Alternative titles; symbols
Other entities represented in this entry:
ORPHA: 49382; DO: 0081025;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p12.3 | Achromatopsia 6 | 610024 | Autosomal dominant; Autosomal recessive | 3 | PDE6H | 601190 |
| 12p12.3 | Retinal cone dystrophy 3 | 610024 | Autosomal dominant; Autosomal recessive | 3 | PDE6H | 601190 |
A number sign (#) is used with this entry because of evidence that retinal cone dystrophy with supernormal rod electroretinogram (RCD3A) can be caused by mutation in the gene encoding the gamma subunit of cone cGMP-phosphodiesterase (PDE6H; 601190) on chromosome 12p13. In addition, achromatopsia-6 (ACHM6) can be caused by homozygous mutation in PDE6H.
Another form of cone dystrophy with supernormal rod electroretinogram (RCD3B; 610356) is caused by mutation in the KCNV2 gene (607604).
Cone Dystrophy With Supernormal Rod Electroretinogram
Cone dystrophy with supernormal rod electroretinogram, also known as retinal cone dystrophy-3 (RCD3), is an autosomal recessive disorder that causes lifelong visual loss combined with a supernormal ERG response to a bright flash of light. The disorder was first described by Gouras et al. (1983) and is characterized by reduced visual acuity, photoaversion, night blindness, and abnormal color vision. Additional cases were described by Sandberg et al. (1990), Kato et al. (1993), and Hood et al. (1996). At an early age, the retina shows subtle depigmentation at the macula and, later, more obvious areas of atrophy. Electroretinography is characteristic and is required to make a specific diagnosis (Wu et al., 2006). An altered phosphodiesterase activity within phosphoreceptors, which leads to an elevation in cGMP levels, had been suggested as a possible disease mechanism.
Piri et al. (2005) reported this rare form of cone dystrophy in a small family with decreased central visual acuity and night blindness rather than the dayblindness usually seen in patients with progressive cone degeneration. Symptoms began in the first or second decade of life. Ophthalmoscopic findings consisted of an atrophic macular lesion. Goldmann visual field testing showed a central scotoma in each eye. Scotopic electroretinograms showed supernormal and delayed rod responses.
Incomplete Achromatopsia
Kohl et al. (2012) studied a Dutch man who had reduced but stable visual acuity and nystagmus since birth. Previous examination at age 45 years showed no abnormalities by slit-lamp or funduscopy. Electroretinography (ERG) recordings showed normal rod, severely reduced cone, and absent 30-Hz flicker responses. Color vision tests revealed a severe red-green color vision defect with relatively normal blue-yellow vision. He was diagnosed as having incomplete achromatopsia, with atypical features. Kohl et al. (2012) also studied a Belgian brother and sister, born of nonconsanguineous parents, who presented with photophobia and normal night vision and were diagnosed with myopia at 3 years of age. ERG under anesthesia in childhood was suggestive of cone dysfunction with absent photopic 30-Hz flicker responses. There was no deterioration of vision over 15 years, suggesting that the cone dysfunction was stationary. Color vision testing at 22 and 20 years of age, respectively, showed mainly deutan (green) color defects with normal tritan (blue) color discrimination. Visual fields were normal in both sibs, and funduscopy revealed optic discs of normal color with large temporal myopic crescents. The retinas presented irregular atrophic depigmentation in the posterior pole with sparing of the macula. Autofluorescence fundus imaging showed a normal posterior pole and macula. Follow-up ERGs in both sibs showed absent photopic responses to a single bright white flash and absent 30-Hz flicker responses. Short wavelength-sensitive (S) cone-specific testing showed absent responses to the amber stimulus but recordable responses to the blue stimulus; the scotopic ERG was normal in both. Responses to a red flash under dark adaptation were reduced with long implicit time, indicating contribution of the rod system component only. Kohl et al. (2012) concluded that the color vision testing and ERG results were consistent with a clinical diagnosis of incomplete achromatopsia with preserved S-cone function.
