opa1 ( omim : 605290 ) is the leading causative gene of autosomal dominant optic atrophy ( doa ) , characterized by insidiously progressive bilateral visual loss , optic disc pallor , dyschromatopsia , and centrocecal scotoma . the visual decline usually manifests in early childhood , but there is a pronounced inter- and intra - familial variability in the severity of visual symptoms and some subjects may be asymptomatic . approximately 20% of opa1 mutation carriers manifests with a multisystem neurological disorder , the doa plus phenotype . bilateral sensorineural hearing impairment in late childhood or early adulthood is a frequent feature , followed by a varying combination of ataxia , myopathy , axonal peripheral neuropathy and progressive external ophthalmoplegia . doa plus phenotype can also manifest with the clinical phenotype of hereditary spastic paraplegia ( hsp ) or multiple sclerosis - like picture accompanied by periventricular white matter lesions and unmatched oligoclonal bands in the cerebrospinal fluid . additional clinical features of doa plus syndrome include non - insulin dependent diabetes and migraine . moreover , opa1 mutations may lead to extraocular organ involvement in the absence of visual symptoms or even optic atrophy , . opa1 is a protein located within the inner mitochondrial membrane and plays a key role in mitochondrial fusion . opa1 pathogenic mutations are scattered through the gene coding regions but concentrate in the gtpase domain and dynamin central region of the protein . mutations in the gtpase domain carry a higher risk of resulting in doa plus phenotype . however , mutations in other domains , such as the n - terminal mitochondrial targeting sequence can lead to a multisystem neurological disorder lacking visual symptoms and optic atrophy . herein , we report the clinical effects of a novel heterozygous missense mutation in the highly basic amino - terminal domain of opa1 . a 58-year - old male presented for evaluation of visual loss and progressive gait dysfunction . his neurological symptoms manifested at age 6  years , when he was noted to have impaired vision and was diagnosed with bilateral optic atrophy . he was able to keep up with his peers , although  uncoordinated  . in his late 20s , he developed progressive gait dysfunction , followed by speech difficulty and dysphagia . around age 40 he started experiencing progressive distal limb numbness , severe constipation sometimes alternating with diarrhea and lack of urge to defecate . in 1.5  years prior to his neurological evaluation he had an unintentional 30 pound - weight loss . family history was noticeable for  color blindness  in the maternal grandmother ; his mother was wearing glasses that corrected her vision but was otherwise healthy until death at age 84 . neurological examination revealed pale optic discs and markedly reduced visual acuity ( he was able to count fingers if placed very close to his eyes ) , mild bi - facial weakness , spastic dysarthria , mild - to - moderate distal upper extremity weakness and moderate distal more than proximal lower limb weakness , severe spastic paraparesis , asymmetric hyperreflexia but absent achilles reflexes , absent plantar responses , and distal pan - modality sensory loss mainly affecting the lower limbs . he was unable to stand independently ; he was able to take a few steps with the walker exhibiting a spastic and steppage gait . the rest of his neurological examination was normal , including extra - ocular movements and hearing . brain and orbit mri showed atrophy of the optic nerves and optic chiasm and mild generalized cerebral and cerebellar atrophy ( fig . emg and nerve conduction studies demonstrated a moderate length - dependent predominantly axonal sensorimotor peripheral neuropathy . motility studies showed normal gastric emptying , above average small bowel transit rate , reduced colonic activity and slow colonic transit at 24 and 48  h. sequencing of all opa1 exons and flanking intronic regions showed a heterozygous novel variant c.312a > g ( p.ile104met ) in exon 2 that is predicted to be pathogenic . isoleucin at codon 104 is a branched amino acid that is highly conserved across species ; the sift and polyphen-2 algorithms suggest that the variant is deleterious . prior to opa1 analysis , the proband had undergone numerous investigations , including normal extensive screening for inborn errors of metabolism and acquired metabolic disorders . csf protein content was mildly increased ( 56  mg / dl , nl  <  35 ) with normal igg index and synthesis rate and no oligoclonal bands ; csf and blood lactate were normal . screening for mitochondrial dna ( mtdna ) mutations associated with leber hereditary optic neuropathy , performed early in the course of the disease , and for several common mtdna point mutations was negative . up to 20% of opa1 mutations result in doa plus phenotype and most of them are located in the gtpase domain of the protein . our patient harbors a novel opa1 missense mutation in the basic domain of the protein and presents with a multisystem disorder featured by optic atrophy , spastic paraparesis , sensorimotor axonal peripheral neuropathy and intestinal dysmotility . only few cases of doa plus syndrome have been linked to the opa1 basic domain , , and none of them had spasticity . our patient had no structural , inflammatory or other metabolic abnormality to account for the spastic paraparesis . the mutated isoleucine ( p.ile104met ) is located within the third putative cleavage site ( rylilgsavg ) of the mitochondrial import signal peptide   which confers the mitochondrial localization of opa1 . the p.ile104met could alter the correct targeting of the opa1 to the mitochondria , and compromise its role in mtdna maintenance , assembly and stability of the respiratory chain complexes . many opa1 mutations have been associated with cytochrome c - oxidase negative fibers on muscle biopsy and muscle mtdna multiple deletions , . we do not know if our patient 's opa1 mutation results in similar abnormalities or in alteration of the muscle mtdna content because the patient did not have a muscle biopsy . intestinal dysmotility can be a facet of various multisystem mitochondrial disorders , such as mngie or polg - associated disease . however , to our knowledge , the patient 's adult onset ( in the 5th decade ) intestinal dysmotility , as suggested by the slow small bowel and colonic transit and reduced colonic activity , is a newly observed finding in opa1-related disease . gastrointestinal dysmotility , mainly consisting of severe constipation , was previously reported in two young siblings , age 3 and 8  years , with opa1 mutations . however , these two children , who manifested with a severe neuromuscular phenotype in addition to early - onset optic atrophy , were compound heterozygous for two pathogenic opa1 mutations . of interest , despite the severe clinical phenotype , they had no mtdna multiple deletions or depletion in the muscle . as previously suggested for other mitochondrial disorders , the intestinal dysmotility associated with opa1 mutations could be the result of a visceral mitochondrial myopathy or of an autonomic neuropathy .
a 58-year - old man with optic atrophy , spastic paraparesis , axonal sensorimotor peripheral neuropathy and intestinal dysmotility harbors a novel heterozygous missense mutation in the mitochondrial import signal peptide of opa1 . 
 the case underscores the role of opa1 in the pathogenesis of spastic paraparesis , so far reported only in very few cases , and it adds intestinal dysmotility to the spectrum of adult - onset clinical manifestation of opa1-associated disease .