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Types of Mitochondrial Diseases

Types of Mitochondrial Disease

Alpers Disease - a progressive, neurodevelopmental, mitochondrial DNA depletion syndrome that begins in early childhood and is characterized by three co-occurring clinical symptoms: psychomotor regression (dementia); seizures; and liver disease.  


Most individuals with Alpers' disease do not show symptoms at birth and develop normally for weeks to years before the onset of symptoms. Symptoms include increased muscle tone with exaggerated reflexes (spasticity), seizures, and loss of cognitive ability (dementia). About 80 percent of individuals with Alpers' disease develop symptoms in the first two years of life. The first symptoms of the disorder are usually nonspecific and may include hypoglycemia secondary to underlying liver disease, failure to thrive, infection-associated encephalopathy, spasticity, myoclonus (involuntary jerking of a muscle or group of muscles), seizures, or liver failure. An increased protein level is seen in cerebrospinal fluid analysis. Cortical blindness (loss of vision due to damage to the area of the cortex that controls vision) develops in about 25 percent of cases. Gastrointestinal dysfunction and cardiomyopathy may occur. Dementia is typically episodic and often associated with an infection that occurs while another disease is in process. Seizures may be difficult to control and unrelenting seizures can cause developmental regression as well. "Alpers-like" disorders without liver disease are genetically different and have a different clinical course.


The cause of this disease appears to be multifactorial, with genetics, metabolic factors, prion like molecules, and mitochondrial issues all playing a role in the expression of this disorder. This autosomal recessive disease is caused by mutations in the gene for the mitochondrial DNA polymerase POLG with the diagnosis established by testing for the POLG gene. The disease occurs in about one in 100,000 persons.


There is no cure for Alpers' disease and no way to slow its progression. Treatment is symptomatic and supportive. Anticonvulsants may be used to treat the seizures, but at times the seizures do not respond well to therapy, even at high doses. Therefore, the benefit of seizure control should be weighted against what could be excessive sedation from the anticonvulsant. Valproate should not be used since it can increase the risk of liver failure. Physical therapy may help to relieve spasticity and maintain or increase muscle tone.



Autosomal Dominant Optic Atrophy (ADOA)  is a neuro-ophthalmic condition which tends to begin in the first ten years of life and is characterized by degeneration of the optic nerves, causing  visual loss. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. About 20% of DOA patients present with additional multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts.

Barth Syndrome / LIC (Lethal Infantile Cardiomyopathy) is a serious X-linked genetic disorder, primarily affecting males and resulting in an inborn error of lipid or fat metabolism and multisystem symptoms. Diagnostic testing includes  DNA sequence analysis (genetic testing) of the tafazzin gene (TAZ, also called G4.5) and cardiolipin analysis of various cells and tissues, Though not always present, cardinal characteristics of this multi-system disorder often include combinations and varying degrees of: cardiomyopathy, neutropenia (Chronic, cyclic, or intermittent), underdeveloped skeletal musculature and muscle weakness, growth delay, exercise intolerance, cardiolipin abnormalities, and 3-methylglutaconic aciduria.  Significant clinical problems may include congestive heart failure, life-threatening bacterial infections, gross motor delay, risk of fatal arrhythmias, short stature through pre-teen years, followed by accelerated growth in mid- to late puberty, extreme fatigue, diarrhea and/or constipation. recurrent mouth ulcers, feeding problems (e.g., difficulty sucking, swallowing, or chewing; aversion to some food textures; selective or picky eating), risk of thrombosis, diminished capacity for exercise, hypoglycemia, including fasting hypoglycemia (especially in the newborn period), chronic headache, abdominal pain, and/or body aches (especially during puberty), osteoporosis, as well as some mild learning disabilities.

Treatment of Barth syndrome is generally symptomatic, requiring the coordinated efforts of a team of medical professionals which includes a pediatrician, pediatric cardiologist,  hematologist, specialist in the treatment of bacterial infections, physical therapist, occupational therapist, and/or other healthcare professionals. Many infants and children  require therapy with diuretic and digitalis medications to treat heart failure. Some affected children are gradually removed from such cardiac therapy during later childhood due to improvement of heart functioning. For affected individuals with confirmed neutropenia, complications due to bacterial infection are often preventable by ongoing monitoring and early therapy of suspected infections with antibiotics. Other treatment for this disorder is typically symptomatic and supportive.


