Primary Mitochondrial Disorders

Resumen

Primary mitochondrial disorders (PMDs) are a group of rare genetic diseases in which the body’s cells cannot produce enough energy to work properly. They are among the most common inherited metabolic and neurological disorders, affecting roughly 1 in 4,000 to 1 in 4,300 people in the general population.^1-3

The root cause is a fault in a process called oxidative phosphorylation, the way mitochondria (the energy-producing structures inside cells) convert nutrients into usable energy.⁴ Oxidative phosphorylation relies on five major protein complexes, along with many other proteins needed to build, maintain, and regulate this energy-producing system.¹ Changes (pathogenic variants) in more than 350 genes have been linked to PMDs.¹ Most cases are caused by variants in nuclear DNA (the DNA housed in the cell’s nucleus), while variants in mitochondrial DNA (DNA found inside the mitochondria themselves) account for about 15% of cases.¹

PMDs can appear at any age, but onset tends to cluster in two periods, early childhood (under age 2) and adulthood (18 and older).⁵ Nuclear DNA variants most often cause disease in infancy or early childhood, while mitochondrial DNA variants can affect both children and adults.⁴ The most common childhood form is Leigh syndrome, a condition involving progressive brain damage, muscle weakness, and loss of previously gained skills.⁴ In adults, the most frequent presentation is chronic progressive external ophthalmoplegia, a gradual weakening of the muscles that move the eyes.⁴

Because mitochondria are found in nearly every cell, PMDs can affect many organs and systems. The nervous system, muscles, heart, liver, and kidneys are most commonly involved.⁴ Symptoms range from problems in a single organ to severe disease affecting the whole body.⁴

Prognosis varies widely, from life-threatening illness in newborns to slowly progressing conditions in adults with near-normal life expectancy.^6-7 A small number of specific forms respond to targeted treatments, such as coenzyme Q10 supplementation or idebenone, but most management remains supportive.⁸

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Sinónimos

Primary mitochondrial diseases
PMDs

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Subdivisiones

Leigh syndrome
Leber hereditary optic neuropathy (LHON)
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
Myoclonic epilepsy with ragged-red fibers (MERRF)
Neurogenic weakness with ataxia and retinitis pigmentosa (NARP)
Chronic progressive external ophthalmoplegia (CPEO)
Kearns-Sayre syndrome (KSS)
Pearson syndrome
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
Alpers-Huttenlocher syndrome
Sensory ataxia neuropathy, dysarthria, and ophthalmoplegia (SANDO)
Primary coenzyme Q10 deficiency
Barth syndrome

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Signos y Síntomas

PMDs can affect many different parts of the body, and symptoms can vary greatly from person to person. They can begin at any age, from the first days of life through adulthood, and can range from mild, slowly progressing problems to severe, life-threatening illnesses. The nervous system, muscles, heart, liver, and kidneys are among the organs and systems most commonly affected. ^{4, 9}

When symptoms begin is one of the most important factors in how a PMD will progress.^6,10 In a review of 29 mitochondrial disease types, 59% began before 18 months of age and 81% before age 18.⁶ People whose first symptoms appear before 6 months of age face a significantly higher risk of early death.¹⁰ Disease progression can be gradual, come and go in episodes, or advance rapidly, and even people in the same family carrying the same genetic variant can have very different experiences.⁷

Neurological problems are among the most common and prominent features of PMDs.⁴ These can include:

Developmental delay or loss of skills a child had already gained (developmental regression)⁴
Seizures⁴
Encephalopathy (a general term for brain dysfunction that can cause confusion, reduced alertness, or behavioral changes)⁴
Stroke-like episodes with sudden neurological symptoms that resemble a stroke but are caused by the mitochondrial disorder⁴
Cerebellar ataxia (poor coordination and balance, caused by problems in the part of the brain that controls movement)⁴
Peripheral neuropathy (damage to the nerves outside the brain and spinal cord, which can cause weakness, numbness, or pain in the hands and feet)⁴
Migraine headaches⁴
Movement disorders, including parkinsonism (slow movement and stiffness), dystonia (involuntary muscle contractions causing abnormal postures), and chorea (involuntary, jerky movements)^4,11

