Leigh syndrome, French Canadian type

Alternate names

Cox deficiency, French Canadian type; Cox deficiency, Saguenay Lac saint Jean type; Leigh syndrome, Saguenay Lac saint Jean type; LSFC; Cytochrome c oxidase deficiency, French Canadian type

Definition

Saguenay-Lac-St. Jean (SLSJ) type congenital lactic acidosis, a French Canadian form of Leigh syndrome , is a mitochondrial disease characterized by chronic metabolic acidosis, hypotonia, facial dysmorphism and delayed development.

Epidemiology

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.

Cause

• SLSJ congenital lactic acidosis is caused by two types of mutations in the LRPPRC gene (2p21).
• The most frequent is a single A354V mutation.
• Only one patient has been identified as a heterozygous carrier of the A354V mutation and the C1277Xdel8 deletion of the same gene.
• LRPPRC codes for the leucine-rich pentatricopeptide repeat-containing protein and appears to be involved in the transport and stability of mature mitochondrial mRNA.
• Biochemically, the cytochrome C oxidase enzyme (COX) involved in the respiratory chain was found to be deficient in all patients, but other proteins in the respiratory chain may also be deficient.

Inheritance

Autosomal recessive inheritance, a 25% chance

The disease follows a monogenic autosomal recessive pattern of inheritance. Genetic counseling can be proposed to couples at risk through identification of heterozygous carriers.

Signs and symptoms

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.

Forms

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", i.e. 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.

Diagnosis

Diagnosis is based on determination of lactate levels in the blood and cerebrospinal fluid, determination of COX activity in fibroblasts, but is made primarily through identification of the A354V mutation, which confirms the diagnosis.

Antenatal diagnosis Since the discovery of the underlying mutations in 2003, prenatal diagnosis is offered to couples that have had an affected child.

Treatment

There is no specific treatment for the disease. A diet with a balanced intake of proteins, carbohydrates and lipids, spread evenly over the day, is recommended in order to reduce the high energy demands of digestion. Rest and strictly complying with the need for sleep are also beneficial.

Prognosis

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.

NIH genetic and rare disease info

• NIH info on Leigh syndrome, French Canadian type

Leigh syndrome, French Canadian type is a rare disease.

Leigh syndrome, French Canadian type Resources
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