Fatty Acid Oxidation Disorders / Beta-oxidation Defects / Fatty Acid Transport and Mitochondrial Oxidation Disorders

Beta-oxidation cycle disorders are among the fatty acid and glycerol metabolism disorders. Acetyl CoA is generated from fatty acids through repeated beta-oxidation cycles. Sets of 4 enzymes (an acyl dehydrogenase, a hydratase, a hydroxyacyl dehydrogenase, and a lyase) specific for different chain lengths (very long chain, long chain, medium chain, and short chain) are required to break down a long-chain fatty acid completely. Inheritance for all fatty acid oxidation defects is autosomal recessive. Fatty acid transport and mitochondrial oxidation disorders include many disorders. See also:

  • Systemic Primary Carnitine Deficiency  - presents with  high urinary carnitine excretion despite very low plasma carnitine, as well as an absence of significant dicarboxylic aciduria. Clinically, patients present with hypoketotic hypoglycemia, fasting intolerance with hypotonia, depressed CNS, apnea, seizures, dilated cardiomyopathy, and developmental delay. The treatment includes carnitine supplementation.

  • Long Chain Fatty Acid Transport Deficiency - presents with low to normal free carnitine. Clinically patients may experience episodic acute liver failure, hyperammonemia, and encephalopathy. Treatment includes liver transplantation.


  • Carnitine Palmitoyl Transferase I (CPT-I) Deficiency  - Patients present with normal to elevated total and free plasma carnitine with no dicarboxylic aciduria. Fasting intolerance, hypoketotic hypoglycemia, hepatomegaly, seizures, coma, and elevated creatine kinase may be noted. Treatment includes avoidance of fasting, frequent feeding, high-dose glucose during acute episodes and replacement of long-chain dietary fat with medium-chain fats.


  • Carnitine/Acylcarnitine Translocase Deficiency - Biochemically, patients presents with low total plasma carnitine, with most of the carnitine conjugated to long-chain fatty acids, and elevated C16 carnitine ester. In the neonatal form, patients may experience fasting intolerance with hypoglycemic coma, vomiting, weakness, cardiomyopathy, arrhythmia, mild hyperammonemia. In the mild form, recurrent hypoglycemia with no cardiac involvement may been seen. Treatment includes avoidance of fasting, frequent feeding, if plasma level is low, carnitine if plasma levels are low, and high-dose glucose during acute episodes.


  • Carnitine Palmitoyl Transferase II (CPT-II) Deficiency - Biochemically, elevated C16 carnitine ester is noted, yet in the classical muscle form, carnitine is usually normal. In the severe form, low total plasma carnitine is noted, with most conjugated to long-chain fatty acids. Clinical features in the classical muscle form include a presentation in adulthood with episodic myoglobinuria and weakness after prolonged exercise, fasting, intercurrent illness, or stress. In the severe form, presentation occurs in the neonatal period or infancy with hypoketotic hypoglycemia, cardiomyopathy, arrhythmia, hepatomegaly, coma, or seizures. Avoidance of fasting, frequent feeding, carnitine if plasma level is low, and during acute episodes, high-dose glucose are the current treatments.


  • Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency -  This deficiency is similar to LCHADD but is commonly associated with significant cardiomyopathy. The biochemical profile includes an elevated saturated and unsaturated C14–C18 acylcarnitine esters, and elevated urinary C6–C14 dicarboxylic acids.  Presentation varies by type of VLCAD. In the VLCAD-C type, arrhythmia, hypertrophic cardiomyopathy, and sudden death are noted, yet in the VLCAD-H type, recurrent hypoketotic hypoglycemia, encephalopathy, mild acidosis, mild hepatomegaly, hyperammonemia, and elevated liver enzymes are more common. Treatment for either type includes: avoidance of fasting, high-carbohydrate diet, carnitine, medium-chain triglycerides, and during acute episodes, high-dose glucose is needed.


  • Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency  - This deficiency is the second most common fatty acid oxidation defect. Elevated saturated and unsaturated C16–C18 acylcarnitine esters, and elevated urinary C6–C14 3-hydroxydicarboxylic acids are typical biochemical findings. Sharing many features of MCADD, LCHADD patients may also have cardiomyopathy, rhabdomyolysis, fasting-induced hypoketotic hypoglycemia, cholestatic liver disease, massive creatine kinase elevations, myoglobinuria with muscle exertion, peripheral neuropathy, retinopathy, and abnormal liver function. Mothers with an LCHADD fetus often have HELLP syndrome (hemolysis, elevated liver function tests, and low platelet count) during pregnancy. Diagnosis of LCHADD is based on the presence of excess long-chain hydroxy acids on organic acid analysis and on the presence of their carnitine conjugates in an acylcarnitine profile or glycine conjugates in an acylglycine profile. LCHADD can be confirmed by enzyme study in skin fibroblasts. Treatment during acute exacerbations includes hydration, high-dose glucose, bed rest, urine alkalinization, and carnitine supplementation. Long-term treatment includes a high-carbohydrate diet, medium-chain triglyceride supplementation, and avoidance of fasting and strenuous exercise.


  • Mitochondrial Trifunctional Protein (TFP) Deficiency - is similar to LCHAD deficiency with clinical features including liver failure, cardiomyopathy, fasting hypoglycemia, myopathy, and sudden death. Treatment is also similar to LCHAD deficiency.


  • Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency - This deficiency is the most common defect in the β-oxidation cycle and has been incorporated into expanded neonatal screening in many states. Biochemically,  elevated saturated and unsaturated C8–C10 acylcarnitine esters, elevated urinary C6–C10 dicarboxylic acids, suberylglycine, and hexanoylglycine, and low free carnitine may be noted. Clinical manifestations typically begin after 2 to 3 months of age and usually follow fasting (as little as 12 hours) and include episodic hypoketotic hypoglycemia after fasting, vomiting, hepatomegaly, lethargy, coma, acidosis, SIDS, and Reye-like syndrome. During attacks, patients have hypoglycemia, hyperammonemia, and unexpectedly low urinary and serum ketones. Metabolic acidosis is often present but may be a late manifestation. Diagnosis of MCADD is by detecting medium-chain fatty acid conjugates of carnitine in plasma or glycine in urine or by detecting enzyme deficiency in cultured fibroblasts; however, DNA testing can confirm most cases. Treatment of acute attacks is with 10% dextrose IV at 1.5 times the fluid maintenance rate; some clinicians also advocate carnitine supplementation during acute episodes. Prevention is a low-fat, high-carbohydrate diet and avoidance of prolonged fasting. Cornstarch therapy is often used to provide a margin of safety during overnight fasting.


  • Short-Chain Acyl-CoA Dehydrogenase (SCAD) Deficiency - In the neonatal form, intermittent ethylmalonic aciduria is noted with neonatal acidosis, vomiting, and growth and developmental delay. In the chronic form, low muscle carnitine is present with progressive myopathy. Treatment for SCAD deficiency includes an avoidance of fasting.


  • Glutaric Aciduria Type II - is caused by a defect in the transfer of electrons from the coenzyme of fatty acyl dehydrogenases to the electronic transport chain affects reactions involving fatty acids of all chain lengths (multiple acyl-coA dehydrogenase deficiency). Oxidation of several amino acids is also affected. Biochemical presentation includes elevated urinary ethylmalonic, glutaric, 2-hydroxyglutaric, 3-hydroxyisovaleric, and C6–C10 dicarboxylic acids and isovalerylglycine, elevated glutarylcarnitine, isovalerylcarnitine, and straight-chain acylcarnitine esters of C4, C8, C10, C10:1, and C12 fatty acids, low serum carnitine, and increased serum sarcosine. Clinical manifestations thus include fasting hypoglycemia, severe metabolic acidosis, hyperammonemia, sudden death, CNS anomalies, myopathy, and possible liver and cardiac involvement. Diagnosis of glutaric acidemia type II is confirmed by increased ethylmalonic, glutaric, 2- and 3-hydroxyglutaric, and other dicarboxylic acids in organic acid analysis, and glutaryl and isovaleryl and other acylcarnitines in tandem mass spectrometry studies. Enzyme deficiencies in skin fibroblasts can be confirmatory. Treatment of glutaric acidemia type II is similar to that for MCADD, except that riboflavin may be effective in some patients. Treatment for this disorder includes avoidance of fasting, frequent feeding, carnitine, riboflavin, and, during acute episodes, high-dose glucose


  • Short-Chain 3-Hydroxyacyl-CoA Dehydrogenase (SCHAD) Deficiency - Ketotic C8–C14 3-hydroxydicarboxylic aciduria is noted which corresponds with the following clinical features: recurrent myoglobinuria, ketonuria, hypoglycemia, encephalopathy, and cardiomyopathy. Avoidance of fasting is noted to be the current treatment.


