Leber's congenital amaurosis: an update

doi:10.1016/S1090-3798(02)00135-6 European Journal of Paediatric Neurology 2003; 07: 13–22

REVIEW ARTICLE

Leber’s congenital amaurosis: an update ELISA FAZZI, SABRINA GIOVANNA SIGNORINI, BARBARA SCELSA, STEFANIA MARIA BOVA, GIOVANNI LANZI Department of Child Neurology and Psychiatry, IRCCS C. Mondino Foundation –Institute of Neurology, University of Pavia, Italy

Leber’s congenital amaurosis (LCA) is a clinically and genetically heterogeneous disorder characterized by severe loss of vision at birth. It accounts for 10– 18% of cases of congenital blindness. Some patients exhibit only blindness of retinal origin whereas others show evidence of a multi-systemic involvement. We review the literature relating to this severe disorder, highlighting unresolved questions, in particular the nature of the association of LCA with mental retardation and with systemic findings and syndromic pictures. In recent years, genetic advances in the diagnosis of LCA have opened up new horizons, also from a therapeutic point of view. A better understanding of this pathology would be valuable for paediatric neurologists. Keywords: Leber’s congenital amaurosis. Congenital blindness. Mental retardation. Stereotypic behaviours. Systemic associations. Genetics.

Introduction Leber’s congenital amaurosis (LCA) is the earliest and most severe form of all the inherited retinal dystrophies responsible for congenital blindness [1]. Its incidence is 2 –3 per 100 000 births [2 –4] and it accounts for 10 –18% of cases of congenital blindness among children in institutes for the blind [5,6] and for 5% of all retinal dystrophies, a percentage that is probably higher in countries with higher rates of consanguinity [1,7,8]. In most cases, LCA presents an autosomal recessive pattern of inheritance, as established by Alstro¨m and Olson in 1957 [5,9]. LCA is unlikely to represent a single disease entity. Some patients exhibit only blindness of retinal origin whereas others show evidence of a multi-systemic involvement that may include renal, cardiac, skeletal and in particular central nervous system anomalies. The first description of LCA dates back to 1869 [3], when Theodor von Leber, a German ophthalmologist, described a disorder characterized by profound visual loss present at or shortly after birth, nystagmus, sluggish pupillary reactions and pigmentary retinopathy. He observed several cases in a school for blind children and concluded that it was a form of

hereditary retinopathy, since 25% of the parents of children affected were consanguineous. Ldeber also described a normal fundus oculi appearance in infancy and a progressive pigmentation later in life. After this initial report, it was not until the middle of the following century that Franceschetti and Dieterle´ (in 1954) [10] added the finding of a markedly reduced or extinguished electroretinogram (in both photopic and scotopic responses); visual evoked potentials (VEPs) can be altered or extinguished. All the above features are now essential for a diagnosis of LCA. The currently recognized (although still debated) criteria for a diagnosis of LCA are the ones proposed by De Laey in 1991 [11]: † onset of blindness or poor vision (appearing early in the first year of life, before 6 months of age); † sluggish pupillary reactions; † roving eye movements/nystagmus; † oculo-digital signs (eye poking, eye rubbing, eye pressing, etc.); † extinguished or severely reduced scotopic and photopic electroretinogram (ERG); † absent or abnormal VEPs;

Received 24.06.02. Revised 07.11.02. Accepted 11.11.02. Correspondence: Professor E Fazzi, Department of Child Neurology and Psychiatry, IRCCS C. Mondino Foundation – Institute of Neurology, University of Pavia, via Palestro, 3, 27100 Pavia, Italy. Tel.: þ 39-382-380280; fax: þ39-382-380286; e-mail: [email protected]

1090-3798/03/07/0013+10 $35.00

Q 2003 European Paediatric Neurology Society

14 † variable fundus (for example, normal, marbled, albinotic with pigmentation). In addition to these ocular symptoms a series of symptoms has been variably described that includes: neurodevelopmental delay, mental retardation, associated systemic anomalies. The differential diagnosis of this disorder is complicated by the fact that several authors have described ocular findings typical of LCA in genetic syndromes (the Senior – Loken, Joubert, and Saldino – Mainzer syndromes) and in metabolic or nervous system degenerative diseases (infantile neuronal ceroid lipofuscinosis, A-betalipoproteinaemia, hyperthreoninaemia, peroxisomal and mitochondrial dysfunction). In this paper we will review the literature reporting the association of LCA and neurological abnormalities trying to establish: (1) the association of LCA with neurological syndromes and the differential diagnosis of these forms; (2) whether the heterogeneous expressions of LCA are a reflection of the genetic heterogeneity of the disease, paying special attention to the correlation between genetic aspects and neurological findings.

Ophthalmological features The ophthalmological signs essential for a diagnosis of LCA are: blindness or poor vision since early childhood, sluggish pupillary reactions, roving eye movements, oculo-digital signs, frequent squint, and either an unrecordable or a markedly abnormal ERG [11]. Some children are photophobic [11]. Other associated ocular signs include: cataract, keratoconus and keratoglobus and, more frequently, enophthalmos. These latter signs are more common in children also presenting oculodigital signs [12], suggesting a possible traumatic origin of these complications [11].

Oculo-digital signs Oculo-digital signs, initially described by Franceschetti in children with rubella embryopathy, are typical and indicate almost complete blindness [11]. These signs are more frequent in young children and tend to disappear during adolescence [11]. Franceschetti’s oculo-digital sign (which consists of three different behaviours: eye poking,

Review article: E Fazzi et al. eye pressing and eye rubbing) is considered pathognomonic, even though it is not exclusively observed in LCA [13]. The significance of oculodigital signs is still controversial (see paragraph on stereotypic behaviours).

Refraction Refraction is variable [11]. Subjects affected by LCA have been found, most commonly, to be hyperopic [9,14,15], but alternatively they may be highly myopic [9]. This altered refraction suggests that severe visual impairment may interfere with the normal process of emmetropic development [9].

Fundus oculi The appearance of the fundus may be extremely variable [9,11,16]. It may be normal [11,16,17] even though it is more usual to observe, particularly later on in childhood, a variety of fundus abnormalities [9,11]. These commonly include: typical retinitis pigmentosa [9,11,18]; retinitis punctata albescens [11,18,19]; macular ‘coloboma’ [9,11,16,18,21]; optic atrophy [20]; marbled fundus [9,11,18,22,23]; peripheral nummular pigmentation [11,18,24]; vascular complications, such as papillary oedema, retinal vasculitis, secondary angiomatosis [11]; and astrocytoma [11]. An appearance reminiscent of retinitis pigmentosa or retinitis punctata albescens is usually observed in older children [11,24] and appears to be the most frequent fundus manifestation [11]. A macular ‘coloboma’ was first described by Margolis et al. in 1977 [16] and corresponds histologically to the destruction of the macular region. It should not be regarded as a true coloboma [11]. It could be that LCA subjects with macular ‘coloboma’ constitute a distinct subset of LCA [12]. Franceschetti and Forni, in 1958, were the first to describe a marbled fundus appearance [23]. This feature consists of irregular yellowish flecks situated in the midperiphery, which do not affect the retinal vessels. They appear remarkably stable, changing little over the years [11,25]. Nummular lesions of the retinal pigment epithelium are round or oval, sharply defined and distributed over the fundus periphery [11]. The appearance of the fundus is often unrelated to visual performance [9].

