Ординатура / Офтальмология / Английские материалы / Neuro-Ophthalmology_Kidd, Newman, Biousse_2008

Additionally, it is also customary to distinguish those disorders in which optic neuropathies feature prominently, with or without associated neurologic and systemic findings, from those primarily neurologic and systemic multisystem diseases in which there may be optic nerve involvement (Table 8–1). Obviously, this distinction is not always clear. The neurologist will often be the first one to see these patients and recognize optic nerve dysfunction.

Leber’s Hereditary Optic Neuropathy

The clinical characteristics of patients with Leber’s hereditary optic neuropathy (LHON) have been known for almost 150 years.1 Since the late 1980s, LHON

TABLE 8–1 Inherited Optic Neuropathies

Primary hereditary optic neuropathies

Leber’s hereditary optic neuropathy

Dominant optic atrophy

Congenital recessive optic atrophy

Sex-linked optic atrophy

Inherited optic neuropathy with other neurologic or systemic signs

Wolfram/DIDMOAD syndrome

Autosomal dominant progressive optic atrophy and deafness

Autosomal dominant progressive optic atrophy with progressive hearing loss and ataxia

Hereditary optic atrophy with progressive hearing loss and polyneuropathy

Opticocochleodentate degeneration

Sex-linked recessive optic atrophy, ataxia, deafness, tetraplegia, and areflexia

Opticoacoustic nerve atrophy with dementia

Dominant optic atrophy, deafness, ophthalmoplegia, and myopathy

PEHO syndrome

Behr’s syndrome

Optic neuropathy in other hereditary degenerative or developmental diseases

Hereditary ataxias

Friedreich’s ataxia

Spinocerebellar ataxias

Hereditary polyneuropathies

Charcot-Marie-Tooth disease

Familial dysautonomia (Riley-Day)

Hereditary spastic paraplegias

Hereditary muscular dystrophies

Storage diseases and cerebral degenerations of childhood (see Table 8–2)

Mitochondrial diseases

Leigh syndrome

MELAS syndrome

MERFF syndrome

CPEO/KSS syndrome

CPEO, chronic progressive external ophthalmoplegia; DIDMOAD, diabetes insipidus, diabetes mellitus, optic atrophy, and deafness; KSS, Kearns-Sayre syndrome; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes; MERRF, myoclonic epilepsy and ragged red fibers; PEHO, progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy.

Figure 8–3 Funduscopic view of the right (A) and left (B) optic nerves of a patient with Leber’s hereditary optic neuropathy who lost vision 6 months prior. Note the pallor of the discs, especially temporally, the latter indicating preferential damage to the papillomacular bundle.

Those patients whose vision improves most substantially appear to have a lower mean age at the time of initial visual loss.6,8 Recurrences of visual failure are extremely rare among those patients both with and without visual recovery.

In the majority of patients with LHON, visual dysfunction is the only significant manifestation of the disease. However, some pedigrees have members with associated cardiac conduction abnormalities, especially the pre-excitation syn-

dromes.1 Minor neurologic abnormalities have been reported in patients with LHON.13,16 Less commonly, pedigrees have been described in which multiple

maternal members demonstrate the clinical features of LHON in addition to more severe neurologic abnormalities, such as movement disorders, dystonia,

encephalopathic episodes, and brainstem syndromes.1 Disease clinically indistinguishable from multiple sclerosis may occur in families with LHON.6,16–18

It is possible that this association between LHON and multiple sclerosis is no greater than the prevalence of the two diseases but that an underlying LHON mutation may worsen the prognosis of optic neuritis in patients with multiple sclerosis.18 Ancillary tests, aside from genetic analysis, are generally of limited usefulness in the evaluation of LHON. Computed tomography and magnetic resonance imaging of the brain are typically normal in patients with LHON.1,4