Leigh syndrome

Leigh syndrome is the most common form of PMD in children.⁴ It causes progressive damage to the brain (neurodegeneration), particularly affecting the brainstem (which controls breathing and basic body functions) and cerebellum (which controls coordination).⁴ Children with Leigh syndrome typically lose motor and mental skills they had previously developed (psychomotor regression) and have low muscle tone (hypotonia).⁴ In one large study, median survival was about 2.1 years.⁷

Eye problems are frequently seen in PMDs and can be an important clue to diagnosis.^4,12-13 The eye problems may include:

Ptosis (drooping of one or both eyelids), which may start on one side but eventually affects both eyes¹²
Progressive external ophthalmoplegia (gradual weakening of the muscles that move the eyes, making it hard to look in different directions)⁴
Optic atrophy (damage to the optic nerve, which carries visual signals from the eye to the brain)⁴
Pigmentary retinopathy (changes to the light-sensitive layer (retina) at the back of the eye that can affect vision)⁴

Leber hereditary optic neuropathy

This specific form of PMD causes painless, subacute (developing over weeks to months) loss of vision in both eyes.^4,9 It predominantly affects males.^4,9

Muscle problems are common and can include:^4,9

Proximal myopathy (weakness in the muscles closest to the body’s center, such as the shoulders, upper arms, hips, and thighs)⁴
Exercise intolerance (becoming unusually tired or weak with physical activity)⁴
Fixed muscle weakness that is present even at rest⁴
Rhabdomyolysis (a serious breakdown of muscle tissue that releases proteins into the bloodstream, which can harm the kidneys)^4,9

Heart problems that may include:⁴

Cardiomyopathy (disease of the heart muscle, which makes it harder for the heart to pump blood)⁴
Cardiac conduction defects (problems with the electrical signals that control the heartbeat)⁴

Cardiomyopathy can be a severe manifestation of PMD and is associated with increased mortality, particularly when it presents early in life.⁷

Causas y Herencia

Primary mitochondrial disorders (PMDs) are caused by variants in DNA that disrupt the way mitochondria produce energy.⁴ Mitochondria are structures found inside the cells in the body. Their main job is to convert nutrients into a form of energy that cells can use, a process called oxidative phosphorylation.⁴ This process depends on five large protein complexes (groups of proteins that work together), numbered I through V.¹When a genetic variant disrupts any part of this system, cells cannot produce enough energy to function properly.⁴

Variants can occur in one of two places:¹

Nuclear DNA (nDNA): the DNA stored in the cell’s nucleus. Nuclear gene variants cause the majority of PMD cases and account for most of the proteins that make up the oxidative phosphorylation system.¹
Mitochondrial DNA (mtDNA): a small, separate set of DNA found inside the mitochondria themselves. Variants here account for about 15% of PMD cases.¹

More than 350 genes have been linked to PMDs.¹

Unlike nuclear DNA, mitochondrial DNA exists in many copies inside each cell. When a cell contains a mix of normal and variant mtDNA copies, this is called heteroplasmy.¹⁴ The proportion of variant copies varies widely from person to person and even from one tissue to another within the same person. This is one reason why people with the same mtDNA variant can have very different symptoms.^14-15

Because mitochondria are present in virtually every cell, a failure in energy production can affect almost any organ or system.⁴ Organs and tissues that need the most energy, such as the brain, muscles, heart, liver, and kidneys tend to be more affected.⁴ This is why PMDs so often cause neurological problems, muscle weakness, heart disease, and organ dysfunction.⁴

When oxidative phosphorylation is impaired, cells in these high-energy tissues cannot keep up with the body’s demands.⁴ In the brain, this can lead to seizures, developmental regression, stroke-like episodes, and progressive neurodegeneration.^4,11 In muscle, it causes weakness, exercise intolerance, and, in severe cases, breakdown of muscle tissue (rhabdomyolysis).^4,9 In the heart, it can lead to disease of the heart muscle (cardiomyopathy) or problems with the electrical signals that control the heartbeat.⁴ In the eyes, it can damage the muscles that move the eyes, the optic nerve, or the light sensitive layer at the back of the eye.^4,12-13

Inheritance

Most genetic information is stored as nuclear DNA in 23 pairs of chromosomes. Mitochondria also contain a small, separate genome called mitochondrial DNA (mtDNA). A person gets one chromosome in each pair from the biologic mother and one from the biological father. Each chromosome contains genes, which are long pieces of DNA that give instructions for making proteins.

