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Optic nerve atrophy
Disease Introduction
Optic nerve atrophy refers to a morphological change caused by any disease that leads to pathological changes in retinal ganglion cells and their axons, resulting in thinning of the optic nerve, and is the result of optic nerve damage. The clinical manifestations include degeneration and disappearance of optic nerve fibers, conduction dysfunction, visual field defects, visual impairment and loss. It is generally divided into two categories: primary and secondary. Hereditary optic atrophy can be classified into autosomal dominant inheritance, recessive inheritance, and X-linked inheritance. Leber hereditary optic atrophy is inherited by mitochondria. The OPA1 gene is considered a common pathogenic gene for hereditary optic neuropathy.
Once the optic nerve atrophy occurs, it is almost impossible to cure it, but it is entirely possible for the remaining nerve fibers to recover or maintain their function. However, the downward optic nerve atrophy caused by pituitary tumor compression of the optic chiasm can lead to astonishing visual recovery in the vast majority of patients after surgical removal of the pituitary tumor.
Introduction to OPA1 gene
The OPA1 gene is located at 3q29, approximately 1.1Mb, and contains 31 exons. It encodes a protein located on the inner membrane of mitochondria and plays a regulatory role in several important cellular processes, including mitochondrial network stability, mitochondrial bioenergy output, and isolation of pro apoptotic cytochrome C oxidase molecules in the mitochondrial cristae space. This protein contains five functional domains: mitochondrial leader sequence (exons 1 and 2), N-terminal helical coil structure (exons 5-7), GTPase region (exons 8-16), central dynamic region (exons 17-24), and C-terminal helical coil structure (exons 27-28). The OPA1 gene selectively cleaves to produce 8 mRNA subtypes, which are expressed in different parts of the human body. In situ hybridization and immunohistochemistry showed that this gene is highly expressed in the retina.
Genetic mode
This gene mutation leads to autosomal dominant inheritance of optic nerve atrophy. The clinical symptoms of optic nerve atrophy caused by this gene mutation vary greatly. 70% of autosomal dominant optic atrophy is caused by mutations in the OPA1 gene. The penetrance rate of OPA1 is around 98%, and its size varies depending on the family.
OPA1 gene mutation
There are more than 300 OPA1 gene variants included in the HGMD database, with over 90% being point mutations or small fragment deletions/insertions, 10% being gene rearrangements, and an exon rate of 40% -100%. Among them, over 90% of pathogenic variants lead to optic nerve atrophy.
The proportion of OPA1 gene missense mutations is relatively high, with exons 27 and 8 being hot mutation regions. Patients carrying OPA1 gene missense mutations have poorer vision, and patients with suspected hereditary optic neuropathy should not ignore OPA1 gene testing.
Other eye developmental abnormalities related to OPA1 gene
The clinical manifestations of Behr syndrome include hearing loss, optic nerve atrophy, nystagmus, cerebellar ataxia, spasms, developmental delay, and gait instability; Other phenotypes are diverse and have different onset periods, mostly in children and adolescents.
Case sharing
Clinical symptoms：The subject, male, 12 years old, was clinically diagnosed with optic nerve atrophy, and his grandmother had the same phenotype.
Testing items：Genetic testing for ophthalmic genetic diseases (441 genes)
Test method ：Extract genomic DNA from the peripheral blood of the subject, construct a genomic library, capture relevant target gene exons and adjacent intron regions through probe hybridization, and enrich them. The enriched target gene fragments were sequenced using a high-throughput sequencing platform, and Sanger sequencing was used to validate the identified pathogenic variants.
Detection result ：Detect a pathogenic gene mutation that matches the clinical phenotype of the subject.
According to the genetic variation classification criteria established by the American Society for Medical Genetics and Genomics (ACMG), mutations are divided into the following five types, with pathogenic mutations represented by pathogenic mutations; Likely pathogenic refers to a variant that may cause disease; Benign mutation; Like benign refers to a mutation that may be benign; Unknown significance refers to mutations with unclear meanings. AD stands for autosomal dominant inheritance; AR stands for autosomal recessive inheritance; X-linked represents X-linked inheritance.
Genetic analysis：(1) The OPA1 (OMIM: 165500) gene mutation mainly causes optic nerve atrophy, which is inherited in an autosomal dominant manner.
(2) The test subject detected the following variant: OPA1 c.870+1G>A, a heterozygous variant, which has been included in the HGMD database and has been reported as a pathogenic variant in literature.
(3) The genetic diagnosis of the subject matches the clinical phenotype, indicating a pathogenic variant.
Genetic counseling advice：(1) The grandmother of the subject did not verify the variant site, and the parental verification results showed that the variant came from the maternal source, but the mother was not sick. It is recommended to confirm the maternal phenotype again. Suggest genetic counseling.
(2) There is a 50% chance that the examinee and other patients in the family will have the disease in the future. Suggest genetic counseling.
First generation verification results：
OPA1 c.870+1G>A, the locus of the subject is a heterozygous variant, the father of the subject is a wild-type locus, and the mother of the subject is a heterozygous variant locus.
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CHIGENOVO Co., Ltd. is an ophthalmic gene therapy company, a national high-tech enterprise focusing on genetic diagnosis of genetic eye diseases and the development of gene therapy drugs. It is committed to providing "one-stop" services for patients with genetic eye diseases.
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