Neuro-Ophthalmology of Mitochondrial Diseases

Valérie Biousse, MD, Ophthalmology and Neurology, and Nancy J. Newman, MD, Ophthalmology, Neurology, and Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia. 

Semin Neurol. 2001;21(3) 

In This Article

Neuro-Ophthalmic Manifestations of Mitochondrial Disease

Optic Atrophy

Bilateral central visual loss, dyschromatopsia, central visual field defects, and pallor of the optic discs characterize dysfunction of the optic nerves. Visual evoked responses are typically abnormal. Standard flash electroretinography, a measurement of outer retinal function, remains normal.

The most common mitochondrial disease with bilateral optic neuropathies is Leber's hereditary optic neuropathy (LHON).[5,6,21,22] Indeed, LHON was one of the first diseases to be etiologically linked to specific mtDNA defects, and it typically has only neuro-ophthalmic manifestations.[23,24] LHON is expressed predominantly in males of the lineage, a predominance ranging from 80 to 90% in most pedigrees.[25,26,27] One pedigree of LHON with the 11778 mutation in which females are predominantly affected has recently been reported.[28] The greater susceptibility of males to visual loss in LHON remains unexplained. The onset of visual loss typically occurs between the ages of 15 and 35 years, but otherwise classic LHON has been noted in patients ranging in age from 1 to 80 years. Age of onset variability is seen even among members of the same pedigree.[26]

Visual loss is painless, central, and occurs in one eye weeks to months before second eye involvement. True simultaneous onset can occur, but frequently a patient may not have recognized initial involvement of the first eye. On rare occasions, visual loss in the second eye may be delayed for years or the disease may remain clinically monocular. Vision worsens in each eye over weeks or months. Typically, there are no other symptoms at the time of visual loss, although transient episodes of visual worsening and classic Uhthoff's symptom (transient worsening with exercise or overheating) have been reported.[25,27]

Maximum visual loss ranges from no light perception to 20/20, but most patients deteriorate to acuities of 20/200 or worse. Color vision is affected early and severely, and visual fields typically show central or cecocentral defects. Spontaneous improvement in the vision of one or both eyes has been reported as long as years after initial visual loss. Depending on the underlying mtDNA point mutation, up to 60% of patients may have some degree of improvement. A younger age at the time of initial visual loss is associated with a better visual outcome.[25,27]

It has been suggested that the pupillary function is relatively preserved in the affected eyes of LHON patients, indicating differential damage to luminance and pupil afferent fibers in the optic nerve.[29,30,31] However, this remains debated.[32]

Funduscopic abnormalities may be seen in patients with LHON and in their asymptomatic maternal relatives. Especially during the acute phase of visual loss, there may be hyperemia of the optic nerve head, dilation and tortuosity of vessels, hemorrhages, circumpapillary telangiectatic microangiopathy, or circumpapillary nerve fiber layer swelling (pseudoedema) (Fig. 1). Unlike true disc edema, the LHON disc does not leak on fluorescein angiography. Although the presence of the classic LHON fundus appearance in patients or their maternal relatives may raise suspicion for the diagnosis, its absence, even during the period of acute visual loss, does not exclude the diagnosis of LHON. Eventually, the only fundus findings will be optic atrophy with nerve fiber layer dropout, especially in the papillomacular bundle. There may be nonglaucomatous cupping of the disc and arterial attenuation.[6,25,26,27]

Figure 1.

(A-C) Funduscopy of a 25-year-old man with Leber's hereditary optic neuropathy. He presented with a 3-month history of progressive painless bilateral visual loss. His visual acuity was 20/200 OU, with a severe color vision deficit. (A,B) Funduscopy at the time of the initial examination showing mild temporal pallor and mild hyperhemia of both optic discs. (C) Goldmann visual fields demonstrating central scotomas in both eyes. (D,E) Funduscopy 6 months later showing bilateral optic disc pallor consistent with optic atrophy. (F) Funduscopy of a patient with Leber's hereditary optic neuropathy and recent onset of visual loss. There is no disc pallor. The disc is hyperhemic and there are some telangiectasia.

