Acta Ophthalmologica 2009

Review Article

Lattice corneal dystrophy, gelsolin type (Meretojas syndrome)

Christian Carrwik and Ulf Stenevi
Department of Ophthalmology, Sahlgrenska University Hospital, Mo lndal, Gothenburg, Sweden

ABSTRACT. Purpose: This paper reviews current knowledge about the pathogenesis, clinical manifestations and treatment of lattice corneal dystrophy, gelsolin type (LCD2, Meretojas syndrome). Methods: Material is derived from literature searches, a case study of a Finnish patient living in Sweden, and interviews in Helsinki with Professor Ahti Tarkkanen and Dr Sari Kiuru-Enari, both of whom have extensive rst-hand experience in treating patients with the disease. Results: The disease is now reported from several countries in Europe, as well as Japan, the USA and Iran. Treatment is symptomatic and is based on eye lubrication combined with rigorous monitoring of intraocular pressure to reduce corneal haze and postpone the need for keratoplasty. When systemic symptoms occur, the ophthalmologist should consult other specialists. Conclusions: The disease is probably under-reported and is almost certainly to be found in more countries, including Sweden. Every ophthalmologist should be vigilant and consider this diagnosis when discovering a corneal lattice dystrophy, especially because the disease is an inherited, lifelong chronic condition with systemic symptoms.
Key words: amyloidosis familial amyloidosis gelsolin type lattice corneal dystrophy LCD2 Meretojas syndrome

Acta Ophthalmol. 2009: 87: 813819

2009 The Authors Journal compilation 2009 Acta Ophthalmol

leads to systemic manifestations such as peripheral paralysis of the facial nerve, cutis laxa and a characteristic facial appearance (Kiuru 1995). There is no cure for the disease and all treatment is symptomatic. Because the ocular symptoms are the rst to arise, the ophthalmologist plays a key role in discovering and diagnosing the disease. Patients with the disease need to maintain lifelong contact with an ophthalmologist and to undergo examinations several times annually (Tarkkanen 2008, personal communication). Knowledge of the molecular aspects of the disease has advanced rapidly, with several new reports published yearly. However, less effort has been made to study the clinical management and treatment of the hundreds of LCD2 patients known worldwide today. The aim of this overview is to summarize the basic facts of the disease and to focus on clinical management from the ophthalmologists point of view.

doi: 10.1111/j.1755-3768.2009.01686.x

Introduction
In August 1968, two men with corneal lattice dystrophy and mask-like faces presented at the Department of Ophthalmology at the University of Helsinki, Finland. Their cases led to the identication of a new disease, rst described by Meretoja (1969). In recent years, new cases been reported from

several other countries, but not yet from Sweden (Kiuru 1998). Lattice corneal dystrophy, gelsolin type (Meretojas syndrome), or lattice corneal dystrophy type 2 (LCD2), is an autosomal dominant inherited amyloidosis. The rst sign of the disease is a corneal lattice dystrophy with amyloid deposits, usually seen in the third decade of life. Deposition of amyloid in other organs eventually

Materials and Methods

We performed a literature search using the following search phrases: Meretoja syndrome, corneal lattice dystrophy type 2, corneal lattice dystrophy type II, familiar amyloidosis of Finnish type, Gelsolin amyloidosis and AGel amyloidosis. Two theses on the subject, by Meretoja (1973a) and Kiuru (1995), were also studied.

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Dr Ahti Tarkkanen, Professor of Ophthalmology, and Dr Sari KiuruEnari, neurologist and senior lecturer, were interviewed in Helsinki, Finland in order to investigate clinically relevant facts about the disease. Furthermore, one of two known patients with Meretojas syndrome in the Va stra Go taland region of western Sweden was interviewed and clinically examined at Sahlgrenska University Hospital, Mo lndal, Sweden. The patients medical records were studied with her consent. This disease is known under several names, including familial amyloidosis Finnish type (FAF), Meretojas syndrome, Kymenlaakso syndrome, familial amyloid neuropathy type IV, AGel amyloidosis and amyloidosis V. According to the classication by the International Committee for Classication of Corneal Dystrophies (IC3D), the correct name of the disease is lattice corneal dystrophy, gelsolin type, or LCD2 in short (Weiss et al. 2008).

or Australia have been published to date. The mortality rate in LCD2 patients was found to be higher than in the Finnish population without the disease (Meretoja 1973a).
Biochemical background