Review article: Leber’s congenital amaurosis: an update

Visual impairment Visual impairment ranges from complete blindness to very severe visual impairment and the clinical course, too, is very variable. It is difficult to evaluate the level of visual impairment in these subjects using traditional methods. Indeed, evaluation is generally based on subjective means: light perception, perception of the tester’s hand movements, capacity to count the number of fingers held up by the tester, etc. Fulton, on the other hand, endeavoured to use more objective methods to ascertain grating acuity (preferential looking techniques) and letter identification acuity [26]. His aims were to quantify vision and to determine whether it changes with increasing age. In his longitudinal study, he demonstrated that half the patients had measurable grating acuity, while only a third were designated as having no light perception (NLP), and the others had measurable dark-adapted visual thresholds. As regards the development of the picture, vision was found to be improved or remained quite stable in the majority of subjects. Fulton suggests that apparent improvements in visual acuity at early ages may be attributable to development of central visual pathways rather than to retinal development after early infancy. Indeed, the dark-adapted visual threshold, which depends on retinal rather than on cortical sensitivity, did not change significantly. There were, nevertheless, a few patients who showed deterioration of vision. This worsening trend suggests a progressive impairment of retinal function as well as a progressive degeneration of the retina. Fulton, like Lambert in a later study [27], found no significant associations between visual course and the rest of the clinical picture, either ocular or systemic. Although deterioration of vision in older patients can also be associated with a macular ‘coloboma’ [18,26,28], the decline in visual acuity is not, as shown in Fulton’s study, restricted to subjects presenting this pattern. Macular ‘colobomas’ cannot therefore be regarded as unequivocal predictors of a decline in visual acuity during childhood [26]; rather, patients presenting with LCA and macular ‘coloboma’ may represent a specific genetic subset of LCA [18]. Investigators are now striving to establish whether there exists any correlation between the clinical visual trend and the LCA genotype (see paragraph on genetics below).

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Neurological and neurodevelopmental findings Much emphasis has been placed, in the numerous and heterogeneous reports appearing in the literature, on the association between neurological and neurodevelopmental features and LCA. The neurological features of LCA need to be clarified through clinical observations designed to identify precise clinical subgroups within the whole LCA spectrum.

Mental retardation Of all the systemic associations found in LCA, mental retardation has been the one most strongly emphasized in the literature. In spite of this, it is important to be aware of the risk of overestimating this feature (a risk generated by the use of tests that are not specific for use with visually impaired children and by the fact that several pictures, in reality presenting a systemic involvement, have been considered under the heading LCA). The above are also reasons that could explain the widely varying percentages of LCA subjects affected by mental retardation reported in the literature. Here we review briefly the findings of some of the most important of these studies. Alstro¨m and Olson (1957) [5], after excluding from their population of subjects with congenital retinal blindness those affected by neuropsychiatric or general medical diseases, found 17% with mental retardation and/or epilepsy. In a similar study, Schappert-Kimmijser et al. (1959) [20] noted a frequent occurrence (26%) of major neurological or psychiatric dysfunction. Dekaban, in 1972 [29], reported the presence of mental deficiency (alone or associated with other neurological disorders) in 18 out of a total of 48 patients with congenital retinal blindness. Later, Vaizey (1977) [30] found moderate or severe mental retardation in 11 out of 21 LCA patients. In the majority of these mentally retarded patients, air encephalography documented the presence of structural central nervous system abnormalities. It is interesting to note that two of the subjects studied by Vaizey were siblings—one presenting with uncomplicated blindness and one in whom the blindness was associated with mental retardation. It can be concluded from this that these cases probably represented phenotypic variants of a single pathology.

16 Referring to the possible association of mental retardation with LCA, Nickel and Hoyt (1982) [31] commented that the underdevelopment of the central nervous system that has been described in some patients with LCA does not necessarily imply that the patient will be mentally retarded or educationally impaired. Schuil (1998) [4], in an effort to establish the presence of mental retardation in various LCA subgroups, found this trait in 19.8% of the entire sample considered (subjects with LCA with or without associated systemic diseases) and in 21.1% of the subgroup apparently presenting only ophthalmological signs of LCA. In this ‘no associated anomalies’ subgroup, 11 families had both mentally normal and mentally retarded siblings. One of these pairs of sibs underwent brain magnetic resonance imaging (MRI), which gave normal findings in both of them. This suggests that mental retardation could be associated with LCA without the coexistence of central nervous system abnormality. According to the author, this proves that mental retardation could be one variable expression of LCA and may not always be related to genetic heterogeneity. It is interesting, at this point, to note that Casteels (1996) [6], had also previously reported a frequency of 21.4% of mental retardation in children without associated anomalies. We can add that an ongoing study of our own seems, in fact, to support a percentage of around 20%. Notwithstanding the need to be aware of the risk of overestimating the presence of mental retardation in LCA, the studies presented in the literature, demonstrating its occurrence in around 20% of ‘pure’ LCA cases, suggest that it may represent an important associated feature of the disease.