  • Short/Medium-Chain 3-Hydroxyacyl-CoA Dehydrogenase (S/MCHAD) - Biochemical presentation includes a marked elevation of MCHADs and acylcarnitines. Liver failure and encephalopathy are common clinical features and avoidance of fasting is key to treatment.


  • Medium-Chain 3-Ketoacyl-CoA Thiolase (MCKAT) Deficiency  - Biochemical presentation includes lactic aciduria, ketosis, and elevated urinary C4–C12 dicarboxylic aciduria (especially C10 and C12). Clinically, fasting intolerance, vomiting, dehydration, metabolic acidosis, liver dysfunction, and rhabdomyolysis are noted and avoidance of fasting is key to treatment.


  • 2,4-Dienoyl-CoA Reductase Deficiency - Hyperlysinemia, low plasma carnitine, and 2-trans,4-cis decadienoylcarnitine in plasma and urine are noted biochemically. Clinical features include neonatal hypotonia, and respiratory acidosis. Treatment has not yet been established.

Carnitine Deficiency - certain fats cannot be utilized for energy, particularly during periods of fasting. Carnitine, a natural substance acquired mostly through the diet, is used by cells to process fats and produce energy. Clinical symptoms typically appear during infancy or early childhood and can include severe brain dysfunction (encephalopathy), a weakened and enlarged heart (cardiomyopathy), confusion, vomiting, muscle weakness, and low blood sugar (hypoglycemia). The severity of this condition varies among affected individuals. Individuals with this disorder are at risk for heart failure, liver problems, coma, and sudden death. Treatment includes avoidance of fasting and carnitine supplementation.


Creatine Deficiency Syndromes - are inborn errors of creatine metabolism and include the two creatine biosynthesis disorders, guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency, and the creatine transporter (CRTR) deficiency. Intellectual disability and seizures are common to all three CDS. The majority of individuals with GAMT deficiency have a behavior disorder that can include autistic behaviors and self-mutilation; about 40% have movement disorder. Onset is between ages three months and three years. Clinically, symptoms in affected males with CRTR deficiency ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, movement disorder and behavior disorder; age at diagnosis ranges from two to 66 years. Clinical symptoms of females for CRTR deficiency ranges from asymptomatic to severe phenotype resembling male phenotype.  Diagnostic testing includes molecular gene testing for GAMT, GATM, and SLC6A8 and cerebral creatine deficiency in brain MR spectroscopy (1H-MRS). Early treatment at the asymptomatic stage of the disease in individuals with GAMT and AGAT deficiencies appears to be beneficial. In those treated with creatine monohydrate, routine measurement of renal function to detect possible creatine-associated nephropathy is warranted.


Co-Enzyme Q10 Deficiency - an autosomal recessive condition with a clinical spectrum that encompasses at least five major phenotypes: (1) encephalomyopathy characterized by the triad of recurrent myoglobinuria, brain involvement and ragged red fibers; (2) severe infantile multisystemic disease; (3) cerebellar ataxia; (4) Leigh syndrome with growth retardation, ataxia and deafness; and (5) isolated myopathy. The variability of phenotypes suggests genetic heterogeneity, which may be related to the multiple steps in CoQ10 biosynthesis. Clinical presentation includes generalized weakness, exercise intolerance, and recurrent myoglobinuria, proximal muscle weakness, seizures, cognitive impairment, cerebellar symptoms, infantile encephalopathy with renal involvement, retinitis pigmentosa, optic nerve atrophy, bilateral sensorineuronal deafness, nephrotic syndrome, progressive ataxia, cardiomyopathy, hypothermia, lactic acidosis, cerebral and cerebellar atrophy, and developmental delay were associated with renal tubulopathy and ventricular hypertrophy. The clinical presentation of the variant isolated myopathy, recently described in four patients, is subacute onset of exercise intolerance and proximal limb weakness at variable ages. Treatment includes high dose oral CoQ10 supplementation.

