Ординатура / Офтальмология / Английские материалы / Advances in Understanding Mechanisms and Treatment of Infantile Forms of Nystagmus_Leigh, Devereaux_2008

IRENE GOTTLOB

ABSTRACT

New developments in genetics and pharmacological treatment of nystagmus are reviewed in this chapter. While cases of nystagmus are frequently sporadic, kindreds in which nystagmus segregated as an autosomal dominant, autosomal recessive, or X-linked trait have been reported. Of these, X-linked pedigrees are the most frequent. By linkage analysis, the major X-linked locus for nystagmus, NYS1, was localized to chromosome Xq26-q27. Linkage analysis and DNA-sequence analysis performed in 26 families with idiopathic congenital nystagmus (ICN) led to the detection of a novel gene named FERM domain containing 7, FRMD7, at Xq26.2 in which we have identified 22 different mutations. Mutations in the FRMD7 gene encode a previously unidentified member of the protein 4.1 superfamily. Several drugs have been used to treat acquired nystagmus; however, pharmacological treatment has so far not been used in congenital nystagmus. A randomized study showed that memantine (up to 40 mg) and gabapentin (up to 2400 mg) can significantly improve visual acuity in ICN and reduce nystagmus in ICN and in nystagmus associated to ocular disease.

Nystagmus consists of periodic to-and-fro movement of the eyes, which can be pendular or jerk type with a slow and fast component. It can be congenital or acquired due to neurological disease.1 The prevalence was estimated at 1 in 10002; however, we have recently

found, in a study specifically directed at people with nystagmus using capture–recapture statistics, that it is more common (approximately 24 per 10,000 population) (The Leicestershire Nystagmus Survey, unpublished data, 2007). Nystagmus has a significant impact on vision—visual function questionnaire scores are worse in people with nystagmus than with age-related macular degeneration—and a significant impact on social functioning.3

Congenital nystagmus can be idiopathic (ICN) or associated with albinism and retinal diseases, such as congenital stationary night blindness, achromatopsia, or blue cone monochromatism (secondary nystagmus [SN]). There is some evidence that in these diseases nystagmus is not caused by low vision but is intrinsic to the disease. For example, carriers of blue cone monochromatism with normal visual acuity have eye movement abnormalities.4 In albinism, neurodevelopmental abnormalities are indicated by misrouting of the nerve fibers in the optic chiasm, with more fibers crossing than in normal individuals. The congenital form of nystagmus can occur in association with visual deprivation in early infancy, for example, due to congenital cataract or optic nerve hypoplasia. This review will focus on two areas where new knowledge has recently emerged: genetics of idiopathic nystagmus and pharmacological treatment.

GENETICS OF IDIOPATHIC NYSTAGMUS

ICN is frequently sporadic, but kindreds in which nystagmus segregates as an autosomal dominant, autosomal

recessive, or X-linked trait have been reported.5 Of these, X-linked pedigrees are most frequently recognized, although penetrance may reach as high as 50% in obligate female carriers.6 By linkage analysis, gene NYS1 has been localized to chromosome Xq26-q27 in three families, ascertained in the United States.6,7 Recently, in a study of extended kindred from China, data were presented showing overlap with NYS1 and potential refinement of the candidate interval.8 Recently, Guo et al.9 also performed linkage analysis in two Chinese families and found that they matched to the NYS1 locus, but they could not reduce the possible genetic interval. Cabot et al.10 reported a large French family with ICN in which linkage to chromosome Xp11.4- p11.3 was demonstrated. However, this region contains several genes implicated in forms of congenital nystagmus associated with retinal diseases. These include congenital stationary night blindness, retinitis pigmentosa, cone dystrophy, and X-linked optic atrophy, thereby raising the possibility that congenital nystagmus in this kindred is allelic with one of these disorders.

We recently identified a novel gene associated with X-linked idiopathic nystagmus.11 We have collected DNA from 26 affected families in which there were multiple affected members, as well as from a cohort of singleton affected subjects (n = 42) with idiopathic congenital nystagmus. Families were of English, Irish, Scottish, German, Italian, Indian, Romanian, Madagascan, and Austrian origin. Only families with no ophthalmic or neurological abnormalities other than nystagmus were included. We performed detailed clinical, electrophysiological studies and eye movement recordings in order to exclude other associated causes of nystagmus, such as retinal diseases or albinism. Electroretinograms and visual evoked potentials (International Society for Clinical Electrophysiology of Vision standards) were obtained from at least one member of each family, and all were normal. All affected subjects had horizontal conjugate nystagmus with predominantly jerk waveforms with increasing slow-phase velocities, typically for idiopathic congenital nystagmus. We found significant variation within and between families in nystagmus amplitude and visual acuity. About 50% of female carriers were affected with nystagmus. For two out of 15 gene carriers analyzed with eye movements, subclinical nystagmus was detected only on eye movement recordings.

