Leigh Syndrome, French Canadian Type
A number sign (#) is used with this entry because the French Canadian type of Leigh syndrome is caused by homozygous or compound heterozygous mutation in the LRPPRC gene (607544) on chromosome 2p21.
DescriptionThe French Canadian type of Leigh syndrome is an autosomal recessive severe neurologic disorder with onset in infancy. Features include delayed psychomotor development, mental retardation, mild dysmorphic facial features, hypotonia, ataxia, and the development of lesions in the brainstem and basal ganglia. Affected individuals tend to have episodic metabolic and/or neurologic crises in early childhood, which often lead to early death (summary by Debray et al., 2011).
For a phenotypic description and a discussion of genetic heterogeneity of Leigh syndrome, see 256000.
Clinical FeaturesTwo clinical forms of cytochrome c oxidase (COX, complex IV) deficiency (220110) are recognized (DiMauro et al., 1990): a 'muscular' form in which marked weakness predominates, and a 'nonmuscular' form presenting with Leigh disease, a neurodegenerative condition of the brainstem, cerebellum, and basal ganglia, with symmetric, well-demarcated regions of necrosis, gliosis, and vascular proliferation (van Erven et al., 1987). Leigh disease can also result from other inborn errors of energy metabolism, such as pyruvate dehydrogenase deficiency (266150), complex I deficiency (252010), and mutation in a mitochondrial DNA gene for complex V (516060).
In the Saguenay-Lac-Saint-Jean (SLSJ) region of Quebec province in Canada, Merante et al. (1993) described a biochemically distinct form of Leigh syndrome with COX deficiency. Thirty-four children were observed to have a similar phenotype consisting of developmental delay, hypotonia, mild facial dysmorphism, chronic well-compensated metabolic acidosis, and high mortality due to episodes of severe acidosis and coma. Enzyme activity was close to normal in kidney and heart, 50% of normal in fibroblasts and skeletal muscle, and nearly absent in brain and liver. The deficiency of enzyme activity appeared to result from a failure to assemble an active enzyme complex. The cDNA sequences of cytochrome oxidase subunits VIa and VIIa were normal. Merante et al. (1993) demonstrated that the underlying defect was deficiency of COX, which was particularly severe in the liver.
Morin et al. (1993) described the clinical findings of 15 of the 34 patients referred to by Merante et al. (1993) who had biochemical evidence of COX deficiency. Fifteen patients in whom clinical findings were reported in detail were aged 6 months to 11 years; 11 children died in episodes of fulminant metabolic acidosis. These patients had elevated blood and cerebrospinal fluid lactate levels, decreased blood bicarbonate levels, and normal blood pH. Characteristic changes of Leigh disease were found in the central nervous system and microvesicular steatosis was found in the liver in all affected patients in whom postmortem examination was performed. Merante et al. (1993) found that the severity of the biochemical defect varied greatly in different tissues. The activity of COX in skin fibroblasts, amniocytes, and skeletal muscle was 50% of normal, while in kidney and heart it was close to normal. Brain and liver, on the other hand, had very low activities. The deficiency of activity appeared to result from a failure of assembly of the cytochrome oxidase complex in liver, but levels of mRNA for both mitochondrially encoded and nuclear-encoded subunits in liver and skin fibroblasts were found to be the same as those in controls. The cDNA sequence of the liver-specific cytochrome oxidase subunits VIa and VIIa were determined in samples from patient liver and skin fibroblasts and showed normal coding sequence. Segregation analysis was consistent with autosomal recessive inheritance.
Debray et al. (2011) retrospectively reviewed the clinical course of 56 patients with genetically confirmed French Canadian Leigh syndrome. The median age at onset was 5 months, and patients presented with neonatal distress, psychomotor delay, failure to thrive, ataxia, and acute metabolic acidosis. Other features during the neonatal period included hypotonia (58%), transient tachypnea of the newborn (47%), poor sucking (44%), tremor (28%), and hypoglycemia (17%). There were mild craniofacial features such as prominent forehead, midfacial hypoplasia, wide nasal bridge, hypertelorism, hirsutism, and arched eyebrows. All had developmental and language delay. Older ambulatory patients had truncal ataxia with wide-based gait and mild intention tremor. Most (90%) had 1 or more episodes of acute metabolic and/or neurologic decompensation, most of which (82%) resulted in death at a median age of 1.6 years. Metabolic crises were often associated with an infectious illness and were characterized by increased serum lactate, hyperglycemia, hypotonia, coma, liver dysfunction, shock, respiratory distress, and multiorgan failure. Neurologic crises were characterized by hypotonia, ataxia, coma, abnormal breathing patterns, seizures, and stroke-like episodes. There was a higher incidence of these acute episodes in patients with LRPPC mutations compared to patients with Leigh syndrome due to SURF1 (185620) mutations (see 256000).
