Mar. 29, 2022
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This article includes discussion of Norrie disease, atrophia bulborum hereditaria, Episkopi blindness, hereditary oculo-acoustic-cerebral degeneration, oculo-acousticocerebral degeneration, persistent hyperplastic primary vitreous, pseudoglioma, and X-linked familial exudative vitreoretinopathy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Norrie disease is a rare, congenital X-linked recessive disorder of the eyes, particularly the retina of affected males, resulting in congenital blindness or progressive visual loss through childhood. Mutations in the NDP gene and absence of the NDP protein norrin are associated with altered development of retinal vasculature. Additional complications are sensorineural deafness, intellectual deficits, and psychosis or other behavioral problems. Information continues to be gained concerning the clinical variability, genetics, and pathogenetic mechanisms of this disease. Vitrectomy with or without lensectomy has benefited some patients.
• Norrie disease is a rare, congenital X-linked recessive disorder of the eyes, particularly the retina, of affected males, resulting in congenital blindness or progressive visual loss through childhood.
• Mutations in the NDP gene and absence of the NDP protein norrin are associated with altered development of retinal vasculature. Information continues to be gained concerning the phenotypic variability, genetics, and pathogenetic mechanisms of this disease.
• Additional complications are sensorineural deafness, seizures, intellectual deficits, autism, and psychosis or other behavioral problems. Other anomalies, particularly involving the CNS, have been reported.
• Vitrectomy with or without lensectomy has benefited some patients.
In 1961 Warburg identified 7 patients from 7 generations of a Danish family as well as an additional 48 patients from 9 families described in the literature; she suggested the name Norrie disease, to reflect Norrie's earlier publication in 1933 (63; 106). The term “Episkopi blindness” derived from a study of a large Greek family (16 males in 5 generations) in Episkopi, Cyprus (98). Some early cases were labeled “pseudotumors” or “pseudoglioma,” but these are nonspecific terms reserved for conditions resembling retinoblastoma and are no longer considered appropriate diagnoses for this condition (67). Two conditions (persistent hyperplastic primary vitreous and familial exudative vitreoretinopathy) are part of the spectrum of Norrie disease. Berger and colleagues and Chen and colleagues isolated a candidate gene for Norrie disease (06; 14). In the following years, the NDP gene and a variety of mutations have been identified as causative (116; 70).
Norrie disease is a congenital X-linked recessive disorder involving the eyes, particularly the retina, of affected males and resulting in congenital blindness or progressive visual loss through childhood. A patient's condition can be placed within the spectrum of Norrie disease if several findings are identified: normal size of eye at birth, normal anterior chamber, clear lenses, additional (bilateral) changes including fibrovascular alterations of retina and vitreous characterized by hemorrhage, and membrane formation or attachment to retina (90). At least one-third of patients have sensorineural deafness and one-half have intellectual deficits, which appear after 3 years and is sometimes complicated by psychosis or other abnormal behavior (68; 90). Patients may manifest depression (2%), anxiety (6%), attention difficulties (8%), labile affect (25%), or autism (27%) (94). Infantile spasms (EEG-demonstrated hypsarrhythmia) have been noted in a profoundly retarded male with congenital blindness (51). The disease is clinically heterogeneous; however, presentations may vary, even within families (116).
The eyes may be normal at birth but within a few months develop a variety of fibrous and vascular changes. These changes range in severity from masses involving the retina, and resulting in complete loss of vision to less severe fibrotic stalks extending from the optic disc to the lens (persistent hyperplastic primary vitreous), or retinal vascular changes with or without fibrosis (familial exudative vitreoretinopathy). The combination of dense stalks, globular dystrophy, and peripheral avascularity of the retina, accompanied by pigmentary changes, may be pathognomonic for Norrie disease (22). By about 10 years, eyes are end-stage and shrunken (phthisis bulbis), with milky corneas, shallow anterior chambers, opaque corneas, leukocoria, dilated pupils with no light reflex, and hypoplastic irides with posterior synechiae. These changes need not develop late, however, and the finding of leukocoria with microphthalmia in early infancy can lead to a diagnosis of Norrie disease (72). Glaucoma can occur secondary to shape changes that produce increased intraocular pressure. Rarely, carrier females and even noncarrier females have ocular changes (retinal detachment or abnormal peripheral retinal vasculature, phthisis bulbi; dragged maculae) or loss of vision (12; 91; 57; 112; 52). Explanations for this occurrence in females include X inactivation or other adverse effects of the mutant allele on the retina during early development.
