Alternative titles; symbols
ORPHA: 178333; DO: 0050630;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.23 | Aland Island eye disease | 300600 | X-linked | 3 | CACNA1F | 300110 |
A number sign (#) is used with this entry because Aland Island eye disease is caused by mutation in the CACNA1F gene (300110). X-linked incomplete congenital stationary night blindness (CSNB2A; 300071), which has a similar phenotype, is caused by mutations in the same gene.
Aland Island eye disease (AIED) is an X-linked recessive retinal disease characterized by fundus hypopigmentation, decreased visual acuity, nystagmus, astigmatism, protan color vision defect (303900), progressive myopia, and defective dark adaptation. Although AIED has been referred to as a form of albinism, there is no misrouting of the optic nerves, which excludes it from the formal diagnosis of classic albinism (King et al., 2001).
Forsius and Eriksson (1964) reported X-linked tapetoretinal degeneration in a family described in a family from the Aland Islands in the Sea of Bothnia. Males in 6 generations were affected with hypopigmentation of the fundus, foveal hypoplasia, marked impairment of vision, nystagmus, myopia, astigmatism, and protan colorblindness. Female carriers showed slight disturbances of color discrimination and electromyographically demonstrable nystagmus. Warburg (1964) described ocular albinism and protanopia in the same Aland Island kindred family. Only 2 of 4 males with ocular albinism showed dyschromatopsia. The absence of characteristic fundus pigmentary pattern in female carriers in the family of Forsius and Eriksson suggested that they had a distinct entity from X-linked Nettleship-Falls ocular albinism (OA1; 300500). Scialfa (1967) reported another family with this disorder.
By electron microscopic study of skin biopsies obtained by Forsius in the Island of Aland, O'Donnell and Green (1978) and O'Donnell et al. (1980) concluded that the Forsius-Eriksson type is morphologically distinct from the Nettleship-Falls type of ocular albinism; no macromelanosomes were present.
By electrophysiologic studies, van Dorp et al. (1985) showed that there is no misrouting of the optic pathways in Aland Eye disease, thus distinguishing it from true albinism. Other differences from albinism, not commented on earlier, included differences in the spontaneous and optokinetic nystagmus.
Maumenee (1986) expressed the opinion that this disorder may be a variety of achromatopsia.
Weleber et al. (1989) pointed out that newer electrophysiologic techniques, including electroretinography, show many differences between this disorder and OA1; however, the disorder showed some similarities to X-linked incomplete congenital stationary night blindness (300071).
Glass et al. (1991, 1993) reported studies of a 6-generation family with 9 affected males and 14 obligatory carriers. Clinical features included severely reduced visual acuity, nystagmus, high axial myopia, foveal hypoplasia, and protanomalous color vision deficiency associated with minor fundal depigmentation. Although impaired night vision was not a symptom, psychophysical and electrophysiologic testing showed that both rod and cone function were abnormal in all affected males. No abnormality was detected in carrier females. The findings were similar to those previously reported in both CSNB2A and AIED.
Jalkanen et al. (2007) stated that although AIED and CSNB2A are allelic disorders, there are a few distinct differences between the symptoms of the patients in the original AIED family and those described as having CSNB2A. AIED has progressive myopic refraction, foveal dysplasia with no foveal reflex, and a protan defect in color vision (303900), whereas CSNB2A is apparently stationary with a normal fovea and mostly normal color vision, with tritan (190900) or mixed defects in some cases. They suggested that the differences my be attributable to differences in genetic background (i.e., other genes or genetic modifiers).
Hawksworth et al. (1995) studied a Welch kindred in which congenital nystagmus and moderate-to-high refractive error segregated as an X-linked trait, with manifestation in some female carriers. Affected males demonstrated myopia, but a high proportion of female carriers and some of the possibly affected males showed hypermetropia. Clinical ophthalmologic examination and electrodiagnostic studies of retinal function were compatible with a diagnosis of either incomplete congenital stationary night blindness or Aland island eye disease. Hawksworth et al. (1995) raised the question of whether the 2 entities are the same.
