Neuroradiological findings expand the phenotype of OPA1-related mitochondrial dysfunction

https://doi.org/10.1016/j.jns.2015.01.008Get rights and content

Highlights

  • Brain imaging abnormalities are frequent and various in patients with OPA1-related optic atrophy.

  • Cerebellar atrophy mainly involving the vermis was observed in almost a quarter of this series of 22 patients.

  • Cerebral abnormalities are more common in patients with a more severe visual impairment and associated deafness.

  • Cerebral abnormalities are consistent with the mitochondrial dysfunction related to OPA1 mutations.

Abstract

Objective

OPA1 mutations are responsible for more than half of autosomal dominant optic atrophy (ADOA), a blinding disease affecting the retinal ganglion neurons. In most patients the clinical presentation is restricted to the optic nerve degeneration, albeit in 20% of them, additional neuro-sensorial symptoms might be associated to the loss of vision, as frequently encountered in mitochondrial diseases. This study describes clinical and neuroradiological features of OPA1 patients.

Methods

Twenty two patients from 17 families with decreased visual acuity related to optic atrophy and carrying an OPA1 mutation were enrolled. Patients underwent neuro-ophthalmological examinations. Brain magnetic resonance imaging (T1, T2 and flair sequences) was performed on a 1.5-Tesla MR Unit. Twenty patients underwent 2-D proton spectroscopic imaging.

Results

Brain imaging disclosed abnormalities in 12 patients. Cerebellar atrophy mainly involving the vermis was observed in almost a quarter of the patients; other abnormalities included unspecific white matter hypersignal, hemispheric cortical atrophy, and lactate peak. Neurological examination disclosed one patient with a transient right hand motor deficit and ENT examination revealed hearing impairment in 6 patients. Patients with abnormal MRI were characterized by: (i) an older age (ii) more severe visual impairment with chronic visual acuity deterioration, and (iii) more frequent associated deafness.

Conclusions

Our results demonstrate that brain imaging abnormalities are common in OPA1 patients, even in those with normal neurological examination. Lactate peak, cerebellar and cortical atrophies are consistent with the mitochondrial dysfunction related to OPA1 mutations and might result from widespread neuronal degeneration.

Introduction

Autosomal dominant optic atrophy (ADOA) (Kjer type; ADOA, MIM 165500) is an inherited optic neuropathy featuring decreased visual acuity, alteration of the central visual field and dyschromatopsia [1], [2], [3]. Progressive loss of retinal ganglion neurons is leading to optic disc atrophy and optic nerve thinning [4] and more than half of ADOA families are linked to heterozygous mutations in OPA1 gene [3]. OPA1-ADOA was originally described as a non-syndromic optic neuropathy. Subsequent studies reported OPA1 patients suffering optic neuropathy associated with deafness [5], [6], [7], [8], or associated with more widespread neuro-muscular features encompassing progressive external ophthalmoplegia, myopathy, ataxia and peripheral neuropathy, or with spastic paraparesis [9], [10], [11], [12]. Multiple muscle mitochondrial DNA (mtDNA) deletions were identified in such patients, and the term “ADOAplus syndrome” was proposed to indicate a multisystemic mitochondrial disorder in which the optic atrophy was the core clinical feature [10]. More recently, the spectrum of ADOAplus syndrome has been expanded by the description of one OPA1 case carrying myopathy and deafness, but without optic atrophy [13].

Descriptions of abnormal brain features by magnetic resonance imaging (MRI) in OPA1 patients are scarce in the literature. Various degrees of cortical or cerebellar atrophy, aspecific white matter hypersignal, brain calcifications, and multiple sclerosis-like white matter lesions, have been described in single case reports [10], [11], [14] and then found in 12 out of 40 ADOAplus patients [15], while no morphological brain abnormality was found in 13 pure ADOA patients [16] (19). More recently, atrophy of the cerebellar vermis, white matter hypersignal and lactate peak were identified in three patients harboring compound heterozygous OPA1 mutation and exhibiting a severe neurosensorial phenotype [17]. Although detection of central nervous system lactate by magnetic resonance spectroscopy (MRS) represents a useful tool to investigate patients with mitochondrial respiratory chain dysfunction [18], [19], brain MRS results have only been rarely reported and were normal in OPA1 ADOA patients [12], [20]. Therefore, the neuroradiological phenotype of patients with OPA1 optic neuropathy remains to be better defined.

The purpose of this study is to describe the clinical and neuroradiological features of patients with OPA1 mutations, in order to delineate the morphological and functional brain imaging characteristics with or without ADAOplus clinical phenotype.

Section snippets

Patients

The study was approved by the local Ethic Committee and the subject's consent was obtained according to the Declaration of Helsinki. Patients with ADOA were enrolled in this study between 2005 and 2013 at the Reference Center for Inherited Sensory Defects and responded to the following criteria: (i) carrier of a deleterious OPA1 mutation, (ii) decreased visual acuity, and (iii) atrophy of the optic disk at fundus examination. Informed consent was obtained from all of the patients or their

Results

This study was conducted between 2005 and 2012 on 22 Caucasian patients, 8 males (36.4%) and 14 females (63.6%) belonging to 17 families, 16 were index cases, while 6 belongs to the same family (Table 1).

Discussion

Autosomal dominant optic atrophy (ADOA) is a rare disease affecting the function and survival of the optic nerve. It is mainly due to mutation in the OPA1 gene that encodes an inner mitochondrial dynamin-related GTPase ubiquitously expressed [23] that is required for mitochondrial fusion, oxidative phosphorylation, mitochondrial genome maintenance and control of apoptosis [24]. One of the most intriguing questions initially raised by this disease is the contrast between the ubiquitous

Conclusion

Our study demonstrates that brain imaging abnormalities are very common in OPA1 patients, even when the patient only manifests progressive visual loss. Our study highlights cerebellar involvement, while the specificity of the superior vermian atrophy will need larger studies. Patients with abnormal MRI are characterized by an older age suggesting that brain neuronal degeneration is a time dependent ongoing process. They are also characterized by a more severe visual impairment with still active

Funding

This study was sponsored by the Centre Hospitalier Universitaire de Montpellier (CHU Montpellier, AOI 2003;UF 7774, France) with the financial support of the French National Institute for Health and Medical Research (INSERM, CIC 0001, Montpellier, France).

Disclosure

All authors certify to have no conflict of interest.

Acknowledgments

We acknowledge patients and their families for participating in the study. We thank Dr. Lagavulin for his helpful discussions.

References (27)

  • P. Kjer

    Infantile optic atrophy with dominant mode of inheritance: a clinical and genetic study of 19 Danish families

    Acta Ophthalmol Suppl

    (1959)
  • G. Lenaers et al.

    Dominant optic atrophy

    Orphanet J Rare Dis

    (2012)
  • M. Votruba et al.

    MRI of the intraorbital optic nerve in patients with autosomal dominant optic atrophy

    Neuroradiology

    (2000)
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