Cone Dystrophy With Supernormal Rod Electroretinogram
In a brother and sister with retinal cone dystrophy-3, Piri et al. (2005) identified a G-to-C transversion in the 5-prime untranslated region of the PDE6H gene (601190.0001). Although the mutation was not found in 95 control individuals, it was found in the patients' father. Their mother and other sibs were not available for study. Piri et al. (2005) speculated that the sibs may have inherited a different mutation from their mother, which would make the disorder an autosomal recessive, or that a genetic factor present only in the father may have mitigated the phenotypic expression. Using in vitro transcription-translation experiments, Piri et al. (2005) demonstrated that the -29G-C substitution could lead to an increase in PDE6H gene expression. If the same effect occurs in vivo, it would lead to PDE6H overexpression in the photoreceptors. Piri et al. (2005) suggested that an excess of PDE-gamma might affect normal cone cGMP-PDE function by inhibiting the catalytic PDE-alpha/beta activity and lead to pathogenic elevation of cGMP and eventual degeneration of cone photoreceptors.
Kohl et al. (2012) noted that no further mutations in PDE6H had been detected in subsequent studies of patients with retinal cone dystrophy with supernormal rod response (see 610356), and referred to the mutation identified by Piri et al. (2005) as a 'variant of unknown significance.'
Incomplete Achromatopsia
Kohl et al. (2012) analyzed the PDE6H gene in 197 patients with achromatopsia who were negative for mutation in known ACHM genes, and identified homozygosity for a nonsense mutation (S12X; 601190.0002) in a Dutch man who had incomplete achromatopsia with atypical features. Analysis of PDE6H in 20 more ACHM patients as well as 394 patients with a clinical diagnosis of cone dystrophy identified 2 Belgian sibs homozygous for the same S12X mutation; the sibs had originally been diagnosed with cone-rod dystrophy but upon subsequent evaluation were given a clinical diagnosis of incomplete achromatopsia with preserved S-cone function. Kohl et al. (2012) estimated that mutations in PDE6H account for only about 0.3% of all autosomal recessive cases of ACHM.
Gouras, P., Eggers, H. M., MacKay, C. J. Cone dystrophy, nyctalopia, and supernormal rod responses: a new retinal degeneration. Arch. Ophthal. 101: 718-724, 1983. [PubMed: 6601944] [Full Text: https://doi.org/10.1001/archopht.1983.01040010718003]
Hood, D. C., Cideciyan, A. V., Halevy, D. A., Jacobson, S. G. Sites of disease action in a retinal dystrophy with supernormal and delayed rod electroretinogram b-waves. Vision Res. 36: 889-901, 1996. [PubMed: 8736222] [Full Text: https://doi.org/10.1016/0042-6989(95)00174-3]
Kato, M., Kobayashi, R., Watanabe, I. Cone dysfunction and supernormal scotopic electroretinogram with a high-intensity stimulus: a report of three cases. Doc. Ophthalmol. 84: 71-81, 1993. [PubMed: 8223112] [Full Text: https://doi.org/10.1007/BF01203284]
Kohl, S., Coppieters, F., Meire, F., Schaich, S., Roosing, S., Brennenstuhl, C., Bolz, S., van Genderen, M. M., Riemslag, F. C. C., the European Retinal Disease Consortium, Lukowski, R., den Hollander, A. I., Cremers, F. P. M., De Baere, E., Hoyng, C. B., Wissinger, B. A nonsense mutation in PDE6H causes autosomal-recessive incomplete achromatopsia. Am. J. Hum. Genet. 91: 527-532, 2012. [PubMed: 22901948] [Full Text: https://doi.org/10.1016/j.ajhg.2012.07.006]
Piri, N., Gao, Y. Q., Danciger, M., Mendoza, E., Fishman, G. A., Farber, D. B. A substitution of G to C in the cone cGMP-phosphodiesterase gamma subunit gene found in a distinctive form of cone dystrophy. Ophthalmology 112: 159-166, 2005. [PubMed: 15629837] [Full Text: https://doi.org/10.1016/j.ophtha.2004.07.011]
Sandberg, M. A., Miller, S., Berson, E. L. Rod electroretinograms in an elevated cyclic guanosine monophosphate-type human retinal degeneration: comparison with retinitis pigmentosa. Invest. Ophthal. Vis. Sci. 31: 2283-2287, 1990. [PubMed: 1700774]
Wu, H., Cowing, J. A., Michaelides, M., Wilkie, S. E., Jeffery, G., Jenkins, S. A., Mester, V., Bird, A. C., Robson, A. G., Holder, G. E., Moore, A. T., Hunt, D. M., Webster, A. R. Mutations in the gene KCNV2 encoding a voltage-gated potassium channel subunit cause 'cone dystrophy with supernormal rod electroretinogram' in humans. Am. J. Hum. Genet. 79: 574-579, 2006. [PubMed: 16909397] [Full Text: https://doi.org/10.1086/507568]