Results
Epidemiology

Lattice corneal dystrophy, gelsolin type (LCD2) was rst reported in the Ha me province in southern Finland by Meretoja (1969). The geographical clustering was striking and further research suggested a prevalence up to 1 : 1040 in that area (Meretoja 1973a). Meretojas total material included 207 patients from 56 families. Today, approximately 400600 patients are known at the University Hospital in Helsinki (Kiuru-Enari 2008, personal communication). It was rst believed that the disease was associated with Finnish ancestry, but it has since been found in patients with no known connections to Finland. Cases have been reported from several countries, including Japan (Ikeda et al. 2007), the USA (Kiuru 1998), Spain (Huerva et al. 2007), France (Chastan et al. 2006), the Netherlands (Donders & Blanksma 1979), Portugal (Conceicao et al. 2003) and the UK (Mearza et al. 1999). Recently, the disease was found in a family in Iran, demonstrating the rst case to be reported from the Middle East (Ardalan et al. 2007). No case reports from South America, Africa

LCD2 is an amyloid disease based on misfolded proteins that form b-sheets instead of a-helices. As in other amyloid diseases, the misfolded proteins lead to brillar structures of amyloid deposits associated with pathology in affected organs (Abbas et al. 2005). LCD2 is one of about 30 inherited corneal diseases that have been mapped to a specic gene locus. Mutations giving rise to corneal disease have been found in 10 different human chromosomes, but LCD2 is the only inherited corneal disease linked to a mutation in chromosome 9 (Klintworth 2003). The point mutation is autosomal dominant (OMIM #105 120) and has a penetrance of 100% (Kiuru 1998). In LCD2, the relevant mutation is located at 9q32-34 in the gene coding for gelsolin, a protein produced in most mammal cells. The mutation is a single base mutation with a transition of guanine to adenine at position 654 (G654A). This leads to a change in codon 187, replacing aspartatic acid by asparigine (D187N). A similar mutation, where aspartatic acid is replaced by tyrosine (D187Y), has been found in patients of Danish and Czech origin. The clinical expression of this phenotype is very similar to the D187N genotype, found in all Finnish patients (Maury et al. 2000; Poulaki & Colby 2008). Gelsolin is a six-domain protein available in two sizes as a result of alternative splicing. The intracellular version has a mass of 81 kDa and the secreted version, found in plasma, has a mass of 83 kDa. Both variants contain the mutation, but only the version found in plasma is responsible for the formation of amyloid (Kangas et al. 1996). Cellular gelsolin is involved in the process of maintaining the motility and architecture of the cell, whereas plasma gelsolin is part of the scavenging system that removes actin laments from the blood (Kazmirski et al. 2002). The name gelsolin derives from its role in the

gelation and solation of actin laments (Kivela et al. 1994). The mutation changes the characteristics of the G2 subunit in the gelsolin molecule. The subunit loses a binding site for Ca2+, required to stabilize the protein. This leads to an abnormal proteolysis in the C-terminal fragment of the molecule, which results in amyloidogenic fragments. Deposits of these 70-residue fragments lead to symptoms in the affected organs, as will be discussed later (Kazmirski et al. 2002).
Clinical ndings Ophthalmology

Lattice dystrophy is a subtype in the vast group of corneal dystrophies, of which dozens of types and subtypes are known (Klintworth 2003). The International Committee for the Classication of Corneal Dystrophies (IC3D) was founded in 2005 to develop a new system of classifying corneal dystrophies which would illustrate the complexity of this group of diseases. The description lattice dystrophy refers to the linear network of subepithelial opacities found in affected corneas. In histological examination, the lattice lines stain positively for amyloid markers such as Congo red. There are ve different types of corneal lattice dystrophies, classied by the location of deposits and clinical features (Poulaki & Colby 2008). Lattice corneal dystrophy, gelsolin type, is characterized by lattice lines concentrated in the anterior and middle stroma, visible on slit-lamp microscopy. The lattice lines tend to be denser in the peripheral part of the cornea. Meretoja (1973a) noted that the lattice lines follow the branches of the ciliary nerves, originating from the trigeminal nerve. However, more recent research suggests that local production of amyloid, rather than degenerated nerves, contributes to the dystrophy (Kivela et al. 1994; Rosenberg et al. 2001). Deposition of amyloid is present under Bowmans layer and in some cases at the level of the epithelial basal membrane. Scar tissue with occasional amyloid deposits sometimes invades the subepithelial space (Kivela et al. 1993). Lattice dystrophy is the rst sign of LCD2 and usually appears in the third decade of life (Meretoja 1973a).