Figure 1.

(A-C) Funduscopy of a 25-year-old man with Leber's hereditary optic neuropathy. He presented with a 3-month history of progressive painless bilateral visual loss. His visual acuity was 20/200 OU, with a severe color vision deficit. (A,B) Funduscopy at the time of the initial examination showing mild temporal pallor and mild hyperhemia of both optic discs. (C) Goldmann visual fields demonstrating central scotomas in both eyes. (D,E) Funduscopy 6 months later showing bilateral optic disc pallor consistent with optic atrophy. (F) Funduscopy of a patient with Leber's hereditary optic neuropathy and recent onset of visual loss. There is no disc pallor. The disc is hyperhemic and there are some telangiectasia.

Figure 1.

(A-C) Funduscopy of a 25-year-old man with Leber's hereditary optic neuropathy. He presented with a 3-month history of progressive painless bilateral visual loss. His visual acuity was 20/200 OU, with a severe color vision deficit. (A,B) Funduscopy at the time of the initial examination showing mild temporal pallor and mild hyperhemia of both optic discs. (C) Goldmann visual fields demonstrating central scotomas in both eyes. (D,E) Funduscopy 6 months later showing bilateral optic disc pallor consistent with optic atrophy. (F) Funduscopy of a patient with Leber's hereditary optic neuropathy and recent onset of visual loss. There is no disc pallor. The disc is hyperhemic and there are some telangiectasia.

Figure 1.

(A-C) Funduscopy of a 25-year-old man with Leber's hereditary optic neuropathy. He presented with a 3-month history of progressive painless bilateral visual loss. His visual acuity was 20/200 OU, with a severe color vision deficit. (A,B) Funduscopy at the time of the initial examination showing mild temporal pallor and mild hyperhemia of both optic discs. (C) Goldmann visual fields demonstrating central scotomas in both eyes. (D,E) Funduscopy 6 months later showing bilateral optic disc pallor consistent with optic atrophy. (F) Funduscopy of a patient with Leber's hereditary optic neuropathy and recent onset of visual loss. There is no disc pallor. The disc is hyperhemic and there are some telangiectasia.

Figure 1.

(A-C) Funduscopy of a 25-year-old man with Leber's hereditary optic neuropathy. He presented with a 3-month history of progressive painless bilateral visual loss. His visual acuity was 20/200 OU, with a severe color vision deficit. (A,B) Funduscopy at the time of the initial examination showing mild temporal pallor and mild hyperhemia of both optic discs. (C) Goldmann visual fields demonstrating central scotomas in both eyes. (D,E) Funduscopy 6 months later showing bilateral optic disc pallor consistent with optic atrophy. (F) Funduscopy of a patient with Leber's hereditary optic neuropathy and recent onset of visual loss. There is no disc pallor. The disc is hyperhemic and there are some telangiectasia.

In most LHON patients, visual loss is the only manifestation of the disease. Some pedigrees have family members with associated cardiac conduction abnormalities, especially preexcitation syndromes. Minor neurologic and skeletal abnormalities have been reported in some patients, as has disease clinically indistinguishable from multiple sclerosis.[33,34,35,36,37,38,39,40,41]

Ancillary tests in LHON are of limited clinical value. Fluorescein angiography may help distinguish the LHON optic disc from true disc edema. Electrocardiograms may show cardiac conduction abnormalities. Formal color vision testing may reveal defects prior to acuity loss, but these findings are not predictive of those who will suffer visual loss. Visual evoked responses are predictably abnormal when there is visual loss. Standard flash electroretinograms are typically normal.[42,43] Electroencephalograms, cerebrospinal fluid, and brain computed tomography (CT) and magnetic resonance imaging (MRI) are generally unremarkable. Bright T2 lesions of the optic nerves have been demonstrated in some affected LHON patients on MRI of the orbits with fat suppression. In one patient, gadolinium enhancement of the optic nerves was observed in the acute phase.[44] Phosphorus-31 magnetic resonance spectroscopy has suggested impaired mitochondrial metabolism within several LHON patient's limb muscles and occipital lobes.[45] Deficiency in respiratory chain complex I function has been demonstrated in muscle and blood samples of some LHON patients.[46]

