Mitochondrial disease refers to a group of disorders caused by dysfunction in the mitochondria, the energy-producing structures within cells.
These disorders can affect various organs and systems in the body, leading to a wide range of symptoms. Types of primary mitochondrial diseases (PMDs) can be classified based on the specific genetic mutations or abnormalities that cause them.
It’s important to note that PMDs can have overlapping symptoms, and the severity and presentation of these disorders can vary widely. Additionally, new discoveries in genetics and mitochondrial research may lead to further classification or refinement of these categories over time.
Below is a list of different PMDs. We continue to add to this list, but some disorders may be absent. If you would like to see a specific disorder added, please reach out to us at: info@mitocanada.org
Onset: any age but most commonly appears in early childhood
Inheritance pattern: Autosomal recessive
Gene: POLG1
Description: Alpers is a progressive neurodevelopmental disease, with symptoms developing, on average, within the first two years of life. Twenty percent of individuals will develop symptoms between the ages of 2 and 25. Symptoms can range from muscle spasticity or twitching, seizures, loss of cognitive abilities, liver disease, low blood sugar, failure to thrive, and headaches. Progression of symptoms can include: blindness, gastrointestinal disorders, movement and coordination decline and/or difficulty swallowing. Alpers is treated using seizure medications, small and frequent low-protein meals, pain relief, occupational, physiotherapy and speech therapy.
Onset: usually in adolescence or early adulthood
Inheritance pattern: autosomal, but may occur sporadically
Features: PEO is often a symptom of mitochondrial disease. In some people, it is a chronic, slowly progressive condition associated with instability to move the eyes and general weakness and exercise intolerance.
Onset: can appear at any age
Inheritance pattern: most commonly autosomal recessive
Gene: TMEM126B, NDUFAF8, TIMMDC1, NDUFA6, ND1, ND2, ND3, NDUFAF2, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NDUFA1, NDUFAF4, NDUFAF5, NDUFA11, NDUFAF3, NUBPL, FOXRED1, NDUFAF1, NDUFB9, NDUFB3, NDUFB10
Description: Complex I is an essential step in mitochondrial energy production. When a change occurs in the complex chain, it impairs energy production. Complex 1 deficiency tends to be cause by inherited defective nuclear genes from both parents.
It can be maternally inherited or caused by a spontaneous genetic mutation in some rare cases. Symptoms include brain and muscle impairment which can include: hearing loss, nerve damage, seizures, coordination challenges, poor muscle tone, heart disease, respiratory decline, and lactic acidosis.
Learn More: https://rarediseases.info.nih.gov/diseases/3908/mitochondrial-complex-i-deficiency AND https://rarediseases.org/gard-rare-disease/mitochondrial-complex-i-deficiency/
Onset: can appear at any age
Inheritance pattern: autosomal recessive
Gene: SDHA, SDHB, SDHD, SDHAF1
Description: Symptoms for Complex II deficiency often vary by individual but is usually more severe in infancy. It can be difficult to identify the underlying gene mutation responsible for Complex II deficiency. Some symptoms include: left ventricular dysfunction, abnormal cardiovascular and eye function, regression of developmental milestones, fatigue, muscle weakness, generalized or focal myoclonic seizures, motor delay or deterioration, spasticity, weight loss or feeding difficulties (infancy), ataxia and others.
Learn More: https://rarediseases.org/gard-rare-disease/mitochondrial-complex-ii-deficiency/
Onset: at birth or early childhood
Inheritance pattern: autosomal recessive, can sometimes be maternal or sporadic inherited
Gene: Nuclear DNA in the BCS1L, UQCRB and UQCRQ genes, inherited autosomal recessive. May also be caused by genetic changes in mitochondrial DNA in the MTCYB gene
Description: Complex III Deficiency can be caused by mutations in nuclear DNA or mitochondrial DNA. It is a severe, multisystem disorder with symptom onset typically from birth to childhood. Some symptoms of Complex III Deficiency include failure to thrive, hypotonia, hypoglycemia, encephalopathy, delayed psychomotor development, lactic acidosis and/or liver disease.
