Retinitis pigmentosa (RP) is a diverse group of retinal dystrophies characterized by night blindness, progressive constriction of the visual field, and bone spicule deposition in the peripheral retina.1 All forms of inheritance have been described, including X-linked, autosomal dominant, autosomal recessive, and mitochondrial, but approximately 42% of cases are simplex (sporadic) with no known family history.1 An unusual case of monozygotic twin sisters discordant for simplex RP is reported here.
Twin A was first seen by us at age 22 years with bilateral vitreous cells and cystoid macular edema (CME). Visual acuity was 20/70 OD and 20/40 OS. She had a moderate initial response to periocular and oral steroids and to oral acetazolamide. Findings from an extensive uveitis workup were unrevealing, and she was otherwise healthy with no evidence of malignancy or systemic autoimmune disorder. She subsequently developed continued visual loss, nyctalopia, visual field constriction, arteriolar narrowing, and pigmentary retinopathy with peripheral bone spicules consistent with a diagnosis of RP (Figure 1). Results of electroretinographic (ERG) studies were very abnormal under phot opic and scotopic conditions (Figure 2), and serial Goldmann visual field examination revealed relentless progression over a 5-year period (Figure 3). There was no family history of any retinal dystrophies, and both parents and all siblings had normal findings from eye examinations. Special attention was paid to the patient's identical twin sister (twin B) who had no ocular symptoms. Results of a dilated fundus examination, ERG, and a visual field examination were all completely normal in twin B (Figure 1, Figure 2, and Figure 3).
Fundus photographs of twins A and B. The posterior pole of twin A (A and B). The peripheral retina of twin A shows bone spicules (C and D). A late-phase fluorescein angiogram of twin A demonstrates cystoid macular edema (E and F). The normal posterior pole of twin B (G and H).
Electroretinograms of twins A and B.
Goldmann visual fields of twin A at age 23 years (A and B) and age 28 years (C and D) and twin B at age 28 years (E and F).
Zygosity determination using DNA polymorphisms was performed at the University of Utah DNA Diagnostic Laboratory (Salt Lake City) using restriction enzyme Hae III and probes ynh24, cmm101, tbq7, and efd52. The twins were concordant for all 4 DNA markers, yielding a monozygotic probability of more than 99%. Likewise, peripheral blood cell metaphase karyotyping and G-banding revealed no abnormalities or discordance. Both twins shared similar environments and preferences as children. The affected twin had her first child at an earlier age than her sister (age 18 years vs age 26 years). The affected twin was a nonsmoker, whereas her unaffected twin sister smoked cigarettes for approximately 10 years.
Circulating serum antibodies to retinal proteins are commonly present in RP patients with prominent CME (90% prevalence), but they are uncommon in RP patients without CME (13% prevalence) and are rarely encountered in the unaffected population (6% prevalence).2 Peripheral blood samples from twins A and B at age 26 years were screened against human retinal proteins under standard Western blot assay conditions.2 Interestingly, both twins exhibited definite immunoreactivity against a variety of human retinal proteins (Figure 4). Among them, we have positively identified immunoreactivity against retinal enolase(46 k Da) and carbonic anhydrase II (30 k Da), antigens that have been previously reported in association with cancer-associated retinopathy (CAR) syndrome3 and RP with CME.2 Interestingly, twin B (the unaffected twin) had a higher titer of antienolase antibodies, whereas twin A had stronger anti–carbonic anhydrase immunoreactivity, as well as unique antibodies against proteins in the 37 to 42 k Da range. It is therefore possible that the detected antibodies to carbonic anhydrase II and to the 37- to 42-k Da proteins may have played an important role in the development of RP with CME in the affected twin. The identity of these other proteins is not known; however, retinal antigens of similar molecular weight have been previously reported in association with RP and autoimmune retinopathies.2- 4 The 22-k Daprotein labeled by our patients' sera has a similar size to the retinal protein recoverin, also known as CAR antigen.4 Antibodies to recoverin have been found in some patients with RP, 4 but additional experiments using purified recombinant human recoverin showed that the immunoreactivity against the 22-k Da antigen was not specific for recoverin. A second Western blot assay of fresh blood samples from both twins 2 years later was unchanged for all protein bands.
Antiretinal antibodies in twins A and B. Western blot analysis was performed using previously described methods2; −C indicates negative control lane; +C, positive control lane; G, Ig G class immunoreactivity; M, Ig M class immunoreactivity; 46K, human enolase standard; 30K, human carbonic anhydrase standard; and 23K, human recoverin standard.
Retinitis pigmentosa is ordinarily considered to be an inherited disorder, 1 but more than 40% of patients with RP have no known family history, and a disproportionately large number of these simplex patients may exhibit clinically significant CME.2 The existence of a pair of monozygotic twins in which only one exhibits classic clinical findings of simplex RP (eg, nyctalopia, bone spicules, progressive visual field loss, and a severely attenuated ERG) is quite remarkable and might provide insights into the pathophysiological mechanisms of RP with CME. In fact, RP in monozygotic twins is itself a rare event—approximately 200 monozygotic pairs with RP would be expected in the United States based on a total population of 275 million people, a prevalence of RP of 1 in 3500, and a frequency of monozygotic twins of 3 per 1000 live births. According to a MEDLINE search, only 1 similar discordant RP pair has been reported—a pair of monozygotic sisters in which only one developed pigmented paravenous retinochoroidal atrophy, an atypical RP syndrome that has never been proven to have an inherited basis.5
How can the discordance be explained? There is no evidence that this is a pseudoretinitis pigmentosa syndrome such as syphilis, a toxic drug reaction, or CAR. Nonmendelian inheritance mechanisms, such as uniparental disomy, or a postfertilization translocation or mutation resulting in somatic mosaicism in one or both twins are possible but exceedingly rare events.5 Uneven lyonization (skewed X-chromosome inactivation) is a possible explanation, 5 but the discordance between these twins is extreme, and there is no history of X-linked RP in the family. Their prominent antiretinal antibodies provide an intriguing clue because it has been speculated that environmental factors may trigger expression of retinal degenerations in individuals harboring antiretinal antibodies.2 Perhaps the early pregnancy of twin A caused an immune alteration that initiated such a reaction.
This case report demonstrates that discordant RP can occur in monozygotic twins and that the presence of antiretinal antibodies such as antienolase that have previously been described in patients with RP does not always correlate with the expression of clinically detectable RP. Furthermore, it suggests that noninherited environmental modifier factors may play an important role in RP and macular dystrophy kindreds that manifest incomplete penetrance or variable clinical phenotypes.
The authors have no relevant financial interest in this article.
This study was supported by grants from Research to Prevent Blindness, Inc, New York, NY. Dr Bernstein is a Research to Prevent Blindness Sybil B. Harrington Scholar in macular degeneration research.
We gratefully acknowledge the contributions of Evan Wolf, MD, PhD (data analysis), Donnell Creel, PhD (electroretinography), and Paul Zimmerman, MD(patient identification and referral).
Corresponding author and reprints: Paul S. Bernstein, MD, PhD, Moran Eye Center, University of Utah School of Medicine, 50 N Medical Dr, Salt Lake City, UT 84132 (e-mail: firstname.lastname@example.org).
Bernstein PS, Aptsiauri N. Discordant Retinitis Pigmentosa in Monozygotic Twins. Arch Ophthalmol. 2003;121(7):1059-1062. doi:10.1001/archopht.121.7.1059