LHON pedigrees follow a maternal inheritance pattern, and the disease has been linked to point mutations in the mtDNA ( Table 4 , Fig. 2).[47,48] The substitution of adenine for guanine at position 11778 in the mtDNA changes the coding for an evolutionarily highly conserved amino acid. Histidine replaces arginine at position 340 in subunit 4 of complex I in the respiratory chain. The 11778 mutation has been found in approximately 40 to 90% of racially varied pedigrees of LHON worldwide and not in controls.[23,47,49,50,51,52,53,54,55,56,57]

Figure 2.

Mitochondrial genome showing the point mutations associated with Leber's optic neuropathy. The primary mutations are located inside of the genome (circle), and the other mutations are shown outside the genome. Mutations with asterisk (*) may be primary mutations, but when found in the absence of one of the three confirmed primary mutations, they each account for only one or a few probands worldwide. Mutations with double asterisks (**) are primary mutations associated with "LHON plus" (14459 is associated with LHON and dystonia, 4160 is associated with LHON and encephalopathy, and 13513 is associated with LHON and MELAS). (Figure courtesy of Marie T. Lott and Douglas Wallace, Department of Genetics and Molecular Medicine, Emory University School of Medicine, Atlanta, GA.).

Several other mtDNA mutations have since been proposed as causal in LHON. Most of them occur in other subunits of the same complex in the respiratory chain (complex I).[58,59,60,61,62,63,64] A mutation at position 3460 changes the coding for subunit 1 of complex I and accounts for approximately 8 to 15% of LHON pedigrees.[65,66,67] A mutation at position 14484 changes the coding for subunit 6 of complex I and accounts for approximately 10 to 15% of pedigrees,[68] although it is the most common mutation found in French-Canadian families.[69] Analysis in the variations in the noncoding regions of mtDNA showed that this predominance of the 14484 mutation in French-Canadian families results from a founder effect with all cases probably descending from a single founder woman.[69]

The 11778, 3460, and 14484 mutations are designated "primary mutations" in that each alone has been associated with LHON and not found in controls.[47,48,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74] They have a primary pathogenic role in LHON.[47,48,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74] The three primary mutations account for approximately 85 to 90% of LHON cases worldwide. Other point mutations have been found with a greater frequency in LHON patients than controls, varying in their degree of amino acid evolutionary conservation and their frequency in the LHON and control populations. Caution must be taken in assuming a causal significance for these secondary mutations. Some may truly be primary mutations but account for only a few pedigrees worldwide.[75,76,77,78,79,80,81] In others, pathogenic significance remains unclear.[5,19,79]

Among the primary mutations, the LHON clinical phenotype is remarkably similar. The only consistent differentiating feature is the better prognosis for visual outcome in those patients with the 14484 mutation.[27,68,82,83] Up to 60% of patients with the 14484 mutation will have some degree of visual improvement compared with only 5% of patients with the 11778 mutation.[27,82,83] Patients with the 3460 mutation may have a better chance of visual recovery than those with the 11778 mutation, but the numbers of patients are too small for meaningful analysis.[27,82,83] Patients with a younger age of onset of visual loss, especially less than 15 years, have a much better visual prognosis, regardless of which mtDNA mutation they harbor.[27,82,83]

Genetic analysis has allowed for a broader view of what constitutes the clinical profile of LHON. Singleton cases, patients without a family history of visual loss, have been reported frequently (57% of one series).[27,49] Some of these cases are women, some outside the typical age range for LHON, and some without any funduscopic abnormalities. The diagnosis of mitochondrial optic neuropathy should be considered in any case of unexplained bilateral optic neuropathy, regardless of age of onset, gender, family history, or funduscopic appearance.[27,84,85]

The genetic defects, however, can not fully explain the determinants of expression in this disease. The presence of an mtDNA mutation is necessary for phenotypic expression, but it is not sufficient.[19,20,51,78,79] Mitochondrial DNA exhibits much greater polymorphism than nuclear DNA because of more rapid accumulation of mutations. The presence of an mtDNA mutation in patients with a specific disease entity does not necessarily indicate a primary or even any pathogenic role for that mutation, and the criteria for assigning pathogenicity to an mtDNA mutation must always be kept in mind. Chinnery et al[19] recently provided a useful review of the criteria that should be applied and the numerous pitfalls that exist.

