LRPPRC – Leigh Syndrome, French-Canadian Type

Leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) is a mitochondrial RNA-binding factor essential for the stability and polyadenylation of mitochondrial transcripts. Pathogenic biallelic variants in LRPPRC cause the French-Canadian variant of Leigh syndrome (LSFC), an autosomal recessive disorder characterized by isolated cytochrome c oxidase (COX) deficiency, severe lactic acidosis and early neurodevelopmental impairment. LSFC originates from a founder missense allele (p.Ala354Val) in the Saguenay-Lac-Saint-Jean region of Québec, but subsequent reports have identified additional non-Québec patients with similar phenotypes.

Genetic evidence includes ten non-Québec probands from seven unrelated families and an isolated case report with compound heterozygous or homozygous LRPPRC variants under an autosomal recessive model (PMID:26510951; PMID:29152527). Segregation of variants with disease has been confirmed in multiple pedigrees. The variant spectrum encompasses missense and null alleles, including c.3130C>T (p.Arg1044Ter) (PMID:29152527), c.3430C>T (p.Arg1144Cys) and c.4078G>A (p.Ala1360Thr).

Functional studies demonstrate that patient fibroblasts and muscle homogenates harbor reduced LRPPRC protein, decreased steady-state levels of mitochondrial mRNAs and isolated COX assembly defects, recapitulated by siRNA knockdown in control cells (PMID:20200222). The 2015 Brain study extended these findings to a multisystem phenotype outside Québec, showing additional cardiomyopathy and congenital malformations alongside COX and complex I assembly defects in diverse ethnicities (PMID:26510951).

Therapeutic insights arise from in vitro studies where low-concentration methylene blue restores metabolic activity and ATP production in LSFC fibroblasts homozygous or compound heterozygous for LRPPRC mutations, highlighting a potential targeted treatment strategy (PMID:22202226).

Collectively, the robust genetic and functional concordance across multiple families and models supports a Strong clinical validity classification. Targeted sequencing of LRPPRC should be included in diagnostic panels for early-onset lactic acidosis with isolated COX deficiency to enable timely management and genetic counseling.

Key Take-home: Biallelic LRPPRC variants underlie autosomal recessive Leigh syndrome, French-Canadian type, and should be tested in infants presenting with early lactic acidosis, neurodevelopmental delay, and COX deficiency.

References

• Child neurology open • 2017 • Novel LRPPRC Mutation in a Boy With Mild Leigh Syndrome, French-Canadian Type Outside of Québec PMID:29152527
• Molecular biology of the cell • 2010 • LRPPRC and SLIRP interact in a ribonucleoprotein complex that regulates posttranscriptional gene expression in mitochondria. PMID:20200222
• Brain : a journal of neurology • 2015 • LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population. PMID:26510951
• Journal of pharmacy & pharmaceutical sciences • 2011 • Low-concentration methylene blue maintains energy production and strongly improves survival of Leigh syndrome French Canadian skin fibroblasts. PMID:22202226

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