Additional extraocular changes are recognized, though incompletely. Central nervous dysfunction with seizures, growth retardation, and immunodeficiency become apparent in later stages in about one-third of cases (08). Because norrin is important to angiogenesis, a number of defects in the vascular system may occur, including peripheral vascular disease (ie, varicose veins, venous stasis ulcers, and erectile dysfunction) (94). Cerebroretinal microangiopathy is associated with calcifications and cysts involving terminal arteriolar zones (eg, basal ganglia) and deep gray nuclei (81). Chronic seizures occur in about 10% of patients (94) and may be refractory (09). In 1 study, epilepsy developed from discharges in the occipital areas of 3 brothers (66).
Hearing loss can progress subtly and does not seem to affect speech. The inner ear (cochlea) appears to be involved, and retrocochlear and brain auditory system function is normal. One study of the inner ears of a 77-year-old patient revealed marked atrophy of the stria vascularis, severe degeneration of hair cells and cochlear neurons, and connective tissue proliferation in the spiral ganglion, osseous spiral lamina, and walls of the membranous vestibular labyrinth (61). In a mouse model for Norrie disease, the primary change was abnormal or decreased vessels of the stria vascularis, in which the cochlear vasculature is located (77).
If deletions of the Norrie disease gene involve adjacent monoamine oxidase genes (MAOA, MAOB), phenotypic and physiologic changes are more severe, including hypogonadism, hypertensive crises, disorganized REM sleep, myoclonus or other involuntary movements, and variable degrees of intellectual deficits (17; 102; 96). Additional anomalies associated with these deletions continue to be uncovered, including short stature, hypotonia, and autism (84).
In severe Norrie disease, visual impairment is congenital, complete or progressive, and irreversible. For patients with Norrie disease and persistent fetal vasculature syndrome, early vitrectomy has been performed, with or without lensectomy, with maintenance or restoration of light perception vision in a majority of cases; most patients experienced no phthisis bulbi postoperatively (103; 104). In less severe forms, vision may be mildly impaired or even normal. Deafness and intellectual deficits are complications in some 50% of cases (78). Hearing loss is bilateral and progressive but responsive to hearing aids; with care, preservation of word recognition is possible (33). The less severe form of the condition may be progressive and treatable. Growth retardation, epilepsy, and behavioral and sleep disturbances are other complications (69; 68; 112). One patient with Norrie disease, complicated by paroxysms of deafness, slurred speech and somnolence, was successfully treated with beta blockers (44). Pancreatic exocrine insufficiency and microvillus inclusion disease have been observed in 1 newborn male (71). One affected adult has been reported with chronic peripheral venous insufficiency, requiring surgery for varicose veins (58). Two patients with microdeletions in the NDP region have been diagnosed with pulmonary hypertension or progressive, eventually fatal dyspnea (95). Parental counseling, with a goal of combating depression, may help improve the long-term developmental outlook of patients (29).
Because Norrie disease is X-linked recessive, affected males inherit the disorder from carrier mothers or acquire it sporadically through a new mutation in the Norrie disease gene, NDP (“Norrie Disease Pseudoglioma”), located at Xp11.4-p11.3 (13). Affected males transmit the (recessive) mutation via the X chromosome, thus affecting their daughters but not their sons. Carrier females have a 50% chance of transmitting the mutation to either male or female children (the former will have Norrie disease, and the latter will be carriers). Four loci have been named EVR1 to EVR4, and mapped to 11p, 11q, and Xp (100). It is likely other loci exist as well (45). To date, a number of variants of 2 genes (LRP5 and FZD4) have been found to cause familial exudative vitreoretinopathy (62); FZD4 may be mutated in some cases of both unilateral and bilateral forms of persistent hyperplastic primary vitreous as well (86). High levels of aqueous VEGF-A in 1 enucleated eye with retinal dysplasia consistent with Norrie disease suggest this cytokine may be involved in pathogenesis as well (42). The mutational spectrum of Norrie disease continues to be expanded and can be suggestive of a founder effect (73). Contiguous deletions involving NDP give rise to diverse findings, depending upon the exact nature of the deletion (43).
