LYRM7 – Mitochondrial Disease

LYRM7 encodes a mitochondrial complex III assembly factor required for Rieske iron-sulfur protein stabilization. Biallelic LYRM7 variants cause an autosomal recessive mitochondrial disorder characterized by complex III deficiency and a distinct leukoencephalopathy (LYRM7; Mitochondrial Disease).

Autosomal recessive inheritance is established by homozygous and compound heterozygous variants in 17 unrelated probands ([PMID:36757047]) with segregation in three families, including an affected sib-pair ([PMID:26912632]).

The variant spectrum includes a start-loss (c.2T>C (p.Met1Thr)), splice-site (c.245-1G>A), frameshift (e.g., c.153_154del (p.Lys51fs)), nonsense (c.214C>T (p.Gln72Ter)), small duplications (c.190TTA[3] (p.Leu66dup)), and missense (c.73G>A (p.Asp25Asn)) changes across cohorts ([PMID:36957047]; [PMID:26912632]). No population-specific founder alleles have been reported.

Functional complementation of patient fibroblasts with wild-type LYRM7 restored complex III activity in vitro ([PMID:27151179]). In parallel, yeast models harboring patient‐derived missense and splice variants exhibited defective complex III assembly that was rescued by expression of wild-type LYRM7, confirming a loss-of-function mechanism ([PMID:26912632]).

Clinically, affected individuals present with fatigue (HP:0012378) and subacute encephalopathy (HP:0001298), recurrent lactic acidosis, metabolic crises, and characteristic MRI findings of multifocal periventricular T2 hyperintensities with or without cavitation. Stroke-like episodes with bilateral central blindness and optic neuropathy have also been observed.

Collectively, definitive genetic and experimental data support LYRM7 as a robust diagnostic target for autosomal recessive complex III deficiency with leukoencephalopathy. Key take-home: consider LYRM7 sequencing in patients with unexplained mitochondrial leukoencephalopathy and metabolic crisis.

References

• American journal of medical genetics. Part A | 2023 | LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes. [PMID:36757047]
• Brain : a journal of neurology | 2016 | LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance. [PMID:26912632]
• Journal of hepatology | 2016 | Severe respiratory complex III defect prevents liver adaptation to prolonged fasting. [PMID:27151179]

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