Recessive genetic disorders occur when a person inherits a disease-causing gene variant from each parent. If a person receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms.

The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) variant in the affected person that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy.

The risk is the same for males and females.

X-linked recessive disorders are caused by disease-causing variants in genes on the X chromosome. These disorders are more likely to cause symptoms in males because males have only one X chromosome. Females have two X chromosomes, so a female with a disease-causing variant on one X chromosome may have no symptoms or may have milder symptoms, depending on the specific condition and other genetic factors. The chance of passing an X-linked variant to a child depends on which parent carries the variant and the specific disorder involved.

When the mother is a carrier of an X-linked recessive disorder and the father is unaffected, each pregnancy has a 25% chance of resulting in a carrier daughter, a 25% chance of a non-carrier daughter, a 25% chance of an affected son, and a 25% chance of an unaffected son

If a male with an X-linked disorder can reproduce, he will pass the gene variant to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.

X-linked dominant disorders are caused by a disease-causing variant in a gene on the X chromosome. Both males and females can be affected, although the frequency and severity of disease in each sex vary depending on the specific disorder.

Mitochondrial DNA (mtDNA) is inherited from the biological mother. Women with a variant present in all copies of their mtDNA, known as a homoplasmic variant, will pass that variant to all of their children. However, whether a child develops symptoms and how severe those symptoms are can vary.

When only some copies of mtDNA carry a variant, this is called heteroplasmy. The proportion of mtDNA carrying the variant can differ greatly among a mother’s children and can also vary between tissues in the same person. Because of this, it can be difficult to predict whether a child will develop symptoms or how severe the condition may be. Genetic counseling can help families understand these risks based on the specific mtDNA variant involved.

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Frecuencia

Primary mitochondrial disorders are among the most common inherited metabolic disorders. Population studies suggest that pathogenic mitochondrial disease-associated variants occur in approximately 1 in 4,300 people, although not everyone who carries such a variant develops clinically apparent disease.^1-3 Among adults specifically, variants in mitochondrial DNA (mtDNA) that cause noticeable disease occur in about 1 in 5,000 people.³

PMDs can affect anyone, but not everyone who carries a relevant genetic variant will develop symptoms. Community-based studies suggest that at least 1 in 250 people carry a pathogenic mtDNA variant, yet many of these people remain asymptomatic, meaning they have no signs of disease.²

PMDs affect both males and females. Sex distribution is relatively balanced overall, though some disease registries have reported a slight male predominance.¹⁶ One specific form, Leber hereditary optic neuropathy, predominantly affects males.⁴

PMDs can begin at any age. Onset tends to cluster in two periods, early childhood (under age 2) and adulthood (age 18 and older).⁵ Variants in nuclear DNA most often cause disease in infancy or early childhood, while mtDNA variants can lead to disease in both children and adults.⁴

Leigh syndrome is one of the most common presentations of PMD in childhood, while in adults chronic progressive external ophthalmoplegia, a gradual weakening of the muscles that move the eyes, is a common presentation.⁴

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Enfermedades con síntomas similares

Many conditions share symptoms with primary mitochondrial disorders (PMDs), which can make diagnosis challenging. Muscle problems, heart disease, eye symptoms, seizures, hearing loss, and nerve damage are more common in PMDs than in most conditions that look similar but significant overlap still exists.¹⁷ Blood tests, imaging, muscle biopsy, and genetic testing can help tell these conditions apart.^2,11,17-18

