Article Text

Paucity of signs in X linked ocular albinism with a 700 kb deletion spanning the OA1 gene
  1. NEL T TIJMES,
  2. ARTHUR A B BERGEN
  1. Netherlands Ophthalmic Research Institute, Department of Ophthalmogenetics
  2. Amsterdam Zuid-Oost, Netherlands
  3. Netherlands Ophthalmic Research Institute, Department of Ophthalmogenetics, Amsterdam Zuid-Oost; Department of Ophthalmology, AMC, Amsterdam Zuid-Oost; and Erasmus University Rotterdam, Department of Epidemiology and Biostatics, Rotterdam, Netherlands
  1. PAULUS T V M DE JONG
  1. Netherlands Ophthalmic Research Institute, Department of Ophthalmogenetics
  2. Amsterdam Zuid-Oost, Netherlands
  3. Netherlands Ophthalmic Research Institute, Department of Ophthalmogenetics, Amsterdam Zuid-Oost; Department of Ophthalmology, AMC, Amsterdam Zuid-Oost; and Erasmus University Rotterdam, Department of Epidemiology and Biostatics, Rotterdam, Netherlands
  1. N T Tijmes, Netherlands Ophthalmic Research Institute, Department of Ophthalmogenetics, PO Box 12141, 1100 AC Amsterdam, Netherlands.

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Editor,—X linked ocular albinism (XLOA) shows great variability in clinical expression between affected males as well as in heterozygote females, even within one sibship. In 1995, the gene implicated in XLOA (OA1) was cloned.1 So far, we have found mutations in the OA1 gene in only 15% of the X linked ocular albinism patients (unpublished). Also Schiaffinio et al2 revealed mutations in only one third of XLOA patients. Here, we report on the clinical features of a person with XLOA in which the entire OA1 gene was missing due to a submicroscopic interstitial deletion in the distal short arm of the X chromosome. The detailed molecular findings were published elsewhere.3 As Winship et al 4 suggested that XLOA and late onset (fourth and fifth decades) sensorineural deafness are allelic variants, or that both entities may be due to contiguous gene defects, we examined our patient for hearing loss.

CASE REPORT

A man, born in 1956, was seen at our department for genetic counselling because of XLOA. Genealogical examination could not reveal consanguinity or a link with other families with XLOA. He had dark blond hair, moles and freckles, and tanned with difficulty.

Visual acuity on the right eye was 20/80 with S +3.5 C −4.25 10°, and on the left eye 20/80 with S +3.75 C −4.75 0°. On ophthalmic examination we found congenital pendular horizontal nystagmus, iris translucency, absent macular reflexes, and an albinotic fundus periphery. Visual evoked potentials showed abnormal neuronal crossing at the optic chiasma, as in albinism.

Macromelanosomes were visible by electron microscopy in a skin biopsy taken from the forearm.

A neurological test set revealed no anosmia or hyposmia, nor could we find kidney abnormalities or hormonal disturbances as in Kallmann syndrome. Audiograms in 1996 showed normal results.

In addition, our case was examined because he complained of fertility problems. In this examination only a reduced number of spermatozoa were found (22.5 × 109/l).

Molecular genetic investigation revealed a deletion of 700 kb in the Xp22.2 region of the X chromosome. All nine exons of the OA1 gene were tested in the DNA of our case and were found to be deleted.2

COMMENT

The ophthalmic features of this case are comparable with those of the affected males described by Charles et al5and van Dorp.6 The albinism in patients described by these authors is most probably caused by a variety of distinct mutations in the OA1 gene. Clinical variability between families may be due to different OA1 mutations in male patients, but can also be accounted for by other genetic factors, such as preferential X inactivation in female carriers. Variation in clinical expression within one sibship is probably not caused by different mutations but by environmental factors or modifying genes.

Since the molecular defect in our case spans the entire OA1 gene we expected relatively severe clinical or functional abnormalities. However, only relatively “mild” XLOA symptoms were found.

The audiograms in our patient showed normal patterns indicating that a separate gene for sensorineural deafness may exist in the genomic vicinity of the OA1 gene but outside the DNA deletion in our case. The fact that we found mutations in only 15% of the XLOA patients may indicate that either the OA1 gene has not been cloned in its entirety, or that a separate, closely linked and as yet not discovered albinism gene exists in the distal part of the X chromosome.

In conclusion, our case, with this 700 kb deletion, showed the mild and classic form of XLOA, in addition to infertility. It is as yet uncertain if this infertility was due to a genetic factor.

Acknowledgments

The authors wish to thank Patricia Apkarian, Mary van Schooneveld, and Gijs F J M Vrensen for their contributions.

References

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