Hypertropic cardiomyopathy (HCM) is a rare, potentially deadly disease of heart muscle. For example, around six per cent of patients listed for paediatric heart transplants have HCM.
A recent paper from ICH scientists tracked down the cause of HCM in one child who sadly died of this condition. Understanding the genetics in this one complex case had a real human benefit – the family can now try for other children without resorting to donor egg IVF.
The paper appears online in Journal of Medical Genetics, 22 Sept. The research team benefits from funding from Great Ormond Street Hospital Children’s Charity.
HCM can have many causes but approximately nine per cent of paediatric HCM cases are caused by an inborn error of metabolism. More than half those metabolic cases come from problems with the energy producing chemical reactions of mitochondria.
Mitochondria are little ‘batteries’ within the cell. They have their own DNA, outside the conventional nuclear genes of the cell. But genes within the cell nucleus still play a crucial role in building of the mitochondria. With 1500 nuclear genes thought to be involved in coding for mitochondria, and complex interplay between nuclear and mitochondrial genes, the mere fact a disease is mitochondrial in nature doesn’t tell you where the genetic problem lies.
Dr Shamima Rahman (UCL Institute of Child Health) and colleagues investigated a severely ill child with HCM at Great Ormond Street Hospital. Metabolic and cardiac doctors together established that her case was an inbuilt error in the mitochondria. A genetic search found mutations in the NDUFAF1 nuclear gene, known to be linked to the assembly of mitochondrial complex I, which is the largest enzyme involved in the mitochondria’s production of energy.
The mutations alone did not cause the child’s illness; a viral infection appears to have triggered the cardiomyopathy. Only the second case in the world to have such a genetic defect identified, it is thought that these mutations would have reduced the ability of heart cells to produce enough internal energy.
Dr Rahman said “There is still a great deal we do not know about mitochondrial disease and its effect on the heart. Understanding how in this one case viral infection and an inherited nuclear gene fault led to fatal heart disease, advances our understanding of HCM. But for the bereaved family, it gave them direct benefit. A mitochondrial mutation could be passed to every child of the mother and the only way round this would be to use donor eggs for future pregnancies. As a recessive nuclear genetic mutation, three quarters of all her children can expect not to have the condition. The family can be offered, if they wish, tailored prenatal diagnosis.”
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