LYRM7‐associated mitochondrial complex III deficiency with non‐cavitating leukoencephalopathy and stroke‐like episodes

Abstract

Defects of respiratory chain complex III (CIII) result in characteristic but rare mitochondrial disorders associated with distinct neuroradiological findings. The underlying molecular defects affecting mitochondrial CIII assembly factors are few and yet to be identified. LYRM7 assembly factor is required for proper CIII assembly where it acts as a chaperone for the Rieske iron–sulfur (UQCRFS1) protein in the mitochondrial matrix and stabilizing it. We present here the seventeenth individual with LYRM7‐associated mitochondrial leukoencephalopathy harboring a previously reported rare pathogenic homozygous LYRM 7 variant, c.2T>C, (p.Met1?). Like previously reported individuals, our 5‐year‐old male proband presented with recurrent metabolic and lactic acidosis, encephalopathy, and fatigue. Further, he has additional, previously unreported features, including an acute stroke like episode with bilateral central blindness and optic neuropathy, recurrent hyperglycemia and hypertension associated with metabolic crisis. However, he has no signs of psychomotor regression. He has been stable clinically with residual left‐sided reduced visual acuity and amblyopia, and no more metabolic crises for 2‐year‐period while on the mitochondrial cocktail. Although the reported brain MRI findings in other affected individuals are homogenous, it is slightly different in our index, revealing evidence of bilateral almost symmetric multifocal periventricular T2 hyperintensities with hyperintensities of the optic nerves, optic chiasm, and corona radiata but with no cavitation or cystic changes. This report describes new clinical and radiological findings of LYRM7‐associated disease. The report also summarizes the clinical and molecular data of previously reported individuals describing the full phenotypic spectrum.

Neuroimaging in Primary Coenzyme-Q10-Deficiency Disorders

“…TPPP plays a crucial role in myelination and in the stabilization of microtubules [ 72 ]. Interestingly, genetic defects of mitochondrial complex II (succinate dehydrogenase) and mitochondrial complex III (cytochrome bc1 complex) are frequently associated with leukoencephalopathy [ 73 , 74 ]. In this context, it is important to know that the activity of complex II/III and the levels of CoQ 10 are correlated, which might play a role in these clinical similarities [ 75 ].…”

Before diagnosing a stroke‐like episode, a stroke‐like lesion must be documented on multimodal cerebral MRI

“…We read with interest the article by Alfattal et al on a 5 years‐old male with a mitochondrial disorder (MID) due to the homozygous variant c.2 T > C in LYRM7 (Alfattal et al, 2023). The patient presented phenotypically with encephalopathy, a stroke‐like episode (SLE), amblyopia, optic atrophy, lactic acidosis, hepatopathy, hyperammonemia, episodic hyperglycemia, and arterial hypertension (Alfattal et al, 2023). The study is excellent but has limitations that are cause for concern and should be discussed.…”

“…In addition, FDG‐positron emission tomography (PET) may show hypometabolism. However, none of these characteristics were described in the index patient (Alfattal et al, 2023). The weak periventricular hyperintensities on DWI could also represent a shining‐through phenomenon of the periventricular T2‐hyperintensities.…”