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Patients often have reduced corneal sensitivity and frequently show erosions of the cornea. Dry eye syndrome is often observed, caused by the involvement of several cranial nerves. The blink reex (trigeminal nerve) is diminished and contraction of the orbicularis muscle (facial nerve) is reduced. Ectropion caused by peripheral facial paralysis increases the evaporation area, which accentuates the problem. Blepharochalasis is another common sign, found in 27 of 30 patients according to Kiuru (1992). Secondary chronic open-angle glaucoma is another eye manifestation. The increase in intraocular pressure (IOP) is thought to reect the result of the effect of mutated gelsolin in the trabecular muscle cells rather than the deposit of amyloid because no amyloid has been found in the trabecular meshwork. Visual loss may occur in patients aged > 60 years (Kiuru 1998). Cataract was mentioned, but not suggested as typical for the disease, in Meretoja (1969) and bilateral cataract was found in one of 30 patients in Kiuru (1992). Despite these gures, clinical experience suggests that cataract is more common in LCD2 patients. As no amyloid has been found in lenses from LCD2 patients, the possible mechanism for this is unknown. It is suggested that amyloid in the ciliary body (see below) or changes in the aqueous humour may change the characteristics of the lens (Kivela et al. 1994; Tarkkanen, interviewed May 2008). Examinations of eyes of LCD2 patients after autopsy reveal more ocular amyloid deposits than those visible in corneal microscopy. In deceased LCD2 patients, amyloid is found in the conjunctiva, sclera, the perineurium of ciliary nerves, the walls of ciliary vessels, the optic nerve sheaths, the stroma of the ciliary body and along the choriocapillaris. The presence of amyloid in avascular as well as in vascularized ocular structures suggests that both local and systemic production is responsible for the deposition. No amyloid was found in control eyes (Kivela et al. 1994). Rosenberg et al. (2001) conducted a study of 20 eyes in 20 patients with LCD2 to measure corneal sensitivity. The diagnosis had been conrmed and had been known to the patients

for between 2 weeks and 30 years. Under slit-lamp microscopy, all the examined corneas showed stromal lattice lines, which, as described above, are typical of the disease. Diminished or absent long nerve bre bundles in the sub-basal nerve plexus were observed in 18 subjects, explaining the reduced corneal sensitivity. Corneal sensitivity was studied with thermal, chemical and mechanical stimulation of the cornea. A statistically signicant difference regarding mechanical stimulation was found in patients with LCD2, who had a higher stimulus threshold than healthy control subjects.
Systemic symptoms

In a more recent study, Rothstein et al. (2002) compared the severity of systemic symptoms with ndings in confocal microscopy. Although based on only three patients, the study demonstrated a positive correlation between the degree of corneal haze and systemic symptoms. This suggests that confocal microscopy is a valuable, non-invasive tool for determining the phase of the disease. In a recently reported case of LCD2 in Iran, the patient was also found to have retinitis pigmentosa (RP). Several members of the patients family were also reported to have RP (Ardalan & Shoja 2007; Ardalan et al. 2007). The authors believe this is not coincidental and a project to study this possible connection between RP and LCD2 is in progress. Peripheral paresis of the upper branch of the facial nerve is the predominant neurological sign of LCD2. This neuropathy, which eventually involves the lower branches, is often apparent after the age of 40 years. Meretoja (1973a) found 137 of 154 patients aged > 40 years had total or partial paresis of the upper branch of the facial nerve. In a homozygote patient, this paresis was already clinically manifest in the early teens. Several other cranial nerves have been observed to be affected. The lattice lines in affected corneas follow the branches of the trigeminal nerve. Reduced or absent corneal sensation, weak masseter function and patchy facial hypaesthesia are possible effects of trigeminal nerve involvement.

Tongue atrophies and fasciculations caused by the involvement of the hypoglossal nerve have been observed in older patients. Glossopharyngeal and vagus nerves may also be affected in elderly patients, leading to dysarthria and tendencies to drooling. Involvement of the accessory nerve has also been reported (Kiuru 1998). Neuropathy of the peripheral nerves has been reported in most families affected by LCD2. Peripheral neuropathy usually begins in the lower extremities, but it sometimes starts distally in the upper extremities. Electrophysiological examinations in Finnish patients show that sensorimotor nerve involvement is common in the fth decade of life. The involvement is mainly sensory, with the vibrational sense affected more than other modalities. Carpal tunnel syndrome, disturbed reexes, muscular weakness and manual clumsiness are other signs of peripheral neuropathy reported in the literature (Meretoja 1973a; Kiuru 1992, 1998). Neuropathological analysis of peripheral nerves from LCD2 patients shows frequent hyaline thickening of the perineurium and blood vessel walls. The myelinated nerve bres have signicantly smaller area and lower density than nerves from healthy controls; nerve bre injury may be caused by ischaemia from amyloid deposits in the vessels supporting the nerves (Kiuru-Enari et al. 2002). Autonomal nerve dysfunction, including orthostatic hypotension, impotence and gastrointestinal problems, has been reported in some cases (Kiuru 1998). Regarding higher central nervous system (CNS) functions, LCD2 patients show a slight impairment in memory and visiospatial abilities in neuropsychological testing. Amyloid deposits have been found in spinal and cerebral blood vessels, and cerebral amyloid angiopathy is a wellknown cause of cerebral haemorrhage, ischaemic infarcation and dementia. Magnetic resonance imaging (MRI) examinations and cerebrospinal uid (CSF) analysis in LCD2 patients also suggest the involvement of the CNS (Kiuru 1998; Kiuru et al. 1999a). Meretoja (1973a) noted that the intelligence of LCD2 patients was normal and that many individuals had