The presence of heteroplasmy (the coexistence of both mutant and normal mtDNA) may be a factor in expression.[5,19,86] In heteroplasmic pedigrees, individuals with a greater amount of mutant mtDNA may be at higher risk for visual loss. However, many individuals with 100% mutant mtDNA never suffer visual loss.[6,27] The interaction of genetic, mitochondrial, or nuclear and environmental factors may complicate the issue of assigning a pathogenic role to individual mtDNA mutations.[5,19] Other mitochondrial or nuclear DNA factors may modify expression of the disease, including X-linkage. Various environmental triggers for the development of visual loss in LHON have been suggested.[87,88,89,90] Systemic illnesses, nutritional deficiencies, head trauma, or toxins that stress the organism's mitochondrial energy production might be detrimental to those individuals already genetically at risk for mitochondrial energy deficiency.[89,90] However, a large recent case-control study showed no association between tobacco or alcohol consumption and visual loss among individuals harboring LHON primary mutations.[91]

Pedigrees have been described with ophthalmic disease clinically indistinguishable from LHON associated with more severe familial neurologic abnormalities. One large Australian pedigree combines optic neuropathies with movement disorders, spasticity, psychiatric disturbances, and acute encephalopathic episodes. The 14484 mutation and a point mutation in the mtDNA at position 4160 (subunit 1 of complex I) have been associated with the expression of this disease.[92] Several pedigrees combine maternally inherited optic neuropathy, dystonia, and basal ganglia lesions, and some of them have been genetically defined as harboring a point mutation at position 14459 in the mtDNA (subunit 6 of complex I) ( Table 3 ).[33,34,35]

Other disorders known to be mitochondrial by clinical, biochemical, or genetic analysis may demonstrate optic atrophy as a variable or secondary manifestation of their disease phenotype.[93] The other, more constant, phenotypic characteristics of these disorders distinguish them from diseases such as LHON in which visual loss secondary to optic neuropathy is the primary clinical feature.[5,6,10] Examples include cases of myoclonic epilepsy and ragged-red fibers (MERRF), mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS),[94,95] chronic progressive external ophthalmoplegia (CPEO), and Leigh's syndrome. Optic neuropathy should be considered a marker of mitochondrial disease.

Chronic Progressive External Ophthalmoplegia

CPEO designates a group of clinical findings characterized by slowly progressive bilateral ocular immobility.[1,5,6,9,96,97,98] The process is usually symmetric and patients tend not to complain of diplopia. Eventually the eyes are unresponsive to even caloric stimulation. After many years, the muscles become fibrotic and forced duction testing may be positive. Pupils are always spared, disturbances of sensation are absent, and ptosis and orbicularis oculi weakness is frequently prominent. The ptosis usually precedes the motility disturbance (Fig. 3). One must exclude other causes of ocular motility abnormalities, including multiple cranial nerve palsies, disorders of the neuromuscular junction, orbital myositis, or thyroid orbitopathy. CPEO may be a nonspecific finding in patients with recognized degenerative or dystrophic disorders of the nervous system, including the spinocerebellar degenerations, Refsum's disease, abetalipoproteinemia, hereditary myopathies, neuropathies, and deficiency states.[97,98] Alternatively, CPEO may be the primary manifestation of disease. This is particularly the case in mitochondrial disorders.[6]

Figure 3.

Extraocular motility in patients with chronic progressive external ophthalmoplegia. (A) Typical facies of a patient with CPEO and ptosis. (B) Motility in the nine cardinal directions of gaze in a patient with CPEO. There is bilateral ptosis associated with severely decreased motility in all directions of gaze.

