Autosomal dominant optic atrophy and cataract "plus" phenotype including axonal neuropathy

Alejandro Horga, Enrico Bugiardini, Andreea Manole, Fion Bremner, Zane Jaunmuktane, Lois Dankwa, Adriana P. Rebelo, Catherine E. Woodward, Iain P. Hargreaves, Andrea Cortese, Alan M. Pittman, Sebastian Brandner, James M. Polke, Robert D.S. Pitceathly, Stephan Züchner, Michael G. Hanna, Steven S. Scherer, Henry Houlden, Mary M. Reilly

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Objective: To characterize the phenotype in individuals with OPA3-related autosomal dominant optic atrophy and cataract (ADOAC) and peripheral neuropathy (PN). Methods: 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. Results: 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 OPA3 variants in all probands: a novel variant (c.23T>C) and the known mutation (c.313C>G) in OPA3. Conclusions: A syndromic form of ADOAC (ADOAC+), in which axonal neuropathy may be a major feature, is described. OPA3 mutations should be included in the differential diagnosis of complex inherited PN, even in the absence of clinically apparent optic atrophy.

Original languageEnglish (US)
Article numbere322
JournalNeurology: Genetics
Issue number2
StatePublished - Apr 1 2019

ASJC Scopus subject areas

  • Clinical Neurology
  • Genetics(clinical)


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