Mitochondriopathy: When Should One Consider This Zebra?

Mitochondriopathies are among the most common inherited neurological conditions and the most prevalent category of inherited metabolic disorders. Mitochondriopathies are genetic disorders affecting the functioning of mitochondria, and they present with a wide variety of symptoms. It is estimated that 1 in 5,000 individuals have a mitochondrial disease.

Mitochondrial disease is caused by mutations in mitochondrial DNA, nuclear DNA in human cells, and/or defects caused by toxin exposure. With rare exceptions, mitochondrial DNA is inherited from the maternal line. A family history of a condition in which all females pass it on to their children, but no males pass on to their children, raises suspicion for mitochondrial inheritance. Consanguinity significantly increases the risk of inheriting a mitochondriopathy by increasing the risk of inherited autosomal recessive mutations of nuclear human genes. Over 1000 genes are associated with mitochondriopathy.

Mitochondrial defects can cause a wide variety of symptoms and conditions, such as neurodegenerative disorders like Parkinson disease or Huntington disease, developmental delay, loss of vision or hearing, male subfertility, premature aging/ovarian failure, cardiomyopathy, atrioventricular conduction defects, diabetes, exercise intolerance, electrolyte disturbance, and myopathy, among others. Any organ system may be affected, with a particular emphasis on neuromuscular and cardiovascular involvement.

A progressive, multisystem condition in a patient adds a mitochondrial disorder to the differential diagnosis. A patient presenting with a complex neurological condition or significant exercise intolerance (in childhood or in adulthood with level of intolerance disproportionate to the level of deconditioning) also warrants evaluation for a mitochondrial disorder.

In patients with suspected mitochondrial disease, initial testing recommended by the Mitochondrial Medicine Society (MMS) includes postprandial plasma lactic acid, urinary organic and amino acids, creatine phosphokinase and uric acid (in cases of suspected myopathy), and, if possible, 3-methylglutaric acid (serum and urine). An elevated lactic acid level suggests mitochondrial dysfunction, and a level greater than 3 mmol/L is supportive of mitochondrial disease (specificity 83%-100%). Elevated lactic acid may be due to a primary mitochondrial disease or other causes of mitochondrial dysfunction, such as organic acidemias, ischemia, toxins, and more. However, a normal lactic acid level does not exclude mitochondrial disease. Genetic testing is used to establish the diagnosis of a mitochondrial disorder. When genetic testing is inconclusive, muscle biopsy may be considered.

Neuroimaging with brain magnetic resonance imaging is recommended in patients with known or suspected central nervous system involvement. Importantly, stroke-like symptoms may occur in patients with some mitochondrial diseases. In patients with a known primary mitochondrial disease who have a stroke-like episode, intravenous arginine hydrochloride is recommended urgently while other causes are being investigated.

Ongoing monitoring of patients with mitochondrial disease includes cardiac monitoring and screening for diabetes. Screening intervals for these and other conditions are based on expert consensus. No known treatments affect the natural history of mitochondriopathies. Gradual exercise training is generally recommended to improve exercise intolerance. Complications related to general anesthesia are more common in patients with mitochondrial disease. Limiting preoperative fasting and adding glucose to perioperative intravenous fluids (unless the patient is on a ketogenic diet) are recommended to reduce this risk. Specific medications that may affect oxidative phosphorylation and mitochondrial function should be avoided in patients with a mitochondrial disorder, including metformin, statins, valproic acid, high-dose acetaminophen, and some antibiotics.

Patients with a mitochondrial disorder should wear a medical alert bracelet and have a detailed care plan in case of acute illness. In general, prevention of a catabolic state is recommended by encouraging the patients to eat regularly (ie, not fast) and administering intravenous fluids containing dextrose.