Figure 3.

Extraocular motility in patients with chronic progressive external ophthalmoplegia. (A) Typical facies of a patient with CPEO and ptosis. (B) Motility in the nine cardinal directions of gaze in a patient with CPEO. There is bilateral ptosis associated with severely decreased motility in all directions of gaze.

In mitochondrial disease, CPEO can occur anytime from infancy to old age, and the onset is typically insidious. Ophthalmoplegia and ptosis may be isolated or associated with other neurologic or systemic abnormalities ( Table 3 ). Some of the more common neurologic findings include facial, bulbar, and limb myopathies, deafness, ataxia, spasticity, peripheral neuropathy, gastrointestinal myopathy and neuropathy, vestibular dysfunction, dementia, episodic encephalopathy or coma, and calcification of the basal ganglia. Associated ocular features include optic atrophy, pigmentary retinopathy, corneal opacities, corneal edema, and cataracts. Systemic manifestations may involve the cardiac, endocrine, skin, or skeletal systems and include cardiac conduction abnormalities, short stature, diabetes mellitus, delayed sexual maturation, hypogonadism, hypomagnesemia, hypoparathyroidism, hypothyroidism, and respiratory insufficiency.

Kearns-Sayre syndrome is a subset of CPEO in which the neurologic and systemic abnormalities figure most prominently. The clinical diagnostic criteria are (1) onset prior to age 20, (2) CPEO, (3) retinal pigmentary degeneration, and (4) at least one of the following: cardiac conduction abnormalities, elevated cerebrospinal fluid protein (greater than 100 mg/dL), or cerebellar dysfunction.[99] The other neurologic and systemic abnormalities listed above also occur more commonly in patients with Kearns-Sayre syndrome. Brain histopathology shows spongiform changes[98,100] and neuroimaging may show abnormalities that correspond to these changes (as well as demonstrating calcification of the basal ganglia).[98,101,102] Ragged-red fibers, as demonstrated on modified trichrome stain, can be seen in limb and extraocular muscles in nearly all cases of Kearns-Sayre syndrome and in some patients with just CPEO.[98]

Serious, even life-threatening, abnormalities may occur in patients with mitochondrial disease in which CPEO is the primary manifestation, especially when the onset of symptoms is at a young age. Cardiac conduction defects can cause heart block and sudden death. Hence, electrocardiograms should be obtained on every patient with CPEO.[1,6,10,98,103] Respiratory insufficiency may result from poor respiratory drive, presumably secondary to spongiform changes in medullary centers, or from diaphragmatic muscle weakness. Endocrine abnormalities can cause metabolic imbalance.[1,6,9]

Mitochondrial DNA analysis of skeletal muscle tissue of some CPEO patients reveals rearrangements of segments of mtDNA in the form of deletions and duplications.[104,105,106,107,108,109,110] Most of the rearrangements occur in regions of the mtDNA normally flanked on either side by identical nucleotide sequences (direct repeat sequences), and these may be pathogenically involved in the formation of deletions. Patients are typically heteroplasmic for these rearrangements, and the mutant mtDNA accounts for 20 to 90% of the total skeletal muscle mtDNA. Different proportions of mutant mtDNA are present in different tissues and may account for some of the variability in clinical expression. For example, KSS patients typically have a greater percentage of mutant mtDNA in their tissues than patients with less severe CPEO syndromes. These rearrangements have been found in over 90% of KSS patients as compared with approximately 50% of CPEO patients. Aside from these general observations, there is poor correlation among the size or site of the rearrangement, biochemical abnormality, and clinical profile. The same mtDNA abnormality can be found in patients with different phenotypes, and different mtDNA rearrangements have been noted in patients with similar clinical presentations.