Clinical and neurodevelopmental features Children affected by LCA, like most congenitally blind children, are frequently hypotonic [32]. Even when neurological disorders are absent, the psychomotor development of blind children can differ from that of sighted children [33,34]. This typically delayed achievement of all gross and fine motor milestones is usually explained by the lack of appropriate opportunities for mastering early motor skills [32,34], and the generalized hypotonia noted in these subjects could be attributed to reduced muscle activity associated with lack of visual stimulation [32].

Review article: E Fazzi et al.

Instrumental investigations Neuroradiological studies Neuroradiological studies have revealed a series of cerebral anomalies in association with LCA, such as microgyria [35,36], polygyria [35,36] and porencephaly [35,36], abnormal maturation of cortical neurons [36,37] and ventricular dilatation [30], but the only consistent finding is hypoplasia of the cerebellar vermis, which can be seen in 10% of infants affected by LCA [9,31]. It should be noted that this condition can also be seen in other entities, such as, in particular, Joubert syndrome [9,38]. The relationship between these two entities needs to be clarified.

Electroencephalography As pointed out by Jan [39], blind children (and thus LCA children) do not, with the exception of those also presenting cerebral damage, show epileptiform abnormalities on EEG. They can, however, show alpha rhythm abnormalities, in particular a ‘floating alpha’ (an alpha rhythm that appears and disappears and is not responsive, for example, to eye closure).

Stereotypic behaviours The prevalence of stereotypic behaviours in LCA is such that they merit special attention here. In particular, as mentioned earlier, Franceschetti’s oculodigital sign is considered pathognomonic. Other stereotypic behaviours particularly marked in LCA are, for example: thumb sucking, head or body rocking, hair touching, finger movements, object manipulation, rubbing movements, facial grimaces, moaning/crying, sniffing. Language also shows a peculiar development: characterized by a very rich vocabulary, it is not always used with communicative intent. Stereotyped behaviours, especially motor ones, are known to occur with great frequency in blind children [40]. These behaviours have been termed blindisms. This term has, given the lack of specificity of these behaviours, been replaced by terms such as ‘stereotypies’ or ‘mannerisms’ in order to underline that the fundamental aspect of these behaviours is their repetitiveness [40,41]. However, due to the fact that they involve the visual system, several of these behaviours (e.g., eye pressing) have been categorized by some authors

Review article: Leber’s congenital amaurosis: an update as ‘oculodigital phenomena’; these phenomena occur prevalently or exclusively in blind or in severely visually impaired children [13,40]. In particular, Jan and Freeman (1994) [13] initially maintained that the explanation of eye-pressing lies in the production—through eye pressing and through activation of the visual cortex, which is still intact—of sensations of light. It may be that these gestures have more to do with a desire on the part of the subject to produce a certain insensitivity to pain (or ‘stress-induced analgesia’) than with the condition of visual impairment itself, as ‘acutely stressful states are known to increase opioid peptides and therefore to produce insensitivity to pain’. Other behaviours, such as body and head rocking, hand and finger movements, and the stereotyped handling of objects, are also very frequently observed in subjects affected by mental retardation and/or psychosis [40]. In these two groups of children, however, unlike blind children, the stereotypies appear to be more entrenched and less responsive to stimulation and environmental changes. It can be argued that children demonstrating stereotypies gain great comfort, and perhaps, some enjoyment from them, and may actually use them in some way to aid the developmental process. Considering the circumstances and way in which they can emerge, certain stereotyped behaviours can be attributed a particular relational significance. For example, as well as occurring in situations of boredom (lack of stimulation), rocking, sucking and eye pressing may also be seen to occur when something is required of the child, in moments of frustration, or in the absence of the mother. In such contexts, these behaviours can be interpreted as self-stimulating or self-comforting gestures on the part of the child. By adopting these behaviours, the child manages to control his anxiety, finding that the sensations which originate from his own body provide an alternative source of satisfaction and a means of containing his emotions. Other behaviours, such as jumping or repetitive hand movements (fluttering), appear almost exclusively when the child is excited and can, in accordance with other authors, be interpreted as a way of reducing tension [40,42].

