PP03.4 – 2660: Recurrent metabolic crises and mitochondrial encephalocardiomyopathy due to mutations in LRPPRC

Abstract

Objective LRPPRC mutations cause a distinct type of Leigh syndrome with cytochrome C oxidase (COX) deficiency (LSFC). To date, all reported patients with LRPPRC mutations originate from the French-Canadian population, and almost all of them have the same homozygous founder mutation. LSFC is an infantile onset neurodegenerative disorder with neonatal distress, psychomotor delay, failure to thrive, ataxia, and episodes of acute metabolic decompensation, which are often fatal. Here we present a Finnish boy with prenatal onset mitochondrial encephalocardiomyopathy and recurrent episodes of acute metabolic crises with frequent hospitalization due to novel homozygous mutation in LRPPRC. Methods Clinical, histological, histochemical, biochemical and molecular characterization of the disease. Results The patient is a 2 year old Finnish boy with encephalocardiomyopathy (hypotonia, psychomotor delay, infantile spasms and cardiomyopathy), and recurrent episodes of acute metabolic decompensation with severe lactic acidosis. He had intrauterine growth retardation and brain MRI showed brain cysts and enlarged ventricles (but no signs of intrauterine infection were found). Because of clinical phenotype, lactic acidosis, recurrent metabolic crises and excretion of citric acid cycle intermediates in his urine, a mitochondrial disease was suspected. Muscle histology did not reveal any specific abnormalities, but biochemical analysis of respiratory chain enzyme analysis from the muscle showed decreased Complex I-activity. Complex I and IV (COX) deficiency was detected by blue native electrophoresis from the patient's fibroblasts. Mitochondrial DNA showed no mutations. To find the genetic cause of his disease, we performed exome analysis, and found a novel homozygous mutation in LRPPRC gene: c.515A>G (p.Y172C). The mutation is highly conserved, very rare, and segregates with the disease in the family. Conclusion Acute metabolic crises in a child with suspected mitochondrial disease is suggestive of a disorder caused by LRPPRC mutations, even in non-French-Canadians. LRPPRC mutations cause not only COX – but can also cause Complex I-deficiency.