Learn More: https://rarediseases.info.nih.gov/diseases/8295/mitochondrial-complex-iii-deficiency AND https://rarediseases.org/gard-rare-disease/mitochondrial-complex-iii-deficiency/
Onset: onset for encephalomyopathy within 6-12 months of birth. Onset for myopathy at birth
Inheritance pattern: likely autosomal recessive
Gene: COX10, COX1, COX2, COX3, COX6B1, COX14, COX4l1, COX20, COA3, COX8A, COX6A2, PET117, COX5A
Description: This deficiency affects different parts of the body, including the heart, brain, liver and skeletal muscles. There are four different types of COX deficiencies based on symptoms and onset:
- benign infantile mitochondrial type,
- French-Canadian type,
- infantile mitochondrial myopathy type,
- Leigh syndrome
Signs and symptoms range. Mild symptoms include muscle weakness and decreases in muscle tone (hypotonia). More severe symptoms include brain dysfunction; heart problems; an enlarged liver; lactic acidosis. Other symptoms include: developmental regression, ataxia, optic atrophy, respiratory problems, seizures and sometimes kidney issues.
Learn More: https://rarediseases.org/rare-diseases/cytochrome-c-oxidase-deficiency/
Onset: Infancy to adulthood
Inheritance pattern: Autosomal recessive
Description: This deficiency occurs when an individual does not have enough or has impaired function of a complex V protein. Most individuals present with neonatal onset and some signs and symptoms can include feeding issues, slow growth, developmental delay, nausea, decreases in muscle tone (hypotonia), higher lactic acid, vomiting, weakness and decreased energy.
Learn More: https://rarediseases.info.nih.gov/diseases/1459/mitochondrial-complex-v-deficiency AND https://medlineplus.gov/genetics/condition/mitochondrial-complex-v-deficiency/#inheritance
Onset: newborns and infants
Inheritance pattern: autosomal recessive
Gene: CPT1A
Description: CPT I Deficiency is an inherited metabolic condition that prevents the body from converting long-chain fatty acids into energy, especially during fasting. Symptoms appear early in life and include low blood sugar, fatigue or lethargy, speech impairment, enlarged liver, loss of consciousness or seizures, muscle weakness or atrophy, elevated levels of carnitine in the blood and low levels of ketones.
Learn More: https://rarediseases.info.nih.gov/diseases/1120/carnitine-palmitoyl-transferase-1-deficiency
Onset: can present at any age
Inheritance pattern: autosomal recessive
Gene: CPT2
Description: CPT II Deficiency is a condition that prevents the body from converting certain fats into energy (especially during periods of fasting). The most prominent symptoms are liver failure, low blood sugar, seizures, exercise intolerance, weakness, heart disease (cardiomyopathy) and myoglobinuria (muscle breakdown).
Learn More: https://rarediseases.info.nih.gov/diseases/1121/carnitine-palmitoyltransferase-2-deficiency
Inheritance pattern: fatty Acid Oxidation Disorders (FAODs)
Description: FAODs are a group of inherited conditions that occur when the enzymes responsible for breaking down fats into fatty acid, are missing or do not work properly. The body needs fatty acids to create energy to sustain life. When fats are not properly broken down, levels of fatty acids increase, causing a build-up in the heart, liver and other organs. Symptoms and treatments vary between different FAODs and individuals
More common FAODs include: SCADD, SCHADD, MCADD, LCHAD, LCAD, VLCADD, CPT1, CPT2
Onset: before age 20
Inheritance pattern: autosomal (mostly sporadic)
Features: PEO (usually as the initial symptom) and pigmentary retinopathy, a “salt-and-pepper” pigmentation in the retina that can affect vision. Other common symptoms include cardiomyopathy, conduction block (a type of cardiac arrhythmia) ataxia, short stature, neuropathy, and deafness.
Onset: at birth
Inheritance pattern: autosomal recessive, maternal or sporadic
Description: Lactic acidosis occurs when the body produces too much lactic acid and cannot metabolize it due to a problem with the body’s oxidative metabolism. Left untreated, lactic acidosis can cause severe, even life-threatening conditions. Lactic acidosis is often caused by an underlying acute or chronic condition. Symptoms can include nausea, vomiting, laboured breathing, weakness. It can also be brought on by illnesses, infections, seizures and asthma attacks.
Learn More: https://www.ncbi.nlm.nih.gov/books/NBK470202/
Onset: infancy to early childhood
Inheritance pattern: autosomal recessive
Gene: HADHA
Description: LCHAD deficiency is a fatty acid oxidation disorder (FAOD) that prevents the body from converting fats/ proteins into energy. Symptoms can be triggered by increased stress while fasting or sickness. Symptoms include difficulties feeding, low energy, low blood sugar, weak muscle tone, liver and light sensitivity problems. With later childhood, patients may experience muscle pain, breakdown of muscle tissue and loss of sensation in arms and legs.
