Associated Ophthalmic Findings with Lissencephaly
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Disease Entity
From the Greek “lissos” meaning smooth and “encephalus” meaning brain, Lissencephaly is a disorder of neuronal migration in the brain during embryologic development which either results in a lack of brain gyri (“agyri”), producing the characteristic smooth surface to the Lissencephalic brain; or it results in an overabundance of gyri (“pachygyri”), producing a cobblestone appearance. Although there have been reports of Lissencephaly being caused by either viral infection in the first trimester[1] or a lack of fetal brain blood flow. Lissencephaly is predominately a genetic disorder.[2][3] In general, Lissencephaly is frequently associated with a number of systemic manifestations such as microcephaly, seizures, unusual facies, limb deformities, failure to thrive, psychomotor retardation and infant death. Ophthalmic manifestations are often associated with Lissencephaly, being more severe and common in Type 2 (Cobblestone) Lissencephaly[4]
Classification
Based on phenotypic appearance, Lissencephaly is usually divided into type 1 and type 2 with some entities not fitting into either category; however, as more genetic links are made, Lissencephaly is now being more appropriately classified by genetic cause.[2][3]
Lissencephaly is a rare disease with few studies investigating the rates of ophthalmic manifestations, but one study from Nabi et al.[4] did specifically investigate the ophthalmic findings of twenty patients with either type 1 or type 2 Lissencephaly. Ocular findings in type 2 Lissencephaly tend to be more common and severe than in type 1 Lissencephaly.
Type 1 (Classic) Lissencephaly
This aptly named classic form of Lissencephaly, in which the majority of the brain is smooth, is the most common form of Lissencephaly, and is caused by neuronal under-migration during development.[5] Type I Isolated Lissencephaly is characteristically associated with a mutation of the gene LIS1 which is the most well-described genetic cause, but several other mutations in other genes can produce this disease as well.
According to the study by Nabi et al.[4] ophthalmic findings associated with Type 1 Lissencephaly include abnormal VEP responses, cortical blindness, optic nerve hypoplasia, macular hypoplasia, optic atrophy and eso or exotropia. Nabi et al.[4] extrapolated that a higher incidence of strabismus in this population likely reflects the higher incidence of strabismus in developmentally delayed children.
Miller-Dieker Syndrome
Another disease entity associated with LIS1 mutation and a mutated gene critical for normal facial development, Miller-Dieker Syndrome, is characterized by intellectual disability, a characteristic facial dysmorphism consisting of macrocephaly, a high forehead, bitemporal atrophy, anteverted nostrils, a long philtrum with an abnormal upper lip, and micrognathia. [6][7][8] There has also been reported association with congenital heart defects and omphaloceles. [9]
On eye exam, these patients may present with microcornea and ptosis. [8]
Type 2 (Cobblestone) Lissencephaly
Type 2 Lissencephaly is caused by neuronal over-migration during development. Although sulci are present in Type 2, they are reduced in size, giving the brain a cobblestone appearance. Type 2 is mostly strongly associated with three similar congenital muscular dystrophies (CMD) which all tend to occur with ophthalmic manifestations such as coloboma, iris hypoplasia, Peter’s anomaly, PFV/PHPV, retinal dysplasia/malformation with or without detachment, optic nerve coloboma, and optic nerve hypoplasia.[4][10][11]
Walker-Warburg Syndrome (WWS)
This syndrome is the most common of the three related muscular dystrophies. Unfortunately, children with this disease often do not survive beyond age 3. [12] Associated systemic findings include cerebellar malformations and posterior encephaloceles, congenital hydrocephalus and ventricular dilation, profound intellectual disability, cleft lip and palate, small testes and cryptorchidism, and imperforate anus.[2][13][14][15]
In addition to being the most common of the three CMDs, WWS has a higher incidence of ophthalmic abnormalities. Dobyns and Truwit[11] studied 40 patients with WWS and their reported ophthalmic findings include:
- Optic nerve hypoplasia (95%)
- Microphthalmia (94%)
- PHPV (80%)
- Abnormal anterior chamber angle (58%)
- Abnormal pupils (58%)
- Cataracts (57%)
- Glaucoma (50%)
- Retinal dysplasia (43%)
- Coloboma (11%)
Additional reported ocular findings include microcornea, corneal opacities, retinal gliosis, failure of retinal development, and “leopard spot” peripheral retinopathy.[14][16]
Fukuyama Congenital Muscular Dystrophy (FCMD)
This syndrome is predominantly seen in patients of Japanese ancestry. It is similar to WWS, but generally less severe phenotypically. Symptoms include severe intellectual disability, microcephaly, seizures, slowly progressive muscle wasting with weakness and increased CK, and possible calf pseudohypertrophy. Progressive hydrocephalus is rare and no cephaloceles have been reported.[14] Steroid therapy has been shown to improve motor functions of advanced stage FCMD patients. [17]
Eye findings in FCDM are rarer than those seen in WWS but include optic pallor, cataracts and retinal mottling/vascular changes.[14]
Muscle-Eye-Brain (MEB) Disease
MEB Disease is classically seen in people of Finnish descent. Systemic phenotypic findings can vary greatly but include neonatal hypotonia, moderate to severe weakness, severe intellectual disability, and seizures.[14][18][19]
Eye findings include juvenile cataracts, progressive myopia, retinal detachments, retinal atrophy, optic nerve hypoplasia and/or atrophy, strabismus, and congenital glaucoma.[14][18][20]
References
- ↑ Joseph LD, Pushpalatha, Kuruvilla S. "Cytomegalovirus infection with lissencephaly." Indian J Pathol Microbiol. 2008 Jul-Sep;51(3):402-4
- ↑ 2.0 2.1 2.2 Forman MS, Squier W, Dobyns WB, Golden JA. "Genotypically defined lissencephalies show distinct pathologies." J Neuropathol Exp Neurol. Oct 2008;64(10): 847–57.
