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 L Zuchner, Michael G. Hanna, Steven S. Scherer, Henry Houlden, Mary M. Reilly

Research output: Contribution to journalArticle

Abstract

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
Volume5
Issue number2
DOIs
StatePublished - Apr 1 2019

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Peripheral Nervous System Diseases
Exome
Phenotype
Cataract
Mitochondria
Fibroblasts
Optic Atrophy
Sural Nerve
Mutation
Hearing Loss
Pancreatitis
Signs and Symptoms
Skeletal Muscle
Differential Diagnosis
Biopsy
Autosomal dominant Optic atrophy and cataract

ASJC Scopus subject areas

  • Clinical Neurology
  • Genetics(clinical)

Cite this

Horga, A., Bugiardini, E., Manole, A., Bremner, F., Jaunmuktane, Z., Dankwa, L., ... Reilly, M. M. (2019). Autosomal dominant optic atrophy and cataract "plus" phenotype including axonal neuropathy. Neurology: Genetics, 5(2), [e322]. https://doi.org/10.1212/NXG.0000000000000322

Autosomal dominant optic atrophy and cataract "plus" phenotype including axonal neuropathy. / Horga, Alejandro; Bugiardini, Enrico; Manole, Andreea; Bremner, Fion; Jaunmuktane, Zane; Dankwa, Lois; Rebelo, Adriana P.; Woodward, Catherine E.; Hargreaves, Iain P.; Cortese, Andrea; Pittman, Alan M.; Brandner, Sebastian; Polke, James M.; Pitceathly, Robert D.S.; Zuchner, Stephan L; Hanna, Michael G.; Scherer, Steven S.; Houlden, Henry; Reilly, Mary M.

In: Neurology: Genetics, Vol. 5, No. 2, e322, 01.04.2019.

Research output: Contribution to journalArticle

Horga, A, Bugiardini, E, Manole, A, Bremner, F, Jaunmuktane, Z, Dankwa, L, Rebelo, AP, Woodward, CE, Hargreaves, IP, Cortese, A, Pittman, AM, Brandner, S, Polke, JM, Pitceathly, RDS, Zuchner, SL, Hanna, MG, Scherer, SS, Houlden, H & Reilly, MM 2019, 'Autosomal dominant optic atrophy and cataract "plus" phenotype including axonal neuropathy', Neurology: Genetics, vol. 5, no. 2, e322. https://doi.org/10.1212/NXG.0000000000000322
Horga A, Bugiardini E, Manole A, Bremner F, Jaunmuktane Z, Dankwa L et al. Autosomal dominant optic atrophy and cataract "plus" phenotype including axonal neuropathy. Neurology: Genetics. 2019 Apr 1;5(2). e322. https://doi.org/10.1212/NXG.0000000000000322
Horga, Alejandro ; Bugiardini, Enrico ; Manole, Andreea ; Bremner, Fion ; Jaunmuktane, Zane ; Dankwa, Lois ; Rebelo, Adriana P. ; Woodward, Catherine E. ; Hargreaves, Iain P. ; Cortese, Andrea ; Pittman, Alan M. ; Brandner, Sebastian ; Polke, James M. ; Pitceathly, Robert D.S. ; Zuchner, Stephan L ; Hanna, Michael G. ; Scherer, Steven S. ; Houlden, Henry ; Reilly, Mary M. / Autosomal dominant optic atrophy and cataract "plus" phenotype including axonal neuropathy. In: Neurology: Genetics. 2019 ; Vol. 5, No. 2.
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T1 - Autosomal dominant optic atrophy and cataract "plus" phenotype including axonal neuropathy

AU - Horga, Alejandro

AU - Bugiardini, Enrico

AU - Manole, Andreea

AU - Bremner, Fion

AU - Jaunmuktane, Zane

AU - Dankwa, Lois

AU - Rebelo, Adriana P.

AU - Woodward, Catherine E.

AU - Hargreaves, Iain P.

AU - Cortese, Andrea

AU - Pittman, Alan M.

AU - Brandner, Sebastian

AU - Polke, James M.

AU - Pitceathly, Robert D.S.

AU - Zuchner, Stephan L

AU - Hanna, Michael G.

AU - Scherer, Steven S.

AU - Houlden, Henry

AU - Reilly, Mary M.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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.

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