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Abstract Details

Complex I Deficiency due to a Nuclear Mitochondrial DNA Mutation of the NDUFAF5 Gene Causing a Leber Hereditary Optic Neuropathy “Plus” Phenotypic Expression
Neuro-ophthalmology/Neuro-otology
P6 - Poster Session 6 (12:00 PM-1:00 PM)
5-012
We report the first known case of a LHON “plus” phenotypic expression associated with  pathogenic mutations of a nuclear (n) DNA gene that encodes, NDUFAF5, a mitochondrial complex I assembly factor. 
Leber hereditary optic neuropathy (LHON) is associated with mutations of the mitochondrial (mt) DNA. The most common point mutations are positions 11778, 3460, and 14484 of subunit ND4, ND1 and ND6, respectively resulting in mitochondrial complex 1 deficiency. 
N/A
An 8-year-old girl presented with two years of progressive bilateral dystonia in her lower extremities. Brain magnetic resonance imaging (MRI) revealed bilateral basal ganglia abnormalities. Brain MR spectroscopy was normal. Testing for organic acids, cerebrospinal (CSF) neurotransmitters, targeted mitochondrial DNA mutations, DYT1 mutation, PANK2 mutation, lysosomal enzymes, heavy metals, paraneoplastic panel, and blood lactate were all normal. A detailed autoimmune workup was normal. Electromyography was normal. Skin, muscle, and brain biopsies were unremarkable. Eye examination was normal.  A mitochondrial disorder was suspected as the cause of her dystonia and bilateral basal ganglia abnormalities but could not be proven at that time. Fifteen years later, she developed bilateral, sequential, painless, vision loss over a period of three months. Ophthalmologic examination revealed bilateral optic disc pallor with MRI showing mild chiasmal enlargement. Whole mtDNA genome sequencing was unrevealing. However, nDNA sequencing revealed heterozygous mutations in NDUFAF5, which has previously been associated with autosomal recessive mitochondrial respiratory complex 1 deficiency syndromes (i.e. Leigh syndrome). 
To our knowledge only 14 cases have been associated with mutations in NDUFAF5 and none with acute visual loss reminiscent of LHON. This case illustrates a novel presentation of acute visual loss due to a nDNA mutation. A patient presenting with acute visual loss suggestive of LHON, with negative testing for the 3 primary point mutations and whole mtDNA sequencing, should undergo nDNA testing. 
Authors/Disclosures
Dev Mehta, DO (New York-Presbyterian Queens)
PRESENTER 		Dr. Mehta has nothing to disclose.
No disclosure on file
Mark A. Whealy, MD (Mayo Clinic Department of Neurology) Dr. Whealy has received publishing royalties from a publication relating to health care.
Deborah L. Renaud, MD No disclosure on file
John Chen John Chen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB. John Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. John Chen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB.
M. Tariq Bhatti, MD (Kaiser Permanente, Northern California) Dr. Bhatti has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Receptos . Dr. Bhatti has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for NIH LHON gene therapy study .