Olahova et al. (2015) reported 10 patients from 7 unrelated families that were not of French Canadian origin who had a severe neurodevelopmental disorder associated with biallelic LRPPRC mutations. Most presented at birth with lactic acidosis, hypotonia, and severely delayed psychomotor development with absent speech, although a few patients had normal early development with episodic decompensation and developmental regression associated with infection. A few patients had mild nonspecific dysmorphic features. Six patients died in infancy or early childhood. Those that survived showed variable neurologic features, including dystonia, ataxia, dysphagia, strabismus, and seizures. Neuroimaging in 2 patients showed features consistent with Leigh syndrome, but lesions were absent in other patients. Three had a striking leukoencephalopathy and 4 had cerebral malformations, such as cerebellar hypoplasia, gyral abnormalities, and hippocampal abnormalities. Other features included hypertrophic cardiomyopathy (in 2 patients), hypospadias (2 patients), anteriorly placed anus (1 patient), polysyndactyly (1 patient), and complex congenital heart disease (1 patient). All patients tested had variably decreased complex IV activity in fibroblasts and/or muscle tissue (range 3 to 70% residual activity).
InheritanceThe transmission pattern of LSFC in the families reported by Olahova et al. (2015) was consistent with autosomal recessive inheritance.
MappingTo identify the gene involved in the Saguenay-Lac-Saint-Jean form of Leigh disease, Lee et al. (1998) performed linkage disequilibrium mapping with a 318-marker genomewide scan using DNA from 14 affected individuals and their parents. One marker on chromosome 2 showed significant linkage disequilibrium. Further testing with additional affected individuals and additional markers spanning approximately 8 to 10 cM and observation of recombination events narrowed the SLSJ cytochrome oxidase deficiency critical region to approximately 1 to 2 cM.
Lee et al. (2001) performed a genomewide linkage disequilibrium scan and localized the LSFC gene to 2p16. By identifying a common ancestral haplotype, they limited the critical region to approximately 2 cM between D2S119 and D2S2174.
Molecular GeneticsLee et al. (2001) performed mutation screening of the COX7A2L gene (605771), which maps to chromosome 2, in patients with LSFC and in controls and found no functional mutations.
In 21 of 22 patients with LSFC, Mootha et al. (2003) identified a homozygous mutation in the LRPPRC gene (607544.0001). The remaining patient was a compound heterozygote; see 607544.0001.
In 10 patients from 7 unrelated families with LSFC who were not of French Canadian origin, Olahova et al. (2015) identified 5 different biallelic mutations in the LRPPRC gene (607544.0003-607544.0007). Patients from 4 unrelated families of Indian or Pakistani origin were homozygous for the same mutation (607544.0003). The mutations were found by whole-exome sequencing or candidate gene sequencing and segregated with the disorder in the families. Studies of fibroblast and muscle tissue from 3 patients showed decreased levels of the LRPPRC protein compared to controls, as well as a significant decrease in the basal oxygen consumption rate. There was almost complete loss of complex IV subunits as well as variable loss of other mitochondrial respiratory subunits, particularly complex I, and decreased levels of steady-state mitochondrial mRNA in patient fibroblasts and muscle tissue.
PathogenesisSasarman et al. (2010) found that mutant LRPPRC was targeted normally to the mitochondrial compartment in immortalized LSFC patient fibroblasts, but that LRPPRC protein content was reduced. In vitro assays revealed that COX activity was reduced in LSFC patient fibroblasts compared with controls. Patient fibroblasts also showed reduced amounts of mitochondrial-encoded COX subunits I (MTCO1; 516030) and II (MTCO2; 516040), with a smaller decrease in the level of nuclear-encoded subunit IV (COX4I1; 123864). LSFC patient fibroblasts showed reduced steady-state levels of mitochondrial mRNAs and had a defect in mitochondrial protein synthesis. Mitochondrial rRNAs and tRNAs were normal in LSFC fibroblasts. Knockdown of LRPPRC in control fibroblasts via siRNA replicated the generalized assembly defect in oxidative phosphorylation complexes. Sasarman et al. (2010) observed that COX mRNAs appeared to be more sensitive than other mRNAs to reduced LRPPRC content in LSFC fibroblasts.
Population GeneticsIn the French Canadian population of the Saguenay-Lac-Saint-Jean region of Quebec province, De Braekeleer (1991) estimated the prevalence at birth of cytochrome c oxidase deficiency to be 1 in 2,473, giving a carrier frequency of 1 in 28.
Morin et al. (1993) estimated the incidence of LSFC at 1 in 2,063 live births between 1979 and 1990, giving a carrier rate of 1 in 23 among inhabitants of the SLSJ region. The genealogic reconstruction of 54 obligate carriers identified 26 ancestors common to all of them. Of these, 22 were 17th-century Europeans, suggesting that the COX-deficient gene was introduced into the French Canadian population by early settlers.