New study links mitochondrial dysfunction to Dravet and other DEEs
Study highlights need for genetic testing to confirm diagnosis
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Dysfunction in mitochondria — the cell’s energy production centers — was frequently seen in children with developmental and epileptic encephalopathies (DEEs), including Dravet syndrome, even when mitochondrial disease was not the underlying cause, a new study found.
Many children with these genetic conditions, which are marked by early-onset seizures and developmental delays, showed laboratory signs of mitochondrial dysfunction that were often used to support a diagnosis of mitochondrial disease. However, genetic testing later revealed that many children initially suspected of having mitochondrial disease instead had DEEs.
Mitochondrial dysfunction seen in nonmitochondrial DEEs
“Our findings indicate that mitochondrial dysfunction is prevalent in nonmitochondrial DEEs,” the researchers wrote, adding that “patients previously diagnosed” with mitochondrial disease only on clinical and laboratory findings “may benefit” from genetic testing to ensure patients receive the correct diagnosis and appropriate treatment.
They also added that “future research should explore whether treatment or prognosis of nonmitochondrial DEEs should be tailored to improve mitochondrial function.”
The study, “Mitochondrial Dysfunction in Monogenic Developmental and Epileptic Encephalopathies,” was published in Pediatric Neurology.
Mitochondrial diseases are a group of genetic disorders that affect how mitochondria function. These conditions can cause a wide range of symptoms, including muscle weakness, organ dysfunction, neurological issues, developmental delays, and epilepsy.
Before advanced genetic testing became widely available, mitochondrial disease was often diagnosed based on clinical symptoms, such as developmental delays and epilepsy, along with laboratory findings, including increased lactate levels — a common marker of mitochondrial dysfunction — in bodily fluids and changes seen in muscle biopsies.
However, muscle weakness, developmental delays, and seizures are also common symptoms in Dravet and other DEEs. As a result, some patients could be misdiagnosed with mitochondrial disease based on overlapping clinical, laboratory, and biopsy findings.
In line with this, genetic studies have shown that many patients initially suspected of having mitochondrial disease were ultimately found to carry mutations in other genes, including those causing Dravet and other neurodevelopmental disorders.
Thus, “the notion that epilepsy is a hallmark manifestation of mitochondrial disease, described in up to 40% of patients with a [mitochondrial disease], may thus need to be reconsidered,” the researchers wrote.
Study revisits children suspected of mitochondrial disease
To clarify how often features of mitochondrial dysfunction occur in DEEs and how they compare with those in mitochondrial disease, researchers in the Netherlands revisited muscle biopsy results and clinical data from 27 children with epilepsy. These children had been suspected of having mitochondrial disease and underwent testing between 2005 and 2015 at the researchers’ hospital.
Of the 27 children in the study, 11 (40.7%) were ultimately diagnosed with DEEs, including one case of Dravet. Four (14.8%) had a genetically confirmed mitochondrial disease, and four (14.8%) were diagnosed with other non-mitochondrial disorders. The remaining eight children (29.6%), for whom no genetic diagnosis was available, continued to be considered suspected cases of mitochondrial disease.
Based on standard diagnostic criteria, 85% of children were deemed to have probable or definite mitochondrial disease. Among those later diagnosed with DEEs, nine children (81.8%) had initially been classified as having probable mitochondrial disease.
Consistent with this, laboratory findings suggested mitochondrial dysfunction. Among children later diagnosed with DEEs, seven (about 64%) had mildly to severely elevated blood lactate levels, while eight (72.7%) had abnormal lactate responses during metabolic stress testing, meaning their blood lactate levels rose more than expected when their body was challenged to produce energy.
However, unlike children later confirmed to have mitochondrial disease, none of these patients had elevated lactate in urine or cerebrospinal fluid (CSF), the fluid surrounding the brain and spinal cord, or increased urine levels of alanine — another substance that can build up when mitochondria are not working properly.
Muscle tests reveal reduced energy production in DEE patients
Muscle biopsy analyses further supported these findings. Among DEE patients with available muscle test data, five (55.6%) showed markedly reduced energy production in muscle cells, indicating impaired mitochondrial activity.
These findings suggest that mitochondrial dysfunction can occur in DEEs even when mitochondria are not the primary cause of the disease. The researchers proposed that some genetic mutations that cause DEEs may directly interfere with mitochondrial processes inside cells. In other cases, repeated seizures and chronic inflammation associated with refractory epilepsy may disrupt cellular energy metabolism, leading to secondary mitochondrial dysfunction.
“This study has provided an overview of the patterns of mitochondrial dysfunction that can occur across DEEs,” the researchers wrote, adding that “several clinical implications can be derived.”
First, genetic testing in patients previously diagnosed with mitochondrial disease could help refine diagnoses and guide treatment decisions. Second, mitochondrial dysfunction in DEEs appears to be complex and not tied to a single cause. Third, the findings may help clinicians better interpret genetic results when distinguishing between mitochondrial disease and DEEs. Finally, the study may support future research into treatment approaches that take mitochondrial function into account.
