Detailed phenotypic and genotypic characterization of bietti crystalline dystrophy.
OBJECTIVE
To provide a detailed phenotype/genotype characterization of Bietti crystalline dystrophy (BCD).


METHODS
Observational case series.


METHODS
Twenty patients from 17 families recruited from a multiethnic British population.


METHODS
Patients underwent color fundus photography, near-infrared (NIR) imaging, fundus autofluorescence (FAF) imaging, spectral domain optical coherence tomography (SD-OCT), and electroretinogram (ERG) assessment. The gene CYP4V2 was sequenced.


METHODS
Clinical, imaging, electrophysiologic, and molecular genetics findings.


RESULTS
Patients ranged in age from 19 to 72 years (median, 40 years), with a visual acuity of 6/5 to perception of light (median, 6/12). There was wide intrafamilial and interfamilial variability in clinical severity. The FAF imaging showed well-defined areas of retinal pigment epithelium (RPE) loss that corresponded on SD-OCT to well-demarcated areas of outer retinal atrophy. Retinal crystals were not evident on FAF imaging and were best visualized with NIR imaging. Spectral domain OCT showed them to be principally located on or in the RPE/Bruch's membrane complex. Disappearance of the crystals, revealed by serial recording, was associated with severe disruption and thinning of the RPE/Bruch's membrane complex. Cases with extensive RPE degeneration (N = 5) had ERGs consistent with generalized rod and cone dysfunction, but those with more focal RPE atrophy showed amplitude reduction without delay (N = 3), consistent with restricted loss of function, or that was normal (N = 2). Likely disease-causing variants were identified in 34 chromosomes from 17 families. Seven were novel, including p.Met66Arg, found in all 11 patients from 8 families of South Asian descent. This mutation appears to be associated with earlier onset (median age, 30 years) compared with other substitutions (median age, 41 years). Deletions of exon 7 were associated with more severe disease.


CONCLUSIONS
The phenotype is highly variable. Several novel variants are reported, including a highly prevalent substitution in patients of South Asian descent that is associated with earlier-onset disease. Autofluorescence showed sharply demarcated areas of RPE loss that coincided with abrupt edges of outer retinal atrophy on SD-OCT; crystals were generally situated on or in the RPE/Bruch's complex but could disappear over time with associated RPE disruption. These results support a role for the RPE in disease pathogenesis.
Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom. Electronic address: stephanie.halford@eye.ox.ac.uk.
Stephanie
S
Halford
Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia; Moorfields Eye Hospital, London, United Kingdom.
Gerald
G
Liew
Moorfields Eye Hospital, London, United Kingdom.
Donna S
DS
Mackay
Moorfields Eye Hospital, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom.
Panagiotis I
PI
Sergouniotis
Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom.
Richard
R
Holt
Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom.
Suzanne
S
Broadgate
Molecular Cytogenetics and Microscopy Core, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Emanuela V
EV
Volpi
Institute of Child Health, London, United Kingdom.
Louise
L
Ocaka
Moorfields Eye Hospital, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom.
Anthony G
AG
Robson
Moorfields Eye Hospital, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom.
Graham E
GE
Holder
Moorfields Eye Hospital, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom.
Anthony T
AT
Moore
Moorfields Eye Hospital, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom.
Michel
M
Michaelides
Moorfields Eye Hospital, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom.
Andrew R
AR
Webster
D000328:Adult; D000368:Aged; D055028:Comparative Genomic Hybridization; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000473:pathology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005091:Exons / Q000235:genetics; D005260:Female; D005451:Fluorescein Angiography; D056726:Genetic Association Studies; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012164:Retinal Diseases / Q000235:genetics* / Q000473:pathology*; D055213:Retinal Pigment Epithelium / Q000473:pathology; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000502:physiology; D055815:Young Adult
D003577:Cytochrome P-450 Enzyme System; C505357:CYP4V2 protein, human; D000072470:Cytochrome P450 Family 4