Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type (ORPHA:70472)
A rare degenerative mitochondrial disease characterized by chronic metabolic acidosis, hypotonia, facial dysmorphism and delayed development.
Epidemiology
The French Canadian form of Leigh syndrome was first described in Saguenay-Lac-Saint-Jean (SLSJ) (Quebec, Canada) where its prevalence at birth is estimated to be 1/2,000. The prevalence of the gene mutation underlying the disorder, estimated to be 1/23 inhabitants, is due to a triple founder effect characterizing the settlement pattern of SLSJ. Patients were identified in all Quebec and elsewhere in the world (China, Italia and Great Britain for example).
Clinical description
Facial dysmorphism is characterized by a prominent forehead, wide nasal bridge, hypertelorism, broad anterior fontanelle, midfacial hypoplasia, broad midline, synophrys, and anarched form of the eyebrows, along with mild hirsutism. There are three 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 14-24 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 who survived several episodes, called "survivors", cross a critical threshold and show less severe symptoms: hypotonia, asthenia, developmental delay (language acquisition and walking) and, in older patients, truncal ataxia, and a characteristic wide-based gait.
Etiology
The disease is caused by mutations in the LRPPRC gene (2p21), the most frequent being A354V mutation. In Quebec where the disease is more frequent, only one patient has been identified as a heterozygous carrier of the A354V mutation and the C1277Xdel8 deletion. Other mutations in LRPPRC have been described in different populations (including Italy, Great Britain and Turkey) but with lower frequency. 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.
Diagnostic methods
The main diagnostic method is identification of a causal mutation. In situations where genetic testing is impossible, clinical diagnosis is based on determination of lactate levels in the blood and cerebrospinal fluid and determination of COX activity in fibroblasts from liver and skin biopsies, which were the strategies employed before the causal mutations were discovered.
Differential diagnosis
Differential diagnosis includes other forms of Leigh syndrome and other possible causes of metabolic acidosis such as MELAS syndrome, glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate dehydrogenase deficiency, and pyruvate carboxylase deficiency.
Antenatal diagnosis
Since the discovery of the underlying mutation, prenatal diagnosis is offered to couples that have had an affected child. A carrier test for future parents, including this disease, has also been implanted for all of Quebec's population. Moreover, private companies are now including single-nucleotide polymorphisms (SNPs) of LRPPRC in their genetic diagnosis panel for metabolic diseases, for which the quarter of these SNPs have unknown biological impact.
Genetic counseling
The disease follows a monogenic autosomal recessive pattern of inheritance. Genetic counseling is proposed to couples at risk through identification of heterozygous carriers.
Management and treatment
There is no specific treatment for this disease but lifestyle changes can upgrade the quality of life of patients. 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 strict compliance with sleeping needs are also beneficial. It is recommended to prevent infections with adequate vaccination and to visit a doctor promptly if the condition of the patient is deteriorating or in case of an infection. Avoidance of tobacco or vaping products and exposition to cigarette smoke and carbon monoxide (from cars or wood heating) is also recommended.
Prognosis
In the neonatal form, the prognosis is very poor. In other patients, life expectancy was often <5 years due to severe episodes of acidosis. Currently, 80% of the patients with this disease present the so-called ''survivor'' form and exceed the age of 5. Clinical comprehension of the symptoms allowed physicians to state guidelines to include in the lifestyle of the patients. Life expectancy of the less severely affected patients can now exceed 20 years of age. The oldest patient with this disease is now 43 years old.

                            Last update: 
                            January 2024


                            - Expert reviewer(s): 
                            Pr Bhérer CLAUDE  - Pr Catherine LAPRISE  - Dr Charles MORIN