Systemic findings and syndromic associations LCA has frequently been associated not only with anomalies of the central nervous system, but also

17 with other systemic (mainly renal, skeletal and cardiac) anomalies. In some cases, the combination of associated signs allows a syndromic diagnosis. In this regard, two syndromes, in particular, can be recalled: the Senior –Loken and Saldino –Mainzer syndromes. Senior et al. [43] and Loken et al. [44] (1961) first described the association of a recessively inherited renal disease, juvenile nephronopthisis (medullary cystic disease) and a tapetoretinal degeneration. This association was subsequently given a number of names, including Senior – Loken syndrome [45], tapetoretinal degeneration and familial juvenile nephronophthisis [46] and familial renal–retinal dystrophy [47]. Since Senior and Loken’s reports many more cases have been published [9,48 –55]. A gene locus for Senior – Loken syndrome has recently been localized to chromosome 3q21-q22 [56] and to chromosome 1p36 [57]. Tapetoretinal degeneration and nephronophthisis have also been observed with many other associated abnormalities [55]. An association has, on rare occasions, been found between these features and cone-shaped epiphyses of the hands and cerebellar hypoplasia. This association was first described by Mainzer et al. [52,58] and has been termed Saldino –Mainzer syndrome [59]. It is also to be noted that Joubert syndrome, an autosomal recessive disease characterized by cerebellar vermis hypoplasia, can also present with retinal dystrophy and renal anomalies and is also considered among the LCA-associated syndromes, since the ocular findings are very similar in the two diseases. In addition to these syndromic associations, the literature also contains numerous reports of systemic associations, such as those mentioned briefly below. Moore and Taylor (1984) [60] reported three LCA subjects affected by a saccadic palsy and head thrusts reminiscent of those seen in ocular motor apraxia. Computed tomography (CT) scan showed cerebellar vermis hypoplasia. Russel-Eggitt et al. (1988) [61] described a group of children with a congenital retinal dystrophy associated with cardiomyopathy, obesity and short stature. In 1997 Ehara et al. [62] described a new autosomal-recessive syndrome of LCA, short stature, growth hormone insufficiency, mental retardation, hepatic dysfunction and metabolic acidosis. About 5% of LCA children show sensorineural hearing loss, an association as yet poorly characterized [48,12].

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Review article: E Fazzi et al.

Differential diagnosis

Table 1. Mandatory and recommended instrumental and laboratory examinations in LCA subjects

There exist several known causes of congenital blindness and these must be differentiated from LCA. The specific hallmark of LCA is seen in the ERG, which, in this disease, is extinguished or severely reduced in both the scotopic and photopic components. Two of the main retinal pathologies of significance in the differential diagnosis of LCA are congenital stationary night blindness and achromatopsia [9,11,63]. LCA also presents numerous analogies with another form of retinal degeneration, known as retinitis pigmentosa (RP). Indeed, some of the genes responsible for LCA (e.g., RPE65, CRX and TULP1) might also be a cause of RP. The distinction between LCA and RP, on the other hand, is mainly based on age at onset of the visual dysfunction. Patients diagnosed before the age of 1 year are likely to be classified as having LCA, and those diagnosed later as having RP. Differentiation between the two conditions is also based on

Generala, neurologicala and ophthalmologicala examination

(1)

(2)

(3)

the ERG (in RP there is relative sparing of the photopic component, at least in the initial phases, while in LCA it is extinguished or markedly reduced from onset); the fact that RP is a progressive pathology while the visual impairment in LCA is more often stable, and the mode of transmission, which can vary in RP (autosomal dominant, autosomal recessive or X-linked) but is almost always autosomal recessive in LCA.