All pedigrees clinically designated as LHON have a maternal inheritance pattern.3,9,10,19–21 In maternal inheritance, all offspring of a woman carrying

the trait will inherit the trait, but only the females can pass the trait on to the subsequent generation. Although both the father and the mother contribute to the nuclear portion of the zygote, the mother’s egg is virtually the sole provider of the zygote’s cytoplasmic contents. Because the intracytoplasmic mitochondria are the only source of extranuclear DNA, maternal inheritance indicates transmission of the abnormal trait via the mitochondrial DNA (mtDNA). Ironically,

the majority of proteins crucial to normal mitochondrial function are encoded on nuclear genes, manufactured in the cytoplasm, and transported into the mitochondria (Fig. 8–4). Hence a “mitochondrial disease” could conceivably result from genetic defects in either the nuclear or the mitochondrial genomes. Inheritance of mitochondrial diseases will be maternal if the genetic defect is an mtDNA point mutation or Mendelian if the genetic defect is on a nuclear gene involved in mitochondrial function.

Three point mutations in the mtDNA, the so-called primary LHON mutations, are believed to account for about 90% of cases of LHON worldwide.1,9,19 They

are located at mtDNA positions 11778 (69% of cases), 3460 (13% of cases), and 14484 (14% of cases). Several other mtDNA mutations may be “primary” but account individually for only a few pedigrees worldwide (Fig. 8–5). Screening for LHON in a patient with visual loss from optic neuropathy should begin with the three primary mutations.19 In those primary mutation-negative patients in whom suspicion remains high, testing for the other mtDNA mutations associated with LHON can be performed in specialized centers, especially for those mutations deemed likely causal in a few previous pedigrees. Alternatively, because

Figure 8–4 Diagram of a proposed common pathophysiology of the hereditary optic neuropathies through mitochondrial dysfunction. This schematic diagram of a cell shows how proteins coded for in the nucleus and in the mitochondrion both contribute to mitochondrial function. The bold arrows indicate where the genetic defects underlying dominant optic atrophy (DOA), Leber’s hereditary topic neuropathy (LHON), and Wolfram syndrome (DIDMOAD) may cause mitochondrial dysfunction and optic atrophy. mRNA, messenger RNA; mtDNA, mitochondrial DNA; oxphos, oxidative phosphorylation. (From Newman NJ: Hereditary optic neuropathies: From the mitochondria to the optic nerve. Am J Ophthalmol 2005;140:517–523.)

Figure 8–5 Mitochondrial genome showing the point mutations associated with Leber’s hereditary optic neuropathy (LHON). More than 90% of all cases of LHON are associated with the three primary mutations located inside the genome, and the other mutations are shown outside the genome. These other mutations vary markedly in their prevalence, degree of evolutionary conservation of the encoded amino acids altered, and frequency among controls. Mutations marked * may be primary, but they each account for only one or a few pedigrees worldwide. Mutations marked *d are primary mutations associated with LHON and dystonia. Mutations marked *m are primary mutations associated with LHON/MELAS overlap syndrome. (Modified from MITOMAP: A Human Mitochondrial Genome Database. http://www.mitomap.org, 2005. December 22, 2005.)

the majority of these other mtDNA mutations reside in genes encoding subunits of complex I, complete sequencing of complex I might also be considered. Finally, sequencing the entire mitochondrial genome is possible, although labor intensive. This should be performed only in those cases of high suspicion and interpreted only by those versed in the complexities of mitochondrial genetics.

Genetic analysis allows a broader view of what constitutes the clinical profile of LHON.1 Most striking is the number of patients without a family history of visual loss. Some of these singleton cases are women, some outside the typical age range for LHON, and some without the classic ophthalmoscopic appearance. Clearly, the diagnosis of LHON should be considered in any case of unexplained bilateral optic neuropathy, regardless of age of onset, gender, family history, or funduscopic appearance.

