Dominant Optic Atrophy:

47-year-old female with chronic, mildly subnormal vision

James G. Howard, MD, and Edwin M. Stone, MD, PhD

August 21, 2005, revised Feb. 21, 2006

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Chief Complaint: Chronic, stable, mildly diminished vision

History of Present Illness: 47-year-old Caucasian female with the presumptive diagnosis of cone dystrophy who was referred to the Retina Clinic at the University of Iowa for further evaluation of chronic, mildly diminished visual acuity and dyschromatopsia. The patient reported that her vision has never been correctable to 20/20. The best visual acuity she remembers having is 20/30 in the left eye.

Ocular History: She was diagnosed with amblyopia (known commonly as "lazy eye") in the right eye as a child and underwent a trial of patching at age ten. She is anisometropic (a significantly different spectacle prescription in each eye) and her vision has always been worse in the right eye, presumably due to amblyopia.

Medical History: None.

Medications: She takes no medications on a regular basis. She has never taken hydroxychloroquine or antipsychotic medications (medicines that can in some patients injure the macula and cause decreased central vision).

Family History: She has several family members with mildly subnormal vision. Her mother, brother, sister, and son all have mildly reduced vision, in the range of 20/30 to 20/50 (see Figure 1). All of the affected family members are able to drive.

Social History: She works as a clerk. Her social history is otherwise unremarkable.

Figure 1: Pedigree exhibiting autosomal dominant inheritance pattern.

OCULAR EXAM:

• Visual Acuity (with corrective lenses):
  • Right eye -- 20/70; Left eye -- 20/40
• Current spectacle correction:
  • Right eye: -0.75 +2.50 x 037
  • Left eye: -3.00 sphere
• Manifest Refraction (MRx) imrpoves the acuity of the right eye to 20/60 while the left eye remains unchanged
• Motility: Orthophoric (normally aligned) in primary gaze; Versions (ability to move the eye in all directions) full.
• Intra-ocular pressure: Right eye --12 mmHg; Left eye --14 mmHg.
• Pupils: Normal in both eyes. No relative afferent pupillary defect.
• External and anterior segment examination: Normal in both eyes.
• Dilated fundus exam: There was optic disc pallor, predominantly temporal, in both eyes. Peripapillary atrophy and grey temporal crescent were noted in the left eye (see Figure 2). The macula, vessels, and periphery were normal in both eyes.

Figure 2

2A: Disc photo, right eye. Optic disc pallor is evident, most notably on the temporal aspect of the disc.	2B: Disc photo, left eye. Optic disc pallor can be seen most notably on the temporal aspect of the disc, peripapillary atrophy, and a temporal grey crescent are evident.

• Ishihara plates: 2/14 OD, 3/14 OS
• Nagel anomaloscope: protanomalous match
• Goldmann Visual Field testing (see Figure 3):
  • Right eye -- baring of blind spot with mildly constricted I2e isopter
  • Left eye -- constricted I2e isopter
• Electroretinogram (ERG): scotopic bright flash 589 microvolts in the right eye, 572 microvolts left eye; scotopic dim flash 405 microvolts right eye, 340 microvolts left eye, photopic bright flash 180 microvolts right eye, 185 microvolts left eye (see ERG waveforms in Figure 4).

Figure 3: Goldmann visual fields reveal some baring of the blind spot with a mildly constricted I2e isopter (shown in red) in the right eye and a constricted I2e isopter in the left eye.

Figure 4: The electroretinogram (ERG) waveforms are normal in this patient.

Course: A blood sample for molecular studies was obtained. The clinical and genetic features of autosomal dominant optic atrophy (the most likely diagnosis) were discussed. More information will follow when results of the genetic testing are complete. The patient returned to the care of her local eye doctor.

Discussion: Autosomal dominant optic atrophy or Dominant Optic Atrophy (DOA) is, as suggested by the name, an autosomal dominantly inherited optic neuropathy characterized by subnormal visual acuity, visual field abnormalities, and optic nerve pallor in the setting of an otherwise normal eye exam. Family history is often positive, but because of variable expressivity, mildly affected family members may go undiagnosed ( e.g., incomplete penetrance). Furthermore, This incomplete penetrance can result in an inheritance pattern that is suggestive of autosomal recesssive or X-linked disease. The penetrance of Dominant Optic Atrophy has been estimated to be as high as 100% ( Thiselton 2002) and as low as 43% ( Toomes 2001), however these percentages appear to depend on the specific mutation.

Vision loss typically begins as the affected individual reaches school age. The onset and progression are insidious – most patients are unable to identify a precise age of onset. As many as 50% of patients with Dominant Optic Atrophy experience a progressive loss of vision with advancing age. Dyschromatopsia (color blindness) is frequently present but its manifestations are variable. Initially, Dominant Optic Atrophy was thought to be most closely associated with blue color vision deficits ( Kline 1979), but more recent studies have demonstrated that mixed color deficits are most common (81%) ( Votruba 1998).