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attained high social positions and advanced education. Physicians who treat LCD2 patients today share this observation, but there has been no systemic analysis (Kiuru-Enari 2008, personal communication; Tarkkanen 2008, personal communication). A case of severe and deleterious ataxia was reported in one Finnish patient. Autopsy revealed amyloid deposits and atrophy at several levels along the proprioceptive pathway, giving a possible explanation for the symptoms (Tanskanen et al. 2007).
Dermatology

Other symptoms

In the rst study of 10 patients in 1969, all were reported to have various dermatological anomalies. Most had thickened or pendulous skin, but atrophic and silky skin was also present (Meretoja 1969). Since the rst description of LCD2 was published, little effort has been applied to investigating its dermatological implications, despite the fact that virtually all patients with the disease show skin manifestations. KiuruEnari et al. (2005) published the rst article describing the pathomechanism of the disease, which was considered to represent a genodermatosis (i.e. an inherited skin disease). The 10 patients studied by KiuruEnari et al. (2005) all had characteristic cutis laxa, which manifests clinically as loose and sagging skin with reduced elasticity and resilience. Loss of body hair, intracutaneous bleeding, dry itching skin and excoriation were also reported in the majority of the patients. Blepharochalasias and abnormal laxity of the scalp and skin of the forehead were typical in younger patients, whereas older patients often had severe scalp and facial laxity and drooping lips and ears. Histological examination showed that all patients had gelsolin amyloid deposits in various cutaneous structures. By using antibodies against gelsolin amyloid, the strongest reactions were found in the basal membranes of the epidermis and sweat glands. Sweat and sebaceous glands and hair follicles were also observed to be reduced or absent. A decrease in the number of dendritic cells, a part of the immune system, suggests that immunological abnormalities may contribute to the disease (Kiuru-Enari et al. 2005).

Meretoja (1973a) described renal involvement as a part of the syndrome and found proteinuria in 49% of patients aged > 40 years. In heterozygotes, the proteinuria is usually mild and intermittent and is today considered less important than manifestations in other organs. However, there are reports of heterozygotes exhibiting nephrotic syndrome in the advanced stage of the disease (Kiuru 1998). In homozygote patients, the renal symptoms are more alarming. A 28year-old woman in Meretoja (1973a) developed nephrotic syndrome and a 25-year-old woman in a recently published Iranian case was affected by end-stage renal disease (Ardalan et al. 2007). This is a sign for nephrologists, as nephrotic syndrome could be the rst presentation of the disease in a young homozygote (Ardalan et al. 2007). Meretoja (1973a) considered various cardiac failures to represent an integral part of the syndrome. He found evidence of cardiac disease in 36 of 153 (23%) patients aged > 40 years. More recent research suggests that cardiac involvement does occur, but not as frequently as was rst thought. Of 30 patients reported by Kiuru (1995), none were found to have symptoms or physical signs of heart failure. All but one patient had normal systolic function and normal left ventricular diameter. Based on case reports, the most common cardiac involvements seem to be various conduction abnormalities. Older patients may even need a pacemaker. Atrioventricular blocks, ranging from rst to third degree, were reported in a French family diagnosed with the disease (Meretoja 1973a; Kiuru 1998; Chastan et al. 2006). Obstructive sleep apnoea syndrome (OSAS) has been reported in LCD2 patients. A study of ve LCD2 patients with snoring problems revealed that four of them had OSAS, with redundant oropharyngeal and hypopharyngeal soft tissue and cranial neuromuscular dysfunction. Although these ndings are based on a small and selected population, they are important because OSAS is a potentially lethal condition (Kiuru et al. 1999b).

