WASHINGTON -- A condition dubbed Sudden Adult Death Syndrome (SADS), affecting young and apparently healthy individuals, may be linked to a specific mitochondrial mutation, said British neurologists after investigating two cases and then a larger cohort.
These neurologists are now developing new guidelines aimed at improving screening for the disease.
"What really drove us to look at these cases was that we had two young people who presented before the age of 30 found dead in bed," said an adult neurologist at the Wellcome Trust Centre for Mitochondrial Research at Newcastle University in the U.K.
Action Points
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
- Two previously healthy young adults harboring the mitochondrial point mutation m.3243A>G died unexpectedly by what is called Sudden Adult Death Syndrome (SADS), which investigators surmise may have been the result of insufficient cytochrome C oxidase in the heart.
- The m.3243A>G mutation exhibits marked genetic and phenotypic heterogeneity with some carriers asymptomatic and others with severe myopathy or other characteristic features of mitochondrial disease.
- The incidence of SADS was investigated in a larger cohort of m.3243A>G carriers (estimated prevalence=1 in 400 in the population), and six further cases were identified over the past 15 years (incidence rate=2.2%).
Gorman presented her research on the condition and its relationship to m.3243A>G mitochondrial myopathy at the here.
This point mutation in the mitochondrial genome disrupts energy production in all of the body's cells, but it affects the brain, heart, and muscles the most, as they require the most energy, Gorman explained.
Both of the subjects Gorman described had appeared healthy and fit, with BMI values of 24 and 22.
While the deceased appeared asymptomatic, both had the m.3243A>G defect, a common pathogenic mitochondrial disease mutation, which presents itself in different ways.
"You can have very minimal symptoms with a little bit of deafness and diabetes, right through to devastating disorder, where you've got recurrent stroke-like episodes and seizures," she said.
Both also had family members with severe mitochondrial disease.
The m3243A>G gene mutation has a prevalence of about one in 400 in the population, but clinical disease is recognized in about one in 5,000 people, Gorman's poster indicated.
Gorman and colleagues questioned whether SADS could be "an unrecognized clinical entity" in these -- and other -- young, previously asymptomatic individuals carrying the mutation.
Gorman and her colleagues began a comprehensive review of other cases of SADS in order to gauge its prevalence in their cohort. They also tried to determine the exact cause of death in the two case subjects.
They conducted clinical investigations, immunohistochemistry, and molecular genetic analyses on different cardiac tissue samples -- including the atrium and ventricles -- and skeletal muscle tissue samples from the two cases.
They also performed Cox proportional hazards regression analysis in individuals with the m.3243A> G mutation who were part of the Newcastle MRC Mitochondrial Disease Patient Cohort, seeking to identify factors associated with cardiac problems.
After post-mortem examination of the two deceased subjects, they were mostly able to exclude alcohol as a factor in the subjects' deaths as the amounts consumed were "negligible." While sudden unexpected death from epileptic seizures was also a possibility, Gorman said she did not see the severity of changes in the brain that she would have expected if such incidents had occurred.
However, she did find "a mosaic pattern" of cytochrome C oxidase deficiency in both patients' skeletal and cardiac muscle tissue.
Cardiac myopathies are common in SADS, she said, describing the resulting arrhythmias as "a wringing action within the septum of the heart.'
"That wringing is abnormal within even people who appear to be asymptomatic," she said.
In the cases of the two subjects, "[w]hen we actually looked at the tissue level at their heart, it was quite severely affected by the disorder."
This was not something that would have been noticed in routine clinical examination, and neither subject had reported any cardiac symptoms.
This finding is significant because, while there is no cure for mitochondrial disease, cardiac myopathy can be reversed with the right intervention, usually beta-blockers and ACE inhibitors.
Inspired by the loss of these two individuals and armed with new knowledge of the disease's prevalence, Gorman helped to create a screening tool for cardiomyopathy.
With this new tool, a provider could input the three risk factors -- age, gender, and heteroplasmy data (the level of mutation in a patient's blood) -- and then assess an individual's potential risk for cardiac myopathy.
In addition to the tool, Gorman has begun developing guidelines, which are being reviewed for publication.
According to these guidelines, which she displayed in a flow chart, any patient who has the m.3432A gene mutations should have a yearly echocardiogram. Those with a family history of sudden death or if the ECG is abnormal should also have a cardiac MRI scan. Such imaging would be indicated as well for individuals at high risk according to the center's cardiomyopathy tool.
If the scan is normal, patients can continue only with regular surveillance, whereas an abnormal MRI should prompt beta-blocker treatment.
Gorman also strongly supported in-depth family tracing for m.3243A> G in every SADS case.
a neurologist at Wakefield Hospital in New Zealand, said that knowing Gorman had a large sample size upon which to base her research allowed him to trust that her information was reliable.
He added that Gorman is "very experienced at dealing with what for most neurologists is a relatively unusual condition."
Disclosures
Gorman and co-authors disclosed no relevant relationships with industry.
Primary Source
American Academy of Neurology
Source Reference: Gorman G, et al "Sudden adult death syndrome: An uncommon or simply unrecognised clinical entity in young, asymptomatic adults with m.3243A>G disease?" AAN 2015; Abstract P2.100.