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Summary Leber's hereditary optic neuropathy (LHON) is a neurodegenerative disorder that selectively affects the retinal ganglion cells (RGCs), consequently leading to optic atrophy and loss of central vision. The primary cause is a metabolic dysfunction of mitochondria due to mitochondrial DNA mutations affecting the respiratory complex I. Despite the metabolic defect is systemic and measurable in post-mitotic tissues, the disease is usually limited to the RGCs and leads to profoundly impaired vision. However, adjunctive neurological features may be present in a subset of LHON patients defining the so-called “plus” variant phenotype. The most frequent neurological features may be a multiple-sclerosis-like disease, basal ganglia involvement with dystonia or spastic dystonia and bilateral striatal necrosis, myoclonus, parkinsonism, peripheral neuropathy, migraine and sensorineural hypoacusia. Neurological exam, brain MRI, MR-spectroscopy and other ancillary exams may be needed to well characterize the “plus” phenotype of LHON patients. The genetic bases of these LHON “plus” cases are currently unclear, but private mtDNA mutations and nuclear genetic variants may be relevant.

Summary Leber's Hereditary Optic Neuropathy (LHON) is a mitochondrial disease due to homoplasmic mtDNA point mutations in complex I, affecting prevalently young males with incomplete penetrance. We recently documented that increase of mitochondrial biogenesis drives incomplete penetrance in LHON, further enhanced by estrogen protection in females. To shed light on nuclear genetic modifiers of LHON penetrance, we combined linkage analysis and association studies with tag and functional SNPs, MitoExome and microarray expression analysis. After computation of relevant co-variates (age, sex, smoke and mtDNA copy number) we obtained a list of candidate genes, the most interesting being implicated in ROS detoxification, mitochondrial biogenesis and cell quality control. A prevalent role of tobacco smoking in penetrance also emerged from our studies, showing that tobacco toxicity triggers LHON by depressing mtDNA copy number and oxidative phosphorylation. Overall, our results indicate that penetrance in LHON is modulated by variants in different genes rather than by a single mutation, and that a complex interaction with environmental factors such as tobacco smoking plays also a major role, representing a confounder for genetic studies. Supported by Telethon-Italy, grant #GGP11182 to VC.

Purpose To evaluate optic nerve and in particular melanopsin retinal ganglion cells (mRGCs) in relation to rest-activity rhythm in Alzheimer disease (AD). Methods Retinal nerve fiber layer (RNFL) thickness measurements by optical coherence tomography were performed in 21 AD and 74 age-matched controls. Actigraphic monitoring was performed in 16 AD patients and 10 age-matched controls. Non-parametric methods were applied to assess interdaily stability (IS), intradaily variability (IV) and relative amplitude (RA) of rest-activity rhythm. We also performed immunohistochemical analysis of mRGCs and axonal count on optic nerve cross-sections in 14 neuropathologically confirmed AD and 13 control post-mortem retinas. Results OCT evaluation showed reduced average (p=0.03) and superior (p=0.005) RNFL thickness in AD patients. Actigraphic monitoring demonstrated an increased IV (p=0.04) and reduced RA (p=0.04) in AD. Furthermore, AD patients were significantly less active during the day (p=0.03). Considering the patients with at least one circadian parameter outside the 2SD from the mean of controls, we found a significant correlation between IV, average (p=0.035), superior (p=0.045) and inferior (p=0.017) RNFL thickness. Melanopsin RGCs density was significantly reduced, independently from age, in AD retinas (p=0.003) and AD optic nerves showed variable degree of age-related axonal loss. Conclusion We demonstrated a subclinical optic nerve involvement in AD patients, both by OCT and histopathology. We also documented rest-activity circadian dysfunction in AD patients. Post-mortem investigation revealed loss of mRGCs and RGCs with a different pattern in AD. The reduction of mRGCs may contribute to circadian rhythm dysfunction in AD.