Complex I, II, III, IV, V Deficiency

Chronic Progressive External Ophthalmoplegia (CPEO) - is a condition characterized by a loss of the muscle functions involved in eye and eyelid movement. Signs and symptoms tend to begin between the ages of 18 and 40 and commonly include weakness or paralysis of the muscles that move the eye (ophthalmoplegia) and drooping of the eyelids (ptosis).


Sometimes, CPEO may be associated with other signs and symptoms. Some affected individuals also have general weakness of the skeletal muscles (myopathy), which may be especially noticeable during exercise. Muscle weakness may also cause difficulty swallowing. In these cases, the condition is referred to as "progressive external ophthalmoplegia plus" (PEO+). Additional signs and symptoms can include hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss), weakness and loss of sensation in the limbs due to nerve damage (neuropathy), impaired muscle coordination (ataxia), a pattern of movement abnormalities known as parkinsonism, or depression.


CPEO can be caused by mutations in any of several genes, which may be located in mitochondrial DNA or nuclear DNA. It has different inheritance patterns depending on the gene involved in the affected individual.  


Treatment of ptosis includes surgical correction, or using glasses that have a “ptosis crutch” to lift the upper eyelids. Strabismus surgery can be helpful in carefully selected patients if diplopia (double vision) occurs. Some individuals with a deficiency of coenzyme Q10 have CPEO as an associated abnormality. Coenzyme Q10 is important for normal mitochondrial function. In individuals with this deficiency, supplemental coenzyme Q10 has been found to improve general neurologic function and exercise tolerance. However, coenzyme Q10 has not been shown to improve the ophthalmoplegia or ptosis in people who have isolated CPEO.



Friedreich’s Ataxia -


Kearns-Sayre syndrome (KSS) - has hallmark symptoms in the eyes and throughout the body typically beginning before age 20 and correlates with specific nuclear DNA mutations that cause problems with many of the organs and tissues in the body. Eye symptoms include progressive external ophthalmoplegia, (weakness or paralysis of the eye muscles that impairs eye movement, causing drooping eyelids (ptosis)), and pigmentary retinopathy, (degeneration of the light-sensing tissue in the retina that gives it a speckled and streaked appearance). The retinopathy may cause loss of vision. Systemically, at least one of the following signs or symptoms is noted: abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects), problems with coordination and balance that cause unsteadiness while walking (ataxia), or abnormally high levels of protein in the cerebrospinal fluid. Other symptoms include muscle weakness in their limbs, deafness, kidney problems, or a deterioration of cognitive functions (dementia). Affected individuals often have short stature. In addition, diabetes mellitus is occasionally seen in people with Kearns-Sayre syndrome. Ragged Red fibers can be seen in the muscle cells indicating an excess of mitochondria. A related condition called ophthalmoplegia-plus may be diagnosed if an individual has many of the signs and symptoms of Kearns-Sayre syndrome but not all the criteria are met.  


Currently, no effective way to treat mitochondrial abnormalities in KSS exists. Treatment is generally symptomatic and supportive, utilizing multiple specialties to support the organs involved, including regular and long-term follow-up with cardiologists. Other consultations may include audiology, ophthalmology, endocrinology, neurology, and neuropsychiatry. Management options include placement of cardiac pacemakers in individuals with cardiac conduction blocks, eyelid slings for severe ptosis, cochlear implants and hearing aids for neurosensory hearing loss, hormone replacement for endocrinopathies, dilation of the upper esophageal sphincter to alleviate achalasia, folinic acid supplementation in individuals with low cerebral spinal fluid folic acid, administration of coenzyme Q10 and L-carnitine, physical and occupational therapy, and treatment of depression. Surveillance includes EKG and echocardiogram every six to 12 months and yearly audiometry and endocrinologic evaluation.


