Neuroradiological findings expand the phenotype of OPA1-related mitochondrial dysfunction
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.
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