Novel LRPPRC Mutation in a Boy With Mild Leigh Syndrome, French–Canadian Type Outside of Québec

Abstract

Background:Leigh syndrome, French–Canadian type is unique to patients from a genetic isolate in the Saguenay–Lac-Saint-Jean region of Québec. It has also been recently described in 10 patients with LRPPRC mutation outside of Québec. It is an autosomal recessive genetic disorder with fatal metabolic crisis and severe neurological morbidity in infancy caused by LRPPRC mutation.Methods and Results:The authors report a boy with a novel LRPPRC compound heterozygous missense mutations c.3130C>T, c.3430C>T, and c.4078G>A found on whole-exome sequencing which correlated with isolated cytochrome c-oxidase deficiency found in skeletal muscle.Conclusion:LRPPRC mutation is a rare cause of cytochrome c-oxidase–deficient form of Leigh syndrome outside of Québec. Our patient broadens the spectrum of phenotypes of Leigh syndrome, French–Canadian type. LRPPRC mutation should be considered in children with early childhood neurodegenerative disorder, even in the absence of metabolic crisis. Early evaluation with whole-exome sequencing is useful for early diagnosis and for genetic counseling.

Mitochondrial respiratory chain complex IV deficiency presenting as neonatal respiratory distress syndrome

“…The French-Canadian variant of cyclo-oxygenase (COX) deficient Leigh syndrome (LSFC) is caused by a founder mutation [c.1061C>T,p. (Ala354Val)] in the LRPPRC gene and unique to Saguenay-Lac-Saint-Jean region of Quebec, Canada 3. These patients present with intermittent severe lactic acidosis and early-onset neurodevelopmental problems with episodes of deterioration, similar to our case.…”

“…There have been reported cases of different genetic variants resembling similar clinical phenotypes outside of this region 4. However, these patients have additional problems of mild hypertrophic cardiomyopathy, congenital malformations, seizures and microcephaly to name a few 3. It could be the unique mutation of our case described presents as neonatal respiratory distress, adding to the complications of the deficiency.…”

“…The prognosis varies according to the form present and can be influenced by other genetic and/or environmental factors 2. There appear to be overlapping trends in certain phenotypes which could be used as a trigger for earlier investigation into Leigh syndrome 3. As our case report presents a unique mutation in the LRPPRC gene presenting as foetal distress and neonatal respiratory distress, we can use this alongside the findings of lactic acidosis and initial elevated pyruvate levels with MRI brain changes to consider Leigh syndrome as a differential diagnosis earlier on in the management plan.…”

Mitochondrial DNA transcription and translation: clinical syndromes

“…LSFC is characterized by Leigh syndrome (a subacute neurodegeneration of the brainstem and basal ganglia), developmental delay, hypotonia, mild facial dysmorphism, and high mortality due to episodes of severe acidosis and coma that typically arise in the first year of life [ 22 ]. Subsequently, LSFC has also been described outside Quebec in ten patients from seven unrelated families of Caucasian, Pakistani, Indian, Turkish, and Iraqi origin [ 23 ] and in a Chinese boy with a milder phenotype [ 24 ]. The phenotype of these patients resembles LSFC, but in addition, neonatal cardiomyopathy or congenital malformations of the heart and the brain were reported.…”

Lipidomics unveils lipid dyshomeostasis and low circulating plasmalogens as biomarkers in a monogenic mitochondrial disorder

“…Mutations in the LRPPRC gene have been identified as the root cause of a distinct monogenic form of Leigh syndrome in the French-Canadian population of the northeastern region of Quebec (Leigh syndrome French-Canadian variant; LSFC; OMIM#220111; ~1 in 2,000 births; carrier rate 1 out of 23) (5), and recently in unrelated families in Europe and China (6,7). LSFC patients exhibit many hallmarks of inherited mitochondrial diseases such as Leigh syndrome and necrotizing encephalopathy, as well as the high occurrence of metabolic and neurological crisis, which is the main cause of mortality in young children (8,9).…”