A Novel Presentation and Variable Phenotypic Spectrum of Homozygous Start-Loss Variant in LYRM7-Associated Mitochondrial Complex III Deficiency.

Abstract

LYRM7-associated mitochondrial complex III deficiency has classically been described in the literature as a childhood-onset episodic leukoencephalopathy with neuroimaging findings of cavitating periventricular and subcortical white matter loss. We describe the heterogeneous clinical and neuroimaging profile of six individuals from south India with the specific homozygous pathogenic variant in the LYRM7 gene (c.2T>C, (p.Met1?)). This is a retrospective case series featuring six cases (four pediatric, one adult, and one adolescent-onset) with the pathogenic start loss LYRM7 variant. The spectrum of neurologic manifestations and brain imaging findings documented over multiple clinic visits was analyzed and described. Vision loss and lactic acidosis were seen in all but one individual. A novel phenotype with adult-onset isolated bilateral simultaneous optic neuropathy was noted. Characteristic cavitating leukoencephalopathy in supratentorial white matter was seen in the brain MRI of three out of six individuals. A comprehensive description of our cases along with the previously published cases is provided in the table highlighting the clinical and imaging variability and the disease course. The phenotype of adult-onset isolated acute optic neuropathy can be a manifestation of LYRM7-related mitochondrial disorder. LYRM7-associated Mitochondrial Complex III deficiency should be considered in the differential diagnosis of para- and post-infectious demyelinating/inflammatory disorders, especially if there is a background of variable developmental delay, recurrence of the episodes, family history, cystic changes in cerebral white matter on imaging, or poor response to immunomodulation. The case series also exemplifies the intra-and inter-familial variability seen with this rare disorder.