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Ophthalmological Features Associated with COL4A1 Mutations

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Ophthalmological Features Associated with COL4A1 Mutations OPHTHALMIC MOLECULAR GENETICS SECTION EDITOR: JANEY L. WIGGS, MD, PhD Ophthalmological Features Associated With COL4A1 Mutations Isabelle Coupry, PhD; Igor Sibon, MD, PhD; Bruno Mortemousque, MD; Franc¸ois Rouanet, MD; Manuele Mine, PharmD, PhD; Cyril Goizet, MD, PhD Objective: To investigate the wide variability of ocular Conclusions: The COL4A1 mutations may be associ- manifestations associated with mutations in the COL4A1 ated with various ophthalmologic developmental anoma- gene that encodes collagen IV␣1. lies of anterior segment dysgenesis type, which are reminiscent of Axenfeld-Rieger anomalies (ARA). Cere- Methods: We clinically evaluated 7 patients from 2 un- brovascular disorders should be added to the list of signs related families in whom ocular features segregated with potentially associated with ARA. COL4A1 mutations that were identified by direct se- quencing. Clinical Relevance: These data suggest that cerebral magnetic resonance imaging may be recommended in Results: The G2159A transition (c.2159GϾA) that leads the clinical treatment of patients with apparently iso- tothemissensemutationp.Gly720Aspwasidentifiedinfam- lated ARA, even when neurological symptoms or signs ily A. An ocular phenotype of variable severity was observed are lacking. in all affected relatives. The missense mutation c.2263GϾA, p.Gly755Arg was identified in family B. One patient from family B also displayed notable ocular features. Arch Ophthalmol. 2010;128(4):483-489 NEW FORM OF HEREDITARY constellation of ocular findings that in- cerebrovascular disorder clude anomalies of the anterior chamber was recently associated angle and aqueous drainage structures (iri- with mutations in the dogoniodysgenesis), iris hypoplasia, ec- COL4A1 gene that en- centric pupil (corectopia), iris tears (poly- Acodes collagen IV␣1.1,2 Mutations in coria), and iridocorneal adhesions COL4A1 were initially associated with ce- traversing the anterior chamber. These rebral microangiopathy (OMIM 607595) anomalies are frequently associated with and familial porencephaly (OMIM a posterior embryotoxon and confer a high 175780).1-4 The clinical spectrum of risk of blindness due to glaucoma.9,10 Author Affiliations: Laboratoire COL4A1 mutations has progressively When extraocular developmental ab- de Ge´ne´tique Humaine, enlarged in humans as well as mice, normalities that affect the teeth, facial Universite´ Victor Segalen with evidence of neonatal and adult bones, and periumbilical skin are associ- Bordeaux 2, Universite´ intracerebral hemorrhages, aneurysms, ated with ARA, the disorder is named Ax- Bordeaux 2, Bordeaux (Drs Coupry and Goizet); ocular manifestations of variable type, enfeld-Rieger or Rieger syndrome (ARS). 3,5-8 Fe´de´ration des Neurosciences and nephropathy. Patients with ARS may also display hypo- Cliniques (Drs Sibon, Rouanet, Associated ocular features were reti- spadias and, more rarely, hydrocephalus, and Goizet), Service nal arteriolar tortuosity with prominent en- hearing loss, cardiac and kidney abnor- d’ophtalmologie largement of perivascular spaces5 and cata- malities, and congenital hip dislocation (Dr Mortemousque), and ract noted in 3 patients with hereditary anomalies. Other syndromic forms of ARA Service de Ge´ne´tique Me´dicale porencephaly and adult stroke.3 Our group have been rarely described with addi- (Dr Goizet), Hoˆpital Pellegrin, previously described another family with tional cardiac malformations, sensorineu- Universite´ Bordeaux 2, CHU ocular anterior segment dysgenesis (ASD) ral hearing loss, oculodentodigital dyspla- Bordeaux, Bordeaux; AP-HP, and small-vessel disease of the brain.6 An- sia syndrome, and severe craniosynostosis Laboratoire de Ge´ne´tique 11-14 Mole´culaire, hoˆpital terior segment dysgenesis represents a syndrome. Lariboisière, Paris (Dr Mine); clinically and genetically heterogeneous We present here ocular features asso- INSERM UMR-S 740, Paris, group of disorders.9 The diagnosis of Ax- ciated with COL4A1 mutations in 2 unre- France (Dr Mine). enfeld-Rieger anomaly (ARA) refers to a lated families. (REPRINTED) ARCH OPHTHALMOL / VOL 128 (NO. 4), APR 2010 WWW.ARCHOPHTHALMOL.COM 483 ©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Table 1. Ophthalmological Features in 2 Families With COL4A1 Mutation Patient Family A Family B Ophthalmological Signs A.I.1 A.II.1 A.II.2 A.II.3 A.III.1 B.I.1 B.II.1 Corneal opacities − ϩϩ −−−− Corneal neovascularization − − ϩ −−−− Irido-corneal synechiae ϩ − ϩ −−−− Congenital cataract ϩϩϩϩϩϩ/− ϩ Iris anomalies ϩϩϩϩϩ − ϩ Microcornea ϩϩϩϩϩ − ϩ High IOP ϩϩϩ −−−− Glaucoma . − ϩ −−−− Optic nerve morphology PA N E NNNN