Dataset Information

Leber Hereditary Optic Neuropathy and Longitudinally Extensive Transverse Myelitis.

ABSTRACT: Leber Hereditary Optic Neuropathy is an inherited optic neuropathy caused by mitochondrial DNA point mutations leading to sudden, painless loss of vision. We report a case of an 8-year-old boy presenting with a radiological phenotype of longitudinally extensive transverse myelitis on a background of severe visual impairment secondary to Leber Hereditary Optic Neuropathy (LHON). He was found to have dual mitochondrial DNA mutations at 14484 (MTND6 gene) and 4160 (MTND1 gene) in a family with a severe form of LHON characterised by not only an unusually high penetrance of optic neuropathy, but also severe extra-ocular neurological complications. The m.14484T>C mutation is a common LHON mutation, but the m.4160T>C mutation is to our knowledge not reported outside this family and appears to drive the neurological manifestations. To our knowledge there have been no previous reports of spinal cord lesions in children with LHON.

SUBMITTER: Bursle C

PROVIDER: S-EPMC6226398 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Leber Hereditary Optic Neuropathy and Longitudinally Extensive Transverse Myelitis.

Bursle C C Riney K K Stringer J J Moore D D Gole G G Kearns L S LS Mackey D A DA Coman D D

JIMD reports 20171217

Leber Hereditary Optic Neuropathy is an inherited optic neuropathy caused by mitochondrial DNA point mutations leading to sudden, painless loss of vision. We report a case of an 8-year-old boy presenting with a radiological phenotype of longitudinally extensive transverse myelitis on a background of severe visual impairment secondary to Leber Hereditary Optic Neuropathy (LHON). He was found to have dual mitochondrial DNA mutations at 14484 (MTND6 gene) and 4160 (MTND1 gene) in a family with a se ...[more]

PMID: 29249004

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Project description:PurposeLeber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly progressive visual loss when caused by a mutation in the mitochondrial gene encoding NADH:ubiquinone oxidoreductase subunit 4 (ND4). We have initiated a gene therapy trial to determine the safety and tolerability of escalated doses of an adeno-associated virus vector (AAV) expressing a normal ND4 complementary DNA in patients with a G to A mutation at nucleotide 11778 of the mitochondrial genome.DesignIn this prospective open-label trial (NCT02161380), the study drug (self-complementary AAV [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. The first 3 participants were treated at the low dose of vector (5 × 10(9) vg), and the fourth participant was treated at the medium dose (2.46 × 10(10) vg). The fifth participant with visual loss for less than 12 months received the low dose. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations.ParticipantsFive legally blind patients with G11778A LHON.Main outcome measuresLoss of visual acuity.ResultsVisual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed. Minor adverse events included a transient increase of intraocular pressure (IOP), exposure keratitis, subconjunctival hemorrhage, a sore throat, and a transient increase in neutralizing antibodies (NAbs) against AAV2 in 1 participant. All blood samples were negative for vector DNA.ConclusionsNo serious safety problems were observed in the first 5 participants enrolled in this phase I trial of virus-based gene transfer in this mitochondrial disorder. Additional study follow-up of these and additional participants planned for the next 4 years is needed to confirm these preliminary observations.

Dataset Information

Leber Hereditary Optic Neuropathy and Longitudinally Extensive Transverse Myelitis.

Publications

Leber Hereditary Optic Neuropathy and Longitudinally Extensive Transverse Myelitis.

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