Most cases of mitochondrial disease associated with CPEO arise sporadically. There are a few pedigrees with maternal inheritance, suggesting an underlying mtDNA point mutation. In most patients with CPEO and mtDNA rearrangements, other family members are not clinically affected and will not have rearrangements on muscle biopsy. In these sporadic cases, it is likely that the rearrangements occurred during embryogenesis. However, autosomal recessive and autosomal dominant inheritance have also been demonstrated in pedigrees in which multiple family members have mtDNA rearrangements on muscle biopsy, implicating nuclear DNA abnormalities.[111] The rearrangements usually vary in size and location among family members and within single individuals. This has suggested that the inherited defect in these pedigrees may be in a nuclear-encoded factor important in mtDNA replication; if this nuclear factor functions improperly, different rearrangements could occur secondary to faulty mtDNA replication.[111,112,113,114,115,116,117,118,119] Recent studies have linked a few pedigrees of autosomal dominant CPEO with mtDNA deletions to chromosomes 10 and 3.[114,118]

CPEO may rarely be a clinical feature in patients with MELAS.[98,120] Some of these patients have the mtDNA point mutation at position 3243 associated with MELAS (see below), while others do not. Furthermore, a subgroup of patients with CPEO without the clinical features of MELAS was found to have the 3243 MELAS point mutation.[98] CPEO may also be part of the syndrome of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).[121,122] MNGIE is an autosomal recessive disorder defined clinically by severe gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy, and leukoencephalopathy. Patients usually die in early adulthood. The disease is caused by mutations in the nuclear gene encoding thymidine phosphorylase, located on chromosome 13.32-qter. The resultant accumulation of thymidine is likely to produce an impairment of mtDNA replication, repair, or both, leading to mtDNA abnormalities.[122] Other genetic causes of CPEO could include as yet unidentified point mutations in the mtDNA or other nuclear gene defects that influence mitochondrial function.

Pigmentary Retinopathy

Pigmentary changes in the retina may occur in patients with mitochondrial disease.[5,6,7,9,22,27,123,124] These findings are usually characterized as "atypical retinitis pigmentosa" to differentiate them from the classic bone spicule pattern see in retinitis pigmentosa. The most common appearance is that of a salt-and-pepper retinopathy (Fig. 4). One may note only fine pigment dusting or punctate clumps of hyperpigmentation, most notably in the periphery (and therefore frequently only visible by indirect ophthalmoscopy by an ophthalmologist through a dilated pupil). These findings typically become more prominent with age. Less common patterns include areas of patchy loss or atrophy of the pigment epithelium and choriocapillaris and true bone spiculing. There may be profound macular involvement. Vascular attenuation is common. Histopathologic examination reveals degeneration of the retinal pigment epithelium and, in some cases, abnormalities of the rods and cones. Visual loss occurs in approximately 50% of patients and is usually mild. Fluorescein angiography and electroretinography may help confirm subtle changes.[22,123,124]

Figure 4.

Pigmentary retinopathy in patients with mitochondrial diseases. (A) Salt-and-pepper retinopathy in a patient with CPEO. There is fine pigment dusting, which is most notable in the periphery of the retina. (B) Typical pigmentary retinopathy in a patient with NARP syndrome and the 8993 mutation. The arteries are attenuated and there are bone-spicule pigmentary changes in the peripheral nasal retina. (C) Goldman visual field of the same patient in (B) above showing multiple small scotomas consistent with the retinal disease. (D) Pigmentary retinopathy with peripheral and macular involvement.

Figure 4.

Pigmentary retinopathy in patients with mitochondrial diseases. (A) Salt-and-pepper retinopathy in a patient with CPEO. There is fine pigment dusting, which is most notable in the periphery of the retina. (B) Typical pigmentary retinopathy in a patient with NARP syndrome and the 8993 mutation. The arteries are attenuated and there are bone-spicule pigmentary changes in the peripheral nasal retina. (C) Goldman visual field of the same patient in (B) above showing multiple small scotomas consistent with the retinal disease. (D) Pigmentary retinopathy with peripheral and macular involvement.

Figure 4.

Pigmentary retinopathy in patients with mitochondrial diseases. (A) Salt-and-pepper retinopathy in a patient with CPEO. There is fine pigment dusting, which is most notable in the periphery of the retina. (B) Typical pigmentary retinopathy in a patient with NARP syndrome and the 8993 mutation. The arteries are attenuated and there are bone-spicule pigmentary changes in the peripheral nasal retina. (C) Goldman visual field of the same patient in (B) above showing multiple small scotomas consistent with the retinal disease. (D) Pigmentary retinopathy with peripheral and macular involvement.