By linkage analysis, Waardenburg et al. (1969) found a recombination fraction of about 0.12 with the Xg blood group locus (Race and Sanger, 1968), suggesting that Aland Island disease and OA1 may be allelic or due to genes at adjacent loci. However, Waardenburg et al. (1969) concluded that the disorder was distinct from X-linked OA1.
From multilocus linkage analysis, Alitalo et al. (1991) concluded that the most probable location of the AIED gene is in the pericentromeric region between DXS7 and DXS72. These results ruled out the more distal localization on Xp proposed by others. The findings did not exclude the possibility that AIED and incomplete congenital stationary night blindness could be allelic.
From studies of a large Danish family with AIED, Schwartz and Rosenberg (1991) likewise located the gene to the proximal part of Xp: proximal to DXS7 and tightly linked to the following cluster of loci--DXS255, TIMP (305370), DXS146, and DXS14.
By linkage analysis in an affected family, Glass et al. (1991, 1993) indicated location of the gene in proximal Xp. Several loci in the Xp11.4-p11.23 region showed positive 2-point lod scores. For example, PFC (300383) showed a maximum lod score of 3.56 at theta = 0.00.
Pillers et al. (1988, 1990) described a 6-year-old adopted boy with an interstitial Xp21 deletion and Aland Island disease plus DMD (310200), GK deficiency (307030), and congenital adrenal hypoplasia (300200). By molecular analysis, including PCR amplification and Southern blotting, Pillers et al. (1989, 1990) defined the deletion in this patient as Xp21.3-p21.2. Weleber et al. (1989) described the ophthalmologic findings in this patient and discussed the similarities to incomplete congenital stationary night blindness as defined by Miyake et al. (1986, 1987).
Wutz et al. (2002) identified mutations in the CACNA1F gene (300110), which is also mutated in the incomplete form of X-linked congenital stationary night blindness (CSNB2A), in a Finnish family and a sporadic Swiss case with an AIED-like phenotype. Reevaluation indicated full compatibility of the patients' ophthalmologic phenotypes with CSNB2A. No CACNA1F mutation by complete DNA sequencing of all 48 exons could be found in a classic AIED family previously shown to map to the pericentromeric region of the X chromosome (Alitalo et al., 1991). Due to similar clinical features of AIED and CSNB2A, Wutz et al. (2002) speculated that the mutation in this family may be located in an intron or in the promoter region.
In affected members of the original family with Aland Island eye disease described by Forsius and Eriksson (1964), Jalkanen et al. (2007) identified homozygosity for a 425-bp deletion mutation encompassing exon 30 and portions of adjacent introns of the CACNA1F gene (300110.0008). The mutation was found in heterozygous state in carrier females of this family and was not found in samples from 121 Finnish male control subjects.
Alitalo, T., Kruse, T. A., Forsius, H., Eriksson, A. W., de la Chapelle, A. Localization of the Aland Island eye disease locus to the pericentromeric region of the X chromosome by linkage analysis. Am. J. Hum. Genet. 48: 31-38, 1991. [PubMed: 1985461]
Forsius, H., Eriksson, A. W. Ein neues Augensyndrom mit X-chromosomaler Transmission: eine Sippe mit Fundusalbinismus, Foveahypoplasie, Nystagmus, Myopie, Astigmatismus und Dyschromatopsie. Klin. Monatsbl. Augenheilkd. 144: 447-457, 1964. [PubMed: 14230113]
Glass, I. A., Fullwood, P., Giles, M. G., Willshaw, H., Good, P., Fielder, A. R., Kilpatrick, M. W., Farndon, P. A. Linkage analysis of Aland eye disease. (Abstract) Cytogenet. Cell Genet. 58: 2065 only, 1991.
