Grand rounds: could occupational exposure to n-hexane and other solvents precipitate visual failure in leber hereditary optic neuropathy?

Abstract

Context: Leber hereditary optic neuropathy (LHON) is a maternally inherited loss of central vision related to pathogenic mutations in the mitochondrial genome, which are a necessary but not sufficient condition to develop the disease. Investigation of precipitating environmental/occupational (and additional genetic) factors could be relevant for prevention.

Case presentation: After a 6-month period of occupational exposure to n-hexane and other organic solvents, a 27-year-old man (a moderate smoker) developed an optic neuropathy. The patient had a full ophthalmologic and neurologic investigation, including standardized cycloergometer test for serum lactic acid levels and a skeletal muscle biopsy. His exposure history was also detailed, and he underwent genetic testing for LHON mitochondrial DNA mutations. The patient suffered a sequential optic neuropathy with the hallmarks of LHON and tested positive for the homoplasmic 11778G--> A/ND4 mutation. Routine laboratory monitoring revealed increased concentrations of urinary 2.5 hexandione (n-hexane metabolite) and hippuric acid (toluene metabolite) in the period immediately preceding the visual loss.

Discussion: In a subject carrying an LHON mutation, the strict temporal sequence of prolonged appreciable occupational exposure followed by sudden onset of visual loss must raise a suspicion of causality (with a possible further interaction with tobacco smoke).

Relevance: In this article, we add to the candidate occupational/environmental triggers of LHON and highlight the need for appropriate case-control (and laboratory) studies to validate the causal effect of mixed toxic exposures.

Figure 1

RNFL thickness in each quadrant of the eye, as measured by optical coherence tomography. (A) Right eye. (B) Left eye. Solid lines refer to the patient’s eyes at 9, 10, or 15 months of follow-up; dashed and dotted lines refer to historical groups of healthy subjects (control) and of patients in an advanced stage of LHON with atrophy of the optic nerve (Barboni et al. 2005).

Figure 2

Three-generation reconstruction of the patient’s maternal line. mtDNA analysis of the patient and his mother and siblings (asterisks) revealed the homoplasmic 11778/ND4 LHON mutation in all four of them; however, the patient was the only family member affected.