CLINICAL SCIENCE Genotype–Phenotype Analysis of Bietti Crystalline Dystrophy in a Family with the CYP4V2 Ile111Thr Mutation Gerardo-Pedro García-García, MD,* María-Pilar López-Garrido, PhD,†‡ Magdalena Martínez-Rubio, MD,* Medina-Azahara Moya-Moya, MD,* José Belmonte-Martínez, MD, PhD,* and Julio Escribano, PhD†‡ Purpose: The purposes of this study were to evaluate the genotypic and phenotypic correlations of Bietti crystalline dystrophy and to investigate the utility of in vivo corneal confocal microscopy in diagnosing this disorder. Methods: A Spanish woman (proband) with a clinical diagnosis of Bietti crystalline dystrophy and 7 members of her family were recruited prospectively for complete clinical ophthalmic examination and genetic study. The medical records of an additional family member were reviewed retrospectively. Genomic DNA was obtained from blood samples, and 11 exons of the CYP4V2 gene were screened for mutations by polymerase chain reaction DNA sequencing. Results: Clinical examination revealed an atypical pattern of corneal dystrophy with central and paracentral distribution not only in the proband but also in 2 elderly heterozygous carriers. Corneal deposits were observed by slit-lamp examination and in vivo corneal confocal microscopy. Genetic analysis revealed the homozygous CYP4V2 Ile111Thr mutation in the proband and identified 5 hetero- zygous carriers. Conclusions: The authors identified a case of Bietti crystalline dystrophy with central and paracentral keratopathy and the molec- ular analysis of the causative gene in a Spanish family. Data suggest a dose-dependent phenotype ranging from subclinical corneal changes in subjects carrying 1 mutant Ile111Thr CYP4V2 allele to the complete manifestation of the disease in homozygous subjects. In vivo corneal confocal microscopy is a useful technique in the diag- nosis of this disorder. Key Words: genotype–phenotype, Bietti crystalline dystrophy, crystalline deposits, in vivo corneal confocal microscopy (Cornea 2013;32:1002–1008) B ietti crystalline corneoretinal dystrophy (BCD) is a chorior- etinal dystrophy characterized by multiple, yellowish, glis- tening crystalline retinal deposits, geographic areas of atrophy of the retinal pigment epithelium (RPE) and the choriocapil- laris, sclerosis of the choroid vessels, and crystalline deposits in the peripheral cornea. This disorder was first reported by Gian Battista Bietti in 1937 in 3 patients, 2 of whom were brothers. 1 These brothers and 6 additional patients were studied by Bagolini and Ioli-Spada, 2 who designated this characteristic pathology as “Bietti tapetoretinal degeneration with marginal corneal dystrophy.” Clinically, the disease manifests itself between the second and fourth decades of life and gradually progresses. Patients have decreased vision, nyctalopia, and early-stage paracentral scotoma, which usually lead to marked visual impairment, peripheral visual field loss, and legal blindness in the fifth and sixth decades of life. 3,4 The inheritance pattern is presumed to be autosomal recessive, but cases of families with an autosomal dominant inheritance have been reported. 5,6 The responsible gene, CYP4V2, has been identified in chromosome 4q35-qter, 7,8 belongs to a member of the cyto- chrome P450 protein superfamily, and is expressed in various tissues (most abundantly in the retina). 9 Patients with BCD were found to have high triglyceride and cholesterol storage levels and reduced metabolism of labeled fatty acid precur- sors into n-3 polyunsaturated fatty acids. These findings sug- gest that the protein encoded by CYP4V2 plays a role in processing lipids and in steroid metabolism. 9,10 The histolog- ical consequence is the formation of crystalline intracellular fatty inclusions in retinal and other type cells, including cir- culating lymphocytes, corneal and conjunctival fibroblasts, and keratinocytes. 3,5,9–11 The objectives of this study were to evaluate the genotypic and phenotypic correlations of BCD in a Spanish family by means of CYP4V2 mutation analysis and clinical examination and to investigate the utility of in vivo corneal confocal microscopy in diagnosing this disorder. PATIENTS AND METHODS A Spanish woman with a clinical diagnosis of BCD (proband) and 7 members of her family were studied prospectively (Fig. 1). The medical records of an additional family member were reviewed retrospectively. Received for publication September 18, 2011; revision received January 24, 2013; accepted January 27, 2013. From the *Department of Ophthalmology, University General Hospital of Alicante, Alicante, Spain; †Laboratory of Human Molecular Genetics, School of Medicine/Research Institute on Neurological Disabilities (IDINE), University of Castilla La-Mancha, Albacete, Spain; and ‡Cooperative Research Network on Age-Related Ocular Pathology, Visual and Life Quality, Health Institute Carlos III, Madrid, Spain. The authors have no funding or conflicts of interest to disclose. Reprints: Gerardo-Pedro García García, Department of Ophthalmology, Univer- sity General Hospital of Alicante, Maestro Alonso St 109, 03010 Alicante, Spain (e-mail: zemfira36@hotmail.com). Copyright © 2013 by Lippincott Williams & Wilkins 1002 | www.corneajrnl.com Cornea  Volume 32, Number 7, July 2013