Charcot-Marie-Tooth (CMT) neuropathy causes progressive weakness in the hands and feet, high-arched feet (pes cavus), and damage to both sensory and motor nerves. Unlike PMDs, CMT usually does not affect multiple body systems, there is typically no drooping eyelids (ptosis), no difficulty moving the eyes (ophthalmoplegia), no digestive problems, no changes to the retina (the light-sensitive layer at the back of the eye), and no white matter changes on brain imaging. Blood lactate levels and muscle biopsy findings are also typically normal in CMT.^8,19
Friedreich ataxia causes progressive problems with balance and coordination (ataxia), loss of the ability to sense position and vibration, spine and foot abnormalities, and heart muscle disease (cardiomyopathy). Like some PMDs, it involves secondary problems with mitochondrial function. However, Friedreich ataxia is caused by a specific type of DNA change (a GAA triplet repeat expansion) in the FXN gene, does not cause drooping eyelids or eye movement problems, and shows a characteristic pattern of iron buildup in the heart and spinal cord changes on imaging that differ from mitochondrial ataxia syndromes.^8,20-22
Congenital myopathies are muscle conditions present from birth that cause low muscle tone (hypotonia), weakness, and feeding difficulties in infants, symptoms that can look very similar to mitochondrial muscle disease. The key difference is in what a muscle biopsy shows: congenital myopathies have their own distinctive features under the microscope, rather than the ragged-red fibers or energy-enzyme deficiencies seen in PMDs. Congenital myopathies also tend to progress more slowly and do not usually cause the wide-ranging, multi-organ deterioration seen in PMDs. However, recent research has found that problems with the energy producing complexes in mitochondria occur in a large proportion of congenital myopathy cases, which can blur the line between the two.^23-27
Muscular dystrophies cause progressive muscle weakness and raised levels of creatine kinase (CK), a protein that leaks into the blood when muscle is damaged. Muscle biopsy in muscular dystrophy shows a different pattern of damage, including muscle fiber death, regeneration, and scarring, rather than the mitochondrial changes seen in PMDs. Limb-girdle muscular dystrophies, in particular, usually do not cause the combination of diabetes, deafness, stroke-like episodes, and heart rhythm problems that are characteristic of many PMDs.^25,28-29
Inclusion body myositis (IBM) is a slowly progressive muscle condition, most often seen in older adults, that mainly weakens the thigh muscles and finger flexors. Muscle biopsy shows a distinctive pattern of inflammation and protein deposits not seen in PMDs. However, IBM also shows significant mitochondrial changes in muscle tissue, including the same energy-enzyme deficiencies and mitochondrial DNA deletions found in PMDs, making the two conditions harder to distinguish. IBM typically does not affect the eye muscles or cause the multi-system features of PMDs.30-34
Polymyositis and dermatomyositis are inflammatory muscle diseases that cause subacute (developing over weeks to months) proximal weakness (weakness in the shoulders, upper arms, hips, and thighs), raised CK, and inflammation visible on muscle biopsy. Dermatomyositis also causes characteristic skin changes. Unlike PMDs, these conditions often respond to treatments that suppress the immune system, and they are associated with specific antibodies in the blood. An overlap syndrome called polymyositis with mitochondrial pathology (PM-Mito) shows features of both inflammation and mitochondrial damage; it may respond to immunosuppression and can progress to IBM.^30-32,34-35
Congenital disorders of glycosylation (CDG) are inherited metabolic diseases that, like PMDs, can affect the nervous system, heart, liver, and hormone-producing glands all at once. CDG is more likely than PMDs to cause unusual fat distribution under the skin, blood clotting problems, excess insulin, and structural birth defects. A specific blood test (transferrin isoform analysis) can detect the glycosylation defect that defines CDG. Persistent lactic acidosis (a buildup of lactic acid in the blood) points more strongly toward a mitochondrial cause.³⁶
Fatty acid oxidation disorders affect the body’s ability to break down fats for energy. They can cause episodes of muscle breakdown (rhabdomyolysis), low blood sugar (hypoglycemia), and heart muscle disease, all of which can also occur in PMDs. The key differences are that fatty acid oxidation disorders cause low blood sugar without the expected rise in ketones (hypoketotic hypoglycemia) during a crisis, show a characteristic pattern on a blood test called an acylcarnitine profile, and do not usually cause the chronic, progressive neurological decline seen in PMDs.37-38
Organic acidemias. including methylmalonic acidemia and glutaric acidemia are metabolic disorders that can cause episodes of metabolic crisis, changes in the brain’s basal ganglia (deep brain structures involved in movement and coordination) on imaging, and developmental regression. These features overlap with Leigh syndrome in particular. Organic acidemias are distinguished primarily by characteristic biochemical abnormalities, including specific patterns on urine organic acid testing. Secondary mitochondrial dysfunction can also occur in these disorders.^9,39-40
Pyruvate dehydrogenase deficiency and pyruvate carboxylase deficiency can both cause basal ganglia changes on brain imaging, lactic acidosis, and developmental regression — a picture very similar to Leigh syndrome. These conditions are distinguished by the specific pattern of metabolic abnormalities in the blood: they tend to raise pyruvate levels disproportionately, rather than showing the high lactate-to-pyruvate ratio seen in mitochondrial energy complex deficiencies.⁴
Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (ALS) can all involve secondary problems with mitochondrial function. However, they are distinguished from PMDs by their characteristic clinical features, their typical onset later in life, the absence of multi-system involvement, and the absence of the specific genetic variants in mitochondrial or nuclear mitochondrial genes that define PMDs.19,41
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired condition that causes progressive weakness and damage to the protective coating (myelin) around nerves. It can resemble MNGIE (mitochondrial neurogastrointestinal encephalomyopathy), a specific PMD that also causes nerve damage. MNGIE is distinguished by severe gastrointestinal dysmotility (the digestive tract does not move food properly), significant weight loss (cachexia), drooping eyelids, eye movement problems, and variants in the TYMP gene.⁸
Stroke can be confused with the stroke-like episodes that occur in MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). The key differences are that MELAS-related episodes tend to occur at a younger age, the brain lesions do not follow the pattern of blood vessel territories the way a true stroke does, and they are accompanied by other features such as seizures, diabetes, hearing loss, and muscle disease. Specialized brain imaging and genetic testing can help confirm the diagnosis.^4,40
Drug-induced mitochondrial toxicity can cause muscle damage (myopathy), nerve damage (neuropathy), or lactic acidosis that closely resembles a primary mitochondrial disorder. Drugs known to cause this include certain HIV medications (nucleoside reverse transcriptase inhibitors), statins, and valproic acid. A temporal relationship between exposure to a potentially mitochondrially toxic medication and the development of symptoms can suggest drug-induced mitochondrial toxicity. Symptoms may improve after the medication is discontinued, although recovery can be incomplete.^29,31

