Abnormal crossing of the optic fibres shown by evoked magnetic fields in patients with ocular albinism with a novel mutation in the OA1 gene

Abstract

Aim: To perform genealogical and clinical studies in Finnish families with X linked ocular albinism (OA1), including characterisation of the potential misrouting of optic fibres by evaluating visual evoked magnetic fields (VEFs), and to determine the mutation behind the disease.

Methods: Three families with OA1 were clinically examined. VEFs were measured in two affected males and in one female carrier to characterise the cortical activation pattern after monocular visual stimulation. The neuronal sources of the VEFs were modelled with equivalent current dipoles (ECDs) in a spherical head model. All coding exons of the OA1 gene were screened for mutations by single strand conformation analysis and direct polymerase chain reaction sequencing.

Results: Genealogical studies revealed that the three families were all related. The affected males had foveal hypoplasia with reduced visual acuity varying from 20/200 to 20/50, variable nystagmus, iris transillumination, and hypopigmentation of the retinal pigment epithelium. The ECD locations corresponding to the VEFs revealed abnormal crossing of the optic fibres in both affected males, but not in the carrier female. A novel point mutation, leading to a STOP codon, was identified in the fifth exon of the OA1 gene.

Conclusions: The data indicate that the novel mutation 640C>T in the OA1 gene is the primary cause of the eye disease in the family studied. VEFs with ECD analysis was successfully used to demonstrate abnormal crossing of the optic fibres.

Figure 1

Pedigree of the Finnish OA1 family. Members of the I–VII generation are all dead, generations VIII–XI as shown. *Indicates individuals who took part in molecular studies. M, patients examined by magnetoencephalography. Black squares, affected males; shaded squares, males having poor eyesight according to church registers; open circles with a black dot, carrier females; and open symbols, unaffected individuals. Question mark indicates that the phenotype is unknown.

Figure 2

Visual evoked magnetic fields (VEFs) to stimulation of the left eye in a control (top) and in patient IX-8 (bottom). In the control, the nasal half field stimulation (blue line) resulted in maximum activation over the ipsilateral occipital area (blue box) and temporal half field stimulation (black line) over the contralateral occipital areas (black box). In the patient, the maximum responses to stimulation of both half fields were over the contralateral visual cortex; in fact, the responses to both half field stimulations were almost identical. The schematic illustration on the left depicts the corresponding organisation of the optic pathways from the two halves of the retinal to the visual cortex.

Figure 3

Isofield contour maps showing the topographic magnetic field distribution at the peak of the P100m VEF deflection. The blue lines indicate magnetic flux entering the head and red lines magnetic flux exiting the head. Data from a control subject are shown at the top and from the two patients in the middle and at the bottom after stimulation of the left eye. In the control, the response to nasal half field stimulation was located ipsilaterally in the left hemisphere, whereas the temporal half field stimulation resulted in activation over the contralateral right hemisphere. In both patients, both the nasal and temporal half field stimulation caused activation over the contralateral right hemisphere. The arrows denote the corresponding ECDs, size of the arrow being proportional to the ECD strength. The contour step is 20 fT/cm.