Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygousOPA1mutation

Abstract

BackgroundInfantile-onset encephalopathy and hypertrophic cardiomyopathy caused by mitochondrial oxidative phosphorylation defects are genetically heterogeneous with defects involving both the mitochondrial and nuclear genomes.ObjectiveTo identify the causative genetic defect in two sisters presenting with lethal infantile encephalopathy, hypertrophic cardiomyopathy and optic atrophy.MethodsWe describe a comprehensive clinical, biochemical and molecular genetic investigation of two affected siblings from a consanguineous family. Molecular genetic analysis was done by a combined approach involving genome-wide autozygosity mapping and next-generation exome sequencing. Biochemical analysis was done by enzymatic analysis and Western blot. Evidence for mitochondrial DNA (mtDNA) instability was investigated using long-range and real-time PCR assays. Mitochondrial cristae morphology was assessed with transmission electron microscopy.ResultsBoth affected sisters presented with a similar cluster of neurodevelopmental deficits marked by failure to thrive, generalised neuromuscular weakness and optic atrophy. The disease progression was ultimately fatal with severe encephalopathy and hypertrophic cardiomyopathy. Mitochondrial respiratory chain complex activities were globally decreased in skeletal muscle biopsies. They were found to be homozygous for a novel c.1601T>G (p.Leu534Arg) mutation in the OPA1 gene, which resulted in a marked loss of steady-state levels of the native OPA1 protein. We observed severe mtDNA depletion in DNA extracted from the patients’ muscle biopsies. Mitochondrial morphology was consistent with abnormal mitochondrial membrane fusion.ConclusionsWe have established, for the first time, a causal link between a pathogenic homozygous OPA1 mutation and human disease. The fatal multisystemic manifestations observed further extend the complex phenotype associated with pathogenic OPA1 mutations, in particular the previously unreported association with hypertrophic cardiomyopathy. Our findings further emphasise the vital role played by OPA1 in mitochondrial biogenesis and mtDNA maintenance.

OPA1 processing in cell death and disease – the long and short of it

“…Although OPA1 is highly expressed in the retina, it is broadly expressed throughout the body and this might reflect the multiple disorders that have presented themselves in patients harboring heterozygous mutations of OPA1, including deafness and dementia (Carelli et al, 2015). Until recently, all OPA1 mutations found in patients have been identified as heterozygous, with the only homozygous OPA1 mutation causing early-onset encephalomyopathy, cardiomyopathy and death during infancy (Spiegel et al, 2016). In mice, homozygous Opa1 mutants die in utero, but heterozygous mutants reflect the main features of human ADOA, as well as additional phenotypes including cardiomyopathy (Alavi et al, 2007;Chen et al, 2012;Davies et al, 2007).…”

A neurodegenerative perspective on mitochondrial optic neuropathies

“…Remarkably, two Italian families carrying different OPA1 missense mutations have been reported with an atypical combination of parkinsonism, dementia and CPEO, but with only subclinical optic neuropathy [34]. More recently, a compound homozygous OPA1 mutation has been identified for the first time in two affected Jewish sisters from consanguineous parents who developed a fatal infantile encephalomyopathy with hypertrophic cardiomyopathy and optic atrophy [123]. However, instead of multiple mtDNA deletions, the muscle biopsy from one sister showed marked mtDNA depletion.…”

Multiethnic involvement in autosomal-dominant optic atrophy in Singapore

“…10 Severe syndromes affecting young children, due to recessive OPA1 inheritance, were also recently reported. 5,11,12 Although ADOA is an ubiquitous condition, [13][14][15][16][17][18] several studies have reported its possibly lower incidence in Asia. 19,20 Our aim was to investigate, for the first time, its occurrence in the multiethnic population of Singapore.…”