Cone-rod dystrophy and amelogenesis imperfecta (Jalili syndrome): phenotypes and environs

Eye (2010) 24, 1659–1668 & 2010 Macmillan Publishers Limited All rights reserved 0950-222X/10 $32.00 www.nature.com/eye IK Jalili Abstract mutations, and the use of red-tinted filter in cone disorders. Eye (2010) 24, 1659–1668; doi:10.1038/eye.2010.103; published online 13 August 2010 Purpose To report a new phenotype with additional data on the oculo–dental syndrome of cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) caused by mutations on CNNM4, a metal transporter, with linkage at achromatopsia locus 2q11 (Jalili syndrome). Methods Three siblings aged 5, 6, and 10 years from a six-generation Arab family in Gaza City underwent full systemic, ophthalmic, and dental examinations, investigations and detailed genealogy. Results Subjects presented at early childhood with visual impairment and abnormal dentition together with photophobia and fine nystagmus increasing under photopic conditions, in the presence of normal fundi. Electrophysiologically, photopic flicker responses were impaired; scotopic responses were extinguished at the age of 10 years. Anterior open bite accompanied AI in all siblings. The syndrome formed 83% of CRD cases in the Gaza Strip, which has a prevalence of 1 : 10 000. Conclusion On the basis of clinical features and electrophysiology, two phenotypes exist: an infancy onset form with progressive macular lesion and an early childhood onset form with normal fundi. More prevalent than previously thought, Jalili syndrome presents a model of the effect of different mutations of the same genetic defect, observations of the same phenotype at different stages of the natural history of the disease, and the influence of epigenetic and tissue-specific factors as causes of phenotypic variability. The paper calls for action to tackle consanguinity in endogamous communities, addresses the possible role of high fluoride levels in groundwater as a trigger for genetic CLINICAL STUDY Cone-rod dystrophy and amelogenesis imperfecta (Jalili syndrome): phenotypes and environs Keywords: amelogenesis imperfecta; cone-rod dystrophy; consanguinity; genetic epidemiology; phenotype variability; fluoride toxicity Introduction Cone-rod dystrophies (CRDs) are part of a wide spectrum of progressive photoreceptor disorders becoming known collectively as retinal ciliopathies.1,2 Photoreceptor dystrophies are categorised on the basis of the photoreceptor cells primarily involved in the disease process as depicted by electrophysiology. Within this spectrum, three main groups are recognised; cone-rod, rod-cone, and mixed receptors dystrophies. In the former (CRD), cones are the cells predominately involved in the disease process, at least initially.3–5 Rod-cone dystrophies (RCD) form the other end of this spectrum whereby rods are the primarily affected cells, the term retinitis pigmentosa (RP) is now commonly reserved for this latter group.6,7 In between lie rarer and more complex clinical entities, mixed receptors dystrophies, in which both photoreceptor types are severely compromised from onset. The commonest entity in the latter is Leber congenital amaurosis (LCA) in which night blindness, as initially described by Leber, is an important feature.8,9 More recently, less recognised conditions with photophobia from different genetic mutations have been included under the term LCA,10 although the term congenital amaurosis of the cone-rod (CACR) was suggested as an alternative for this subgroup London Eye Diagnostic Centre, London, UK Correspondence: IK Jalili, 68 Roman Bank, Stamford, Lincs. PE9 2ST, UK Tel: þ 44 (0)1780 755 955; Fax: þ 44 (0)1780 755 955. E-mail: Received: 15 February 2010 Accepted in revised form: 18 June 2010 Published online: 13 August 2010 CRD and amelogenesis imperfecta (Jalili syndrome) IK Jalili 1660 to identify them as separate clinical entities.11 Retinal ciliopathies can occur as isolated retinal conditions or in combination with other ciliopathies, which encompass ectodermal, cerebrorenal, and metabolic disorders and are caused by a wide array of genetic mutations.1,11–28 Hereditary amelogenesis imperfecta (AI) is a fairly common group of generalised enamel disorders, inherited as autosomal dominant, autosomal recessive, or X-linked traits, affecting both primary and secondary dentition. It can manifest in isolation or as part of syndromatic disorders. Depending on the timing of the disturbance at embryonic development two main types exist, a hypoplastic and a hypomineralised. The hypoplastic type results from disturbances at the secretory stage of matrix formation leading to deficient matrix and thin hypoplastic enamel. Hypomineralised AI is the outcome of impairment at the maturation stage of enamel formation. Both types can overlap and there is no agreed method of classification.29 AI is diagnosed on the basis of the structural and morphological abnormalities in the enamel. Genetic anterior open bite (AOB), a form of malocclusion, is skeletal in origin and has been reported in both types of AI.30,31 AI has also been described in association with other eye conditions including RP,32 oculo–dentodigital dysplasia with microphthalmia,33 iris coloboma,34 myopia,35 and other abnormalities of the ocular adnexa.36 The recessive oculo–dental syndrome of CRD and AI (OMIM 217080) was identified by the author during blind schools survey between 1985 and 1987 in 34 patients from three families from the Gaza Strip (GS). The condition in 29 patients (first extended Gaza family described type A (Gaza A)) from an extended family was reported first.37 Clinical features of the second family (family reported in this paper type B (Gaza B)), which exhibited a different phenotype and an additional singleton, have not been published previously. A linkage at the achromatopsia locus on chromosome 2q11 with the causative gene residing in the same chromosomal region (2q) was established.38 Recently, the syndrome has been reported in several other ethnically diverse families in different world regions with different mutations on CNNM4, a metal transporter gene, and the name Jalili syndrome proposed. This finding establishes a connection between tooth biomineralisation and retinal function and the roles of metal transport in these processes.14,15,39 Materials and methods Three siblings, two females aged 5 and 6 and a male aged 10 years from a six-generation Arab family living in Gaza City (Gaza B, Figure 1: VI:1, VI:5, and VI:6) first presented to the author as part of 18 sibships who shared Figure 1 Family tree of Gaza B sibship with CRD and AI type B (Jalili syndrome phenotype B). Eye CRD and amelogenesis imperfecta (Jalili syndrome) IK Jalili 1661 an oculo–dental association (pupils at UNRWA School for the Blind, Gaza City) in the course of a blind schools survey between 1985 and 1987 (http://jalili.co/covi/). Full ophthalmic, systemic, and dental examinations together with psychophysical and electrophysiological tests were performed. The latter incl (...truncated)