Lactic Acidosis - occurs when lactate and other molecules, called protons, accumulate in bodily tissues and fluids faster than the body can remove them. Lactic acidosis can have many different causes and is often present in severely ill patients hospitalized in intensive care units. Congenital (present at birth) lactic acidosis is a rare form of lactic acidosis and is typically due to a genetic defect in an enzyme in the mitochondria responsible for helping the body convert carbohydrates and fats into energy. These defects are either inherited from one or both parents or arise spontaneously in the developing embryo. The enzyme deficiencies that give rise to congenital lactic acidosis can potentially affect many different organ systems of the body and, therefore, lead to a wide variety of symptoms and signs. Whereas some individuals may have persistently elevated levels of lactic acid in blood, cerebrospinal fluid and urine, other persons may have only occasional increases in lactic acid that are brought on by another illness, such as an infection, a seizure or an asthmatic attack. In some cases (especially those with a severe enzyme defect), symptoms of congenital lactic acidosis develop within the first hours or days of life and may include loss of muscle tone (hypotonia), lethargy, vomiting and abnormally rapid breathing (tachypnea). Eventually, the condition may progress to cause developmental delay, mental retardation, motor abnormalities, behavioral issues, abnormalities of the face and head and, ultimately, multi-organ failure. In some individuals in whom the disease is due to a mutation in mitochondrial DNA, the complications of congenital lactic acidosis may not appear until adolescence or adulthood. Pyruvate dehydrogenase complex (PDC) deficiency is generally considered to be the most common cause of biochemically proven cases of congenital lactic acidosis.

Although genetic mitochondrial diseases are the most common causes of congenital lactic acidosis, additional conditions that are present at birth can result in the disorder, including biotin deficiency, bacterial infection in the bloodstream or body tissues (sepsis), certain types of glycogen storage disease, Reye syndrome, short-bowel syndrome, liver failure, a defect in the heart or blood vessels that leads to a deficiency in the amount of oxygen reaching the body’s tissues (hypoxia) and bacterial meningitis (which causes elevated lactic acid in cerebrospinal fluid).

Treatment is generally symptomatic and individualized. Vitamins and certain co-factors (for example, carnitine and coenzyme Q) are frequently administered to patients with congenital lactic acidosis, but there is no proof that such agents are effective, except in extremely rare cases of PDC deficiency that respond to high doses of thiamine. For many years so-called “ketogenic” diets that are very high in fat and very low in carbohydrate have been used in patients with PDC deficiency, with beneficial effects reported in the scientific literature. Dichloroacetate (DCA) has been investigated as a potential therapy for individuals with congenital lactic acidosis. Various studies have shown the drug to be well-tolerated in children and to lead to a reduction in lactic acid levels in many patients with various causes of congenital lactic acidosis. However, the clinical benefit of chronic DCA treatment for any type of congenital lactic acidosis has not yet been demonstrated by controlled clinical trials. In addition, the drug has been shown to worsen or to cause reversible peripheral nerve damage in some individuals with congenital lactic acidosis, especially in older adolescents and adults. Recent studies, however, indicate that this potential side effect may be mitigated or prevented by careful dosing, based on a person’s particular genotype.



Leighs Disease is a severe neurological disorder that usually becomes apparent in the first year of life. This condition is characterized by progressive loss of mental and movement abilities (psychomotor regression) and may result in death during childhood, usually due to respiratory failure. A small number of individuals do not develop symptoms until adulthood or have symptoms that worsen more slowly. The first signs of Leigh syndrome seen in infancy are usually vomiting, diarrhea, and difficulty swallowing (dysphagia), which disrupts eating. These problems often result in an inability to grow and gain weight at the expected rate (failure to thrive). Severe muscle and movement problems are common in Leigh syndrome. Affected individuals may develop weak muscle tone (hypotonia), involuntary muscle contractions (dystonia), and problems with movement and balance (ataxia). Loss of sensation and weakness in the limbs (peripheral neuropathy), common in people with Leigh syndrome, may also make movement difficult. Several other features may occur in people with Leigh syndrome, including:

  • weakness or paralysis of the muscles that move the eyes (ophthalmoparesis)

  • rapid, involuntary eye movements (nystagmus)

  • degeneration of the nerves that carry information from the eyes to the brain (optic atrophy)

  • severe breathing problems

  • hypertrophic cardiomyopathy, which is a thickening of the heart muscle that forces the heart to work harder to pump blood.

  • Elevated lactate levels in blood, urine and cerobrospinal fluid


The signs and symptoms of Leigh Syndrome are caused in part by patches of damaged tissue (lesions) that develop in the brains of people with this condition as seen on MRI. The brain lesions are often accompanied by loss of the myelin coating around nerves (demyelination), which reduces the ability of the nerves to activate muscles used for movement or relay sensory information from the rest of the body back to the brain.

