Mutation screening of mitochondrial DNA as well as OPA1 and OPA3 in a Chinese cohort with suspected hereditary optic atrophy.

PURPOSE: Leber's hereditary optic atrophy (LHON) and autosomal dominant optic atrophy (DOA) are the two most common forms. The objective of this study was to define the fractional prevalence of LHON and DOA in a cohort of Chinese patients with suspected hereditary optic neuropathy. METHODS: We recruited 520 unrelated patients with bilateral optic atrophy for genetic analysis: 174 patients had a positive family history of visual failure and 346 were sporadic cases. A total of 14 primary LHON-causing mtDNA mutations was screened by PCR-based sequencing methods for all patients except the individuals with a paternal family history. All coding exons and exon-intron boundaries of the OPA1 and OPA3 gene were screened for mutations by PCR-based DNA sequencing for all patients with paternal family history and for the LHON-negative patients. A large genomic DNA arrangement of the OPA1 gene was detected further by multiplex ligation probe amplification (MLPA) assay for the patients with paternal family history, but results were negative for the OPA1 and OPA3 mutation screenings. RESULTS: We found molecular defects in 323 (62%) of the 520 probands screened. Among these, 271 patients (83.9%) had an mtDNA mutation, 50 patients (15.5%) carried an OPA1 mutation, and 2 patients (0.6%) had an OPA3 mutation. Coexistence m.3460 G>A and m.11778G>A was found in one patient. We identified 40 intragenic mutations and six large genomic DNA arrangements of the OPA1 gene, 23 of which were novel. CONCLUSIONS: The LHON-mtDNA mutations are the most common genetic defects, followed by the OPA1 mutations, in this Chinese cohort.

Screening for CRX gene mutations in Chinese patients with Leber congenital amaurosis and mutational phenotype.

PURPOSE: To screen for possible disease-causing mutations in the CRX gene in Chinese patients with Leber congenital amaurosis (LCA) and to enrich the understanding of its mutational phenotype. METHODS: Genomic DNA was collected from 27 patients with LCA. The coding sequences of the CRX gene were analyzed using the PCR-heteroduplex-SSCP method. Mutations were confirmed by DNA sequencing. RESULTS: We identified two heterozygous variations in the CRX gene in two patients with LCA. One was a deletion (GCC-->-CC, A181D1bp) leading to a frameshift and protein truncation. This mutation was present in a patient with LCA, but not in his healthy parents. The ocular manifestations of this A181Delta1bp mutation are described. An intronic variation (IVS1-13G-->C) was found in a patient with LCA as well as in his healthy father. CONCLUSION: A heterozygous A181D1bp mutation in the CRX gene caused an LCA phenotype in a Chinese patient.

Exclusive homoplasmic 11778 mutation in mitochondrial DNA of Chinese patients with Leber's hereditary optic neuropathy.

PURPOSE: To investigate the degree of heteroplasmy of the 11778 mtDNA mutation in Chinese patients with Leber's hereditary optic neuropathy (LHON). METHODS: Seventeen Chinese Leber's pedigrees, including 24 patients, 17 unaffected maternal lineages, 4 internal controls, and 6 unrelated controls, were screened for the 11778 mtDNA mutation. This was carried out by analysis of the restriction fragment length polymorphism, single-strand conformation polymorphism, and DNA sequencing. RESULTS: All patients and unaffected maternal lineages, regardless of their symptoms, had homoplastic 11778 mtDNA mutation, which was revealed by restriction fragment length polymorphism analysis and single-strand conformation polymorphism analysis. CONCLUSION: Exclusive homoplasmy of the 11778 mtDNA mutation in Chinese LHON patients was found in this study. Homoplasmy of the 11778 mtDNA mutation cannot account for the variation in the clinical phenotype of Chinese Leber's patients.

High incidence of pre-excitation syndrome in Japanese families with Leber's hereditary optic neuropathy.

Cardiac conduction abnormalities have been reported in families with Leber's hereditary optic neuropathy (LHON). The pre-excitation syndrome Wolff-Parkinson-White syndrome or Lown-Ganong-Levine syndrome, is reportedly common in Finns with LHON, being seen in 14 (9%) of the 163 individuals with mitochondrial DNA (mtDNA) mutations. While this syndrome is thought to be rare in other ethnic groups with LHON, the present study of 35 Japanese LHON families confirmed that it is also relatively common among Japanese families, being seen in 5 (8%) of the 63 individuals with mtDNA mutations. It remains to be determined whether the high incidence of the pre-excitation syndrome in Finnish and Japanese LHON families is due to a particular genetic composition of ethnic groups such as in Finland and in Japan, or only to a reporting bias.

Leber's hereditary optic neuropathy among Japanese.

This article reviews the literature on point mutation of mitochondrial DNA (mtDNA) among Japanese and the authors' research data on pupil reaction in patients with Leber's hereditary optic neuropathy (LHON). Among Japanese, a higher frequency (80-90%) of point mutation at nucleotide position 11778 of mtDNA was found; other point mutations found were at nucleotide positions 3460, 14484, 13708, 7444, and 3394. Although pupil reaction to light stimulus is usually defective in all types of optic neuropathy, in patients with LHON the reaction was well maintained even when vision was reduced. W cells in the retina may be preserved or less damaged, even when the degenerative process progresses in both X and Y cells. Possible treatment is also described.

Three subgroups of patients from the United Kingdom with Leber hereditary optic neuropathy.

Variations in classic Leber hereditary optic neuropathy (LHON) include recovery of vision and association with other neurological abnormalities. Sixteen multi-generational Australian families originating from the United Kingdom with LHON were studied by the one examiner, using the same protocol. In particular, recovery of vision and other neurological abnormalities were noted. One very large family (Tas2) and one small family (Vic2) were found to have frequent recovery of vision (50% of patients). They both had the 14484 T to C mutation in their mitochondrial DNA (mtDNA). One apparently unique family (Qld1) was found to have frequent juvenile encephalopathy and peripheral neurological signs. They had the 4160 T to C and 14484 T to C mutations. The remaining 13 families rarely showed visual recovery or associated neurological abnormalities. They had the common 11778 G to A or the 3460 G to A mutations. Thus mitochondrial genotypes in LHON are associated with variable phenotypes.

The two locus control of Leber hereditary optic neuropathy and a high penetrance in Japanese pedigrees.

The maternal transmission of Leber hereditary optic neuropathy (LHON) can be explained by the mitochondrial DNA mutation. However, the characteristic mode of inheritance, i.e. male predominance and reduced penetrance with late onset in females, suggests the simultaneous involvement of an X-linked gene in development of optic atrophy. We have assessed such a two-locus model of mitochondrial and X-linked genes in Japanese LHON pedigrees. The goodness-of-fit test on individual male sibship data with a presumed heterozygous mother from maternal lines showed an excellent fit for the 1:1 segregation of a putative X-linked gene, thus supporting the two-locus model in the Japanese pedigrees tested. A calculated frequency of the X-linked gene was 0.10. We could not determine whether the present value is different from the reported one (= 0.08). On the other hand, the estimated penetrance for a heterozygous female was 0.196 +/- 0.039, which was about twice as high as the reported value (= 0.111) with a 5% level of significance. Such a high penetrance may primarily arise from a low threshold of LHON manifestation, suggesting the ethnic difference between the LHON pedigrees in Japan and in other countries.