirmed by flash VEP response. No patients showed substantial visual improvement on serial examinations. Anterior Segment Three of 5 patients with cobblestone lissencephaly had anterior segment anomalies. One patient had bilateral Peter’s anomaly, with corneal diameters of 8.75 mm. The second patient had bilateral persistent fetal vasculature with corneal diameters of 7.75 and 8.25 mm and bilateral cataracts. The third patient had iris hypoplasia with iris transillumination. The ocular abnormalities seen in our patients are summarized in Table 2.
DISCUSSION Ophthalmologic abnormalities have not been consistently recognized in patients with classic lissencephaly.22,24 Therefore, it is not surprising that only 15 of 31 patients (48.4%) identified in our study were referred to an ophthalmologist, whereas all patients with cobblestone lissencephaly had been referred for ophthalmic assessment. A review of the literature concerning patients with classic lissencephaly showed ocular abnormalities in 6 of 31 patients (19.3%), including no ocular fixation or tracking,23 poor visual tracking, nystagmus, variable esotropia, corneal clouding, oculomotor apraxia,36 abnormal irides, and tortuous fundal vessels,10 and delayed visual maturation.37 In our study, classic lissencephaly was associated with milder ocular abnormalities than was cobblestone lissencephaly. We found a higher incidence of ocular and visual abnormalities, however, in patients with classical lissencephaly than was previously reported.22 These included optic nerve and macular hypoplasia, optic nerve atrophy, refractive errors, and cortical visual impairment. Neither retinal nonattachment, retinal dysplasia, nor anterior segment anomalies were observed. The relatively high incidence of exotropia most likely reflects the more common occurrence of exotropia in developmentally delayed children. The rotary nystagmus found in both cases of MillerDieker syndrome was most likely either of central vestibular origin, or it may have been a type of congenital nystagmus. To some extent, our higher incidence figures might be explained by referral bias. Patients are often referred only if the primary care physician suspects or notes an ocular problem; both in the subjects we reviewed
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as well as subjects in other studies, no specific effort was made to conduct a full ocular examination in every patient. Many series in the literature have described syndromes that include both cobblestone lissencephaly and ocular abnormalities (Table 1).3,8,38 – 40 Many of the syndromes require retinal dysplasia as a diagnostic criterion. Dobyns and Truwit2 reported 40 patients with Walker-Warburg syndrome. They found microphthalmia in 15 of 16 patients (93.7%), retinal dysplasia in 10 of 23 (43.4%), optic nerve hypoplasia in 20 of 21 (95%), coloboma in 3 of 28 (10.7%) and anterior chamber abnormalities such as glaucoma in 13 of 26 (50%), angle abnormalities in 14 of 24 (58.3%), cataract in 16 of 28 (57.1%), pupil abnormalities in 14 of 24 (58.3%), and persistent hyperplastic primary vitreous in 12 of 15 (80%). Micropthalmos (n ⫽ 2), cataracts (n ⫽ 3) and retinal malformation (n ⫽ 3) were reported in 3 patients with Walker-Warburg syndrome. Nystagmus (n ⫽ 2), strabismus (n ⫽ 3), and mild myopia (n ⫽ 2) were reported in 3 patients with Dobyns-PattonStratton syndrome, often defined as cobblestone lissencephaly with “normal eyes.” All children with Walker-Warburg syndrome in our series of 5 patients had retinal abnormalities and 3 had anterior segment malformation. Given the small number of patients, we cannot compare our data with that of Dobyns and Truwitt.2 It is apparent from both studies, however, that anterior and posterior segment abnormalities are commonly found, and vision is often poor. Lissencephaly is a neuronal migration disorder.41 The gene implicated in type I lissencephaly with profound cerebellar hypoplasia is RELN mapped to 17q22,42 which manufactures the protein, reelin.43 This protein is believed to be involved in extracellular matrix signalling by involving the very–low-density lipoprotein and apolipoprotein E receptor-2 cell surface receptors and, in turn, the intracellular adaptor protein distabled-1 (Dab1) pathway, which activates