Masquerading maculopathy: The importance of correct diagnosis

In the case discussed here, a maculopathy caused by a mitochondrial point mutation was misdiagnosed as “atypical” age-related macular degeneration, although it can also be confused with other macular dystrophies, such as Stargardt disease. Careful consideration of the factors discussed can help not only give patients the treatment they need but avoid giving them treatment that they don’t.

Patients who are misdiagnosed not only lose the opportunity of knowing what they really have but are also deprived of the proper treatment and/or knowledge of other systemic findings associated with their diagnosis. More seriously, they may be forced to undergo unnecessary treatments that have no chance of treating their disorders.

Presented here is an “atypical” case of misdiagnosis where the patient was proactive. The patient was told she had an atypical case of age-related macular degeneration. She did not like the word “atypical” and investigated further. 

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Case: Atypical AMD or not
A 56-year-old white female presented for a second opinion. Another eyecare practitioner had diagnosed her in her 40s with atypical age-related macular degeneration (AMD). She was concerned about the word “atypical.” 

Having heard how macular degeneration can lead to legal blindness, she wanted to know if she was going to progress. In addition, her mother died in her 50s but was already using low-vision aids for her “macular degeneration” due to poor vision. Health history was notable for type 2 diabetes and high cholesterol. Her mother also had diabetes.

Best-corrected visual acuities were 20/25-2 OD and 20/25-3 OS. External examination of the eyes revealed normal pupils, clear corneas and lenses, full eye movements in all fields of gaze, and intraocular pressures (IOP) of 18 mm Hg in each eye.

Retinal exam revealed normal optic nerve heads with 0.25 cup-to-disc ratios, normal vasculature, and normal peripheral fundus grounds.

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Examination of the maculas, however, were noted for symmetric paramacular rings of circular or nummular areas of geographic atrophy of the retinal pigment epithelium (RPE) and scattered areas of pigment migration (Figure 1).

Fundus autofluorescent (AF) imaging revealed symmetric paramacular circular areas of hypo-AF with scattered areas of hyper-AF (Figure 2). Optical coherence tomography (OCT) through the macula revealed distinct areas of outer retinal thinning and RPE atrophy corresponding to the atrophic circular lesions in both eyes (Figure 3).

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Discussion
It is easy to understand why this patient was originally diagnosed with “atypical” AMD. However, several characteristics need to be considered before making this diagnosis. First, she was diagnosed in her 40s, and AMD is a degenerative disease typically affecting individuals aged 50+ years. Second, fundus appearance was very symmetric, which is suggestive of a hereditary disease or macular dystrophy. Third, the AF images demonstrated hyper-AF areas, which are indicative of lipofuscin deposition, yet the patient had no drusen in either eye.

Maculopathy in this patient is typical of a disease caused by an A3243G mitochondrial point mutation.1 This mutation occurs on the mitochondrial DNA in the cytoplasm of the cells, not the nuclear DNA, and is inherited through the mother. It is associated with a variety of systemic abnormalities and is a specific type of maculopathy that can be mistaken for AMD and other macular dystrophies.

This mutation was originally reported to be associated with “mitochondrial encephalopathy, lactic acidosis, and stroke-like” episodes, known as MELAS, but has since been associated with maternally inherited diabetes, as in this patient, deafness, cardiomyopathy, chronic progressive external ophthalmoplegia (CPEO), a pure myopathy, gastrointestinal dysmotility, and renal failure. Short stature has also been reported.

The so-called “mutation load” (the number of cells affected by the mutation) is directly associated with the severity of the disease manifestations. The maculopathy can vary but generally results in a circumferential distribution of parafoveal atrophy, with speckled areas of hyper-AF surrounding the areas of atrophy, as seen in this patient.

In addition to AMD, this maculopathy can be confused with other macular dystrophies, such as Stargardt disease. It is the widespread speckled AF, which cannot be predicted on the basis of fundoscopy, that is a feature of this maculopathy and differentiates it from other forms of macular dystrophy and degenerations.

The patient was advised to obtain genetics tests to confirm this mutation and hearing tests, although she denied hearing loss. She was also told to consult her primary-care practitioner for other systemic manifestations of this condition.

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References:

1. Rath PP, Jenkins S, Michaelides M, et al. Characterisation of the macular dystrophy in patients with the A3243G mitochondrial DNA point mutation with fundus autofluorescence. Br J Ophthalmol. 2008 May;92(5):623-9.