Low vision due to cerebral visual impairment: differentiating between acquired and genetic causes

Abstract

BackgroundTo gain more insight into genetic causes of cerebral visual impairment (CVI) in children and to compare ophthalmological findings between genetic and acquired forms of CVI.MethodsThe clinical data of 309 individuals (mainly children) with CVI, and a visual acuity ≤0.3 were analyzed for etiology and ocular variables. A differentiation was made between acquired and genetic causes. However, in persons with West syndrome or hydrocephalus, it might be impossible to unravel whether CVI is caused by the seizure disorder or increased intracranial pressure or by the underlying disorder (that in itself can be acquired or genetic). In two subgroups, individuals with ‘purely’ acquired CVI and with ‘purely’ genetic CVI, the ocular variables (such as strabismus, pale optic disc and visual field defects) were compared.ResultsIt was possible to identify a putative cause for CVI in 60% (184/309) of the cohort. In the remaining 40% the etiology could not be determined. A ‘purely’ acquired cause was identified in 80 of the patients (26%). West syndrome and/or hydrocephalus was identified in 21 patients (7%), and in 17 patients (6%) both an acquired cause and West and/or hydrocephalus was present. In 66 patients (21%) a genetic diagnosis was obtained, of which 38 (12%) had other possible risk factor (acquired, preterm birth, West syndrome or hydrocephalus), making differentiation between acquired and genetic not possible. In the remaining 28 patients (9%) a ‘purely’ genetic cause was identified.CVI was identified for the first time in several genetic syndromes, such as ATR-X, Mowat-Wilson, and Pitt Hopkins syndrome. In the subgroup with ‘purely’ acquired causes (N = 80) strabismus (88% versus 64%), pale optic discs (65% versus 27%) and visual field defects (72% versus 30%) could be observed more frequent than in the subgroup with ‘purely’ genetic disorders (N = 28).ConclusionsWe conclude that CVI can be part of a genetic syndrome and that abnormal ocular findings are present more frequently in acquired forms of CVI.

Novel genetic causes for cerebral visual impairment

“…Previously, CVI has been reported as part of congenital disorders of glycosylation (CDG) type 1a (PMM2), type 1q (SRD5A3), and type 1v (NGLY1). 8,28,30,31 The phenotype of patient 2 with NGLY1 variants is similar to the previously reported patients, including the microcephaly, hypotonia, movement disorder, and alacrima. 28,32,33 Variants in SLC35A2 lead to CDG type 2m, featured by ID, epilepsy, facial dysmorphisms, and transient abnormalities in transferin testing.…”

“…[3][4][5] CVI can occur in isolation, but more often additional features are present, such as intellectual disability (ID), epilepsy and/or deafness. [6][7][8] An important cause of CVI is acquired damage to the brain, mainly the result of perinatal problems (eg, cerebral hemorrhage or periventricular leukomalacia), but also other types of acquired damage, such as congenital infection, hypoglycemia, meningitis, or head trauma, can be causal. 2 Furthermore, West syndrome and hydrocephalus can result in CVI.…”

Symbol Discrimination Speed in Children With Visual Impairments

“…3,4,6,7 Cerebral visual impairment (CVI) results from diverse developmental disorders and brain injuries, such as genetic disorders, malformations of cortical development, preterm birth, closed head trauma, encephalitis, hypoxia, and epilepsy. [8][9][10] Because of its diverse etiology, a wide variety of visual problems may occur in CVI, ranging from deficits in lower visual functions, such as visual acuity, visual field, and contrast sensitivity, to higher visual functions, such as visual attention, movement processing, and visual search. 8,10,11 Thus, the WHO definition of visual impairment may be too narrow for children with CVI, as well as for children with other visual impairments.…”

Cerebral visual impairment and intellectual disability caused by PGAP1 variants

“…[1][2][3] Acquired damages, for example, due to preterm birth, are well known causes of CVI, whereas genetic factors are largely unidentified. 4 Several chromosomal aberrations have been associated with CVI, such as Phelan-McDermid syndrome (22q13.3 deletion) and 1p36 microdeletion syndrome. 5 Moreover, single-gene disorders can be implicated in CVI, and, recently, we identified de novo variants in NR2F1 as a cause of CVI.…”

“…6 In addition, in several congenital disorders of glycosylation (CDG type 1a, type 1q and type 1v) CVI has been reported. 4,[7][8][9] Glycosylation disorders are caused by a defect in the glycosylation of glycoproteins and glycolipids, and one subclass is the defect in glycosylphosphatidylinositol (GPI) anchor glycosylation. 10 GPI anchor many cell-surface proteins with various functions, so called GPI-anchored proteins (GPI-APs), to the membrane of eukaryotic cells.…”