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HEREDITARY MONOGENIC DISEASES

           

Leigh Syndrome, French-Canadian type (LSFC)

The Leigh Syndrome, French-Canadian type, also called Congenital Lactic Acidosis, Saguenay-Lac-St. Jean type is a mitochondrial disease characterized by chronic metabolic acidosis, hypotonia, facial dysmorphism and developmental delay.

The exact prevalence of this disorder is not known. It was first described in Saguenay-Lac-Saint-Jean (Quebec, Canada) where its prevalence at birth is estimated to be 1/2,000. In this region, the prevalence of the gene mutation underlying the disorder is estimated to be 1/23 inhabitants, and may be due to a founder effect.

The disease follows an autosomal recessive pattern of monogenic.

Facial dysmorphism is characterized by a prominent forehead, wide nasal bridge, hypertelorism, broad anterior fontanelle, midfacial hypoplasia, broad midline, synophrys, and a characteristic arched form of the eyebrows, along with mild hirsutism.

There are 3 forms of the disease corresponding to varying degrees of severity: a neonatal form, a classic form and a so-called “survivor” form. The neonatal form is characterized by fulminant acidotic states. The classic form can occur from birth with severe lactic acidosis, or manifest between 14 and 24 months by ataxic gait. This form is associated with episodes of lactic acidosis that can be triggered by physical exertion, emotional stress, infection or a heavy meal, and/or metabolic crises. Patients known as “survivors”, those who have survived several episodes, cross a critical threshold and show less severe symptoms including hypotonia, asthenia, developmental delay (language acquisition and walking) and, in older patients, truncal ataxia, and a characteristic wide-based gait.

The Leigh Syndrome, French-Canadian type is caused by two types of mutation in the gene LRPPRC (2p21). This gene encodes the protein containing repeats of leucine-rich pentatricopeptido and appears to be involved in transport and mitochondrial mature mRNA stability. Biochemically, it was found that the enzyme cytochrome oxidase C (COX) involved in the respiratory chain was deficient in all patients, but other proteins in the respiratory chain also may be deficient.

The diagnosis is based on the determination of lactate levels in blood and cerebrospinal fluid, in determining COX activity in fibroblasts, but mostly is performed through the c.1061C>T mutation identification, confirming the diagnosis.

The differential diagnosis includes other forms of Leigh syndrome and other causes of metabolic acidosis as MELAS syndrome, the deficit of glucose 6-phosphate dehydrogenase (G6PD), pyruvate dehydrogenase deficiency and pyruvate carboxylase deficiency.

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

GENE OR REGION STUDIED


  • LRPPRC