Myopia ϩϩϩ −−−− Retinal detachment − ϩϩ −−−− Macular hemorrhages ϩ −−−−−− Abbreviations: E, excavation; ellipses, not interpretable; IOP, intraocular pressure; N, normal; PA, peripapillary atrophy; ϩ, present, −, absent. REPORT OF A CASE Patient A.III.1 was the 8-year-old girl daughter of the proband. At birth, malformations of the eyes were obvi- A detailed description of the personal medical histories ous including a bilateral congenital cataract, iris hypo- and associated neurological phenotypes of family A has plasia, and microcornea (Figure 1C) without congenital been previously published.6 glaucoma. Infantile hemiparesis was noted during the neonatal period.6 At 8 years of age, she presented with FAMILY A strabismus and slight amblyopia of the left eye. Fundus examination did not show optic disc anomalies, retinal The main ocular findings observed in this family are sum- arteriolar tortuosity, or any retinal hemorrhage or exu- marized in Table 1. The G2159A transition (c.2159GϾA) dates. Findings of IOP measurement were normal. leading to the substitution of a glycine by aspartic acid Fluorescein angiography showed no abnormality; the at position 720 (p.Gly720Asp) was identified by direct arteriolar caliber was normal, and there was no leakage sequencing in COL4A1 in all of the affected relatives.6 We of fluorescein or capillary dropout. Neurological exami- have obtained complementary data on the ophthalmo- nation revealed spastic hemiparesis in the right eye with logical history of these relatives and reexamination of the a porencephalic cavity and a diffuse periventricular leu- index case. koencephalopathy on MRI in the left eye (Figure 2C). Patient A.II.1, the index case, was a 38-year-old woman Patient A.I.1 was the 58-year-old mother of the pro- born after uneventful pregnancy and delivery. A bilateral band. She had bilateral iridogoniodysgenesis with irido- congenital cataract with iris hypoplasia was discovered early corneal synechiae, iris hypoplasia, microcornea in life. This bilateral cataract was surgically treated at 12 (Figure 1D), congenital cataract surgery at 55 years of years of age by anterior phakophagia without intraocular age, and high myopia with retinal complications repre- lens implantation. Bilateral aphakia and myopia were cor- sented by bilateral macular hemorrhages. Fundus ex- rected by contact lens use. Her ophthalmological history amination showed peripapillary atrophy, choroidal at- indicated a surgically treated right retinal detachment and rophy, and scars of macular hemorrhages (Fuchs spots) high intraocular pressure (IOP) treated with hypotensive but no arterial tortuosity. Bilateral high IOP was discov- eye drops since 23 years of age. Later, treatment by latano- ered (26 mm Hg) and efficiently treated with hypoten- prost reduced IOP to 16 mm Hg in both eyes (reference sive eye drops. Findings of neurological examination were value, Ͻ21 mm Hg). At 35 years of age, ophthalmological normal. A marked periventricular leukoencephalopa- examination found bilaterally decreased visual acuity pre- thy was obvious on brain MRI (Figure 2B). dominating in the left eye as a consequence of severe am- Patient A.II.2 was the 35-year-old brother of the pro- blyopia. Bilateral microcorneal and peripheral corneal band. His major ophthalmological history included bi- opacities were present with corectopia (Figure 1, A and lateral microcornea, high myopia, congenital cataract, B). Fundus examination showed normal optic discs with- and juvenile glaucoma. The cataract was operated on out retinal hemorrhages or arteriolar tortuosity. The vi- during childhood, with occurrence of bilateral aphakia sual field appeared normal in the right eye and unavail- and severe left amblyopia. At 32 years of age, his IOP able in the left, considering the low visual acuity. She had was 23 to 24 mm Hg bilaterally; the patient was treated a cerebral small deep infarct at 35 years of age. Neuro- with a combination of 3 hypotensive eye drops in the logical examination revealed right spastic hemiparesis and left eye, and he had undergone glaucoma surgery in the a right central facial palsy. Brain magnetic resonance right eye. Ophthalmologic examination showed bilat- imaging (MRI) showed diffuse periventricular leukoen- eral microcornea, central and peripheral corneal opaci- cephalopathy (Figure 2A). ties with corneal neovascularization and iridocorneal (REPRINTED) ARCH OPHTHALMOL / VOL 128 (NO. 4), APR 2010 WWW.ARCHOPHTHALMOL.COM 484 ©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 A D B E C F Figure 1. Ophthalmological features observed in family A. The glance of case A.II.1 is characterized by bilateral microcornea (A) and a postsurgical (congenital cataract) corectopia (B). C, The right eye of case A.III.1 presents microcornea (arrow);
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