Optic disc pallor is one of the defining characteristics of Dominant Optic Atropy. About half of the affected individuals have disc pallor that is limited to the temporal side of the disk while the remaining patients have diffuse disc pallor. The degree of pallor tends to correlate with the severity of vision loss. In a recent series of patients with proven OPA1 mutations (see below), 69% had peripapillary atrophy, 31% had a temporal grey crescent, and 48% had a cup to disc ratio of >0.5 ( Votruba 2003). The most common visual field defects are central or cecocentral scotomas, although altitudinal defects also have been described in patients with documented OPA1 mutations ( Brown 1997). Histopathologic studies have shown loss of retinal ganglion cells, especially in the papillomacular bundle, and diffuse atrophic changes of the optic nerve (Johnston 1979).

The vast majority of Dominant Optic Atrophy cases are caused by mutations in the gene OPA1, located on chromosome 3q ( Votruba 2004). OPA1 is most abundantly expressed in the retina and brain ( Votruba 2004). Over 70 different variations in OPA1 have been observed in patients with a DOA phenotype ( Votruba 2004). Genetic testing for mutations in OPA1 will soon be available through the Carver Laboratory for Molecular Diagnosis (www.carverlab.org), a nonprofit laboratory dedicated to providing molecular diagnostic studies for heritable eye conditions. Other sources for genetic testing of DOA can be found at www.genetests.org. A smaller fraction of patients with DOA have been linked to OPA4 on chromosome 18 ( Kerrison 1999). X-linked optic atrophy has been linked to OPA2 ( Assink 1997), while mutations in OPA3 are associated with at least one type of autosomal recessive optic atrophy ( Anikster 2001).

Summary: Dominant Optic Atrophy (DOA)

GENERAL Incidence is approximately 1 in 50,000, but may be as high as 1 in 10,000 in Denmark Equally affects males and females

SIGNS Insidious mild to moderate vision loss, typically in a school-aged child (4-6 years of age), with potential for progressive vision loss later in life (30-50%) Distribution of visual acuity: 40% are 20/60 or better, 45% are between 20/60 and 20/200, and 15% are below 20/200 Central or cecocentral visual field defects are most typical, although altitudinal defects may occur as well Generalized dyschromatopsia (color blindness) – both blue-yellow and red-green defects have been described Optic nerve pallor which may affect only the temporal aspect of the nerve (52%) or the entire nerve (48%) Peripapillary atrophy (69%) Temporal grey crescent (31%) Enlarged cup to disc ratio, >0.5 (48%)

SYMPTOMS Mild to moderately diminished visual acuity, typically beginning around school age. This may progress later in life, resulting in more severe loss of visual acuity.

TREATMENT There is currently no way to reverse the vision loss associated with dominant optic atrophy. However, many patients may be helped significantly with low vision aids. A blood sample may be obtained for definitive molecular diagnosis. Genetic counseling and discussion of recent research (Newman 2004) is also helpful.

Differential Diagnoses for Dominant Optic Atrophy

• Normal tension glaucoma

  disk cupping, usually not familial, more rapidly progressive than DOA

• Leber's hereditary optic neuropathy (LHON)

  In LHON, the vision is initially normal and drops suddenly and catastrophically (usually 20/400 or worse) in one eye at a time. The second eye is typically affected within weeks or months of the first eye but the two eyes are rarely affected at the same time. There may be a positive family history but unlike dominant disease, the affected individuals are always connected through females. That is, males never transmit the disease to their descendents.

• Compressive optic neuropathy

  Less likely to be bilateral than DOA, usually more rapidly progressive, patients have a history of normal vision in the past, less likely to have a positive family history of a similar disease (unless it is in the context of neurofibromatosis) neuroimaging is diagnostic

• Infiltrative or inflammatory optic neuropathy

  Usually more rapidly progressive, patients have a history of normal vision in the past, less likely to have a positive family history of a similar disease, disks show more evidence of swelling than atrophy, there may be other inflammatory stigmata elsewhere in the fundus

• Toxic or nutritional optic neuropathy

  History of exposure to a toxin (especially large amounts of alcohol) and or an unusual diet (e.g., tea and toast). In addition, usually more rapidly progressive than DOA, patients have a history of normal vision in the past and are less likely to have a positive family history of a similar disease than patients with DOA.

• Optic nerve hypoplasia (septo-optic dysplasia)

  Disks are smaller than normal and may exhibit a "double ring sign". Septo-optic dysplasia and other central nervous system abnormalities are present in up to 75% of cases which can be seen on neuroimaging. It is important to diagnose septo-optic dysplasia because there are frequently significant endocrine abnormalities associated with this congenital malformation. Unlikely to have a positive family history of a similar disease.

Septo-Optic Dysplasia	Double Ring Sign

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