Corneal endothelial changes and trinucleotide repeat expansion of DRPLA gene
- Dr Abe, Department of Ophthalmology, Tohoku University School of Medicine, 1–1 Seiryoumachi, Aobaku, Sendai, Miyagi 980, Japan.
- Accepted 18 August 1998
Editor,—Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant disorder that manifests in a combination of chorea, myoclonus, seizure, ataxia, and dementia. It is caused by the unstable expansion of a CAG trinucleotide repeat coding for glutamine in the DRPLA gene.1 Several other genes with an unstable trinucleotide repeat expansion of CAG were cloned in some types of spinocerebellar degeneration (SCD). Several reports have also suggested an association between ocular changes and SCD.2 3 We report here the association of ocular changes in patients with an expanded allele of the trinucleotide repeat of the DRPLA gene.
CASE REPORTS
A 46 year old woman (IV-2 in Fig 1) noticed gait disturbance and truncal ataxia at age 36 years. When we visited her, her general condition was very severe, and visual acuities were not examined. Pupils, ocular media, and fundus examination showed normal findings. Corneal endothelial cell density was 762 cells/mm2 right eye and 540 cells/mm2 left eye by specular microscopy (Fig 2). DNA
Pedigree of the family with spinocerebellar degeneration and trinucleotide examination of DRPLA gene showing generations (roman numerals) of affected (solid symbols) and unaffected (open symbols) members. Squares indicate male members; circles, female; X, examined; and slash, deceased. The results of PCR showed that the affected patients (IV-2 and IV-4) had expanded allele of DRPLA gene, when they were compared with an unaffected family member (III-7) or normal healthy control (Nc). Primers used for amplification of the gene were described elsewhere.4 N is a negative control without DNA and P is a positive control as we previously reported.4M is a marker of 123 base pair. The arrow in the left margin indicates the larger bands due to expanded allele of the DRPLA gene.
Specular microscopy reveals that patients with the mutated allele of DRPLA gene show severely decreased cell density in the corneal endothelium. Endothelial photographs of (A) patient IV-4 in Figure 1; (B) patient IV-2 in Figure 1; (C) family member III-7 in Figure 1 (2724 cells/mm2); and (D) a patient with Machado–Joseph disease who has a trinucleotide expansion allele with a normal repeat allele of the Machado–Joseph disease gene (2814 cells/mm2). Actual cell densities are reported in the text.
analysis from peripheral lymphocytes revealed that she had an expanded allele of the DRPLA gene with a normal allele (expanded/normal allele; 67/20), which was estimated by a fluorescein isothiocyanate (FITC) labelled primer used for polymerase chain reaction (PCR) amplification, according to our previous methods.4
A 39 year old woman (IV-4 in Fig 1) noticed truncal ataxia at age 36 years, and the symptoms have gradually increased. When she consulted us her visual acuity was 1.0 in both eyes. Pupillary reactions, intraocular pressures, ocular media, and fundus examination results; Humphrey visual field analysis; Ishihara colour vision; and ERG examination findings were normal. Corneal endothelial cell density was 951 cells/mm2 right eye and 866 cells/mm2left eye by specular microscopy (Fig 2). DNA analysis from peripheral lymphocytes revealed that she had an expanded allele of the DRPLA gene with a normal allele (expanded/normal allele; 66/19).
COMMENT
Neither patients had a history of trauma, inflammation, or surgery of the eye. The difference in corneal endothelial cell density was statistically significant, compared with that in healthy members of the family; in patients with Machado–Joseph disease, who have a trinucleotide repeat expansion allele with a normal repeat allele of the Machado–Joseph disease gene; and in age matched normal healthy controls in our clinic (p=0.004, unpaired ttest) (data not shown).5 The enlargement of the cell may be generated by a cytopathological condition of the cell due to an impropriety function of the DRPLA protein (termed atrophin-1), which may be expressed in corneal endothelial cells or adjacent cells. Previously, decreased corneal endothelial cell density, optic atrophy, and mild attenuation of oscillatory potentials observed on ERG in patients with spinocerebellar degeneration with trinucleotide expansion of spinocerebellar ataxia type 1 (SCA1) gene have been reported.3 However, our patients showed only decreased corneal endothelial cell density and were free of other ocular changes. Although we will continue to follow these patients for other ocular symptoms, our patient IV-2 has had a long history of the disease (10 years), and we believe that the findings are specific to the mutation of the DRPLA gene. We will also examine other families with the mutation of the DRPLA gene to exclude of the possibility of corneal endothelial dystrophy.
Acknowledgments
We thank Ms Maxine A Gere for correcting the manuscript.