In addition there exist other ocular pathologies that can resemble the clinical picture of LCA. These include optic atrophy, optic nerve hypoplasia, and some inflammatory conditions [9]. LCA-like pictures have also been described in several metabolic or nervous system degenerative diseases (infantile neuronal ceroid lipofuscinosis, A-betalipoproteinaemia, hyperthreoninaemia, peroxisomal and mitochondrial dysfunction). Interesting examples of such reports include Ek’s description (1986) [64] of a boy with psychomotor delay, sensory hearing loss, hepatomegaly and LCA—this child had biochemical findings suggesting the presence of a peroxisomal disorder—and Castro-Gago’s description (1996) [65] of two 6-month-old girls affected by LCA with associated mitochondrial dysfunction. Clearly, in view of these possible associations, accurate measurement of the markers for these disorders is essential.

ERGa, VEPsa, EEGb, BAEPsb Brain MRIa Abdomen– pelvis (renal) ultrasounda Hand X-raya Complete liver and renal functions evaluationa Metabolic investigationsb: VLCFA, blood lactate and pyruvate, urinary organic acids, aminoacidaemia and aminoaciduria, phytanic acid, electrofocusing of sialotransferin Muscle enzymesb

a b

BAEPs: Brainstem auditory evoked potentials. VLCFA: Very long chain fatty acids. Mandatory examinations. Recommended examinations.

Mandatory and recommended instrumental and laboratory examinations in LCA subjects are presented in Table 1.

Genetics LCA is a highly heterogeneous disease not only clinically, but also genetically. The genetic heterogeneity of LCA has been suspected since Waardenburg’s report (1963) [66] of normal children born to affected parents. The genes implicated in LCA— seven have been mapped to date and two new loci have been identified, but many more genes are thought to exist—are involved in retinal development, retinal function and retinal protection. In most cases, LCA shows an autosomal recessive pattern of inheritance.

The known genes To date, seven genes implicated in LCA have been mapped (Table 2). Additional loci have been mapped to chr 14q24 (LCA3) [77] and to chr 6q11-16 (LCA5) [78], but to date no genes have been identified in these regions. RetGC1, photoreceptor specific guanylate cyclase gene, is an essential protein implicated in the phototransduction cascade. Mutations in this gene cause an impaired production of cGMP in the retina, with permanent closure of cGMP-gated cation channels. As specific guanylate cyclase activating proteins (GCAPs) are required for activity of the retina-specific guanylate cyclase, Perrault et al. (1996) [68] raised the question of whether some

Review article: Leber’s congenital amaurosis: an update Table 2.

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Leber’s congenital amaurosis: the known genes

Gene

Chromosome

Type of LCA

Protein

RetGC1 (GUCY2D)a RPE65b CRXc AIPL1d RPGRIP1e CRB1f TULP1g

17 (17p13) 1 (1p31) 19 (19q13.3) 17 (17p13.1) 14q11 1q31-q32.1 6p21.3

LCA1 LCA2 – LCA4 LCA6 – –

Photoreceptor specific guanylate cyclase RPE65 Transcription factor Arylhydrocarbon-interacting protein-like-1 Retinitis pigmentosa GTPase regulator interacting protein CRB1 Tubby-like protein 1

a

Camuzat et al. (1995) [67]; Perrault et al. (1996) [68]. Gu et al. (1997) [69]; Marlhens et al. (1997) [70]. Freund et al. (1998) [71]. d Sohocki et al. (2000) [72]. e Dryja et al. (2001) [73]; den Hollander et al. (2001) [74]. f Lotery et al. (2001) [75]. g Lewis et al. (1999) [76]. b c

