Direct treatment that stimulates the pyruvate dehydrogenase complex (PDC), provides alternative fuels, and prevents acute worsening of the syndrome. However, some correction of acidosis does not reverse all the symptoms. CNS damage is common and limits a full recovery. Ketogenic diets, with high fat and low carbohydrate intake have been used to control or minimize lactic acidosis and anecdotal evidence shows successful control of the disease, slowing progress and often showing rapid improvement. No study has yet been published demonstrating the effectiveness of the ketogenic diet for treatment of PDCD.

There is some evidence that dichloroacetate reduces the inhibitory phosphorylation of pyruvate dehydrogenase complex and thereby activates any residual functioning complex. Resolution of lactic acidosis is observed in patients with E1 alpha enzyme subunit mutations that reduce enzyme stability. However, treatment with dichloroacetate does not improve neurological damage. Oral citrate is often used to treat acidosis.

Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid and to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system. Pyruvate carboxylase deficiency is a rare condition, with an estimated incidence of 1 in 250,000 births worldwide. This disorder appears to be much more common in some Algonkian Indian tribes in eastern Canada.

Malonyl-CoA decarboxylase deficiency (MCD), or Malonic aciduria is an autosomal-recessive metabolic disorder caused by a genetic mutation that disrupts the activity of Malonyl-Coa decarboxylase. This enzyme breaks down Malonyl-CoA (a fatty acid precursor and a fatty acid oxidation blocker) into Acetyl-CoA and carbon dioxide.

2,4 Dienoyl-CoA reductase deficiency is an inborn error of metabolism resulting in defective fatty acid oxidation caused by a deficiency of the enzyme 2,4 Dienoyl-CoA reductase. Lysine degradation is also affected in this disorder leading to hyperlysinemia. The disorder is inherited in an autosomal recessive manner, meaning an individual must inherit mutations in "NADK2," located at 5p13.2 from both of their parents. NADK2 encodes the mitochondrial NAD kinase. A defect in this enzyme leads to deficient mitochondrial nicotinamide adenine dinucleotide phosphate levels. 2,4 Dienoyl-CoA reductase, but also lysine degradation are performed by NADP-dependent oxidoreductases explaining how NADK2 deficiency can lead to multiple enzyme defects.

2,4-Dienoyl-CoA reductase deficiency was initially described in 1990 based on a single case of a black female who presented with persistent hypotonia. Laboratory investigations revealed elevated lysine, low levels of carnitine and an abnormal acylcarnitine profile in urine and blood. The abnormal acylcarnitine species was eventually identified as 2-trans,4-cis-decadienoylcarnitine, an intermediate of linoleic acid metabolism. The index case died of respiratory failure at four months of age. Postmortem enzyme analysis on liver and muscle samples revealed decreased 2,4-dienoyl-CoA reductase activity when compared to normal controls. A second case with failure to thrive, developmental delay, lactic acidosis and severe encephalopathy was reported in 2014.

2,4-Dienoyl-CoA reductase deficiency was included as a secondary condition in the American College of Medical Genetics Recommended Uniform Panel for newborn screening. Its status as a secondary condition means there was not enough evidence of benefit to include it as a primary target, but it may be detected during the screening process or as part of a differential diagnosis when detecting conditions included as primary target. Despite its inclusion in newborn screening programs in several states for a number of years, no cases have been identified via neonatal screening.

Pyruvate dehydrogenase deficiency (also known as pyruvate dehydrogenase complex deficiency or PDCD) is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism. PDCD is an X-linked disease that shows heterogeneous characteristics in both clinical presentation and biochemical abnormality. The pyruvate dehydrogenase complex (PDC) is a multi-enzyme complex that plays a vital role as a key regulatory step in the central pathways of energy metabolism in the mitochondria.

A diet with carefully controlled levels of the amino acids leucine, isoleucine, and valine must be maintained at all times in order to prevent neurological damage. Since these three amino acids occur in all natural protein, and most natural foods contain some protein, any food intake must be closely monitored, and day-to-day protein intake calculated on a cumulative basis, to ensure individual tolerance levels are not exceeded at any time. As the MSUD diet is so protein-restricted, and adequate protein is a requirement for all humans, tailored metabolic formula containing all the other essential amino acids, as well as any vitamins, minerals, omega-3 fatty acids and trace elements (which may be lacking due to the limited range of permissible foods), are an essential aspect of MSUD management. These complement the MSUD patient's natural food intake to meet normal nutritional requirements without causing harm. If adequate calories cannot be obtained from natural food without exceeding protein tolerance, specialised low protein products such as starch-based baking mixtures, imitation rice and pasta may be prescribed, often alongside a protein-free carbohydrate powder added to food and/or drink, and increased at times of metabolic stress. Some patients with MSUD may also improve with administration of high doses of thiamine, a cofactor of the enzyme that causes the condition.