Many questions remain unanswered regarding the determinants of phenotypic expression in LHON. For instance, does the specific mtDNA mutation dictate particular clinical features? Although those pedigrees with LHON “plus” demonstrate that certain mtDNA mutations may result in specific disease patterns of Leber’s-like optic neuropathies with other neurologic abnormalities,1,9 few significant clinical differences have been demonstrated to date among those LHON patients positive for the 11778 mutation, those with other mtDNA mutations, and those as yet genetically unspecified. One major exception is the difference in spontaneous recovery rates among those patients with the 11778 mutation and those with the 14484 mutation. Among 136 patients with the 11778 mutation, only 5 (4%) reported spontaneous recovery,15 compared with 37% to 65% of 14484 patients.6,8 Furthermore, the ultimate visual acuities in patients with the 14484 mutation are significantly better than those with the 11778 and 3460 mutations.6

An mtDNA mutation will be present in all maternally related family members of patients with LHON, even though many will never become symptomatic. Hence, whereas the presence of an mtDNA mutation may be necessary for phenotypic expression, it may not be sufficient. Nuclear-encoded factors modifying mtDNA expression, mtDNA products, or mitochondrial metabolism may influence phenotypic expression of LHON. Although most studies have not been able to confirm X-linkage as an explanation of the male predominance of visual loss in LHON, the X-linkage hypothesis may still be viable.9 Environmental factors, both internal and external, may play a role. Systemic illnesses, nutritional deficiencies, medications, or toxins that stress or directly or indirectly inhibit mitochondrial metabolism have been suggested to initiate or increase phenotypic expression of the disease. Although some reports suggest a possible role for tobacco and excessive alcohol use as precipitants of visual loss,22 one large case-control study of sibships23 failed to confirm this. Other agents known to be toxic to the optic nerve, such as ethambutol, or to mitochondrial function, such as antiretroviral therapy, may have a heightened toxicity in patients with the LHON mutations and already compromised mitochondrial function.1

Theories on the pathogenesis of LHON must reconcile how multiple different mtDNA mutations located in different genes encoding different proteins result in an essentially identical clinical phenotype that is expressed only in the optic nerve, suddenly and bilaterally.10,19 Pathogenetic theories include reduction in ATP production and/or free-radical damage with resultant apoptosis of retinal ganglion cells. Selective involvement of the ganglion cell or its axon may be explained on a vascular, mechanical, or regional basis, with several studies suggesting a high degree of mitochondrial respiratory activity within the unmyelinated, prelaminar portion of the optic nerve.19 This portion of the visual system may be particularly vulnerable to mitochondrial dysfunction, especially abnormalities of complex I.24

A

Figure 8–7 Funduscopic view of the right (A) and left (B) optic nerves of a patient with dominant optic atrophy. Note the pallor and excavation of the discs, especially temporally, the latter indicating preferential damage to the papillomacular bundle.

autosomal-dominant optic atrophy have no additional neurologic deficits. However, sensorineural hearing loss is not uncommon and tends to cluster within families.1 The hearing loss may be severe and congenital, or subclinical, requiring audiology for detection. In most cases, it is unclear whether these pedigrees represent a phenotypic variant of DOA, a genetically distinct disorder, or a genetically heterogeneous group of disorders with a similar phenotype. In one remarkable family in which ophthalmoplegia and ptosis accompanied DOA and hearing loss,27 a chromosome 3 missense mutation was found, a mutation which in other pedigrees resulted solely in nonsyndromic optic atrophy.

DOA is likely to be a primary degeneration of central retinal ganglion cells but not the exclusive result of either parvocellular or magnocellular cell loss.26,28 Although a linkage study of one large DOA pedigree localized the gene responsible for DOA with the Kidd blood group antigen, subsequently localized to a region on the long arm of chromosome 18 (18q12.2–12.3),29 most of the pedigrees

with DOA have genetic homogeneity in their linkage to the telomeric portion of the long arm of chromosome 3 (3q28–29).1,25,28 Thirty percent to 90% of DOA

families have been found to harbor more than 90 different missense and nonsense mutations, deletions, and insertions in a gene within this region that has been designated the OPA1 gene.28 The product of the OPA1 gene is targeted to the mitochondria and appears to exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity.28 Downregulation of the OPA1 leads to fragmentation of the mitochondrial network and dissipation of the mitochondrial membrane potential with cytochrome c release and caspasedependent apoptosis.30 Interestingly, linkage analysis of patients with normal tension glaucoma has shown an association with polymorphisms of the OPA1 gene.31 These findings, coupled with the typical expression of both DOA and LHON