Leigh Syndrome, French-Canadian type (LSFC)

Mitochondrial disease characterized by chronic metabolic acidosis, hypotonia, facial dysmorphism and developmental delay.

French-Canadian Leigh Syndrome (FCLS), also called Saguenay-Lac-St. Jean Congenital Lactic Acidosis, after the region of Qebec (Canada) where it was first described, is a mitochondrial disease characterised by chronic metabolic acidosis, hypotonia, facial dysmorphism and developmental delay.

The disease is caused by mutations in the LRPPRC gene, which codes for a protein essential in the interaction of the cellular cytoskeleton with multiple biological processes. The disease follows an autosomal recessive pattern of inheritance.

The prevalence of this syndrome in the general population is unknown, although it is known to be quite high in Saguenay-Lac-Saint-Jean and is detected in approximately 1 in 2,000 births. In 95% of cases in this region, the mutation responsible is the one studied here, c.1061C > T (p.Ala354Val). This variant is present in one in 23 people from Saguenay-Lac-Saint-Jean.

Symptoms

Three forms of CFCL are distinguished according to severity: neonatal form, classical form and the so-called ''survivors'' form. The neonatal form is characterized by very severe acid states. The classic form can occur from birth with severe lactic acidosis, or manifest between 14 and 24 months of age by atonic gait. Crises of lactic acidosis can be triggered by physical exertion, emotional stress, infections or a heavy meal, and metabolic crises. Patients known as ''survivors'' (those who have survived several episodes of acidosis) show less severe symptoms such as hypotonia, asthenia, delayed language and gait development and, in older patients, truncal ataxia, and unsteady gait.

Disease management

There is no specific treatment for the disease. In the neonatal form, the prognosis is very poor. In other patients, life expectancy is often less than 5 years due to severe episodes of acidosis.

Genes analyzed

LRPPRC

Bibliography

Bchetnia M, Tardif J, Morin C, et al.Expression signature of the Leigh syndrome French-Canadian type. Mol Genet Metab Rep. 2022 Feb 5;30:100847.

Mol Genet Metab Rep. 2022 Feb 5;30:100847.

Mootha VK, Lepage P, Miller K, et al.Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):605-10. doi: 10.1073/pnas.242716699.

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