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Autosomal dominant optic atrophy and cataract "plus" phenotype including axonal neuropathy
Alejandro Horga1, Enrico Bugiardini1, Andreea Manole1
1Department of Neuromuscular Diseases (A.H., A.C., M.G.H., M.M.R.), UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, University College London Hospitals; Department of Molecular Neuroscience (A.M.P., H.H.), UCL Queen Square Institute of Neurology; Department of Neuro-ophthalmology (F.B.F.R.C.O.), the National Hospital for Neurology and Neurosurgery, University College London Hospitals; Division of Neuropathology (Z.J., S.B.), the National Hospital for Neurology and Neurosurgery, University College London Hospitals; Department of Clinical and Movement Neurosciences (Z.J.), UCL Queen Square Institute of Neurology, London, United Kingdom; Department of Neurology (L.D., S.S.S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Department of Human Genetics and Hussman Institute for Human Genomics (A.P.R., S.Z.), University of Miami, FL; Department of Neurogenetics (C.E.W., J.M.P.), the National Hospital for Neurology and Neurosurgery, University College London Hospitals; Neurometabolic Unit (I.P.H.), the National Hospital for Neurology and Neurosurgery, University College London Hospitals; and Department of Neurodegenerative Disease (S.B.), UCL Queen Square Institute of Neurology, London, United Kingdom.
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.