Except for DNA verication, there is no laboratory test of diagnostic signicance for LCD2. Findings of proteinuria, increased total protein in CSF, and elevation of a2 and b2 fractions in serum protein electrophoresis have been described (Kiuru 1998). In the 207 patients reported by Meretoja (1973a, 1973b), eight cases of neoplastic disorders were veried. Five of them were malignant. None of them were considered as a cause of the amyloidosis and no other research indicates a correlation between LCD2 and cancer.
Diagnosis and treatment

The diagnosis LCD2 is typically made by observation of the lattice dystrophy in combination with a pedigree compatible with autosomal dominant inheritance. Lattice dystrophy and pedigree were the inclusion criteria in the study of 30 patients with the disease carried out by Kiuru (1995), which represents the largest study since Meretojas original work. Analysis of the patients DNA conrmed that the diagnoses in all cases matched the criteria above (Kiuru 1995). Today, DNA analysis is widely available and any laboratory for clinical genetics can search for the point mutation in the gelsolin gene. Mapping of the whole gene, however, is not routinely performed in laboratories outside Finland. In Finland, the only country in which LCD2 patients are diagnosed on a more regular basis, DNA is not analysed in every case. If the disease is already DNA-veried in the family, a new test provides only limited new information; however, if a clinically healthy person from an affected family seeks genetic counselling, DNA testing may be indicated. Because the disease may still be asymptomatic in patients in their late 20s, the result of a DNA test in combination with qualied counselling may affect family planning decisions (Kiuru-Enari 2008, personal communication; Tarkkanen 2008, personal communication). There is no cure or general treatment for LCD2. As the main manifestations are ocular, the ophthalmologist has the main role in the symptomatic treatment of LCD2 patients. Regular examinations with slit-lamp microscopy and IOP measurements are

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recommended for all patients with the disease. Eyelid function should also be checked on a regular basis. At least three annual visits are recommended, although the frequency of consultation may vary depending upon the severity of the symptoms. Monthly visits are not uncommon (Tarkkanen 2008, personal communication). The deposition of amyloid in the cornea cannot be stopped; keratoplasty is the only way to give the patient a clear cornea. The graft will eventually accumulate amyloid, but a graft will postpone the natural process of the disease for approximately 5 years (Tarkkanen 2008, personal communication). Phototherapeutic keratectomy (PTK) has been used with excellent primary results, but with later recurrence (Fagerholm 2003). The main strategy for postponing keratoplasty is rigorous IOP control. Clinical experience shows that corneal haze increases with rising IOP. Given the prevalence of glaucoma and corneal erosions in the disease, IOP control becomes even more important. The aim is to maintain IOP at < 12 mmHg in patients whose visual acuity (VA) is affected. To reach this, traditional topical pressure-reducing agents without preservatives are used because of the subjects low tolerance of preservatives. Acetazolamide should be avoided because of its renal effects. Note that traditional applanation tonometry may be unreliable in LCD2 patients because of the altered biomechanics of the cornea. If glaucoma surgery is needed, the prognosis is the same as in patients without LCD2 (Tarkkanen 2008, personal communication). Managing dry eye syndrome is of paramount importance in LCD2 patients. Not only do dry eyes increase the risk for corneal erosions, but these erosions may more easily remain unnoticed as a result of reduced corneal sensitivity. Therefore, protective contact lenses and the avoidance of sunlight are recommended. A common combination for keeping the eyes lubricated involves using lubrication drops without preservatives several times daily and vitamin A ointment before going to bed. Gaining patient compliance for aggressive anti-dry eye treatment is challenging for the ophthalmologist because the patients perception of his

or her dry eyes is reduced as a result of the loss of sensitivity. If facial nerve paralysis and ectropion increases the evaporating surface, plastic surgery may be indicated. Punctal plugs are another option, but the experience in LCD2 patients is disappointing (Tarkkanen 2008, personal communication). Cataract in LCD2 patients can be treated with intraocular lens (IOL) implantation as in other patients, but the surgical approach is somewhat different. Visibility for the surgeon may be poor as a result of corneal haze and, if so, a planned extracapsular cataract extraction should be considered rather than standard phacoemulsication (Tarkkanen 2008, personal communication). For the LCD2 patient, the ophthalmologist is the most frequently consulted doctor. Other specialties should not be forgotten, however. In addition to visiting their family doctors, LCD2 patients are advised to make regular visits to neurologists and cardiologists. A yearly check-up at the neurologist includes a thorough neurological history and examination. Other examinations, such as MRI or electroneuromyography (ENMG), may be carried out on special indication. The cardiological examination recommended is an annual 24-hour electrocardiogram (ECG) and echocardiography. A nephrologist may be consulted if proteinuria is found by the family doctor or another specialist (Chastan et al. 2006; Kiuru-Enari, interviewed May 2008). According to a survey (Laine 2007, unpublished data), 83% of LCD2 patients were satised with their social life, compared with 85% of the control group (n = 273). This suggests that the facial deformities are manageable and do not lead to social isolation. Nevertheless, cosmetic plastic surgery is an option for LCD2 patients who suffer as a result of distortions in their appearance. For Finnish patients, this is funded by the public health system (Tarkkanen 2008, personal communication).