Figure 4.

Pigmentary retinopathy in patients with mitochondrial diseases. (A) Salt-and-pepper retinopathy in a patient with CPEO. There is fine pigment dusting, which is most notable in the periphery of the retina. (B) Typical pigmentary retinopathy in a patient with NARP syndrome and the 8993 mutation. The arteries are attenuated and there are bone-spicule pigmentary changes in the peripheral nasal retina. (C) Goldman visual field of the same patient in (B) above showing multiple small scotomas consistent with the retinal disease. (D) Pigmentary retinopathy with peripheral and macular involvement.

Pigmentary retinopathy is one of the major diagnostic criteria in Kearns-Sayre syndrome.[98] In addition, retinal pigmentary degeneration can be seen in patients with CPEO and no other neurologic or systemic abnormalities, as well as in otherwise unaffected relatives of patients with more extensive mitochondrial disease. Furthermore, pigmentary retinopathy can occur in patients with mitochondrial disease who do not have CPEO, including patients with MELAS.[123,124,125,126] This finding is likely more common among patients with mitochondrial disease than previously realized and deserves systematic study with complete ophthalmologic evaluation.

A macular dystrophy has been reported in patients with the 3243 mutation,[125,126,127,128,129] a mutation that typically manifests as MELAS but also as the syndrome of maternally inherited diabetes and deafness (MIDD). Massin et al[128,129] prospectively evaluated 35 French patients with MIDD and found bilateral macular dystrophy in 30 (86%) of these patients. The macular lesions were bilateral and symmetric, and ranged from small, localized pigmented lesions in the macula and around the optic disc to large areas of retinal pigment epithelium and choroidal atrophy affecting the maculae. In most cases, these lesions were asymptomatic with a visual acuity of 20/25 or better. The same findings were reported in an English family with the MIDD syndrome.[127] This macular dystrophy may also be observed in patients with the 3243 mutation and otherwise typical MELAS,[126] emphasizing the clinical overlap of syndromes.

Pigmentary retinopathy figures prominently in pedigrees who carry the mtDNA point mutation at position 8993 in the ATPase-6 gene.[6,7,123,124,130,131] This mutation was initially described in a maternal lineage with pigmentary retinopathy, developmental delay, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy and was designated as NARP (neurogenic muscle weakness, ataxia, retinitis pigmentosa). The term retinitis pigmentosa was used to emphasize the classic retinal bone spiculing seen in this lineage. However, other patients who carry this mutation have since been identified with no retinopathy, subtle pigmentary retinopathy, or the severe bone spicule pattern. Kerrison et al[131] reported the evolution over 8 years from a salt-and-pepper appearance to typical retinitis pigmentosa with peripheral bone spicule formation in a patient with NARP syndrome due to the 8993 mutation. This same mtDNA mutation has now been associated with approximately one-third of patients with the classic presentation of Leigh's syndrome.[132,133,134,135,136,137] Leigh's syndrome is an encephalopathy of infancy or early childhood with psychomotor delay, hypotonia, brainstem abnormalities, lactic acidosis, spongiform changes in the brainstem and basal ganglia and central respiratory hypoventilation. Nystagmus and supranuclear ocular motility disturbances, as well as optic atrophy, may be noted in patients with Leigh's syndrome.[132,133,134,135,136,137] Patients with the 8993 mutation are usually heteroplasmic for the mutation, and this may account for the wide phenotypic heterogeneity within the same maternal pedigree.

Genetic defects noted in patients with pigmentary retinopathy include mtDNA point mutations and rearrangements. As with the other clinical findings, there is no consistent correlation among the presence or type of pigmentary retinal changes, type of genetic defect, biochemical abnormality, and other clinical features. However, the presence of a pigmentary retinopathy in a patient with an undefined neurologic or systemic illness should raise suspicion for a mitochondrial disease.

