In the case described here, the acute onset associated with back pain and the spinal cord MRI alteration in the region of the anterior spinal cord artery could first suggest an arterial infarction. Indeed, LHON can be associated with cardiac arrhythmias and can predispose individuals to embolic events [
5]. The patient’s symptoms improved rapidly after corticosteroid treatment, and there was a significant reduction of the signal in the spinal cord MRI ten days later, a pattern more consistent with an inflammatory origin of the lesions. A condition characterized by MS-like neuropathological and clinical findings in the presence of an LHON mtDNA mutation was described by Harding and referred to as “Harding disease” or “LHON-MS”. LHON-MS is characterized by recurrent episodes of visual loss associated with ocular pain and central nervous system demyelination along with unmatched cerebrospinal fluid oligoclonal bands. In past years, authors have extensively discussed the possibility that LHON-MS syndrome could be coincidental; an interesting point addressed in these discussions was whether and how the two diseases reciprocally influence their natural histories [
6]. Upregulation of mitochondrial manganese superoxide dismutase and increased expression of inducible nitric oxide synthase within the inflammatory lesions have been described.
The 3460G > A mtDNA mutation occurs in the ND1 gene, which encodes a subunit of complex-I of the electron transport chain, NADH: ubiquinone oxidoreductase; the mutation reduces the rotenone- and ubiquinone-dependent electron transfer activity of complex without affecting the activity of proximal NADH dehydrogenase [
7]. We speculate that the energy imbalance produced by this genetic defect could lead to the spinal cord manifestations seen in this patient due to the high energetic demand of the spinal cord anterior horn. In some mitochondrial diseases (e.g., MELAS), stroke-like lesions in the brain are the consequence of an energy imbalance between the demand for and the availability of ATP in neurons, astrocytes and endothelial cells [
3]. Some MELAS/LHON cases have been reported, but none of these cases had spinal cord involvement. Some authors have suggested that the mitochondrial dysfunction acts as a driver of neurodegeneration both in the classic LHON presentation and in the MS-like pathology through energy deficiency, hypoxic-like tissue injury and exposure of mtDNA-encoded proteins as histocompatibility antigens [
1,
8]. A progressive metabolic axonopathy was reported by Jaros [
9] in a case of LHON as a result of a lifelong pathology, and no evidence of demyelination was observed in the autoptic spinal cord; it has been speculated that different mtDNA mutations predispose different neuronal types to specific susceptibility to neurodegeneration [
9‐
11]. Spinal cord involvement during the onset of two cases of LHON mimicking neuromyelitis optica has recently been described [
12,
13], emphasizing the necessity of better characterizingin its early stages. We acknowledge the possibility that our patient might have co-occurrence of the LHON mutation and inflammatory CNS pathology; indeed, it is possible that the two diseases reciprocally influence each other’s natural history. However, neither the criteria of seronegative NMO nor the MS clinical diagnostic criteria were fulfilled at one-year follow-up [
14,
15]. To our knowledge, this is the first reported case of a pediatric spinal cord acute lesion that could represent the onset of neurological manifestations in a patient carrying a typical LHON mutation. Incomplete penetrance is not uncommon in LHON, and factors including additional mtDNA variants [
16] and mtDNA haplogroups [
17] have been proposed to influence the onset and progression of disease in patients with the LHON mutation. Direct sequencing of full mtDNA in our case ruled out a synergic role of other mtDNA mutations, and no experimental data support a role of the predicted H27 haplogroup as a genetic modifier in LHON. We cannot exclude the possibility that other factors, such as nuclear background [
18,
19], might be relevant to protecting our patient from optic nerve pathology or might influence the peculiar aspects of her clinical presentation.