Learn More: https://www.umdf.org/lcha-deficiency/ AND https://rarediseases.info.nih.gov/diseases/6867/lchad-deficiency
Onset: Infancy or childhood
Inheritance pattern: autosomal recessive
Gene: ACADL
Description: LCAD is a genetic fatty acid oxidation disorder (FAOD) caused by a deficiency in the LCAD enzyme that metabolizes long-chain fatty acids. Symptoms can appear in infancy or childhood and may be triggered by fasting, illness or exercise. In infants, LCAD symptoms can include failure to thrive, hypoglycemia, enlarged liver, enlarged heart, lethargy, decreased muscle tone or muscle weakness.
Learn More: https://rarediseases.info.nih.gov/diseases/9700/lcad-deficiency
Onset: infancy (3-24 months) or early childhood
Inheritance pattern: maternal, autosomal recessive, X-linked
Features: Brain abnormalities that can result in abnormal muscle tone, ataxia, seizures, impaired vision and hearing, developmental delays, and respiratory problems. Infants with the disease have a poor prognosis.
Note: when inherited through mtDNA, it may be called MILS or Maternally Inherited Leigh Syndrome
Onset: may present between age 15 to 35
Inheritance pattern: maternally inherited
Gene: MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, and MT-ND6
Description: LHON is a maternally inherited form of vision loss. A large number of patients with the mutation never develop any symptoms. Blurred vision is typically the first symptom and the vision loss is usually sudden and painless. The vision loss can occur simultaneously with both eyes but usually starts in one eye and the other eye is usually affected weeks or months later. Symptoms include decrease in visual acuity, blurred vision, central or centrocecal scotoma, or optic atrophy. Vision loss usually results in patients becoming legally blind.
Onset: infancy, childhood, adolescence, adulthood
Inheritance pattern: maternally inherited
Gene: MT-ND1, MT-ND4, MT-ND6, NDUFS2, DNAJC30, ATP6, COX3, CYTB, ND1, ND2, ND4, ND4L, ND5, ND6
Description: A rare inherited mitochondrial disease characterized by the clinical features of Leber hereditary optic neuropathy in addition to other systemic or neurological abnormalities. These abnormalities include: postural tremor, motor disorder, multiple sclerosis-like syndrome, spinal cord disease, skeletal changes, Parkinsonism with dystonia, anarthria, motor and sensory peripheral neuropathy, spasticity, mild encephalopathy, and cardiac arrhythmias.
Learn More: https://jnnp.bmj.com/content/jnnp/59/2/160.full.pdf
Onset: childhood
Inheritance pattern: maternally inherited
Description: Luft Disease is a rare mitochondrial disease that can cause hypermetabolism, fevers, heat intolerance, profuse perspiration, extreme hunger (polyphagia), excessive thirst (polydipsia), muscular wasting and weakness, weight loss, ragged-red fibers and high heart rate (resting tachycardia).
Exercise intolerance can also be a sign or symptom. Vitamin therapy, high-caloric diet and heat protection/management are the current management strategies used as there currently is no cure.
Learn More: https://www.sciencedirect.com/science/article/abs/pii/B9780123786302001225 AND https://www.ourbiochemistry.com/knowledge-base/case-study-lufts-syndrome/#:~:text=In%20Luft%20syndrome%2C%20the%20uncoupling,in%20the%20form%20of%20heat.&text=Resting%20tachycardia.
Onset: within 1 and 24 months of age, sometimes into adulthood
Inheritance pattern: autosomal recessive (inherited)
Gene: ACADM
Description: MCAD Deficiency is an inherited metabolic disorder caused by a lack of a specific enzyme needed to metabolize medium-chain fatty acids, thus converting this fatty acid into energy. Symptoms usually include muscle weakness, vomiting, lack of energy, low blood sugar and seizures, especially during periods of prolonged fasting and illness.
Learn More: https://rarediseases.org/rare-diseases/medium-chain-acyl-coa-dehydrogenase-deficiency/
Onset: infancy or childhood
Inheritance pattern: maternally inherited
Gene: ATPase 6
Description: MILS is a progressive brain disorder caused by changes in mitochondrial DNA. The age at which symptoms appear tend to be in infancy or early childhood. Symptoms include vomiting, lactic acidosis, seizures, heart disease (cardiomyopathy), ataxia, muscle weakness, dystonia, failure to thrive, breathing issues and developmental delays and others. Symptoms and their severity can vary between patients and among family members.