At least 3 major phenotypic varieties of Norrie disease are distinguished (90). In the classic and most severe form, gray-yellow masses of fibrovascular tissue replace the retina; these have sometimes been described as pseudotumors or pseudoglioma. This change is associated with severe or total loss of vision. With time, a variety of additional changes may occur, including formation of cataracts or synechiae, opacified cornea, atrophic iris, altered shape of globe or individual chambers, or band keratopathy. In persistent hyperplastic primary vitreous, a fibrotic white stalk containing hyaloid vessels connects the optic disc and posterior lens capsule; the lens is variably opacified and the retina variably folded or detached. This change is apparent at birth, and the extent of progression is unknown; the degree of visual loss is variable. An apparently rare, novel nonsense mutation of the Norrie disease gene has been identified in 1 family with 2 sons affected by persistent hyperplastic primary vitreous (34). Familial exudative vitreoretinopathy is manifested by peripheral zones of retinal avascularity, sometimes with retinal folds, which can cause dragging and displacement of the macula (macular ectopia), or fibrous tissue bands, which are apparent at birth. These changes are associated with normal or reduced vision and can progress throughout the first 2 decades of life, causing eventual retinal detachment. Neonatal retinal folds and/or vitreoretinal traction can be signs of Norrie disease or other retinopathy (18). Retinal detachment may also occur in fetal life or infancy (108; 27). The term “exudative” derives from the exudation of serous fluid from capillaries in the (abnormal) retinal vasculature. Microscopically, the retina appears immature and dysplastic, with little or no normal structure; the retinal vasculature is underdeveloped as well (24; 101). These changes are thought to arise early in development, possibly from changes in cells of the inner optic cup wall (68).
Defects in the Wnt signaling pathway are found in patients with familial exudative vitreoretinopathy and Norrie disease (107; 38). The Wnt pathway plays multiple roles in embryonic development, including regulation of ocular growth and development (49; 35). The exact pathogenesis is complex and continues to be elucidated. The NDP protein (norrin) binds to at least 3 proteins and serves as an antagonist to BMP as well as activating the Wnt pathway (19). Norrin also has a function in progenitor proliferation in the retina that is independent of its function in the developing vasculature of the retina (56). A further complication is that the same mutation may be responsible for different phenotypes (78). Regardless, vascularization is abnormal in the peripheral retina of all forms of Norrie disease (88) and norrin, the protein product of NDP, appears to be part of a signaling system important to vascular development in the eye and ear (110). It has been suggested that aberrations in normal apoptosis play a role (86) and that the proliferation of endothelial cells in the retinal vascular plexus is reduced (117). The endothelial cell-specific protein PLVAP (plasmalemma vesicle-associated protein) is involved in vascular permeability, leukocyte migration, and angiogenesis; it is upregulated in Norrie disease and thus may be a target for future therapy (30).
Norrin is also important to extraocular angiogenesis (76; 58; 115). Homologies with known proteins and other modeling data suggest that mutations also alter the regulation of cell interaction, differentiation, or proliferation (11; 05). In approximately 70% of patients, single base pair changes are found; in about 24%, partial or complete deletions are identified. More than 100 sequence variations, including intragenic deletions, nucleotide substitutions, or splicing variants, cause the disease (83; 58). Most are unique and confined to single patients and families. Phenotypes can vary among family members carrying the same mutation or be misdiagnosed, given the wide variation in allelic variants. It has been suggested that milder mutations in the Norrie disease gene are associated with less severe retinal disease, or that deletions may be associated with more severe forms (46; 79). Certain mutations result in significant phenotypic heterogeneity (01). This latter observation suggests that phenotypic definitions of Norrie disease variants may not be the most appropriate nomenclature.
A mouse knockout model will be helpful in understanding disease progression (50). In the model, numerous photoreceptor cell-specific gene transcripts are absent or down-regulated in older (ie, 2 years), but not younger (ie, 1 year), animals. Without the Norrie disease gene product, photoreceptor cells cannot survive in this model. Such animals manifest a failure of retinal angiogenesis, with lack of deep capillary layers of the retina and blindness (64). This has been confirmed in studies, wherein the role of norrin in retinal vascular development continues to be elucidated (85). The gene product also influences the regression of hyaloid vessels that otherwise are a component of retrolental membranes in knockout mice (65). Vessel density (but not cell number) is also reduced in the cerebellum of knockout mice (55). It seems that reproductive tissues can also be affected, for female mice homozygous for the Norrie disease pseudoglioma homolog (Ndph) are almost uniformly infertile; heterozygous females and hemizygous males are not (54). The role of hypoxia and reduced induction of vascular endothelial growth factor (VEGF) on retinal vascularity has been investigated in one experimental model (74).