In the 16 largest families, linkage analysis confirmed linkage to Xq26. Microsatellite analysis reduced the linkage interval to 80 genes in Xq26 (Fig. 10.1). Systematic screening of more than 40 genes within this interval revealed mutations in a novel gene named FRMD7 (FERM domain containing 7, known as LOC90167) at Xq26.2.

We have identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic nystagmus, which suggests that mutations in FRMD7 are a common

cause of familial nystagmus. Screening of 42 singletons cases of idiopathic congenital nystagmus (28 males and 14 females) yielded 3 mutations (7%). (see Fig. 10.2)

EXPRESSION OF FRMD7

Studies of the expression of FRMD7 in human tissue using reverse transcriptase-polymerase chain reaction (RT-PCR) showed that the mRNA is present in most tissues at a low level. RT-PCR detected expression in human adult kidney, liver, pancreas, heart, and brain. We have also shown, using in situ hybridization probes from the 3’UTR FRMD7, that it is expressed in early human embryos at ≈ 56 days post-ovulation, where there is expression in the ventricular layer of the forebrain, midbrain, cerebellar primordium, spinal cord, and developing neural retina.

Mutations in FRMD7 encode a previously unidentified member of the protein 4.1 superfamily. The function of the FRMD7 protein is unknown, but blast search analysis revealed that it has close amino acid sequence homology to FARP1 (FERM, RhoGEF, and pleckstrin domain protein 1; chondrocyte-derived ezrin-like protein) and FARP2 proteins.12,13 The homology is concentrated at the N terminus of the protein, where B41 and FERM domains are present. The location relative to these domains is shown in Figure 10.2.

The length and the degree of branching in neurons and organization of cytoskeleton of the embryonic rat cortex is modulated by the homologous protein FARP2.12,13 Similarly, it is possible that changes in neurite length and branching caused by mutations in FRMD7 during development, for example, in the midbrain, cerebellum, and retina, lead to nystagmus. Taken together, these data implicate FRMD7 as the major X-linked idiopathic nystagmus locus. Knowledge about the gene function will shed light on the mechanism of nystagmus and possibly other eye movement disorders.

PHARMACOLOGICAL TREATMENT OF NYSTAGMUS

Treatment of nystagmus remains largely empirical. One symptomatic approach is to weaken the extraocular muscles by botulinum toxin injections,14-16 but the effect is transient and carries significant side effects. Optical methods to stabilize images on the retina17 have not proved practical. Prisms or surgery of extraocular muscles can be used to dampen nystagmus.18-20

Studies using pharmacological inactivation have clarified the neurotransmitters involved in neuronal integration of ocular motion. Microinjection of drugs into the region of the nucleus prepositus hypoglossi– medial vestibular nucleus showed that agents with either

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agonist or antagonist action of GABA, glutamate, and kainate receptors all caused gaze-evoked nystagmus.21-24 Several reports note nystagmus improvements in response to pharmacological substances. For example, GABAb agonist baclofen was reported to abolish periodic alternating nystagmus due to clinical or experimental lesions,25,26 as well as downbeat nystagmus.27 In one patient with multiple sclerosis, smoking cannabis reduced nystagmus.28 Anticholinergic drugs, sodium or potassium channel blockers, alcohol, clonazepam, and other anticonvulsants have been administered for nystagmus.29 Potassium channel blocker 3,4-amino-

pyridine has been effective in downbeat nystagmus.30 The reports of GABAergic projection into the neu-

ral integrator21-24 prompted a double-blind study of two

GABAergic agents, baclofen and gabapentin.31 Gabapentin, but not baclofen, reduced nystagmus substantially in 10 out of 15 patients with pendular acquired nystagmus. In a single-masked study comparing gabapentin to vigabatrin, gabapentin was more effective.32 Since vigabatrin is a pure GABAergic drug but gabapentin is not selectively GABAergic, the authors postulated that the effect of gabapentin is related to non-GABAergic mechanisms of action, such as interference with glutamate transmission. This hypothesis is further supported by a report about memantine, which also has antiglutaminergic action, on acquired pendular nystagmus. Memantine caused complete cessation of nystagmus in 11 out of 11 patients with acquired pendular nystagmus.33

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Figure 10.2 Schematic diagram of FRMD7 showing the location and mutations identified to date. Source: Tarpey P, Thomas S, Sarvananthan N, et al. Mutation in FRMD7, a newly identified member of the FERM family, causes X-linked idiopathic congential nystagmus. Nat Genet. 2006;38(11):1242–1244. Reprinted with permission.