Learn More: https://rarediseases.org/rare-diseases/maternally-inherited-leigh-syndrome-and-narp-syndrome/
Onset: early onset
Inheritance pattern: autosomal recessive
Gene: POLG1
Description: MIRAS is a rare syndrome characterised by early onset cerebellar ataxia. It can include symptoms such as difficulties with balance, difficulty speaking (dysarthria), damage to the peripheral nervous system (peripheral neuropathy), movement disorders, epilepsy, headaches, cognitive impairment, paralysis of the eye muscles and psychiatric symptoms.
Onset: infancy to adulthood
Inheritance pattern: autosomal
Features: A myopathic form of MDDS is characterized by weakness that eventually affects the respiratory muscles. Some forms of MDDS, such as Alpers syndrome, are marked by brain abnormalities and progressive liver disease. The anticonvulsant sodium valproate should be used with caution in children with Alpers syndrome because it can increase the risk of liver failure.
Onset: childhood to early adulthood – Sometimes onset may be as late as 40 years old
Inheritance pattern: maternal
Features: the hallmarks of MELAS are encephalomyopathy with seizures and/or dementia, lactic acidosis, and recurrent stroke-like episodes. These episodes are not typical strokes, which are interruptions in the brain’s blood supply that cause sudden neurological symptoms. However, the episodes can produce stroke-like symptoms in the short term (such as temporary vision loss, difficulty speaking, or difficulty understanding speech) and lead to progressive brain injury. The cause of the stroke-like episodes is unclear.
Onset: infancy to adulthood, usually before age 20
Inheritance pattern: autosomal recessive
Features: this disorder is characterized by PEO, ptosis, limb weakness, and gastrointestinal (digestive) problems, including vomiting, chronic diarrhea, and abdominal pain. Another common symptom is peripheral neuropathy (a malfunction of the nerves that can lead to sensory impairment and muscle weakness).
Onset: late childhood to adolescence
Inheritance pattern: maternal
Features: the most prominent symptoms of MERRF are myoclonus (muscle jerks), seizures, ataxia, and muscle weakness. The disease also can cause hearing impairment and short stature.
Onset: infancy to adulthood
Inheritance pattern: maternal
Features: NARP is caused by an mtDNA mutation that is also linked to MILS, and the two syndromes can occur in the same family. In addition to the core symptoms for which it is named, NARP can involve developmental delay, seizures, and dementia. (Retinitis pigmentosa refers to a degeneration of the retina in the eye, with resulting loss of vision).
Onset: infancy
Inheritance pattern: autosomal (often sporadic)
Features: this syndrome involves severe anemia and malfunction of the pancreas. Children who have the disease usually go on to develop Kearns-Sayre syndrome.
Onset: infancy to adulthood
Inheritance pattern: most commonly autosomal recessive
Gene: POLG1, POLG2
Description: More than 300 POLG mutations have been associated with a number of diseases and syndromes, including mitochondrial disease.
POLG mutations can be divided into two broad groups: multiple mtDNA deletions and mtDNA depletion.
POLG mutations inhibit the body’s ability to process energy, in turn causing symptoms in multiple organ systems including high energy systems such as the central nervous system, muscles and liver. Symptoms can also vary from mild to severe and include muscle weakness, epilepsy, liver failure and ophthalmoplegia. Because PolG mutations cause such a wide range of symptoms and affects so many different organ systems, it is very difficult to diagnose and treat.
Learn More: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8796686/#:~:text=For%20example%2C%20homozygosity%20for%20the,ANS%20and%20SANDO67%2C68. AND https://polgfoundation.org/what-is-polg/#:~:text=Mutations%20in%20those%20genes%20impair,weakness%2C%20epilepsy%20and%20liver%20failure
Onset: typically appear in early infancy or early childhood, sometimes onset may present in adulthood
Inheritance pattern: autosomal recessive
Gene: SLC22A5
Description: Primary Carnitine Deficiency is a genetic condition that stops the body from using fats for energy or causes an accumulation of fats in the liver, muscle and heart. Severity can vary and present at different ages. Symptoms in infants may include poor feeding, tiredness, irritability and low blood sugar. These symptoms also present in childhood along with heart and muscle abnormalities. In adults, symptoms can be mild or asymptomatic. Other symptoms include brain functioning, seizures, confusion, muscle weakness and/or vomiting.
