Leber’s Hereditary Optic Neuropathy (LHON) is a disorder that causes a rapid, painless loss of central vision, typically affecting young adults. It is one of the most common inherited causes of sudden blindness, resulting from damage to the optic nerve. In Vitro Fertilization (IVF) is a medical technology primarily used for reproduction, but it has been repurposed to prevent the transmission of genetic diseases. This intersection of a mitochondrial disorder and advanced reproductive technology offers families a method to have a biological child while significantly reducing the risk of passing on LHON.
The Genetics of LHON
The biological mechanism behind LHON is unique because the mutation is located in the mitochondrial DNA (mtDNA), not the cell’s nucleus. Mitochondria are organelles responsible for generating most of the cell’s energy and possess their own small, circular DNA genome. This distinction means that LHON follows a strict pattern of maternal inheritance, as mitochondria are passed down exclusively from the mother’s egg.
The condition is most commonly linked to one of three specific point mutations (m.11778, m.3460, and m.14484) that impair the function of Complex I in the mitochondrial energy production pathway. A central concept in transmission is heteroplasmy, which describes the presence of a mixture of both healthy and mutant mtDNA within the same individual.
The severity and likelihood of disease expression correlate directly with the level of heteroplasmy, or the percentage of mutant mtDNA molecules present. If the proportion of mutated mitochondria exceeds a threshold, energy production drops, causing cellular dysfunction in high-energy demand tissues like the optic nerve. The goal of prevention is to select an embryo carrying a low enough percentage of mutant mtDNA that disease expression is highly unlikely.
Accessing Embryos Through IVF
Traditional conception offers no mechanism to screen the resulting embryo for its mitochondrial mutation load. IVF provides the necessary access point for genetic analysis before implantation. The process begins with controlled ovarian stimulation, where the mother receives hormone injections to produce multiple eggs.
The mature eggs are retrieved through a minor surgical procedure and fertilized outside the body (in vitro fertilization). The fertilized eggs are cultured for several days until they reach the blastocyst stage. Culturing multiple embryos is necessary because not all will be genetically suitable or viable for transfer.
At the blastocyst stage, the embryo has differentiated into the inner cell mass (which forms the fetus) and the trophectoderm (which forms the placenta). The embryo is then ready for a biopsy, which provides the material for genetic testing. This IVF process serves the purpose of generating multiple embryos that can be screened for LHON transmission risk.
Preimplantation Testing for LHON Risk
The specific method used to assess LHON transmission risk is Preimplantation Genetic Testing for Monogenic Disorders (PGT-M). This procedure involves embryo biopsy, where a small cluster of cells (typically five to ten) is delicately removed from the blastocyst’s trophectoderm. The removal does not compromise the embryo’s viability, and the embryo is cryopreserved while the sample is analyzed.
The core of the PGT-M analysis is the precise measurement of the heteroplasmy level in the biopsied cells. Advanced molecular techniques, such as quantitative polymerase chain reaction (qPCR) or next-generation sequencing (NGS), are employed to count mtDNA molecules and determine the ratio of mutant to healthy mtDNA. This ratio estimates the genetic risk carried by the entire embryo.
The most suitable embryos for transfer have the lowest, or ideally undetectable, levels of mutant mtDNA. Clinical practice aims to select embryos with a heteroplasmy load below a theoretical pathogenic threshold, often striving for less than 5% mutant mtDNA. Infants born after successful PGT-M cycles have demonstrated heteroplasmy levels ranging from undetectable up to 7% in their blood, significantly reducing the risk of disease expression.
Mitochondrial Replacement Therapy (MRT)
An alternative, more definitive approach is Mitochondrial Replacement Therapy (MRT). This technique involves transferring the nuclear DNA from the mother’s egg into a donor egg containing healthy mitochondria, effectively replacing the faulty mitochondria entirely. However, because MRT involves the heritable modification of genetic material, it remains a highly restricted procedure, and PGT-M is the most common method for reducing LHON risk.
Outcomes and Regulatory Landscape
The practical outcome of using PGT to prevent LHON is generally favorable for patients who produce a sufficient number of embryos. One study of PGT for mitochondrial disorders reported that approximately 41% of patients achieved a clinical pregnancy, resulting in multiple live births and confirming the method’s effectiveness in selecting low-risk embryos.
The primary challenge in PGT is the difficulty of finding an embryo with a sufficiently low mutation load for transfer. The main reason for not having an embryo available is the failure to obtain a low-load embryo, especially for women with a high baseline heteroplasmy level. The cost of a single IVF cycle with PGT-M is also a significant barrier, typically ranging between $20,000 and $30,000 USD.
The regulatory environment for these technologies varies significantly across the globe. PGT for mitochondrial disorders is licensed in several countries, providing a pathway for genetic selection. Conversely, MRT is subject to much stricter control. The United Kingdom and Australia have enacted specific legislation to permit MRT under strict regulatory oversight. However, the use of MRT in the United States is currently prohibited due to a Congressional amendment that bans federal funding for research involving heritable genetic modification.