The disease is rare, with 150 to 200 cases reported. In 1 study of 109 pediatric patients with vitreoretinopathy, 11 (10%) were proven by molecular means to have Norrie disease (109). In another review of familial exudative vitreoretinopathy, 6% of patients carried mutations in the Norrie disease gene (48). Over time, the genetic details of specific patient populations are becoming known. A study of 44 patients from China, for example, demonstrated the population differences in prevalence of NDP mutations (113). Several novel mutations in NDP have been recognized in a sample of Indian patients with familial exudative vitreoretinopathy (60).
Avoidance of pregnancy by carrier females is the only way to prevent the disorder. De novo mutations cannot be predicted or prevented.
Norrie disease manifests as a spectrum, with several phenotypes that overlap considerably (81). These include Norrie disease, Coats, Coats plus, leukoencephalopathy with calcifications and cysts, and cerebroretinal microangiopathy with calcifications and cysts. Some cases of retinoblastoma may prove to be Norrie disease or related phenotypes (02). Diagnosis is facilitated by identifying intraocular changes and by identifying mutations in the Norrie disease gene. Some workers have held that patients (3% of advanced cases in 1 study) labeled as having retinopathy of prematurity in fact have Norrie disease, the diagnosis of which can be substantiated by clinical and molecular means (87; 32; 39). Evidence is mounting that the presence of certain mutations in the Norrie disease gene may predispose some patients to severe retinopathy of prematurity (97; 31). In 1 study, 6 of 54 (11%) infants with severe retinopathy of prematurity had polymorphisms in Norrie disease gene (NDP) (40). However, other investigators have failed to identify mutations in their patients (47). It is also possible that X-linked primary retinal dysplasia is part of this spectrum, although studies to date have been incomplete (75). Coats disease (exudative retinopathy) and congenital or juvenile retinoschisis can be differentiated by clinical and molecular means (07; 37; 36). One patient with Coats disease, Turner syndrome, and type 1 von Willebrand disease was negative for mutations in NDP (20). Mutations involving the Norrie disease gene and contiguous genes may result in more complex phenotypes (80; 84).
Diagnosis is achieved through clinical (chiefly ophthalmologic and otolaryngologic) workup and identification of a mutation in the Norrie disease gene at Xp11. Identification of the mutation has been possible in approximately 70% of affected males (90). The presence of retinal changes is not helpful in identifying carrier patients (45). Prenatal diagnosis is valuable to confirm the presence of disease, counsel families, and prepare for possible postnatal therapy (15; 70; 92). It is especially sought in cases of recurrent familial disease and has been successful as early as 11 weeks’ gestation, using chorionic villus sampling (28). Preimplantation genetic diagnosis is also possible for parents using in vitro fertilization (111). Ocular anomalies can also be identified ultrasonographically, which can be especially helpful when corneal opacity precludes more traditional examination (59). Persistent hyperplastic primary vitreous has been diagnosed in the early third trimester by ultrasound (25). Large vitreous cavity opacities and retinal detachment have been visualized in a fetus at 36 weeks, with Norrie disease subsequently confirmed by Sanger sequencing (108). Molecular analysis of members of affected pedigrees is, of course, fundamental to understanding familial disease (21), and such workups may reveal adults that have been carried for years with incorrect diagnoses (10). The use of microarray technology to study retinopathies in large populations shows great promise (82). Copy number analysis is successful as well (03). Given the clinical variability within families, it is likely that additional genetic and environmental factors remain to be discovered (26).
Genetic factors are involved in some 50% of cases of profound hearing loss, including Norrie disease (04). To assess hearing loss, brainstem-evoked responses can be measured and electrocochleography performed.
The identification of cerebellar atrophy and motor or mental disorders in 3 affected members a Chinese family is indication for additional imaging workup (53).
Treatment by ophthalmologists, otolaryngologists, and pediatricians is necessary. Medical geneticists will be helpful in discerning the hereditary status of the disorder and with family counseling. Ophthalmologic surgery is more often palliative than curative but may be performed for cataracts, detached retina, or drainage of vitreous (vitrectomy), which may prevent shrinkage of the eyes but does not improve vision. Newer surgical techniques hold promise (89) and appear to be especially valuable when instituted early, even in the newborn period (103; 104; 105; 23; 99). Vitrectomy and laser photocoagulation of avascular retinal tissue are examples (16; 103; 104). Anti-VEGF injections have been used in cases of familial exudative vitreoretinopathy (93). Cochlear implants have proven successful in patients with Norrie disease prior to the onset of total deafness (41).
Surgical procedures can be performed on both eyes during a single operation, with the goal of minimizing patient discomfort and exposure to anesthesia (114).
Joseph R Siebert PhD
Dr. Siebert of the University of Washington has no relevant financial relationships to disclose.See Profile
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