Autosomal dominant optic atrophy and cataract “plus” phenotype including axonal neuropathy

Abstract

<h3>Objective</h3> To characterize the phenotype in individuals with <i>OPA3</i>-related autosomal dominant optic atrophy and cataract (ADOAC) and peripheral neuropathy (PN). <h3>Methods</h3> Two probands with multiple affected relatives and one sporadic case were referred for evaluation of a PN. Their phenotype was determined by clinical ± neurophysiological assessment. Neuropathologic examination of sural nerve and skeletal muscle, and ultrastructural analysis of mitochondria in fibroblasts were performed in one case. Exome sequencing was performed in the probands. <h3>Results</h3> The main clinical features in one family (n = 7 affected individuals) and one sporadic case were early-onset cataracts (n = 7), symptoms of gastrointestinal dysmotility (n = 8), and possible/confirmed PN (n = 7). Impaired vision was an early-onset feature in another family (n = 4 affected individuals), in which 3 members had symptoms of gastrointestinal dysmotility and 2 developed PN and cataracts. The less common features among all individuals included symptoms/signs of autonomic dysfunction (n = 3), hearing loss (n = 3), and recurrent pancreatitis (n = 1). In 5 individuals, the neuropathy was axonal and clinically asymptomatic (n = 1), sensory-predominant (n = 2), or motor and sensory (n = 2). In one patient, nerve biopsy revealed a loss of large and small myelinated fibers. In fibroblasts, mitochondria were frequently enlarged with slightly fragmented cristae. The exome sequencing identified <i>OPA3</i> variants in all probands: a novel variant (c.23T&gt;C) and the known mutation (c.313C&gt;G) in <i>OPA3</i>. <h3>Conclusions</h3> A syndromic form of ADOAC (ADOAC+), in which axonal neuropathy may be a major feature, is described. <i>OPA3</i> mutations should be included in the differential diagnosis of complex inherited PN, even in the absence of clinically apparent optic atrophy.