strabismus, she remained healthy during childhood and adolescence. Her mother, now deceased, was diagnosed with LCD2 by Meretoja (1973a) and included in his study. The diagnosis was later veried with DNA analysis (Kiuru-Enari, interviewed May 2008). Patient L has two sisters, neither of whom have been diagnosed with LCD2 (Fig. 1). In her late teens, L moved to Sweden. Around the age of 25 years, her vision became somewhat impaired and she now recalls it as a bilateral haze. A doctor, a non-ophthalmologist, examined her without reaching a diagnosis. The haze diminished without treatment. After the age of 30 years, she began to have difculty frowning, suggesting that the facial nerve was affected. As her mother was known to have an amyloidosis, gastric and rectal biopsies were taken. However, histopathological examination showed no amyloid deposits in the biopsies. In 1991, the ocular problems escalated and L underwent keratoplasty in her left eye. Because of allograft reactions, the procedure was repeated twice. In 1993, another keratoplasty was performed in the same eye as a result of increasing haze. The ocular symptoms were manageable and L continued to work fulltime as a nurse. In February 2002, she experienced a sudden IOP increase in the right eye and received acute treatment with timolol and acetazolamide. Trabeculectomy was discussed, and

Case Report
Patient L, a 59-year-old woman, was born in the Kymenlaakso district in southeastern Finland. Except for mild

Fig. 1. This pedigree shows the inheritance in patient Ls family. L is the only affected female in the second generation. None of Ls three children have been diagnosed with the disease. However, the older daughter (born in 1971) has ocular symptoms similar to those L rst experienced.

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she was referred to Sahlgrenska University Hospital. With successful pharmacological treatment, including latanoprost (Xalatan), the trabeculectomy was cancelled. In September 2003, another keratoplasty was performed in the left eye as a result of increasing haze. An episode of endotheliitis caused by herpes simplex occurred in 2006. Patient L was hospitalized and treated successfully with aciklovir. As of May 2008, patient L is examined monthly by an ophthalmologist. She wears protective contact lenses in both eyes and these are changed during her monthly visits. She works fulltime as a nurse with administrative duties and does not require the optical aids offered by her employer. Her eyes are often dry, she suffers from photophobia and always carries a pair of sunglasses with her. She prefers working in rooms with dimmed light and avoids sunlight. Her current medication consists of timolol (without preservatives, one drop twice daily in both eyes), latanoprost (one drop at bedtime in both eyes), chloramphenicol (one drop every morning in both eyes), and ocular lubricant (Bion tears) administered four to six times daily. The only nonophthalmologic medication she uses is simvastatin 20 mg daily, prescribed for hyperlipidaemia. Patient Ls VA uctuates as a result of the current status of haze and erosions in the non-transplanted cornea of the right eye. When erosions cover the optical zone of the cornea, the VA in that eye is close to zero (Fig. 2). The patients VA with protective contact lenses is 0.5 in the right eye and 0.65 in the left eye; IOP is 10 mmHg and 9 mmHg in the right and left eyes, respectively. Pupil reaction and eye motility are normal. She has corneal sensitivity and corneal reex in both eyes. Microscopic examination reveals a stromal haze of the right cornea, with lattice lines concentrated in the periphery. The left eye has a corneal graft and clearer stroma with small lattice lines (Figs 24). Neurological examination shows peripheral palsy of the upper branch of the facial nerve. In both upper extremities, the patient reports numbness starting from the elbow and proceeding distally. In the lower left

Fig. 2. Right eye, photograph taken several months before Fig. 3. The patient has a clearly visible erosion in the central optical zone, causing pain and reducing visual acuity.

