LHON plus with Leigh-like phenotype

Chiara La Morgia, MD, PhD1-2; Valerio Carelli1-2

1Unit of Neurology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy

2IRCCS, Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria, Bologna, Italy

The occurrence of bilateral brainstem lesions is a typical brain MRI finding in patients with mitochondrial disorders carrying complex I deficiency and is considered as a hallmark of this condition, particularly in association with basal ganglia lesions (Le Febre et al, 2010). However, the occurrence of Leigh-like lesions has been rarely reported also in associations with Leber’s Hereditary Optic Neuropathy (LHON) mutations, even with the classic LHON mutations (Funalot et al, 2002). We here report 3 LHON cases carrying rare LHON mutations (14459/MT-ND6, 3890G>A/MT-ND1 and m. C4171A-ND1) all characterized by the occurrence of bilateral brainstem lesions. The association of subacute visual loss leading to optic atrophy should point to a complex I defect and, thus, a genetic screening for LHON including the complete mtDNA sequencing is warranted in these cases.


Case 1

This is a 29-year-old male carrying the mitochondrial DNA (mtDNA) 14459/ND6 mutation, heteroplasmic in blood cells (90% of mutant mtDNA) and homoplasmic (100% of mutant mtDNA) in the urinary epithelium.

Family history is relevant for the presence of a brother carrying the same mutation affected by Leigh syndrome and optic atrophy. The brother is a 26-year-old male who presented spastic dystonia since 4 years of age with evidence at brain MRI of bilateral striatal necrosis. He underwent internal globus pallidus implant for deep brain stimulation at 16 years of age. At 17 years of age he presented bilateral visual loss with subsequent optic atrophy compatible with the diagnosis of LHON. A therapy with idebenone at the dosage of 450 mg/day was started with some improvement in visual acuity.

The patient complained since childhood bradykinesia and clumsiness with the upper right arm with some rigidity involving also the right lower limb. He noticed difficulty in running. These disturbances were stable over time.

Brain MRI revealed the presence of atrophy and hyperintensity on T2-weighted images of the left putamen (Figure 1). Optical coherence tomography (OCT) (Heidelberg, Spectralis) showed normal thickness the retinal nerve fiber layer and segmentation analysis displayed thickness of the GCL within normal limits (not shown). Lactic acid evaluation disclosed normal rest values and increase lactic acid levels after standardized exercise (32.4 mg/dl, nv 5-22).

Case 2

This is a 40 year-old male who suffered at 31 years of age vertigo and vomiting.

Brain MRI showed bilateral vestibular nuclei T2 hyperintensity, which completely resolved after 3 months. After three months he also presented subacute loss of vision in the left eye (LE) followed after two months by the right eye (RE) involvement. Visual acuity progressively worsened over time and after one year bilateral optic atrophy was evident at fundus examination. At 33 years of age the presented bilateral tinnitus. Brain MRI performed at that time disclosed righ inferior colliculus hyperintensity (Figure 2, A-B). Brain MRI performed after 2 years (at 35 years) showed bilateral inferior colliculi lesions (Figure 2, C)

At the last follow-up OCT showed bilateral diffuse RNFL thinning (Figure 3).

Last evaluation of lactic acid at 40 years of age revealed abnormally elevated lactic acid values after standardized exercise (58.3 mg/dl) and after recovery (41.4 mg/dl, nv 5-22 mg/dl).

Genetic analysis disclosed the presence of non-synonymous homoplasmic variant at position m.3890G>A/MT-ND1 which has been demonstrated to be pathogenic for LHON (Caporali et al, 2013).

The full clinical history has been already reported in details in Caporali et al, 2013.

Case 3

This is a 20 year old-male who presented at 12 years of age bilateral visual loss after a febrile episode. At 16 years of age with acute onset of vomiting and vertigo. Family history disclosed the presence of optic atrophy in the proband’s mother and sister.

Brain MRI showed bilateral vestibular nuclei lesions (Figure 4, A). Vertigo and vomiting progressively improved with a complete resolution of the symptoms after a few months. A therapy with idebenone was started with improvement of visual function (for details see La Morgia et al, 2014). Brain MRI performed after 6 months showed a complete recovery of the vestibular nuclei lesions and the appearance of a new asymptomatic lesion involving the left inferior colliculus (Figure 4, B). The last brain MRI follow-up at 18 years of age showed an improvement of the lesion affecting the left inferior colliculus (Figure 4, C).

OCT at last evaluation showed the presence of diffuse RNFL thinning (Figure 5).  Complete mtDNA sequence revealed the presence of homoplasmic mtDNA mutation (m. C4171A-ND1) and three additional non-synonymous homoplasmic transition affecting ND2 (for details see La Morgia et al, 2014).


Figure legends

Figure 1: Brain MRI shows left putaminal hyperintensity in T2-weighted images (upper line) and left putaminal hypointensity in T1-weighted images (lower line).

Figure 2. Hyperintensity in T2-weighted image affecting the right inferior colliculus (A), hypointense in T1 (B). Bilateral hypointensity of the inferior colliculus was evident at 35 years of age (C).

Figure 3. OCT of the optic nerve shows a diffuse RNFL thinning in both eyes

Figure 4

A: Bilateral hyperintense T2 lesions affecting the vestibular nuclei. B Left inferior colliculus hyperintense T2 lesion C: Last brain MRI showing an improvement of the left colliculus lesion (modified from La Morgia et al, 2014).

 Figure 5. OCT shows a diffuse RNFL thinning in both eyes



Caporali L, Ghelli AM, Iommarini L, Maresca A, Valentino ML, La Morgia C,

et al. Cybrid studies establish the causal link between the mtDNA

m.3890G>A/MT-ND1 mutation and optic atrophy with bilateral brainstem lesions. Biochim Biophys Acta 2013;1832:445-52.

Funalot B, Reynier P, Vighetto A, Ranoux D, Bonnefont JP, Godinot C, et al. Leigh-like encephalopathy complicating Leber’s hereditary optic

neuropathy. Ann Neurol 2002;52:374-377.

La Morgia C, Caporali L, Gandini F, Olivieri A, Toni F, Nassetti S, et al.

Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions. BMC Neurol 2014;14:116.

Lebre AS, Rio M, Faivre d’Arcier L, Vernerey D, Landrieu P, Slama A, et al. A common pattern of brain MRI imaging in mitochondrial diseases with complex I deficiency. J Med Genet. 2011;48:16-23.

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