LHON is a mitochondrial disorder that mainly affects the eye. It is characterized by bilateral painless subacute vision loss that begins in the second and third decades of life. It usually has onset between 15-30 years of age, and leads to rapid, progressive blindness. Visual acuity usually deteriorates to 20/200 or worse.

No evidence-based U.S. testing guidelines were identified for LHON.

Although not specific to genetic testing for LHON, the Mitochondrial Medicine Society (2015) developed consensus recommendations for the diagnosis and management of mitochondrial disease. Testing strategies, including strategies for genetic testing, were discussed.

• Recommendations for DNA testing include the following:
  • “Massively parallel sequencing/NGS of the mtDNA genome is the preferred methodology when testing mtDNA and should be performed in cases of suspected mitochondrial disease instead of testing for a limited number of pathogenic point mutations.
  • Patients with a strong likelihood of mitochondrial disease because of a mtDNA mutation and negative testing in blood, should have mtDNA assessed in another tissue to avoid the possibility of missing tissue-specific mutations or low levels of heteroplasmy in blood; tissue-based testing also helps assess the risk of other organ involvement and heterogeneity in family members and to guide genetic counseling.
  • Heteroplasmy analysis in urine can selectively be more informative and accurate than testing in blood alone, especially in cases of MELAS due to the common m.3243 A>G mutation.
  • When considering nuclear gene testing in patients with likely primary mitochondrial disease, NGS methodologies providing complete coverage of known mitochondrial disease gene is preferred. Single-gene testing should usually be avoided because mutations in different genes can produce the same phenotype. If no mutation is identified via known NGS panels, then whole exome sequencing should be considered.”

The European Federation of Neurological Sciences (2009) provide consensus-based guidelines for LHON genetic testing: "If the phenotype suggests syndromic mitochondrial disorder due to mtDNA point mutations (MELAS, MERRF, NARP, LHON), DNA-microarrays using allele-specific oligonucleotide hybridisation, real-time-PCR or single-gene sequencing are indicated."

The Clinical Molecular Genetics Society of the United Kingdom (2008) provided practice-based guidelines for the molecular diagnosis of mitochondrial disease: "Investigation for the G3460A, G11778A and T14484C mutations are indicated for all LHON referrals."

A 2016 expert-authored review suggests the following testing strategy for those with a known or suspected diagnosis of LHON:

• Three common mtDNA pathogenic variants account for 90%-95% of LHON. Targeted analysis for one of these three variants should be performed first."
• "A multi-gene panel that includes the mitochondrial genes that encode subunits of NADH dehydrogenase, MT-ND1, MT-ND2, MT-ND4, MT-ND4L, MT-ND5, and MT-ND6, which are known to cause LHON and other genes of interest may also be considered."
• "Complete mtDNA sequencing may be considered if use of targeted testing and/or a multi-gene panel did not identify a pathogenic variant, clinical suspicion remains high, and there is no evidence of paternal transmission.

For those seeking predictive testing (e.g. they are not currently affected), this review states:

• "Testing of at-risk asymptomatic adults for LHON is possible. Such testing is not useful in predicting age of onset, severity, or rate of progression in asymptomatic individuals."
• Testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate.