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Clinical and molecular findings in three Lebanese families with Bietti crystalline dystrophy: report on a novel mutation.

Haddad NM, Waked N, Bejjani R, Khoueir Z, Chouery E, Corbani S, Mégarbané A - Mol. Vis. (2012)

Bottom Line: Two mutations in CYP4V2 were found: p.I111T (c.332T>C) in exon 3 in two families and the novel p.V458M (c.1372G>A) mutation in exon 9 in one family.Variation in disease severity and electroretinographic responses suggests that environmental or additional genetic factors influence the course of the retinal disease.The CYP4V2 p.I111T (c.332T>C) mutant allele may be especially prevalent among patients with BCD in Lebanon, resulting from a single founder.

View Article: PubMed Central - PubMed

Affiliation: Service d’Ophtalmologie, Hôtel-Dieu de France Hospital, Beirut, Lebanon.

ABSTRACT

Purpose: Bietti crystalline dystrophy (BCD) is a rare autosomal recessive disorder caused by mutation of the cytochrome P450, family 4, subfamily V, polypeptide 2 (CYP4V2) gene and characterized by retinal pigmentary abnormalities and scattered deposits of crystals in the retina and the marginal cornea. The aim of this study was to investigate the spectrum of mutations in CYP4V2 in Lebanese families, and to characterize the phenotype of patients affected with BCD.

Methods: Nine patients from three unrelated Lebanese families were clinically and molecularly investigated. Detailed characterization of the patients' phenotype was performed with comprehensive ophthalmic examination, color vision study, fundus photography, visual field testing, retinal fluorescein angiography, electroretinography, and electrooculography. One family was followed for 12 years. The 11 exons of the CYP4V2 gene were sequenced.

Results: Symptoms consisting of night blindness, loss of paracentral visual field, and disturbed color vision were apparent during the third decade of life. Ophthalmoscopy revealed posterior pole crystalline deposits and areas of retinal pigment epithelium atrophy. Fluorescein angiography disclosed geographic areas of the pigment epithelium layer and choriocapillaris atrophy in the posterior pole and fundus periphery. The most striking findings were those of normal electroretinographic responses in some patients and clinical heterogeneity. Two mutations in CYP4V2 were found: p.I111T (c.332T>C) in exon 3 in two families and the novel p.V458M (c.1372G>A) mutation in exon 9 in one family.

Conclusions: These patients are affected with Bietti crystalline dystrophy without corneal involvement. Variation in disease severity and electroretinographic responses suggests that environmental or additional genetic factors influence the course of the retinal disease. The CYP4V2 p.I111T (c.332T>C) mutant allele may be especially prevalent among patients with BCD in Lebanon, resulting from a single founder.

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Haplotypes of families 2 and 3 using D4S2924, D4S3051, and D4S2921 STR markers. Alleles are given in bp.
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f5: Haplotypes of families 2 and 3 using D4S2924, D4S3051, and D4S2921 STR markers. Alleles are given in bp.

Mentions: The analysis of the CYP4V2 gene showed an abnormality in the three families. In family 1, a novel mutation was found: p.V458M (c.1372G>A). This variation was predicted as damaging to the protein function according to SIFT (Sorting Intolerant From Tolerant) software. A 12-year follow-up showed a mild exaggeration of symptoms, with progressive and moderate visual acuity reduction with the surprising findings of normal ERGs. This suggests the existence of less severe forms of BCD related to relatively mild CYP4V2 mutations. In families 2 and 3, a previously reported mutation was found, the p.I111T (c.332T>C) [10]. Both families denied any relation with each other. However, as the families share the same haplotype (Figure 5), we can postulate that this mutation derived from an ancestral mutation that was geographically restricted. Clinical comparison of the families did not show any phenotype-genotype correlation. Indeed, at the age of 39 and 37, patients V-2 and V-4 of family 3, respectively, presented a severe clinical phenotype; whereas patients II-3 and II-5 of family 2 aged 34 and 30, respectively, presented a less severe disease suggesting the possible involvement of genetic, epigenetic, or even environmental factors in the pathogenesis of BCD. In terms of environmental factors, lipid metabolism, and therefore diet, may play a role in the disease. Indeed, researchers have shown that CYP4V2 may play a role in fatty acid and steroid metabolism, which might be consistent with biochemical studies of patients with BCD [6,15]. Abnormal choroidal fibroblast inclusions are similar to those found in circulating lymphocytes, keratocytes, and conjunctival and skin fibroblasts [3]. Cultured lymphocytes from patients with BCD lack two fatty acid-binding proteins of 32 and 45 kDa, in comparison to age-matched controls [16].