Glass, I. A., Good, P., Coleman, M. P., Fullwood, P., Giles, M. G., Lindsay, S., Nemeth, A. H., Davies, K. E., Willshaw, H. A., Fielder, A., Kilpatrick, M., Farndon, P. A. Genetic mapping of a cone and rod dysfunction (Aland Island eye disease) to the proximal short arm of the human X chromosome. J. Med. Genet. 30: 1044-1050, 1993. [PubMed: 7907666] [Full Text: https://doi.org/10.1136/jmg.30.12.1044]
Hawksworth, N. R., Headland, S., Good, P., Thomas, N. S. T., Clarke, A. Aland island eye disease: clinical and electrophysiological studies of a Welsh family. Brit. J. Ophthal. 79: 424-430, 1995. [PubMed: 7612552] [Full Text: https://doi.org/10.1136/bjo.79.5.424]
Jalkanen, R., Bech-Hansen, N. T., Tobias, R., Sankila, E.-M., Mantyjarvi, M., Forsius, H., de la Chapelle, A., Alitalo, T. A novel CACNA1F gene mutation causes Aland Island eye disease. Invest. Ophthal. Vis. Sci. 48: 2498-2502, 2007. [PubMed: 17525176] [Full Text: https://doi.org/10.1167/iovs.06-1103]
King, R. A., Hearing, V. J., Creel, D. J., Oetting, W. S. Albinism. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. II. (8th ed.) New York: McGraw-Hill (pub.) 2001. Pp. 5587-5627.
Maumenee, I. H. Personal Communication. Baltimore, Md. 7/16/1986.
Miyake, Y., Horiguchi, M., Ota, I., Shiroyama, N. Characteristic ERG flicker anomaly in incomplete congenital stationary night blindness. Invest. Ophthal. Vis. Sci. 28: 1816-1823, 1987. [PubMed: 3499417]
Miyake, Y., Yagasaki, K., Horiguchi, M., Kawase, Y. On- and off-responses in photopic electroretinogram in complete and incomplete types of congenital stationary night blindness. Jpn. J. Ophthal. 31: 81-87, 1987. [PubMed: 3498069]
Miyake, Y., Yagasaki, K., Horiguchi, M., Kawase, Y., Kanda, T. Congenital stationary night blindness with negative electroretinogram: a new classification. Arch. Ophthal. 104: 1013-1020, 1986. [PubMed: 3488053] [Full Text: https://doi.org/10.1001/archopht.1986.01050190071042]
O'Donnell, F. E., Green, W. R., McKusick, V. A., Forsius, H., Eriksson, A. W. Forsius-Eriksson syndrome: its relation to the Nettleship-Falls X-linked ocular albinism. Clin. Genet. 17: 403-408, 1980. [PubMed: 7398111] [Full Text: https://doi.org/10.1111/j.1399-0004.1980.tb00170.x]
O'Donnell, F. E., Jr., Green, W. R. Personal Communication. Baltimore, Md. 11/24/1978.
Pillers, D. M., Buist, N. R. M., Hanna, C. E., Weleber, R., Powell, B., Magenis, R. E. Congenital adrenal hypoplasia, glycerol kinase deficiency and Duchenne-type muscular dystrophy in association with ocular hypopigmentation in a boy with 46,del(X)(p21p21),Y. (Abstract) Am. J. Hum. Genet. 43 (suppl.): A65 only, 1988.
Pillers, D. M., Towbin, J. A., Chamberlain, J. S., Wu, D., Ranier, J., Powell, B. R., Magenis, R. E., Weleber, R. G., McCabe, E. R. B. Aland Island eye disease localized by molecular genetic analysis to Xp21.3-p21.2 in a patient with Duchenne muscular dystrophy, glycerol kinase deficiency, congenital adrenal hypoplasia, and a chromosomal deletion. (Abstract) Cytogenet. Cell Genet. 51: 1059-1060, 1989.
Pillers, D. M., Towbin, J. A., Chamberlain, J. S., Wu, D., Ranier, J., Powell, B. R., McCabe, E. R. B. Aland Island eye disease (MIM 30060) localized between DXS67 and Duchenne muscular dystrophy locus (DMD) in the Xp21.3-21.2 region. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A157 only, 1989.
