This peer-reviewed case series examines LYRM7-associated mitochondrial complex III (CIII) deficiency, a rare and typically neurodegenerative mitochondrial disorder, expanding its known phenotypic spectrum through two newly described cases and a literature review.

This investigational report describes two brothers from a consanguineous family who share the same pathogenic LYRM7 variant but demonstrated marked intrafamilial variability and atypical inflammatory demyelinating-like presentations, complicating diagnosis. One patient experienced relapsing ataxic episodes initially suggestive of inflammatory demyelination, including longitudinally extensive transverse myelitis (LETM) and optic neuritis mimicking neuromyelitis optica spectrum disorder (NMOSD), while the younger sibling followed a more rapidly progressive course with early mortality.

Neuroimaging revealed cystic white matter changes suggestive of mitochondrial leukodystrophy and LETM in both patients, distinct from classic acquired inflammatory demyelinating patterns. Whole-exome sequencing with confirmatory Sanger testing identified a pathogenic LYRM7 variant, reinforcing the role of early genetic evaluation in children with recurrent demyelinating-like episodes, atypical disease progression or familial neurologic disease.

The case series expands the known phenotypic spectrum of LYRM7-associated CIII deficiency and underscores an important diagnostic pitfall: mitochondrial disorders may masquerade as inflammatory demyelinating disease. The findings emphasize the value of early genetic diagnosis for accurate counseling, prognostication and management.

Alireza Tavasoli, MD, et al., a neurologist at Phoenix Children’s, is a co-author of this research, reflecting Phoenix Children’s commitment to advancing clinical understanding of complex pediatric neurogenetics and mitochondrial disease. Read the Case Series

Phoenix Children's Neuroimmunology Program accepts referrals for children with neuroimmune conditions, including presentations of inflammatory or demyelinating-like neurologic disease requiring diagnostic workup. To refer a patient or request a consultation, call 602-933-KIDS (5437) or submit a referral online.

REFERENCE

Khan GS, Bayat S, Azizimalamiri R, et al. Expanding the Clinical Spectrum of LYRM7-Associated Mitochondrial Complex III Deficiency: Insights from New Cases and Literature Review. J Mol Neurosci. 2026;76:72. doi:10.1007/s12031-026-02527-8.