Fig. 4. Left eye. This eye has a corneal graft with less haze than the right eye. Nevertheless, microscopic examination reveals small lattice lines in the graft. Note the protective contact lens.

extremity, a burning sensation is felt when touching the dorsal side of the foot. The affected area corresponds to the area typically innervated by the supercial bular nerve. The patient reports no cardiac symptoms, but a preoperative ECG performed in 2003 revealed a somewhat irregular rhythm. Pulse and blood pressure are normal. There are no signs of renal dysfunction and serum creatinine was normal at the last test in 2003. There is no record of urine testing for proteinuria. At her own expense, patient L has undergone plastic surgery twice because of facial skin laxity. The procedures have yielded good results. She has an absence of forehead lines, but no other abnormal dermatological ndings (Fig. 5). Except for the ophthalmological problems described earlier, patient L describes her quality of life as good. However, she has seen her own mother suffer from the disease and knows its natural progress too well. This, she concedes, may encourage her to avoid becoming involved in

more thorough medical investigations than the monthly visit to the ophthalmologist. Patient L has two daughters, born in 1971 and 1973, respectively, and a son born in 1982. None of them are diagnosed with LCD2.

Discussion
Although it was rst thought to represent one of many Finnish genetic disorders, LCD2 is now reported from several countries and continents. As knowledge about the disease spreads in the medical community, the discovery of more cases is anticipated. Because the ocular symptoms are the rst to arise, the ophthalmologist must be vigilant and consider this diagnosis when discovering a corneal lattice dystrophy. Case reports from countries other than Finland indicate that LCD2 patients have visited ophthalmologists for many years and have often been diagnosed with corneal lattice dystrophy without further sub-typing (Mearza et al. 1999; Huerva et al. 2007). Other erroneous diagnoses in LCD2 patients are leucocoria, blepharitis and even chronic conjunctivitis

Fig. 3. Right eye. The central corneal haze. In slit-lamp microscopy the lattice lines are clearly visible. This photograph was taken when the patients symptoms were relatively mild.

Fig. 5. Note the absence of forehead lines.

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(Tarkkanen 2008, personal communication). Symptomatic treatment and clinical management of LCD2 patients is based on empirical knowledge. The lack of written sources is an obvious limitation in this overview. The need for evidence-based treatment and controlled clinical trials rises as the disease is discovered in more countries around the world. Given new discoveries in the molecular eld, the discovery of a systemic treatment for the disease is no longer considered utopian. However, the usefulness of a future cure or treatment depends on identifying the individuals affected with the disease. The ophthalmologist has an important role to play in discovering patients affected by this interesting disease at the earliest possible stage.

Acknowledgements
This work was supported by grants from the Herman Svensson Foundation and Gunnar and Ma rtha Bergendals Foundation. The authors are grateful for all the help, suggestions and support provided by Professor Ahti Tarkkanen and Dr Sari Kiuru-Enari. This work was performed as a project carried out during the undergraduate programme in medicine at Sahlgrenska University Hospital, Mo lndal, Sweden.

References
Abbas AK, Fausto N, Kumar V, Robbins SL & Cotran RS (2005): Robbins and Cotran Pathologic Basis of Disease. Philadelphia, PA: Elsevier Saunders 258264. Ardalan MR & Shoja MM (2007): Reply to Ardalan Shoja Kiuru syndrome hereditary gelsolin amyloidosis plus retinitis pigmentosa. Nephrol Dial Transplant 23: 1071 1072. Ardalan MR, Shoja MM & Kiuru-Enari S (2007): Amyloidosis-related nephrotic syndrome due to a G654A gelsolin mutation: the rst report from the Middle East. Nephrol Dial Transplant 22: 272275. Chastan N, Baert-Desurmont S, SaugierVeber P, Derumeaux G, Cabot A, Frebourg T & Hannequin D (2006): Cardiac conduction alterations in a French family with amyloidosis of the Finnish type with the p.Asp187Tyr mutation in the GSN gene. Muscle Nerve 33: 113119.