Patients with mitochondrial disease may have visual loss not ascribable to optic nerve or retinal dysfunction, but rather a reflection of disruption of the retrochiasmal visual pathways. As dictated by the anatomy, such lesions would result in homonymous hemianopic defects or cortical blindness with identical left and right eye visual acuities (assuming there are no additional abnormalities of the anterior visual pathways) (Fig. 5). Pupillary reactions and funduscopic appearance would be normal. Electroretinograms would be normal but visual evoked responses, especially if performed with half-field stimulation, might be abnormal.

Figure 5.

15-year-old boy with MELAS. (A,B) T2-weighted MRIs demonstrating a hypersignal in the left parietooccipital region, consistent with MELAS. (C) Goldman visual showing a complete right homonymous hemianopia.

Figure 5.

15-year-old boy with MELAS. (A,B) T2-weighted MRIs demonstrating a hypersignal in the left parietooccipital region, consistent with MELAS. (C) Goldman visual showing a complete right homonymous hemianopia.

Figure 5.

15-year-old boy with MELAS. (A,B) T2-weighted MRIs demonstrating a hypersignal in the left parietooccipital region, consistent with MELAS. (C) Goldman visual showing a complete right homonymous hemianopia.

The mitochondrial disease most consistently associated with retrochiasmal visual loss is MELAS.[1,3,6,7,8,9,98,138,139,140,141,142] MELAS is characterized by recurrent abrupt attacks of headache, vomiting, and focal and generalized seizures, lasting hours to days. Onset is usually before the age of 15 years. Loss of consciousness is common. Transient, focal neurological deficits may follow including hemiplegia, hemianopia, and cortical blindness. There appears to be a posterior cerebral predilection for damage, and visual disturbances have been reported in more than half of patients. The prognosis for recovery of neurologic function is better than for patients with cerebrovascular infarction. However, there is evidence to suggest that progressive neurologic and mental deterioration may be related to the number of repeated attacks. Psychiatric abnormalities may precede or accompany the episodes, and hearing loss, muscle weakness, and short stature are noted frequently in patients and maternal family members. Although not typical of the MELAS syndrome, it is not uncommon for patients to have chronic progressive external ophthalmoplegia, pigmentary retinopathy,[94,98,125,126] or optic atrophy.[6,94,95]

Elevated serum and cerebrospinal fluid (CSF) lactate levels are nearly always documented in MELAS patients. CSF protein content may also be abnormally high. Ragged-red fibers are present on muscle biopsies in up to 90% of patients. Abnormal mitochondria have also been demonstrated in the smooth muscle cells of blood vessels. This may have pathogenic importance for the strokelike episodes in MELAS.[138,139,140,141] CT scans may show bilateral basal ganglia calcification and focal low-density areas in the cerebral cortex, the latter corresponding to the areas of neurologic dysfunction.[98] MRI is more sensitive in revealing these lesions, which are usually posteriorly situated and confined to the cortex, relatively sparing the deep white matter (Fig. 4).[98,101,143] Diffusion-weighted MRI has suggested that these transient abnormalities may represent vasogenic edema.[144] The lesions cross customary vascular borders and may completely disappear over time.[98,101,143]

MELAS may occur sporadically or be familial, usually with maternal inheritance. Approximately 90% of patients with MELAS harbor the mtDNA mutation at position 3243 in the gene that codes for a transfer RNA (tRNALeu(UUR)). At least four other mutations have been associated with MELAS, two in the same tRNA gene, at positions 3271 and 3291, one in the ND4 subunit at nt11084, and one in the ND5 subunit at nt 13513.[95,139,140,141,142,145] As expected, these point mutations are inherited maternally. Maternally related family members may have only mild clinical indicators of disease such as migraines, hearing loss, diabetes, or even maculopathies. Heteroplasmy of the point mutations may account for some of this clinical variability. Some patients with MELAS do not carry any of these point mutations, yet are clinically indistinguishable from those that do. Patients with clinical features of both CPEO and MELAS with mtDNA deletions have been reported.

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