There are no proven therapies for Leigh Syndrome, therefore, treatment recommendations are directed toward the specific symptoms in each individual. Treatment may require the coordinated efforts of a team of specialists. The most common treatment for Leigh syndrome is the administration of thiamine (Vitamin B1) or thiamine derivatives. Some people with this disorder may experience a temporary symptomatic improvement and a slight slowing of the progression of the disease. In those patients with Leigh syndrome who also have a deficiency of pyruvate dehydrogenase enzyme complex, a high fat, low carbohydrate diet may be recommended. Genetic counseling is recommended for families of affected individuals with this disorder. Other treatment is symptomatic and supportive.


LBSL - Leukodystrohpy



Leigh Disease or Syndrome

LHON -is an inherited form of vision loss, resulting insudden painless loss of central vision due to optic nerve atrophy, typically occurring in young adults. Although this condition usually begins in a person's teens or twenties, rare cases may appear in early childhood or later in adulthood. For unknown reasons, males are affected much more often than females. Blurring and clouding of vision are usually the first symptoms of LHON. These vision problems may begin in one eye or simultaneously in both eyes; if vision loss starts in one eye, the other eye is usually affected within several weeks or months. Over time, vision in both eyes worsens with a severe loss of sharpness (visual acuity) and color vision. This condition mainly affects central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. Vision loss results from the death of cells in the nerve that relays visual information from the eyes to the brain (the optic nerve). Although central vision gradually improves in a small percentage of cases, in most cases the vision loss is profound and permanent. Some LHON patients (LHON Plus) also experience neurological symptoms such as tremor, neuropathy, myopathy, and movement disorders.


Genetic testing for LHON requires a simple blood draw. LHON is rare and follows a maternal inheritance pattern, meaning that the mutation is passed down via mitochondrial mitochondria  by the mother only. Mutations in the MT-ND1, MT-ND4, MT-ND4L, or MT-ND6 gene can cause LHON. These genes are found in the DNA of cellular structures called mitochondria, which convert the energy from food into a form that cells can use. A significant percentage of people with a mutation that causes LHON do not develop any features of the disorder. Specifically, more than 50 percent of males with a mutation and more than 85 percent of females with a mutation never experience vision loss or related health problems. Additional factors may determine whether a person develops the signs and symptoms of this disorder. Environmental factors such as smoking and alcohol use may be involved, although studies have produced conflicting results. Researchers are also investigating whether changes in additional genes contribute to the development of signs and symptoms. Genetic counseling is recommended.


Management of affected individuals is largely supportive, with the provision of visual aids, help with occupational rehabilitation, and registration with the relevant social services. ECG may reveal a pre-excitation syndrome in individuals harboring a mtDNA LHON-causing pathogenic variant; referral to cardiology can be considered and treatment for symptomatic individuals is the same as that in the general population. A multidisciplinary approach for those affected individuals with extraocular neurologic features (ataxia, peripheral neuropathy, nonspecific myopathy, and movement disorders) should be considered to minimize the functional consequences of these complications.


Individuals harboring a mtDNA LHON-causing pathogenic variant should be strongly advised to moderate their alcohol intake and not to smoke. Avoiding exposure to other putative environmental triggers for visual loss, in particular industrial toxins and drugs with mitochondrial-toxic effects, also seems reasonable.

Luft Disease

MELAS - Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is  caused by abnormalities in mitochondrial DNA (mtDNA). More than 80% of MELAS cases have a common m.3243A>G mutation in the MTTL1 gene. Onset of MELAS can vary from age 4 to 40 but most of them show symptoms before 20.

MELAS causes recurrent stroke-like episodes in the brain, migraine-type headaches, vomiting and seizures, and can lead to permanent brain damage. Other common symptoms include PEO, general muscle weakness, exercise intolerance, hearing loss, diabetes and short stature. Failure of energy production due to faulty mitochondria and overproduction of ROS is a common feature of the disease.

