A clinically complex form of dominant optic atrophy (OPA8) maps on chromosome 16.

Dominant optic atrophy (DOA) is genetically heterogeneous and pathogenic mutations have been identified in the OPA1 and OPA3 genes, both encoding for mitochondrial proteins. We characterized clinical and laboratory features in a large OPA1-negative family with complicated DOA. Search for mitochondrial dysfunction was performed by studying muscle biopsies, fibroblasts, platelets and magnetic resonance (MR) spectroscopy. Genetic investigations included mitochondrial DNA (mtDNA) analysis, linkage analysis, copy number variation (CNV) analysis and candidate gene screening. Optic neuropathy was undistinguishable from that in OPA1-DOA and frequently associated with late-onset sensorineural hearing loss, increases of central conduction times at somato-sensory evoked potentials and various cardiac abnormalities. Serum lactic acid after exercise, platelet respiratory complex activities, adenosine triphosphate (ATP) content in fibroblasts and muscle phosphorus MR spectroscopy all failed to reveal a mitochondrial dysfunction. However, muscle biopsies and their mtDNA analysis showed increased mitochondrial biogenesis. Furthermore, patient's fibroblasts grown in the galactose medium were unable to increase ATP content compared with controls, and exhibited abnormally high rate of fusion activity. Genome-wide linkage revealed a locus on chromosome 16q21-q22 with a maximum two-point LOD score of 8.84 for the marker D16S752 and a non-recombinant interval of ∼ 6.96 cM. Genomic screening of 45 genes in this interval including several likely candidate genes (CALB2, CYB5B, TK2, DHODH, PLEKHG4) revealed no mutation. Moreover, we excluded the presence of CNVs using array-based comparative genome hybridization. The identification of a new OPA locus (OPA8) in this pedigree demonstrates further genetic heterogeneity in DOA, and our results indicate that the pathogenesis may still involve mitochondria.

Blue cone monochromatism: clinical findings in patients with mutations in the red/green opsin gene cluster.

BACKGROUND: X-linked blue cone monochromatism (BCM) has to be differentiated from x-linked cone dystrophy and autosomal recessive rod monochromatism. METHODS: In nine male patients with congenital cone dysfunction (one family, six single cases; age range: 9-55 years), mutations in the red/green opsin gene cluster were confirmed. Clinical findings were analyzed retrospectively. RESULTS: In one family and three single cases, a single red-green hybrid gene was found carrying a Cys203Arg mutation. Two patients had multiple opsin genes, a red/green hybrid gene and at least one green pigment gene, all carrying the Cys203Arg mutation. In one patient, a large deletion of the locus control region and parts of the red pigment gene were detected. Two patients (ages: 45 and 55 years) complained about progression. Two patients presented with nystagmus. Refractive errors (+8.0 and -11.0 D) and visual acuity were variable (0.05-0.3). Only four patients had a visual acuity > or = 0.1. In two patients, visual acuity could be improved using blue filter glasses. Four of five patients > or = 25 years had dystrophic alterations in the macula. Severe color vision defects and relative central scotoma were present in all patients. In the electroretinogram, residual cone responses were detected in 2/8 patients. CONCLUSIONS: Hybrid red/green opsin genes carrying the Cys203Arg mutation are a frequent cause of BCM in German patients. Molecular genetic evaluation is mandatory for adequate diagnosis of patients since from the clinical data only two patients were diagnosed as having BCM. In the other patients, either rod monochromatism or cone-rod dystrophy could not be excluded with certainty. The patients should be cautioned that macular dystrophy may develop in adults older than 30 years.