Pillers, D. M., Towbin, J. A., Chamberlain, J. S., Wu, D., Ranier, J., Powell, B. R., McCabe, E. R. B. Deletion mapping of Aland Island eye disease to Xp21 between DXS67 (B24) and Duchenne muscular dystrophy. Am. J. Hum. Genet. 47: 795-801, 1990. [PubMed: 2220819]
Pillers, D. M., Weleber, R. G., Powell, B. R., Hanna, C. E., Magenis, R. E., Buist, N. R. M. Aland Island eye disease (Forsius-Eriksson ocular albinism) and an Xp21 deletion in a patient with Duchenne muscular dystrophy, glycerol kinase deficiency, and congenital adrenal hypoplasia. Am. J. Med. Genet. 36: 23-28, 1990. [PubMed: 2159212] [Full Text: https://doi.org/10.1002/ajmg.1320360106]
Race, R. R., Sanger, R. Blood Groups in Man. (5th ed.) Philadelphia: F. A. Davis Co. (pub.) 1968. P. 549.
Schwartz, M., Rosenberg, T. Aland eye disease: linkage data. Genomics 10: 327-332, 1991. [PubMed: 2071141] [Full Text: https://doi.org/10.1016/0888-7543(91)90315-6]
Scialfa, A. C. Albinisme oculaire et dyschromatopsie. Arch. Ophthal. 27: 483-494, 1967.
van Dorp, D. B., Eriksson, A. W., Delleman, J. W., van Vliet, A. G. M., Collewijn, H., van Balen, A. T. M., Forsius, H. R. Aland eye disease: no albino misrouting. Clin. Genet. 28: 526-531, 1985. [PubMed: 4075563] [Full Text: https://doi.org/10.1111/j.1399-0004.1985.tb00421.x]
van Vliet, A. G. M., Waardenburg, P. J., Forsius, H., Eriksson, A. W. Nystagmographical studies in Aland eye disease. Acta Ophthal. 51: 782-790, 1973. [PubMed: 4545068] [Full Text: https://doi.org/10.1111/j.1755-3768.1973.tb06047.x]
Waardenburg, P. J. Some notes on Aland eye disease (Forsius-Eriksson syndrome). J. Med. Genet. 7: 194-199, 1970. [PubMed: 5489090] [Full Text: https://doi.org/10.1136/jmg.7.3.194]
Waardenburg, P. J., Eriksson, A. W., Forsius, H. Aland eye disease (syndroma Forsius-Eriksson). Prog. Neuro-Ophthal. 2: 336-339, 1969.
Warburg, M. Ocular albinism and protanopia in the same family. Acta Ophthal. 42: 444-451, 1964. [PubMed: 14213931] [Full Text: https://doi.org/10.1111/j.1755-3768.1964.tb03636.x]
Weleber, R. G., Pillers, D. M., Powell, B. R., Hanna, C. E., Magenis, R. E., Buist, N. R. M. Aland Island disease (Forsius-Eriksson syndrome) associated with contiguous gene syndrome at Xp21: similarity to incomplete congenital stationary night blindness. Arch. Ophthal. 107: 1170-1179, 1989. [PubMed: 2667510] [Full Text: https://doi.org/10.1001/archopht.1989.01070020236032]
Wutz, K., Sauer, C., Zrenner, E., Lorenz, B., Alitalo, T., Broghammer, M., Hergersberg, M., de la Chapelle, A., Weber, B. H. F., Wissinger, B., Meindl, A., Pusch, C. M. Thirty distinct CACNA1F mutations in 33 families with incomplete type of XLCSNB and Cacna1f expression profiling in mouse retina. Europ. J. Hum. Genet. 10: 449-456, 2002. [PubMed: 12111638] [Full Text: https://doi.org/10.1038/sj.ejhg.5200828]