Abstract Details

Title Expanding the Spectrum of COXFA4-Related Disease: A Case of a Reclassified Pathogenic Variant

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P8 - Poster Session 8 (11:45 AM-12:45 PM)

Poster/Presentation
Number 9-008

Objective NA

Background

The gene COXFA4, previously designated as NDUFA4, encodes a subunit of mitochondrial complex IV (cytochrome C oxidase). Pathogenic variants have been shown to cause Leigh syndrome, a mitochondrial encephalopmyopathy characterized by progressive neurodegeneration, elevated lactate, and symmetric basal ganglia and brainstem lesions as a result of defects in oxidative phosphorylation. Leigh-like syndrome shares features of classical Leigh syndrome but presents with atypical or incomplete features. Leigh syndrome and Leigh-like syndromes together are the most genetically heterogeneous among the mitochondrial disorders.

Design/Methods NA

Results We report two cases of sisters (A and B) who presented with mitochondrial encephalomyopathy phenotype, one of whom had undergone genetic testing. Sibling A presented with cognitive and motor developmental delay, short stature, ataxia, and spasticity. She was found to have elevated lactate, and her MRI at age 19 showed T2 signal changes in periventricular and centrum semiovale white matter. Genetic testing in 2018 was positive for homozygous COXFA4 c.43-1G>A, which at the time was deemed a variant of undetermined significance (VUS). Sibling B had a similar, albeit milder, presentation to her sister and is awaiting the results of genetic testing.

Conclusions The present the first reported case of a mitochondrial encephalomyopathy in a patient with the COXFA4 c.43-1G>A variant. While this variant was previously classified as a VUS, emerging evidence has reclassified it as pathogenic due to its likely disruption of the canonical splice-site and resultant complex IV dysfunction in analogous variants. Namely, data from splice-site variants (c.42+4G>C, c.42+1G>A) have demonstrated loss of normal transcripts and complex IV deficiency. Our report of a reclassified variant further expands the disease spectrum associated with COXFA4 mutations. The familial recurrence noted in these cases supports the clinical relevance of this variant and highlights the importance of re-evaluating previously uncertain data, thereby enabling more accurate genetic counseling and clinical surveillance.

Authors/Disclosures
Shehroz T. Rana, MD PRESENTER	Dr. Rana has nothing to disclose.
Danielle Giammarco, MD	Dr. Giammarco has nothing to disclose.
Courtney Fitch, GC, CGC	Mrs. Fitch has nothing to disclose.
Connie G. Tang, MD (Lehigh Valley Health Network)	Dr. Tang has nothing to disclose.

��ɫ��

��ɫ��