Learn More: https://rarediseases.org/?s=Carnitine+deficiency&rdb-search=true&post_type%5B%5D=rare-diseases&post_type%5B%5D=gard-rare-disease AND https://medlineplus.gov/genetics/condition/primary-carnitine-deficiency/#inheritance
Onset: adulthood
Inheritance pattern: autosomal recessive
Gene: POLG
Description: SANDO is a rare mitochondrial disorder with adult onset. Its most common features are sensory ataxia, neuropathy, hearing impairment, difficulty speaking (dysarthria), proximal muscle weakness, ragged-red muscle fibres, cognitive impairment, gastroparesis, ptosis, and weakness/paralysis of muscles in the eye (ophthalmoparesis).
Learn More: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298093/ AND https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=70595#:~:text=Sensory%20ataxic%20neuropathy%2Ddysarthria%2Dophthalmoparesis%20syndrome&text=A%20rare%20mitochondrial%20disease%20characterized,and%20hearing%20loss%2C%20among%20others
Onset: usually presented in Infancy or early childhood
Inheritance pattern: autosomal recessive
Gene: ACADS
Description: SCAD deficiency is a rare genetic fatty acid oxidation disorder (FAOD) that prevents the body from breaking down short-chain fatty acids into energy because of a deficiency in an enzyme called short-chain acyl-CoA dehydrogenase. When there aren’t enough enzymes present to break down the short-chain fatty acids, ammonia and fatty acids begin to accumulate in the body causing poor growth, neurodevelopmental delays, respiratory distress, seizures, lethargy or lack of energy.
Learn More: https://rarediseases.org/rare-diseases/short-chain-acyl-coa-dehydrogenase-deficiency-scad/
Onset: infancy or early childhood
Inheritance pattern: autosomal recessive
Gene: Short chain: ACADS gene. Medium chain: ACADM gene
Description: SCHAD is a fatty acid oxidation disorders, which affects the body’s ability to break down certain fats. Some initial signs for the deficiency are behavioural and sleep changes, irritability, poor appetite, fever, vomiting, low blood sugar, seizures, diarrhea and difficulties breathing. But most individuals with SCHAD never experience serious symptoms.
Onset: usually presented in infancy or early childhood
Inheritance pattern: autosomal recessive
Gene: HADH
Description: SCHAD deficiency occurs when the short chain 3-hydroxyacyl CoA dehydrogenase enzyme is either missing or not working properly. The symptoms of SCHADD are highly variable and may include behavioural and sleep changes, irritability, poor appetite, fever, vomiting, low blood sugar, seizures, diarrhea and difficulties breathing. Things that cause stress, such as lack of sleep, lack of food, illness, or infection are thought to trigger episodes of illness called metabolic crises in some children with SCHADD but not in others. Most individuals with SCHAD never experience serious symptoms.
Learn More: https://www.newbornscreening.info/schadd-short-chain-3-hydroxyacyl-coa-dehydrogenase-deficiency/#1
Onset: infancy or childhood
Inheritance pattern: autosomal recessive
Gene: TRNT1
Description: SIFD is characterized by the onset of severe sideroblastic anemia which presents in neonatal or infancy. Those affected by SIFD show delayed psychomotor development and neurodegeneration. Symptoms can include hearing loss, effects on the retina (retinitis pigmentosa), kidney issues (nephrocalcinosis) and heart disease (cardiomyopathy). Throughout infancy and childhood fevers are recurrent without infection.
Onset: infancy to adulthood
Inheritance pattern: autosomal recessive
Gene: ACADVL
Description: VLCAD occurs when the body is unable to breakdown very long-chain fatty acids into energy. Symptoms may include low blood sugar, low energy and muscle weakness as symptoms. When present in children more severe forms are at risk of liver abnormalities and acute heart problems.
Learn More: https://rarediseases.org/gard-rare-disease/vlcad-deficiency/
Onset: infancy to adulthood
Inheritance pattern: autosomal recessive
Gene: ACADVL
Description: VLCAD occurs when the body is unable to breakdown very long-chain fatty acids into energy. Symptoms may include low blood sugar, low energy and muscle weakness as symptoms. When present in children more severe forms are at risk of liver abnormalities and acute heart problems.
Learn More: https://rarediseases.org/gard-rare-disease/vlcad-deficiency/