The major morbidity is a risk of fasting hypoglycemia, which can vary in severity and frequency. Major long-term concerns include growth delay, osteopenia, and neurologic damage resulting in developmental delay, intellectual deficits, and personality changes.

No sexual predilection is observed because the deficiency of glycogen synthetase activity is inherited as an autosomal recessive trait.

Glutathione synthetase deficiency is a rare autosomal recessive metabolic disorder that prevents the production of glutathione. Glutathione helps prevent damage to cells by neutralizing harmful molecules generated during energy production. Glutathione also plays a role in processing medications and cancer-causing compounds (carcinogens), and building DNA, proteins, and other important cellular components.

Keeping MSUD under control requires careful monitoring of blood chemistry, both at home and in a hospital setting. DNPH or specialised dipsticks may be used to test the patient's urine for ketones (a sign of metabolic decompensation), when metabolic stress is likely or suspected. Fingerstick tests are performed regularly and sent to a laboratory to determine blood levels of leucine, isoleucine, and valine. Regular metabolic consultations, including blood-draws for full nutritional analysis, are recommended; especially during puberty and periods of rapid growth. MSUD management also involves a specially tailored metabolic formula, a modified diet, and lifestyle precautions such as avoiding fatigue and infections, as well as consuming regular, sufficient calories in proportion to physical stress and exertion. Without sufficient calories, catabolism of muscle protein will result in metabolic crisis. Those with MSUD must be hospitalised for intravenous infusion of sugars and nasogastric drip-feeding of formula, in the event of metabolic decompensation, or anorexia, diarrhea or vomiting. Food avoidance, rejection of formula and picky eating are all common problems with MSUD. Some patients may need to receive all or part of their daily nutrition through a feeding tube.

Researchers have identified at least three types of pyruvate carboxylase deficiency, which are distinguished by the severity of their signs and symptoms.

The signs and symptoms of this disorder typically appear in early childhood. Almost all affected children have delayed development. Additional signs and symptoms can include weak muscle tone (hypotonia), seizures, diarrhea, vomiting, and low blood sugar (hypoglycemia). A heart condition called cardiomyopathy, which weakens and enlarges the heart muscle, is another common feature of malonyl-CoA decarboxylase deficiency.

Some common symptoms in Malonyl-CoA decarboxylase deficiency, such as cardiomyopathy and metabolic acidosis, are triggered by the high concentrations of Malonyl-CoA in the cytoplasm. High level of Malonyl-CoA will inhibits β-oxidation of fatty acids through deactivating the carrier of fatty acyl group, CPT1, and thus, blocking fatty acids from going into the mitochondrial matrix for oxidation.

A research conducted in Netherlands has suggested that carnitine supplements and a low fat diet may help to reduce the level of malonic acid in our body.

There is no proven treatment for congenital lactic acidosis. Treatments that are occasionally used or that are under investigation include the ketogenic diet and dichloroacetate. Other treatments aim to relieve symptoms – for example, anticonvulsants may be used to relieve seizures.

Multiple carboxylase deficiency is a form of metabolic disorder involving failures of carboxylation enzymes.

The deficiency can be in biotinidase or holocarboxylase synthetase.

These conditions respond to biotin.

Forms include:

- Holocarboxylase synthetase deficiency - neonatal;

- Biotinidase deficiency - late onset;

If left untreated, the symptoms can include feeding problems, decreased body tone, generalized red rash with skin exfoliation and baldness, failure to thrive, seizure, coma, developmental delay, foul smelling urine, lactic acidosis, and high levels of ketones and ammonia in the blood.

There are no treatments for MDDS, but some of the symptoms can be managed. For survivors living with MDDS, there are drugs to control epilepsy, and physical therapy can help with muscle control. Liver transplants may benefit people with liver involvement.

A 2005 study on rats suggested that hyperprolininemia causes cognitive dysfunction.

DGUOK, POLG, and MPV17 related forms result in defects to the liver. Liver dysfunction is progressive in the majority of individuals with both forms of DGUOK-related MDS and is the most common cause of death. For children with the multi-organ form, liver transplantation provides no survival benefit.