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Diagnóstico

Diagnosing primary mitochondrial disorders (PMDs) can be challenging because their symptoms overlap with many other conditions. Doctors use a combination of genetic testing, blood tests, and, when needed, tissue samples to reach a diagnosis.

Broad genomic sequencing has become an important first-line approach to diagnosing PMDs.2,4 Depending on the test and laboratory, sequencing can evaluate nuclear DNA and mtDNA together, ^{2, 4} although the ability to detect low-level heteroplasmy, mtDNA deletions, and other structural variants varies by assay. 2,4

One important advantage is that samples can be collected in noninvasive ways, such as a blood draw, a cheek swab, a saliva sample, or a urine sample.⁴ This matters because harmful variants in mitochondrial DNA (called heteroplasmic variants meaning only some copies of the mitochondrial DNA carry the change) tend to show up at higher levels in cheek swabs and urine than in blood.⁴

Whole genome sequencing, the most comprehensive form of this testing covers both the nuclear and mitochondrial genomes at once and identifies the cause of disease in approximately 50–54% of people tested.²

Blood tests can provide supporting evidence for a PMD. Doctors often measure lactate and pyruvate, two substances that build up when the mitochondrial energy system is not working properly.⁴ Lactate alone has limited usefulness: its sensitivity (how reliably it detects disease when it is present) ranges from 34–62%, and even when elevated it does not always point specifically to a mitochondrial problem.⁴

A more informative measure is the ratio of lactate to pyruvate in the blood. When blood lactate is elevated, the lactate-to-pyruvate ratio can help distinguish an oxidative phosphorylation defect from some disorders of pyruvate metabolism. A ratio above approximately 20 may support an oxidative phosphorylation defect, but a normal ratio does not exclude a PMD.⁴

Two newer blood markers, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), show better diagnostic performance,^4,11 particularly in some mitochondrial myopathies, but their diagnostic performance varies among patient populations and neither can confirm or exclude a PMD on its own. In some people these markers may actually be more sensitive than a muscle biopsy.^4,11

When genetic testing does not provide a clear answer, doctors may recommend a biopsy, a small sample of muscle or liver tissue examined in a laboratory.⁴ When blood testing is unrevealing, molecular analysis of DNA obtained from affected tissue, particularly muscle, can help detect some mtDNA deletions, rearrangements, or other variants that may be present at low or undetectable levels in blood.⁴

Under the microscope, muscle tissue from a person with a PMD may show several characteristic findings:⁴

