Jalili Syndrome

A number sign (#) is used with this entry because Jalili syndrome, consisting of cone-rod dystrophy and amelogenesis imperfecta, is caused by homozygous or compound heterozygous mutation in the CNNM4 gene (607805) on chromosome 2q11.

Clinical Features

In an inbred, extensive Arab family from the Gaza strip, Jalili and Smith (1988) described 29 persons with a combination of cone-rod dystrophy (CRD) of the retina and amelogenesis imperfecta (AI). The inheritance was clearly autosomal recessive. There was at least 1 instance of quasidominant inheritance. All affected members suffered from photophobia and nystagmus, starting in the first two years of life, and achromatopsia. There was no night blindness. In all affected members, the teeth were abnormally shaped and discolored as soon as they erupted.

Michaelides et al. (2004) ascertained a 2-generation family from Kosovo with autosomal recessive cone-rod dystrophy and amelogenesis imperfecta. Two affected brothers presented in the first few years of life with photophobia, pendular nystagmus, and reduced central vision. Night vision difficulties were reported by the end of the first decade. The ocular disorder was associated with the hypoplastic/hypomineralized variant of amelogenesis imperfecta.

Polok et al. (2009) described a sister and brother from Kosovo who presented at ages 14 and 7 years, respectively, with poor vision, photophobia, and pendular nystagmus. Both patients' fundi showed optic disc pallor, narrow vessels, macular atrophy with pigment mottling, and peripheral deep white dot deposits mainly in the inferonasal retina. The sister, who was functionally less affected, also had peripheral bone spicules and superotemporal scotoma on static perimetry, and markedly decreased macular autofluorescence due to atrophy as well as severe retinal pigment epithelium (RPE) changes in the inferonasal peripheral retina. Optical coherence tomography (OCT) showed decreased foveal and retinal thickness, attenuation of retinal lamination suggesting extensive loss of retinal cells, and hyperreflectivity in the choroids due to RPE and choriocapillaris atrophy. Photopic ERGs were nonrecordable; under scotopic conditions, b-wave amplitudes were markedly reduced in the sister and severely reduced in her brother; over 7 years of follow-up, the remaining scotopic b-wave in the sister dropped to 40% of the lower limit for age. Both children also had amelogenesis imperfecta affecting the deciduous and permanent teeth, which were dysplastic and yellow-brown in color, lacking the enamel layer and showing numerous caries. Polok et al. (2009) also reported a 5-generation consanguineous Lebanese family, in which 2 sisters and a male cousin displayed an ocular and dental phenotype very similar to that of the Kosovo sibs. The authors also described an unrelated 38-year-old woman who had been legally blind and severely photophobic from 6 years of age, who also had severe erosion of all teeth by 24 years of age due to absence of enamel and caries. Neurologic and cognitive examination was normal in all patients.

Parry et al. (2009) studied the 2 families with cone-rod dystrophy and amelogenesis imperfecta originally reported by Jalili and Smith (1988) and Michaelides et al. (2004), respectively, and ascertained 5 additional unrelated families of diverse ethnicities cosegregating CRD and AI. Phenotypic characterization demonstrated consistent dental and ocular phenotypes between families, for which the authors proposed the term 'Jalili syndrome.' In all affected members of these pedigrees, the enamel of the primary and secondary dentitions was grossly abnormal and prone to rapid posteruptive failure, in part reflecting hypomineralization. The consistent presence of taurodont permanent molar teeth implicated a coexisting abnormality of morphology involving dentin. Significant visual impairment was evident in all affected individuals in infancy or early childhood, with nystagmus often representing the first clinical sign of abnormal vision, and there was marked photophobia, impairment of color vision, and progressive loss of vision with advancing age.

Parry et al. (2009) analyzed 2 exfoliated deciduous molar teeth from an affected Scottish individual and compared them to matched control teeth. Ultrastructural analysis demonstrated that affected enamel was mineralized only to approximately 50% of the value for normal enamel and was similar to that for dentin. They stated that the resulting radiographic appearance is similar to that seen in hypomaturation amelogenesis imperfecta caused by mutation in the MMP20 (604629) and KLK4 (603767) genes; see AI2A2 (612529) and AI2A1 (204700), respectively.

Clinical Variability

Jalili (2010) restudied the 3 affected sibs from the 'Gaza B' family that Parry et al. (2009) originally found to be homozygous for a nonsense mutation in the CNNM4 gene, and compared them to the family designated 'Gaza A,' in which affected members were homozygous for a CNNM4 missense mutation (607805.0005; see MOLECULAR GENETICS). Jalili (2010) stated that the 'Gaza B' sibs, ages 5, 6, and 10 years, had ocular features that were milder and of later onset than in the 'Gaza A' family; the 'Gaza B' family developed onset of visual impairment in early childhood rather than infancy, and they had fundi that were normal except for minor peripheral retinal epithelial defects in the oldest sib. The sibs denied night blindness and exhibited fine nystagmus that increased under photopic conditions. On ERGs, photopic flicker responses were impaired, and scotopic responses were extinguished by 10 years of age; in the 'Gaza A' family, scotopic responses gradually declined from age 20 years. All 3 'Gaza B' sibs had amelogenesis imperfecta similar to that seen in other patients with Jalili syndrome, as well as anterior open bite, which was seen in only 2 patients from the 'Gaza A' family. On the basis of clinical features and electrophysiology, Jalili (2010) proposed that 2 phenotypes exist: an infancy-onset form with progressive macular lesions, and an early childhood-onset form with normal fundi.

Mapping

By linkage analysis of members from the large pedigree reported by Jalili and Smith (1988), Downey et al. (2002) identified a disease locus refined to a 2-cM (5-Mb) interval between markers D2S2209 and D2S373 on chromosome 2q11 (maximum lod score of 7.03 at marker D2S2187). No mutations were detected in the CNGA3 gene.

Michaelides et al. (2004) described a 2-generation family from Kosovo with autosomal recessive cone-rod dystrophy and amelogenesis imperfecta in which screening of the CNGA3 gene (600053) did not identify any disease-causing sequence variants; however, segregation analysis of the adjacent microsatellite marker D2S2187 provided evidence supporting disease association with chromosomal region 2q11.

Polok et al. (2009) performed whole-genome linkage analysis on a family from Kosovo in which 2 sibs had cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) and identified a 5.4-Mb region of homozygosity spanning the centromere of chromosome 2, between rs2970925 and rs953320, overlapping the previously reported area of linkage for this disease.

Parry et al. (2009) studied 7 unrelated and ethnically diverse families cosegregating CRD and AI, including the 2 families originally reported by Jalili and Smith (1988) and Michaelides et al. (2004), respectively, and found that all linked or were consistent with linkage to chromosome 2q11.

Molecular Genetics

In a family from Kosovo in which 2 sibs had cone-rod dystrophy and amelogenesis imperfecta, Polok et al. (2009) identified homozygosity for a 1-bp duplication in the CNNM4 gene (607805.0001) in both affected individuals. Sequence analysis of a 5-generation Lebanese family and an unrelated 38-year-old woman with a similar phenotype revealed homozygosity for 2 missense CNNM4 mutations in the affected individuals (see 607805.0002 and 607805.0003, respectively). All parents were heterozygous for their respective mutation.

In 7 unrelated and ethnically diverse families cosegregating CRD and AI, including the 2 families originally reported by Jalili and Smith (1988) and Michaelides et al. (2004), respectively, Parry et al. (2009) identified homozygosity or compound heterozygosity for 9 different mutations in the CNNM4 gene (see, e.g., 607805.0001 and 607805.0003-607805.0007).