OPA1 is a dynamin-like GTPase protein anchored to the mitochondrial inner membrane which controls the fusion of mitochondrial membranes occurring in the physiological remodeling of mitochondrial network [1,12]
. Up to now more than 200 pathogenic mutations, along OPA1 coding region, have been associated to human disease. Beside optic atrophy, about 20% of patients bearing OPA1
mutations also develop additional neuromuscular complications, mostly including deafness, progressive external ophthalmoplegia and myopathy, starting from the third decade of life onwards 
Our study further extends the mutational spectrum of OPA1 leading to the discovery of a novel mutation in a proband with a clinical picture of syndromic optic atrophy. This patient harbors a microdeletion located within the GED sequence confirming the importance of the integrity of this domain, responsible for the interaction between OPA1 and its partners involved in mitochondrial fusion process. The GED domain and its flanking regions in fact represent an OPA1
mutational hotspot, since about 28% of mutations are located in this region. These findings suggest that not only missense mutation but also in frame-deletion preserving a terminal abnormal transcript, could lead to the extraneurological features observed in OPA1-plus patients [6,7]
Skeletal muscle analysis in our patient reveals mild mitochondrial defects consisting in the presence of COX-negative fibers and the occurrence of multiple deletions in mtDNA as detected by PCR analysis. The occurrence of these histological findings is frequently detected in OPA1-mutated patients with a 4-to-1 ratio in OPA1-plus patients respect to individuals with pure optic nerve involvement 
The mutation identified in Family 2 has been previously described in a Chinese pedigree showing an incomplete penetrance 
. On the contrary, in our family the c.985-2A > G mutation was associated with an early-onset and a complete penetrance disease. The disclosure of the same variant in the affected members of the Italian and Chinese pedigrees supports its pathogenic nature, since it arose independently in independent genetic backgrounds. Whereas in Chinese family no mutated subjects developed any additional extraocular symptom even in late adulthood, a member of our family (the proband's aunt) showed an early onset sensorineural hearing impairment.
In our probands, transcript analysis was fundamental to characterize the effect of the genomic variants on OPA1 mRNA, but this tool is not always able to predict the resulting phenotype. In fact, in frame-deletions have been reported not only in ADOA or OPA1-plus phenotypes but even also in a multisystemic disorder in the absence of optic atrophy 
Recently, multiplex ligation probe amplification (MLPA) assay has allowed to detect OPA1 rearrangements in a large cohort of Danish ADOA probands, revealing that heterozygous deletions involving whole exons represent a remarkable proportion among OPA1 mutations, ranging between 10% and 19% 
. These defects are usually missed by standard sequencing methods which are not able to detect large scale deletions as well as variants located within promoter or intronic regions.
In our opinion a combined strategy involving different techniques applied to genomic and transcript analysis could offer the most valuable option to investigate the OPA1 defects underlining the several forms of inherited optic neuropathy