Clinical and molecular findings in three Lebanese families with Bietti crystalline dystrophy: report on a novel mutation.

Haddad NM, Waked N, Bejjani R, Khoueir Z, Chouery E, Corbani S, Mégarbané A - Mol. Vis. (2012)

Haplotypes of families 2 and 3 using D4S2924, D4S3051, and D4S2921 STR markers. Alleles are given in bp.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351416&req=5

f5: Haplotypes of families 2 and 3 using D4S2924, D4S3051, and D4S2921 STR markers. Alleles are given in bp.
Mentions: The analysis of the CYP4V2 gene showed an abnormality in the three families. In family 1, a novel mutation was found: p.V458M (c.1372G>A). This variation was predicted as damaging to the protein function according to SIFT (Sorting Intolerant From Tolerant) software. A 12-year follow-up showed a mild exaggeration of symptoms, with progressive and moderate visual acuity reduction with the surprising findings of normal ERGs. This suggests the existence of less severe forms of BCD related to relatively mild CYP4V2 mutations. In families 2 and 3, a previously reported mutation was found, the p.I111T (c.332T>C) [10]. Both families denied any relation with each other. However, as the families share the same haplotype (Figure 5), we can postulate that this mutation derived from an ancestral mutation that was geographically restricted. Clinical comparison of the families did not show any phenotype-genotype correlation. Indeed, at the age of 39 and 37, patients V-2 and V-4 of family 3, respectively, presented a severe clinical phenotype; whereas patients II-3 and II-5 of family 2 aged 34 and 30, respectively, presented a less severe disease suggesting the possible involvement of genetic, epigenetic, or even environmental factors in the pathogenesis of BCD. In terms of environmental factors, lipid metabolism, and therefore diet, may play a role in the disease. Indeed, researchers have shown that CYP4V2 may play a role in fatty acid and steroid metabolism, which might be consistent with biochemical studies of patients with BCD [6,15]. Abnormal choroidal fibroblast inclusions are similar to those found in circulating lymphocytes, keratocytes, and conjunctival and skin fibroblasts [3]. Cultured lymphocytes from patients with BCD lack two fatty acid-binding proteins of 32 and 45 kDa, in comparison to age-matched controls [16].

Bottom Line: Two mutations in CYP4V2 were found: p.I111T (c.332T>C) in exon 3 in two families and the novel p.V458M (c.1372G>A) mutation in exon 9 in one family.Variation in disease severity and electroretinographic responses suggests that environmental or additional genetic factors influence the course of the retinal disease.The CYP4V2 p.I111T (c.332T>C) mutant allele may be especially prevalent among patients with BCD in Lebanon, resulting from a single founder.

View Article: PubMed Central - PubMed

Affiliation: Service d’Ophtalmologie, Hôtel-Dieu de France Hospital, Beirut, Lebanon.

ABSTRACT

Purpose: Bietti crystalline dystrophy (BCD) is a rare autosomal recessive disorder caused by mutation of the cytochrome P450, family 4, subfamily V, polypeptide 2 (CYP4V2) gene and characterized by retinal pigmentary abnormalities and scattered deposits of crystals in the retina and the marginal cornea. The aim of this study was to investigate the spectrum of mutations in CYP4V2 in Lebanese families, and to characterize the phenotype of patients affected with BCD.

Methods: Nine patients from three unrelated Lebanese families were clinically and molecularly investigated. Detailed characterization of the patients' phenotype was performed with comprehensive ophthalmic examination, color vision study, fundus photography, visual field testing, retinal fluorescein angiography, electroretinography, and electrooculography. One family was followed for 12 years. The 11 exons of the CYP4V2 gene were sequenced.

Results: Symptoms consisting of night blindness, loss of paracentral visual field, and disturbed color vision were apparent during the third decade of life. Ophthalmoscopy revealed posterior pole crystalline deposits and areas of retinal pigment epithelium atrophy. Fluorescein angiography disclosed geographic areas of the pigment epithelium layer and choriocapillaris atrophy in the posterior pole and fundus periphery. The most striking findings were those of normal electroretinographic responses in some patients and clinical heterogeneity. Two mutations in CYP4V2 were found: p.I111T (c.332T>C) in exon 3 in two families and the novel p.V458M (c.1372G>A) mutation in exon 9 in one family.

Conclusions: These patients are affected with Bietti crystalline dystrophy without corneal involvement. Variation in disease severity and electroretinographic responses suggests that environmental or additional genetic factors influence the course of the retinal disease. The CYP4V2 p.I111T (c.332T>C) mutant allele may be especially prevalent among patients with BCD in Lebanon, resulting from a single founder.

Show MeSH
Related in: MedlinePlus