fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3

Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 (sometimes abbreviated COXPD3) is a severe disorder that affects the body’s energy-producing structures, the mitochondria. Pathogenic variants in the single known gene, TSFM, interfere with oxidative phosphorylation, the process cells use to generate most of their energy. Symptoms begin in the newborn period, and both boys and girls can be affected. The condition is extremely rare, with fewer than one in a million people—only about five individuals worldwide—reported in the medical literature.

Severity and symptoms vary widely between individuals. Early in life, affected infants present with marked low muscle tone (neonatal hypotonia) and episodes of severe lactic acidosis, which can cause rapid breathing, poor feeding, and low energy levels. Laboratory testing consistently shows reduced activity of mitochondrial complexes I, III, and IV along with high blood lactate and an elevated lactate-to-pyruvate ratio. As the disease progresses, multiple organ systems become involved. Neurological features may include progressive encephalopathy, seizures, and episodes of respiratory failure related to muscle weakness. Cardiac involvement ranges from concentric hypertrophic cardiomyopathy in many infants to dilated cardiomyopathy in a smaller subset; heart failure and arrhythmias can occur. Some children develop liver dysfunction, hyperammonemia, or rhabdomyolysis during metabolic stress. Less common findings such as ventriculomegaly, hyponatremia, or patent ductus arteriosus have been reported. Not all individuals experience every feature, and the timing and severity of complications can differ considerably, even among those with the same TSFM variants.

The condition is caused by pathogenic variants in the TSFM gene, which lead to combined impairment of several mitochondrial respiratory chain complexes. Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 is inherited in an autosomal recessive pattern: a child must receive one altered copy of TSFM from each parent to be affected. Parents who each carry one altered copy are called carriers and typically have no symptoms themselves. When both parents are carriers, each pregnancy has a 25 percent chance of resulting in an affected child, a 50 percent chance of producing a carrier child, and a 25 percent chance of producing a child with two working copies of the gene. Because this condition requires inheriting two altered copies, it may occur more frequently in families where parents share a common ancestor, as this increases the likelihood that both carry the same rare variant. Carrier testing and genetic counseling are recommended for family members to clarify individual risks and to support informed family-planning decisions.

Currently, management focuses on supportive care and symptom control, tailored to each individual’s needs. Acute episodes of lactic acidosis require prompt metabolic stabilization with intravenous fluids, careful glucose management, and correction of electrolyte imbalances. Respiratory support, nutritional optimization (including consideration of gastrostomy feeding), and aggressive treatment of infections help reduce metabolic stress. Because cardiac complications can develop or progress, serial echocardiograms and electrocardiograms are important. Liver function, serum lactate, and ammonia levels should be monitored regularly, especially during intercurrent illness. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. A multidisciplinary team—typically including metabolic specialists, neurologists, cardiologists, pulmonologists, dietitians, and physical therapists—coordinates care, guides monitoring schedules, and supports families in day-to-day management. No targeted or disease-modifying therapies are currently approved, but patients should discuss emerging research and potential clinical trial opportunities with their healthcare team. Genetic counseling provides additional support for reproductive planning.

Available reports suggest that the disease can progress rapidly and may be life-limiting, particularly when severe lactic acidosis or heart failure occurs early. Nonetheless, outcomes depend on many factors, including the specific complications that develop, the timing of diagnosis, and access to specialized care. Intensive metabolic management, proactive cardiac monitoring, and ventilatory support when needed can improve both survival and quality of life. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with expert centers, metabolic specialists, and genetic counselors who can tailor surveillance plans, provide anticipatory guidance, and share information about support resources and emerging therapies.