These results make memantine a strong candidate for pharmacological treatment of acquired nystagmus. Memantine preferentially blocks excessive glutaminergic activity, and its actions involve effects on NMDA, AMPA, and dopaminergic pathways.34 Gabapentin likely acts by binding to the α-2 δ subunit of voltagedependent calcium channels.35 The mechanisms by which these drugs suppress nystagmus are currently unclear. The recent discovery of FRMD7, a novel gene mutated in X-linked ICN, may lead to the elucidation of nystagmus mechanisms and the beneficial effects of these drugs.11

Congenital nystagmus is usually not treated pharmacologically. Since there have been no reports of drugs being effective in congenital nystagmus, we first investigated the effect of gabapentin in congenital nystagmus in case studies. Gabapentin reduced the nystagmus in a patient with congenital corneal dystrophy, increasing his visual acuity by two lines.36

In a retrospective case series including 16 patients with neurological nystagmus and 7 with congenital nystagmus, we found that all 7 congenital patients improved in visual function and had reduced nystagmus amplitude with gabapentin. 37

These results encouraged us to perform a randomized, placebo-controlled study in congenital nystagmus using gabapentin and memantine.38 We included 48 patients (47 completed the first four examinations) with ICN and patients with SN associated to ocular disease, mainly albinism, who were randomized in six groups: (1) ICN receiving up to 40 mg memantine (n = 6); (2) SN receiving up to 40 mg memantine (n = 10); (3) ICN receiving up to 2400 mg gabapentin (n = 8);

(4)SN receiving up to 2400 mg gabapentin (n = 8);

(5)ICN receiving placebo (n = 6); and (6) SN receiving placebo (n = 9).

We found LogMAR visual acuity (VA) improved significantly with memantine and gabapentin but not with placebo for the ICN group. Figure 10.3 illustrates that LogMAR VA in ICN improved up to the last visit where drugs were administered and, after drug cessation, had not returned to baseline after 2 weeks. However, at the last examination, 2 months after cessation of drug intake, ICN had returned. Figure 10.4 shows the absolute

(A) and relative (C) improvement of VA before and after memantine, gabapentin, and placebo administration.

Quantitative analysis of nystagmus showed significant improvements in eXpanded Nystagmus Acuity Function (NAFX) (predicted VA estimated from foveation) and nystagmus intensity for both drugs for patients with ICN and SN (Figs. 10.4B,10.4D, 10.4E, 10.4F). Drug tolerability was good. There were no serious adverse events and no major side effects. In the memantine group, 9 out of 16 patients had side effects (6 reduced the dosage). In the gabapentin group, 9 out of 16 patients had side effects (2 reduced the dosage). In the placebo group, 5 out of 15 subjects had side effects (none reduced the number of capsules). Side effects were similar in all groups and included dizziness, tiredness, sleeplessness, light-headedness, nausea, headaches, shakiness, weakness, and drowsiness. On reduced dosage, participants tolerated drugs well.

Twenty-six patients opted to continue drug treatment, and a long-term effect for up to 18 months was documented. Several patients were able to start driving on treatment, and 2 patients started to work. Our findings show for the first time that pharmacological agents

such as memantine and gabapentin can improve VA, reduce nystagmus intensity, and improve foveation in congenital nystagmus.

CONCLUSIONS

Mutations in the newly detected FRMD7 gene are a major cause of X-linked ICN. The first insights into the potential function of FRMD7, and thus to the understanding of the mechanisms of nystagmus, are emerging. On the one hand, there is a homology between FRMD7 and FARP2, which modulates the

length and degree of branching of neurites in rat embryonic neurons. On the other hand, expression of FRMD7 has been shown in brain areas likely to be responsible for eye movements and the retina. Our finding that neurotransmitters can reduce congenital nystagmus supports a new treatment approach. We hope that advances in genetics and pharmacological treatment will lead to better understanding and, ultimately, new possibilities of treatment for nystagmus.

ACKNOWLEDGMENTS The authors wish to acknowledge The Ulverscroft Foundation, Medisearch, and the Nystagmus Network, UK, for supporting this study.

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