- ↑ 3.0 3.1 Devisme L, Bouchet C, Gonzales M, et al. “Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies.” Brain. 2012;135:469–482.
- ↑ 4.0 4.1 4.2 4.3 4.4 Nabi NU, Mezer E, Blaser SI, Levin AA, Buncic JR. “Ocular findings in lissencephaly.” J AAPOS. June 2003;3(3):178-184.
- ↑ de Rijk-van Andel JF, Arts WF, Hofman A, Staal A, Niermeijer MF. “Epidemiology of lissencephaly type I.” Neuroepidemiology. 1991;10:200-4.
- ↑ 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.
- ↑ Guerrini R, Filippi T. “Neuronal migration disorders, genetics, and epileptogenesis.” J Child Neurol. 2005;20:287-99.
- ↑ 8.0 8.1 Baker EK, Brewer CJ, Ferreira L, Schapiro M, Tenney J, Wied HM, Kline-Fath BM, Smolarek TA, Weaver KN, Hopkin RJ. Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome. Am J Med Genet A. 2023 Feb;191(2):526-539. doi: 10.1002/ajmg.a.63057. Epub 2022 Nov 25. PMID: 36433683; PMCID: PMC10099970.
- ↑ Cera AJ, Mokha S, Sunderji S, Cortez D, Bautista GM. Acute Bowel Ischemia in a Premature Neonate with Miller-Dieker Syndrome and Anomalous Right Coronary Artery From the Pulmonary Artery. Pediatr Ann. 2023 Aug;52(8):e283-e291. doi: 10.3928/19382359-20230613-02. Epub 2023 Aug 1. PMID: 37561828; PMCID: PMC10878796.
- ↑ Rodgers BL,Vanner LV, Pai GS, Sens MA. “Walker-Warburg syndrome: report of three affected sibs.” Am J Med Genet. 1994;49:198- 201.
- ↑ 11.0 11.1 Dobyns WB, Truwit CL. “Lissencephaly and other malformations of cortical development: 1995 update.” Neuropediatrics. 1995;26:132-4.
- ↑ Aref F, Shaaban A, Ahmed A, Gubari M, Hassan J, Alharbi M, Alsubhi K, Alsalhi K, Albalawi S, Ali M, Ali H, Filfilan N, Shmailah E, Ahmed A. Walker-Warburg syndrome: A case report of congenital muscular dystrophy with hydrocephalus. Radiol Case Rep. 2024 Aug 20;19(11):5063-5065. doi: 10.1016/j.radcr.2024.07.149. PMID: 39253050; PMCID: PMC11381981.
- ↑ Martinez-Lage JF, Garcia Santos JM, Poza M, Puche A, et al. “Neurosurgical management of Walker-Warburg syndrome.” Childs Nerv Syst. 1995;11:145-53.
- ↑ 14.0 14.1 14.2 14.3 14.4 14.5 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.
- ↑ Shi Y, Fu Y, Tao Z, Yong W, Peng H, Jian W, Chen G, Guo M, Zhao Y, Yao R, Guo D. A novel pathogenic deletion in ISPD causes Walker-Warburg syndrome in a Chinese family. Genes Genomics. 2023 Mar;45(3):359-365. doi: 10.1007/s13258-022-01296-z. Epub 2022 Aug 11. PMID: 35951155.
- ↑ Sukhija J, Isher HK, Kaur S, Korla S, Kaur A, Raj S. Ocular presentation of Walker-Warburg syndrome with POM2 mutation. Indian J Ophthalmol. 2022 Jul;70(7):2626-2627. doi: 10.4103/ijo.IJO_2128_21. PMID: 35791178; PMCID: PMC9426142.
- ↑ Murakami T, Sato T, Adachi M, Ishiguro K, Shichiji M, Tachimori H, Nagata S, Ishigaki K. Efficacy of steroid therapy for Fukuyama congenital muscular dystrophy. Sci Rep. 2021 Dec 20;11(1):24229. doi: 10.1038/s41598-021-03781-z. Erratum in: Sci Rep. 2022 Aug 2;12(1):13263. doi: 10.1038/s41598-022-17588-z. PMID: 34930981; PMCID: PMC8688455.
- ↑ 18.0 18.1 Yis, Uyanik, Rosendahl, et al. “Clinical, Radiological, and Genetic Survey of Patients With Muscle-Eye-Brain Disease Caused by Mutations in POMGNT1.” Pediatric Neurology. 2014;50:491-497.
- ↑ Godfrey C, Clement E, Mein R, et al. “Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan.” Brain. 2007;130:2725-2735.
- ↑ Godfrey C, Clement E, Mein R, Brockington M, Smith J, Talim B, Straub V, Robb S, Quinlivan R, Feng L, Jimenez-Mallebrera C, Mercuri E, Manzur AY, Kinali M, Torelli S, Brown SC, Sewry CA, Bushby K, Topaloglu H, North K, Abbs S, Muntoni F. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain. 2007 Oct;130(Pt 10):2725-35. doi: 10.1093/brain/awm212. Epub 2007 Sep 18. PMID: 17878207.