LCA cases unlinked to 17p13 could be accounted for by mutations in the gene encoding guanylate cyclase activator-1 on 6p21.1. RPE65 is a specific retinal pigment epithelium gene. The protein RPE65 is implicated in the metabolism of vitamin A, the precursor of the photoexcitable retinal pigment (rhodopsin). The CRX-gene, a cone – rod homeobox gene, encodes for a transcription factor for several retinal genes. CRX is essential for photoreceptor maintenance [71]. AIPL1, the gene encoding arylhydrocarboninteracting protein-like-1, is a photoreceptor/ pineal-expressed gene. RPGRIP1 gene encodes for the ‘retinitis pigmentosa GTPase regulator interacting protein (RPGRIP1)’. The biochemical function of CRB1 is currently unknown. Comparison of CRB1 with the homologous Drosophila melanogaster crumbs protein (CRB) suggests that it may be involved in neuronal development of the retina [79]. TULP1 encodes for the tubby-like protein 1 and has been associated with the LCA phenotype only in a single family from the Dominican republic [76].

Correlations of genotype with phenotype and clinical course Various attempts have been made to correlate genotype with phenotype and clinical course. The most important of these are the studies by Perrault et al. (1999) [80] and Dharmaraj et al. (2000) [81]. Perrault considered the different functional outcome of RetGC1 and RPE65 gene mutations. As regards onset (age at and mode of onset) and fundus appearance, no significant differences emerged

between the two groups. On the contrary, the RetGC1 group showed no visual improvement with age and severe photophobia and significant hyperopia, while the RPE65 subjects showed night blindness and a transient improvement (noted by the parents). The RPE65 subjects also showed moderate or no hyperopia and sometimes low myopia. According to Dharmaraj et al. on the other hand, the visual evolution in patients with mutations in RetGC1 remained stable, while RPE65 subjects showed progressive visual loss. This latter study also considered CRX gene subjects and observed a stable clinical course.

Therapeutic outlook As far as the possible therapy of LCA is concerned, various lines of investigation are currently open. These include retinal and stem cell transplantation, drug therapies (for patients with normal but inactive retina) and gene therapy. Here, we focus on the latter. In 2001, Acland et al. [82] were the first to show that gene therapy can restore vision in a large-animal model of human retinopathy. Not only was this study the first instance of the use of a large animal, it was also the first time that gene therapy had successfully been used to restore visual function (rather than just slow down its degeneration). Their method was based on the use of a recombinant adenoassociated virus (AAV) carrying wild-type RPE65 (AAV-RPE65) in a dog suffering from early and severe visual impairment similar to that seen in human LCA. This therapy has been demonstrated as efficient only for RPE65 mutations. Despite these advances, a concrete and widely applicable treatment for LCA is still a very distant prospect. In view of this, the importance of early intervention in affected subjects cannot be over

20 emphasized. Focusing on observation of the child, early intervention programmes are intended to provide support for the child’s family, in particular psychological support for the mother. Their aims should be: to facilitate the progression of postural achievement by means of tactile and auditory stimulation; to maximize and integrate these compensatory functions; and to ensure that the child enjoys environmental and emotional stability.

Concluding remarks As emerges clearly from this review of the literature, LCA is a highly heterogeneous disorder in which much remains to be clarified [83,84]. In particular, an adequate classification is yet to be developed and the differences between the various clinical forms need to be established, as does the relationship between these and the genetic subtypes. The methods of clinical and instrumental assessment of these children require unification and adequate therapies need to be found.

Acknowledgements We thank our co-workers Fiammetta Boni, President of IALCA, for her continuous and friendly support and help, Professor PE Bianchi, of the Ophthalmological Institute of the University of Pavia, Drs E Georgen and J Lanners of the Robert Hollman Foundation of Cannero Riviera for their help in evaluating LCA subjects. Supported by a grant from the Italian Ministry of Health (RC 2002) and by IALCA (Italian Association for Leber’s Congenital Amaurosis) Pavia, Italy (www.amaurosicongenitaleber.com).

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