Conceicao I, Sales-Luis ML, De Carvalho M et al. (2003): Gelsolin-related familial amyloidosis, Finnish type, in a Portuguese family: clinical and neurophysiological studies. Muscle Nerve 28: 715721. Donders PC & Blanksma LJ (1979): Meretoja syndrome. Lattice dystrophy of the cornea with hereditary generalized amyloidosis. Ophthalmologica 178: 173180. Fagerholm P (2003): Phototherapeutic keratectomy: 12 years of experience. Acta Ophthalmol Scand 81: 1932. Huerva V, Velasco A, Sanchez MC, Mateo AJ & Matias-Guiu X (2007): Lattice corneal dystrophy type II: clinical, pathologic, and molecular study in a Spanish family. Eur J Ophthalmol 17: 424429. Ikeda M, Mizushima K, Fujita Y et al. (2007): Familial amyloid polyneuropathy (Finnish type) in a Japanese family: clinical features and immunocytochemical studies. J Neurol Sci 252: 48. Kangas H, Paunio T, Kalkkinen N, Jalanko A & Peltonen L (1996): In vitro expression analysis shows that the secretory form of gelsolin is the sole source of amyloid in gelsolin-related amyloidosis. Hum Mol Genet 5: 12371243. Kazmirski SL, Isaacson RL, An C, Buckle A, Johnson CM, Daggett V & Fersht AR (2002): Loss of a metal-binding site in gelsolin leads to familial amyloidosis-Finnish type. Nat Struct Biol 9: 112116. Kiuru S (1992): Familial amyloidosis of the Finnish type (FAF). A clinical study of 30 patients. Acta Neurol Scand 86: 346353. Kiuru S (1995): Familial amyloidosis, Finnish type (FAF) clinical, histological and amyloid protein studies. PhD thesis. Helsinki: Department of Neurology, University of Helsinki. Kiuru S (1998): Gelsolin-related familial amyloidosis, Finnish type (FAF), and its variants found worldwide. Amyloid 5: 5566. Kiuru S, Nieminen T & Partinen M (1999b): Obstructive sleep apnoea syndrome in hereditary gelsolin-related amyloidosis. J Sleep Res 8: 143149. Kiuru S, Salonen O & Haltia M (1999a): Gelsolin-related spinal and cerebral amyloid angiopathy. Ann Neurol 45: 305311. Kiuru-Enari S, Somer H, Seppalainen AM, Notkola IL & Haltia M (2002): Neuromuscular pathology in hereditary gelsolin amyloidosis. J Neuropathol Exp Neurol 61: 565571. Kiuru-Enari S, Keski-Oja J & Haltia M (2005): Cutis laxa in hereditary gelsolin amyloidosis. Br J Dermatol 152: 250257. Kivela T, Tarkkanen A, McLean I, Ghiso J, Frangione B & Haltia M (1993): Immunohistochemical analysis of lattice corneal dystrophies types I and II. Br J Ophthalmol 77: 799804. Kivela T, Tarkkanen A, Frangione B, Ghiso J & Haltia M (1994): Ocular amyloid deposition in familial amyloidosis, Finnish: an analysis of native and variant gelsolin in

Meretojas syndrome. Invest Ophthalmol Vis Sci 35: 37593769. Klintworth GK (2003): The molecular genetics of the corneal dystrophies current status. Front Biosci 8: 687713. Maury CP, Liljestrom M, Boysen G, Tornroth T, de la Chapelle A & NurmiahoLassila EL (2000): Danish type gelsolin related amyloidosis: 654G-T mutation is associated with a disease pathogenetically and clinically similar to that caused by the 654G-A mutation (familial amyloidosis of the Finnish type). J Clin Pathol 53: 9599. Mearza AA, Ajao M & Etchells DE (1999): Familial amyloidosis of the Finnish type. Br J Ophthalmol 83: 1311. Meretoja J (1969): Familial systemic paramyloidosis with lattice dystrophy of the cornea, progressive cranial neuropathy, skin changes and various internal symptoms. A previously unrecognized heritable syndrome. Ann Clin Res 1: 314324. Meretoja J (1973a): Inherited systemic amyloidosis with lattice corneal dystrophy. PhD thesis. Helsinki: Department of Ophthalmology, University of Helsinki. Meretoja J (1973b): Genetic aspects of familial amyloidosis with corneal lattice dystrophy and cranial neuropathy. Clin Genet 4: 173185. Poulaki V & Colby K (2008): Genetics of anterior and stromal corneal dystrophies. Semin Ophthalmol 23: 917. Rosenberg ME, Tervo TM, Gallar J, Acosta MC, Muller LJ, Moilanen JA, Tarkkanen AH & Vesaluoma MH (2001): Corneal morphology and sensitivity in lattice dystrophy type II (familial amyloidosis, Finnish type). Invest Ophthalmol Vis Sci 42: 634641. Rothstein A, Auran JD, Wittpenn JR, Koester CJ & Florakis GJ (2002): Confocal microscopy in Meretoja syndrome. Cornea 21: 364367. Tanskanen M, Paetau A, Salonen O, Salmi T, Lamminen A, Lindsberg P, Somer H & Kiuru-Enari S (2007): Severe ataxia with neuropathy in hereditary gelsolin amyloidosis: a case report. Amyloid 14: 8995. Weiss JS, Moller HU, Lisch W et al. (2008): The IC3D classication of the corneal dystrophies. Cornea 27(Suppl. 2): 183.

Received on December 3rd, 2008. Accepted on May 25th, 2009. Correspondence: Professor Ulf Stenevi Department of Ophthalmology Sahlgrenska University Hospital SE-431 80 Mo lndal Sweden Tel: + 46 31 343 3250 Fax: + 46 31 825710 Email: ulf.stenevi@oft.gu.se

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