Ragged-red fibers, muscle fibers with an abnormal, frayed appearance caused by a buildup of abnormal mitochondria
Ragged-blue fibers, a similar finding seen with a different staining method
Decreased cytochrome c oxidase staining reduced activity of a key mitochondrial enzyme (cytochrome c oxidase) in the muscle fibers
Paracrystalline inclusions, abnormal crystal-like structures visible under electron microscopy (a very high-powered type of imaging)

These findings can support a diagnosis of mitochondrial disease but are not present in every PMD and are not individually specific for PMDs

Laboratory tests on the biopsy tissue can also measure the activity of the respiratory chain enzymes, the proteins that carry out oxidative phosphorylation, and can sequence the mitochondrial DNA directly from the tissue.^4,11 These steps can help clarify whether a genetic variant of uncertain significance is truly causing disease.^4,11

After a diagnosis of primary mitochondrial disorders (PMDs) is confirmed, doctors carry out a thorough evaluation of many body systems. Because PMDs can affect almost any organ, this initial check-up is important even when a person feels well, some problems, such as heart disease, can be present without causing noticeable symptoms.⁴²

The heart needs to be checked at the time of diagnosis in every person with a PMD, whether or not they have heart symptoms.¹² Two tests are used:

Electrocardiography (ECG), records the electrical signals that control the heartbeat and can detect rhythm problems (arrhythmias) and conduction defects (problems with how electrical signals travel through the heart)¹²
Echocardiography uses sound waves to create a picture of the heart and can detect thickening of the heart muscle (hypertrophic cardiomyopathy) and other structural changes¹²

In one large study, up to 61% of people with PMDs showed structural heart abnormalities on echocardiography.⁴³ Hypertrophic cardiomyopathy can remain silent until it is advanced, which is why testing is recommended even without symptoms. ¹² People with specific genetic variants, particularly the m.3243A>G variant and single large-scale deletions in mitochondrial DNA, need especially close heart monitoring over time.^12,44

An eye examination is recommended for all people with a PMD.⁴⁵ Studies show that 81% of people with PMDs have eye abnormalities.⁴⁵ The examination should include:^12,45

A check of visual sharpness (visual acuity)
Examination of the back of the eye (fundoscopy), which can reveal damage to the light-sensitive layer (retinopathy) or the optic nerve (optic atrophy)
Electroretinography (a test that measures how well the light-sensitive cells in the eye respond to light) when the doctor considers it necessary12,45

Drooping eyelids (ptosis), gradual weakening of the eye muscles (progressive external ophthalmoplegia), and retinal changes are among the most common findings.⁴⁵

Hearing should be tested at diagnosis. Sensorineural hearing loss, damage to the inner ear or the nerve that carries sound to the brain, is common in PMDs, although its frequency varies considerably by genetic diagnosis and patient population. It often gets worse over time.46-47

Screening for hormone-related problems is an important part of the initial evaluation.^48-49 The most common endocrine problem in PMDs is diabetes mellitus (high blood sugar caused by problems with insulin).^48-49 Doctors also look for:^48-49

Growth hormone deficiency
Hypogonadism (reduced function of the sex glands, which can affect puberty and fertility)
Adrenal insufficiency (when the adrenal glands do not produce enough of certain hormones the body needs)

A brain MRI (a detailed scan that uses magnetic fields to create images of the brain) is recommended for people who have signs of nervous system involvement.^4,9 Certain findings on MRI can point strongly toward a specific PMD. For example, damage to the basal ganglia (deep brain structures involved in movement) is a hallmark of Leigh syndrome, while stroke-like lesions are characteristic of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes).^4,9

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Tratamiento

Management of primary mitochondrial disorders (PMDs) is largely supportive, because a Cochrane review found no clear evidence supporting most interventions.⁵⁰ Evidence for most therapies remains limited to case series and expert opinion.^51-52 However, a small number of specific forms do respond to targeted treatments.