tyrosine phosphorylation of Dab1.44 Phosphorylation of the microtubule-associated protein, Tau, is necessary for neuronal migration.45,46 Likewise, the LIS1 gene mapped to 17p13.3, which is mutated or deleted in 65% of classic type I lissencephaly47 and deleted in 93% of Miller-Dieker syndrome,9,29 is also believed to be involved with microtubule function via its role as a subunit in the brain lipid messenger platelet-activating factor acetylhydrolase 1B,48 its interaction with the microtubule motor cytoplasmic dynein in mice,49,50 and its association with the nuclear distribution gene F (NudF) because Nud proteins are known to be involved with microtubules. Xlinked dominant lissencephaly in male patients as well as and 20% of classic lissencephaly are caused by mutations in the DCX gene mapped to Xq22.3-q23,51 which manufactures doublecortin and is yet another protein that affects microtubule function.52,53 Dab1 was found to be normally expressed in a specific type of retinal amacrine cells and is expressed during the first postnatal week during the time at which amacrine
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cells extend neurites and form synaptic connections in the inner plexiform layer in the mouse retina. This raises the possibility that the reelin–Dab1 signaling pathway contributes to formation of intraretinal circuitry in the neural retina.54 This might explain the macular hypoplasia seen in 2 of our patients with classic lissencephaly. The genes for Walker-Warburg syndrome, muscleeye-brain disease (MEB), and Fukayama-type muscular dystrophy (FCMD) are unknown, although the latter two have been mapped to 1p32 and 9q31, respectively.55–57 There is some evidence to suggest that Walker-Warburg syndrome and FCMD might be genetically identical.58 An ancient retrotransposal insertion, 3 kb long, was reported to cause FCMD.59 Mutations in the POMGnT1 gene, which catalyzes the second glycosyl transfer step in the biosynthesis of mammalian O-mannosyl glycans, were recently shown to be the primary genetic defect in MEB.60 It is more difficult to explain the ocular abnormalities seen in cobblestone lissencephaly until the genes have been characterized.
CONCLUSION Of 20 patients with lissencephaly seen by an ophthalmologist, only 1 had an normal ocular examination. Sixty seven percent of patients with type 1 lissencephaly had ocular abnormalities, contrasting with the 100% anomaly rate in type 2 disease. These children have a spectrum of visual ability ranging from light perception to moderate form vision. Cobblestone lissencephaly is more commonly associated with severe anomalies of the anterior and posterior segment. Anterior segment disease occurred only in type 2 lissencephaly. We recommend full eye examination of all children with lissencephaly. Nota bene: While the present article was in press, a paper was published that is relevant to the pathogenesis of WWS, MEB, and FCMD61. The article illustrates that mutations in the POMT1 gene cause some cases of WWS. The gene encodes the enzyme O-mannosyltransferase 1, which catalyzes the addition of the first of 4 residues of O-mannosyl glycan. Loss-of-function on target proteins in the eye may be secondary to defective glycosylation of proteins yet unknown. POMGnT1, the MEB gene product,60 adds the second residue, an N-acetylglucosamine. The function of the Fukutin is unknown, but it has been hypothesized also to be a glyucosyltransferase.62,63 Hypoglycosylated ␣-dystroglycan, an extracellular matrix O-glycan, crucial for the correct contraction of muscle, causes muscular dystrophy. The observation in muscle tissue from patients with mutations in POMGnT1, and FCMD of hypoglycosylation of ␣-dystroglycan indicates the implication of a common glycan synthesis disorder. Other possible O-mannosylation targets may include diffusible brain development factors, reelin, a glycoprotein, mentioned earlier in our discussion, and tenascin-J1, which shows repellent activity on neurite extension in neuroblast culture.64 These observations suggest an important role of glycosylation in neural migration. The authors thank Dr Venita Jay for providing the photograph of smooth brain with lissencephaly and Dr Carol Westall for her contri-
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