Spotlight Case: Forty-five with Fishtail Flecks

 

James Berg, MD Baylor College of Medicine, Cullen Eye Institute, Houston, TX

  

Rishabh Date, MD Baylor College of Medicine, Cullen Eye Institute, Houston, TX

  

Christina Y. Weng, MD, MBA Baylor College of Medicine, Cullen Eye Institute, Houston, TX



Case History:

A 45-year-old Caucasian male with no known ocular history presented with slowly progressive, painless bilateral vision over the past 6 years.  He states that he has had poor color vision since childhood, but denies any flashes or floaters, trauma, or inciting event.  Past medical history is significant only for well-controlled hypertension and hypercholesterolemia.  Family history is notable for an older sibling also with poor bilateral vision; remaining family members including parents and children have normal vision.

Best-corrected visual acuity measured 20/60 OD and 20/50-1 OS with minimal myopic correction OU.  His pupils, intraocular pressure, motility, and visual fields were within normal limits.  Ishihara color plates were 4/17 OD and 3/17 OS.  Anterior segment exam was notable for early nuclear sclerosis OU.  Dilated funduscopic examination revealed bilateral yellow-white pisciform lesions located within the macula and throughout the periphery (Figure 1).

Spectral-domain optical coherence tomography (OCT) showed bilateral subfoveal atrophy with parafoveal ellipsoid layer irregularities (Figure 2).  Fluorescein angiography demonstrated hyperfluorescence corresponding to the areas of the retina lesions along with a dark choroid (Figure 3). 

Figures:

Figure 1. Color fundus photographs with bilateral yellow-white pisciform lesions throughout the macula and periphery.

Figure 2. Spectral-domain OCT shows bilateral subfoveal atrophy and parafoveal ellipsoid zone and outer retinal loss.

Figure 3. Fluorescein angiography of the right eye demonstrates diffuse hyperfluorescence of the pisciform lesions with the background of a dark choroid.

What’s Your Diagnosis?:

Fundus flavimaculatus (FFM)

Discussion:

The patient’s history and exam findings are consistent with the autosomal recessive macular dystrophy known as fundus flavimaculatus (FFM).  This condition can present with findings similar to those of Stargardt disease which is also typically an autosomal recessive condition with ‘pisciform flecks’.  However, the lesions in Stargardt disease are generally concentrated within the posterior pole as compared to the diffuse distribution in FFM1.  Additionally, Stargardt patients are typically diagnosed within the first two decades of life whereas FFM is often not diagnosed until adulthood.  Both conditions are linked to mutations affecting the photoreceptor cell-specific ATP-binding cassette transporter or ABCA4 gene.  This gene produces the critical enzyme that transports the toxic visual chromophore, all-trans-retinal, to the cytoplasmic side of the internal disc membranes where it is recycled and re-enters the visual pathway.  When this cytotoxic byproduct is left within the outer segment disc membranes, it leads to lipofuscin accumulation and eventual cellular death of the photoreceptors2.  

Symptoms of fundus flavimaculatus typically begin in the fourth or fifth decade of life and include decreased visual acuity and color vision3.  Exam will show numerous yellow-white pisciform flecks throughout both the macula and fundus periphery.  Outer retinal atrophy and ellipsoid zone loss is often observed in the central macula, sometimes forming a “bullseye” configuration.  Like Stargardt disease, FFM may have a “dark choroid” on fluorescein angiography from the accumulation of lipofuscin within the RPE which blocks fluorescence from the underlying choroidal vasculature.  On fundus autofluorescence, the pisciform lesions will be hyperautofluorescent4.  Those affected may have vision that ranges from 20/20 to 20/200; it seldom deteriorates past 20/400.  Visual dysfunction appears to be related to age of symptom onset with earlier presentation being related to worse prognosis.  Compared to Stargardt disease, FFM is considered to be a milder condition with slower and less severe visual deterioration in general.

While there are currently no FDA-approved therapies for Stargardt disease or fundus flavimaculatus, there are several clinical trials underway. Sanofi is leading a Phase I/IIa investigation involving the subretinal administration of a lentivirus vector-based gene therapy (SAR422459)5.  Another Phase I/IIa clinical trial is investigating subretinal transplantation of human embryonic stem cell-derived RPE (hESC-RPE) cells6.  There is also an ongoing Phase II randomized, double-blinded clinical trial involving oral administration of ALK-001, a chemically-modified form of vitamin A designed to prevent formation of the toxic vitamin A derivatives that accumulate in ABCA4 mutant patients7.  Hopefully, there will be treatments to offer affected patients in the near future.

 

Take-Home Points:

-   Fundus flavimaculatus (FFM) and Stargardt disease (STGD) are likely disease variants that present with yellowish pisciform flecks in the retina and outer retinal atrophy in the macula that lead to decreased visual acuity and color vision.  FFM has a later onset than Stargardt disease which typically presents in childhood or adolescence.

-   The majority of affected patients have a mutation of the ABCA4 gene inherited in an autosomal recessive pattern.  The mutation leads to an impaired ability to recycle all-trans-retinal with subsequent accumulation of toxic metabolites that lead to photoreceptor death.

-  There are several ongoing clinical trials investigating potential therapies for Stargardt disease and fundus flavimaculatus, but no FDA-approved treatments currently exist. 

 

References:

  1. Klein BA, Krill AE. Fundus flavimaculatus. Clinical, functional and histopathologic observations. Am J Ophthalmol. 1967;64(1):3-23.
  2. Allikmets R, Singh N, Sun H, et al. A photoreceptor cell‐specific ATP‐binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997;15(3):236–46. 
  3. Haji Abdollahi S, Hirose T. Stargardt-Fundus flavimaculatus: recent advancements and treatment. Semin Ophthalmol. 2013;28(5-6):372-6.
  4. Lois N, Halfyard AS, Bird AC, et al. Fundus autofluorescence in Stargardt macular dystrophy‐fundus flavimaculatus. Am J Ophthalmol. 2004;138(1):55-63.
  5. Sanofi. A study to determine the long-term safety, tolerability and biological activity of SAR422459. In: ClinicalTrials.gov. Bethesda, MD: National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT01736592. Accessed May 1, 2018.
  6. Astellas Institute for Regenerative Medicine. Safety and tolerability of sub-retinal transplantation of human embryonic stem cell derived retinal pigmented epithelial (hESC-RPE) cells in patients with Stargardt’s macular dystrophy (SMD). In: ClinicalTrials.gov. Bethesda, MD: National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT01469832. Accessed May 1, 2018.
  7. Alkeus Pharmaceuticals. Phase 2 tolerability and effects of ALK-001 on Stargardt Disease. In: ClinicalTrials.gov. Bethesda, MD: National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT02402660. Accessed May 1, 2018.

 

 

Financial Disclosures:
Dr. Berg: None
Dr. Date: None
Dr. Weng: Allergan, Inc. (C), Alimera Sciences, Inc. (C)