Targeted treatments for specific forms may include:

Primary coenzyme Q10 deficiency can be treated with coenzyme Q10 supplementation and can improve symptoms in some affected individuals, particularly when treatment begins early.⁸
MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), historically treated with intravenous L-arginine during acute stroke-like episodes and orally for prevention. However, a 2026 international consensus concluded that the efficacy of both acute intravenous L-arginine and preventive oral L-arginine is unproven. Management of stroke-like episodes includes prompt recognition and treatment of seizures and other complications, with treatment individualized by specialists experienced in mitochondrial disease..^{8,51, 53}
Leber hereditary optic neuropathy, a form that causes vision loss has shown benefit from idebenone, which can improve visual recovery.⁸
MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) can be treated with allogeneic hematopoietic stem cell transplantation, a procedure that replaces the patient’s blood-forming cells with those from a donor. It can correct the underlying biochemical defect in MNGIE and may stabilize or improve disease in appropriately selected patients. However, transplantation carries substantial treatment-related risks, particularly in people with advanced disease.^8,11
Thiamine-responsive Leigh syndrome may improve with supplementation of thiamine.
Barth syndrome received, in the United States, received FDA accelerated approval of the medication elamipretide (Forzinity) in 2025 to improve muscle strength in adults and children with Barth syndrome who weigh at least 30 kg. Continued approval may depend on confirmation of clinical benefit in a post approval trial.

Supportive and symptomatic care

For most people with a PMD, treatment focuses on managing symptoms, preventing complications, and supporting the organs affected by the disease. Treatment is individualized because symptoms can vary greatly from one person to another.

Depending on the person’s symptoms, treatment may include medicines to control seizures, treatment for diabetes and other hormone problems, hearing aids or other hearing support, treatment for heart disease or abnormal heart rhythms, and physical, occupational, or speech therapy. Nutritional support may be needed for people who have difficulty eating, swallowing, or maintaining a healthy weight. Respiratory support may also be necessary when breathing muscles are affected.

Some treatments are used based on their biochemical rationale and expert consensus rather than strong evidence from large clinical trials. These may include: ⁵¹

Enzymatic cofactors, which are substances that help enzymes work, such as riboflavin (vitamin B2) and thiamine (vitamin B1)⁵¹
Antioxidants such as vitamin E and N-acetylcysteine, which help protect cells from damage⁵¹
Creatine supplements ⁵

People with PMDs may be particularly vulnerable when the body is under stress, such as during an infection, dehydration, prolonged fasting, or surgery. During these situations, care may include maintaining adequate fluids, nutrition, and energy intake and treating infections or other illnesses promptly. Plans for illness, surgery, and anesthesia should be discussed with the person’s mitochondrial disease care team because individual needs and risks vary.

Some medications can interfere with mitochondrial function or pose greater risks for people with certain PMDs. Patients should tell their healthcare providers about their mitochondrial disorder before starting a new medication so that the potential benefits and risks can be considered. Some medications may require special caution or monitoring depending on the person’s specific genetic diagnosis and medical history.⁵³

Diet and exercise programs should be individualized based on the person’s diagnosis, symptoms, abilities, and medical needs.⁵⁴

Multidisciplinary care

Because PMDs can affect many organs at once, care from a team of specialists is important.⁵³ This team may include specialists in neurology (the brain and nervous system), cardiology (the heart), endocrinology (hormones), ophthalmology (the eyes), audiology (hearing), and other fields depending on which organs are affected.⁵⁴

Treatment guidelines

Families and clinicians should be aware that published treatment guidelines exist to support the management of PMDs. Specific guideline recommendations inform the monitoring and care described in this report. 12,45,48-49

Genetic counseling

Genetic counseling is strongly recommended for people with a PMD and their families.⁵⁴ Because the inheritance of PMDs is complex, varying depending on whether the causative variant is in mitochondrial DNA or nuclear DNA, assessing the risk to other family members requires identifying the specific genetic defect.^15,55

Reproductive options are available and should be discussed with specialized centers, with guidance tailored to the specific genetic defect involved.^11,55-56

Options may include:^11,55-58

Preimplantation genetic testing, in which embryos created through in vitro fertilization are tested to identify those with a lower predicted risk of developing or transmitting mtDNA disease. The interpretation of heteroplasmy levels depends on the specific mtDNA variant and its known relationship to disease risk.^56-57
Prenatal diagnosis, testing during pregnancy, which may be appropriate for certain variants or when the mother carries a low level of the harmful variant^57,59
Mitochondrial donation, including pronuclear transfer, uses nuclear genetic material from the intended parents together with donor-derived mitochondria to greatly reduce transmission of disease-causing maternal mtDNA variants. This approach is available only in select jurisdictions.^11,58
Oocyte (egg) donation, using a donor’s eggs when other approaches are not suitable¹¹^,59

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Investigaciones

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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Referencias

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