In addition to energy failure and oxidative stress, there has been growing evidence that nitric oxide (NO) deficiency play a central role in the pathogenesis of the stroke-like episodes. Arginine is the substrate of nitric oxide synthase, which produces NO, therefore arginine is a promising treatment for MELAS patients (trial numbers NCT01603446, JMA-IIA00023, and JMA-IIA00025. Other studies in their preliminary stages have shown more potent effect of citrulline than L-arginine in stroke-like episodes in MELAS patients (NCT01339494). Some of the other molecules investigated in clinical trials for patients with MELAS include pyruvate (JMA-IIA00093), taurine (UMIN000011908), and supplemental medium chain triglycerides (NCT01252979); however, those results of trials are still pending.



Mitochondrial Cytopathy

Mitochondrial DNA Depletion

Mitochondrial Encephalopathy

Mitochondrial Myopathy - A mitochondrial disease causing significant muscular problems is referred to as mitochondrial myopathy, while a mitochondrial disease that causes significant neurological and muscular problems is termed as mitochondrial encephalomyopathy. Organs such as brain, skeletal muscles and cardiac muscles have very high energy requirements, so they are disproportionately affected by mitochondrial dysfunction. Recent studies have reported two mtDNA mutations in mitochondrial myopathy patients. Specific mutations in certain mitochondrial genes (MTTK gene, MIEF2 gene; separate studies) may lead to imbalanced mitochondrial dynamics and a combined respiratory chain enzyme defect in skeletal muscle, leading to mitochondrial myopathy.


Symptoms: Muscle weakness, muscle atrophy, and exhaustion caused by physical exertion (exercise intolerance) are some of the main symptoms of mitochondrial myopathy. Muscle weakness begins with eye muscles and eyelids progressing to ptosis, paralysis of eye movements, blindness (retinitis pigmentosa, optic atrophy), cataracts, cardiomyopathy; liver failure (uncommon except in babies with mtDNA depletion syndrome), fatty liver, Fanconi’s syndrome (loss of essential metabolites in urine), difficulty swallowing, vomiting, feeling of being full, chronic diarrhea, symptoms of intestinal obstruction; diabetes. In addition to these, patients with mitochondrial encephalomyopathy might experience seizures, spasms, developmental delays, deafness, dementia, stroke (often before age 40), visual system defects, poor balance, problems with peripheral nerves. Mitochondrial myopathies can be managed by approaches such as physical therapy, speech therapy or respiratory therapy. While these cannot reverse the disease course, they may significantly improve the patients’ mobility, functioning, and strength. Additionally, inclusion of dietary supplements has also shown to help in certain cases. These supplements aim at bypassing the defective mitochondria and are based on three natural substances involved in ATP production in our cells- creatine, L- carnitine and coQ10.


Scarpelli et al. (2018) Bartsakoulia et al. (2018) Ahuja, A (2018)


Multiple Mitochondrial Dysfunction Syndrome - Children suffering from the neurodevelopmental disorder are affected with early onset of neurological deterioration, seizures, extensive white matter abnormalities, cortical migrational abnormalities, lactic acidosis and early demise. Journal of Human Genetics, (March 2017) doi:10.1038/jhg.2017.35




Pearson Syndrome

Primary Mitochondrial Myopathy - Primary mitochondrial myopathies (PMM) are a group of disorders that are associated with changes in genetic material (e.g. depletions, deletions, or mutations) found within the DNA of mitochondria (mtDNA) or with genes outside the mitochondria (nuclear DNA), affecting predominantly the skeletal muscle. Mitochondria, found by the hundreds within every cell of the body, regulate the production of cellular energy and carry the genetic blueprints for this process within their own unique DNA (mtDNA). These disorders often hamper the ability of affected cells to break down food and oxygen and produce energy. Mitochondria provide more than 90% of the energy used by the body’s tissues; mitochondrial disorders are characterized by a lack of sufficient energy for cells of the body to function properly. High-energy tissues like muscle, brain, or heart tissue are most likely to be affected by mitochondrial disorders. In most mitochondrial disorders, abnormally high numbers of defective mitochondria are present in the cells of the body. Mitochondrial diseases often affect more than one organ system of the body. Most mitochondrial diseases affect the muscles (myopathy). Sometimes, muscle disease is the only or predominant sign of a mitochondrial disorder, thus defined as PMM. There are no disease-modifying treatments for PMM; treatment is aimed to improving or resolving specific symptoms.  (Content provided by NORD) 

Pyruvate Carboxylase Deficiency

Pyruvate Dehydrogenase Deficiency (PDCD/PDH)


POLG2 Mutations