Case 5: Leber optic atrophy: sudden onset of visual loss

Contents

Background
Initial Examination
Diagnosis
Family history
Outcome
Genetic counselling
Epilogue
Further Reading

1. Background

One day Joseph awakens and notices that he has blurry vision when looking to the left. In addition he sees spots in front of his left eye. There is no associated pain, and he feels well otherwise. At first, he wonders whether this might be an eye infection or whether it might be related to the way he slept. The blurry vision continues through the day and, after lunchtime, Joseph calls his family doctor. He is seen later that same day, and a general physical examination is entirely normal. He is referred to an ophthalmologist, who sees him several days later. The left optic nerve is noted to be slightly swollen, and the right eye is normal. His visual field is constricted in the left eye. An optic neuropathy is diagnosed in Joseph, and a number of studies are arranged, including a brain magnetic resonance imaging (MRI) scan and immunologic tests. Pending the results of these tests, Joseph is not started on any medication.

Sudden onset of blurry vision can occur from a number of causes, including infections, inflammatory diseases, vascular disorders, and other problems. The occurrence of swelling of the optic nerve suggests the likelihood of an inflammatory process, such as optic neuritis. This can occur in isolation or as part of a process such as multiple sclerosis. Swelling of the optic nerve can be a sign of increased intracranial pressure, which might occur in the setting of a brain tumor. It would be unusual for the swelling to be unilateral in such cases, however. Magnetic resonance imaging provides pictures of the inside of the brain. Immunologic tests would be appropriate to consider the possibility of an inflammatory disorder.

2. Initial examination

The MRI is read as normal, and the immunologic studies also are normal. Approximately 1 month after the onset of his left visual disturbance, Joseph begins to lose vision in his right eye. He first notes blurry vision in the right eye while reading a book. Within 2 weeks, he finds that he cannot read street signs. Over a 4-week period, his vision deteriorates from 20/15 in the right eye to 20/200. Joseph is in a panic, facing total loss of vision over a period of a month. He is referred to a specialist who performs another ophthalmologic examination. She finds that both optic discs are swollen, and there are bilateral central scotomas. Visually evoked responses are tested and are found to be markedly attenuated.

It would be common for inflammatory optic neuritis to be associated with a normal MRI scan, and immunologic studies also might be normal. It is unusual, though, for isolated optic neuritis to progress so rapidly to involve both eyes. Visually evoked response testing involves measuring electrical activity in the brain resulting from visual stimulation with flashes of light or a changing pattern. An abnormal response indicates a delay in conduction of nerve impulses along the optic nerve or the visual pathways in the brain. Central scotomas are blind spots that correspond to loss of vision surrounding the swollen optic nerves. All these data point to the optic nerves as the site of pathology.

3. Diagnosis

Joseph receives a diagnosis of Leber hereditary optic neuropathy. An extensive medical history is obtained. Joseph has been in good health and he does not smoke. When in tenth grade, Joseph was noted to have palpitations during a routine physical examination. He was evaluated for a cardiac problem, but no specific diagnosis was made. He is a college student and has a night-time job as a cashier.

The clinical data fit with the diagnosis of Leber hereditary optic neuropathy (LHON). The disorder presents with relatively acute onset of visual loss. It usually begins with blurring of vision in one eye that then rapidly progresses to involve both eyes. There is a rapid decrease of visual acuity, which eventually tends to stabilize. Initially, the optic nerves are swollen and there is a proliferation of small blood vessels. Eventually, the optic nerves appear pale and atrophic, due to loss of nerve fibers. LHON tends to affect men more often than women. Men also have an earlier age of onset (in the second to fourth decades), compared with onset beyond the third decade in women. The major pathology of LHON is confined to the eye. In some individuals, however, there can also be cardiac conduction defects. Usually, these do not cause major clinical problems, although cardiac arrhythmias can occur in some cases.

4. Family history

The ophthalmologist explains that Leber optic neuropathy is a hereditary disorder and questions Joseph about his family history. Joseph is the eldest of three siblings. He has a brother, Tom, who is 16 years old and a sister, Ellen, age 14. Both are in good health and have no history of visual problems. Joseph's mother has been treated for breast cancer and his father is in good health. Neither parent has a history of visual problems. It is arranged for Tom and Ellen to have their eyes examined. Tom has microvascular changes indicative of early Leber optic neuropathy, but Ellen's eyes are normal.

It has long been known that LHON is a familial disorder, but the pattern of transmission has been enigmatic. More than 75% of affected individuals are male, but males never transmit the disorder, although they are fertile. A high proportion of the sons of female carriers are affected, however. These features are suggestive of maternal transmission and have provided evidence that the basis of the disorder might be mitochondrial dysfunction.

5. Outcome

Three months have passed since Joseph received the diagnosis. His vision has stabilized, but there has been little improvement. He has registered with the state commission for the blind, and he is meeting with a rehabilitation specialist to help him adapt to his visual problem and continue his studies. He is referred to a geneticist who has experience with mitochondrial disorders. A blood sample is drawn and tested for mutations known to be associated with Leber hereditary optic neuropathy (Fig.1).

It is common for visual loss to stabilize eventually in those with LHON and, in fact, some degree of improvement can occur over a long period of time.

The observation of maternal transmission supported the notion that LHON might be a mitochondrial disorder, and this notion was strongly bolstered by the finding of a mitochondrial mutation common to a number of affected individuals from different families. The mutation occurs at position 11,778 of the mitochondrial genome, causing an amino acid substitution in one subunit of complex I. This mutation is not found as a polymorphism in the general population but rather is invariably associated with LHON in a family. Mutations in individuals with LHON are usually homoplasmic. Two other mutations have been found commonly in other families with LHON. These are at nucleotides 3,460 and 14,484. The 3,460 mutation affects peptide ND1; the 11,778 mutation affects NF4; the 14,484 mutation affects NF6. All of these are subunits of complex I.

The pathogenesis of LHON remains a mystery, despite evidence that mitochondrial mutations are involved. Various hypotheses have been proposed, including modifier genes either in the nucleus or modifier mutations in the mitochondrial genome, as well as a role for environmental toxins such as tobacco or alcohol exposure. It is possible that the optic nerve suffers from intracellular energy failure, but it is not clear why the effect is so tissue-specific, why it occurs many years after birth, and why it affects men more often than women.

6. Genetic counselling

The blood test confirms the clinical diagnosis. Tom and Ellen are found also to carry the mutation, as is their mother. Ellen is counseled about her risk of transmitting the disorder to her offspring. Both Joseph and Tom are started on vitamin C, vitamin E, and coenzyme Q₁₀.

In accordance with the expectation of maternal transmission, all the offspring of a carrier female will carry the mitochondrial mutation responsible for LHON. It is difficult to predict the course in an individual, however, although age of onset correlates to some extent with the particular mutation. Unfortunately, there is little to offer to known carriers other than education and close follow-up, as no treatment has been demonstrated to prevent or reverse visual dysfunction. Vitamins E and C have antioxidant properties, serving as surrogate electron acceptors, and coenzyme Q₁₀ likewise provides an alternative electron acceptor in the respiratory chain. Although it makes sense to use these medications and they do not appear to have significant side effects, there is relatively little evidence that they are effective.

7. Epilogue

Two years have passed. There has been some slight improvement in Joseph's vision, but he has learned Braille and is classified as legally blind. He has graduated from college and now is taking graduate courses in engineering. His brother, Tom, recently has experienced blurring of his vision and already is preparing for the possibility of blindness. Ellen remains in good health, with normal vision. Her major concern is the risk of passing the trait on to her children.