Liver disease typically progresses to liver failure in affected children with MPV17-related MDS and liver transplantation remains the only treatment option for liver failure. Approximately half of affected children reported did not undergo liver transplantation and died because of progressive liver failure – the majority during infancy or early childhood. A few children were reported to survive without liver transplantation.

Hyperprolinemia, also referred to as prolinemia or prolinuria, is a condition which occurs when the amino acid proline is not broken down properly by the enzymes proline oxidase or pyrroline-5-carboxylate dehydrogenase, causing a buildup of proline in the body.

Glutathione synthetase deficiency can be classified into three types: mild, moderate and severe.

- "Mild" glutathione synthetase deficiency usually results in the destruction of red blood cells (hemolytic anemia). Rarely, affected people also excrete large amounts of a compound called 5-oxoproline (also called pyroglutamic acid, or pyroglutamate) in their urine (5-oxoprolinuria). This compound builds up when glutathione is not processed correctly in cells.

- Individuals with "moderate" glutathione synthetase deficiency may experience symptoms beginning shortly after birth including hemolytic anemia, 5-oxoprolinuria, and elevated acidity in the blood and tissues (metabolic acidosis).

- In addition to the features present in moderate glutathione synthetase deficiency, individuals affected by the "severe" form of this disorder may experience neurological symptoms. These problems may include seizures; a generalized slowing down of physical reactions, movements, and speech (psychomotor retardation); intellectual disability; and a loss of coordination (ataxia). Some people with severe glutathione synthetase deficiency also develop recurrent bacterial infections.[citation missing]

Glutaric acidemia type 2 is an autosomal recessive metabolic disorder that is characterised by defects in the ability of the body to use proteins and fats for energy. Incompletely processed proteins and fats can build up, leading to a dangerous chemical imbalance called acidosis.

Glycogen storage disease type VI (GSD VI) is a type of glycogen storage disease caused by a deficiency in liver glycogen phosphorylase or other components of the associated phosphorylase cascade system. It is also known as "Hers' disease", after Henri G. Hers, who characterized it in 1959. The scope of GSD VI now also includes glycogen storage disease type VIII, IX (caused by phosphorylase b kinase deficiency) and X (deficiency protein kinase A).

The incidence of GSD VI is approximately 1 case per 65,000–85,000 births, representing approximately 30% all cases of glycogen storage disease. Approximately 75% of these GSD VI cases result from the X-linked recessive forms of phosphorylase kinase deficiency, all other forms are autosomal recessive.

Congenital lactic acidosis (CLA) is a rare disease caused by mutations in mitochondrial DNA (mtDNA) that affect the ability of cells to use energy and cause too much lactic acid to build up in the body, a condition called lactic acidosis.

Succinic acid has been used successfully to treat MELAS syndrome, and also Leighs disease. Patients are managed according to what areas of the body are affected at a particular time. Enzymes, amino acids, antioxidants and vitamins have been used.

Also the following supplements may help:

- CoQ10 has been helpful for some MELAS patients. Nicotinamide has been used because complex l accepts electrons from NADH and ultimately transfers electrons to CoQ10.

- Riboflavin has been reported to improve the function of a patient with complex l deficiency and the 3250T-C mutation.

- The administration of L-arginine during the acute and interictal periods may represent a potential new therapy for this syndrome to reduce brain damage due to impairment of vasodilation in intracerebral arteries due to nitric oxide depletion.

- There is also a case report where succinate was successfully used to treat uncontrolled convulsions in MELAS patients, although this treatment modality is yet to be thoroughly investigated or widely recommended.

Glutaric acidemia type 2 often appears in infancy as a sudden metabolic crisis, in which acidosis and low blood sugar (hypoglycemia) cause weakness, behavior changes, and vomiting. There may also be enlargement of the liver, heart failure, and a characteristic odor resembling that of sweaty feet. Some infants with glutaric acidemia type 2 have birth defects, including multiple fluid-filled growths in the kidneys (polycystic kidneys). Glutaric acidemia type 2 is a very rare disorder. Its precise incidence is unknown. It has been reported in several different ethnic groups.

Although research is ongoing, treatment options are currently limited; vitamins are frequently prescribed, though the evidence for their effectiveness is limited.

Pyruvate has been proposed in 2007 as a treatment option. N-acetyl cysteine reverses many models of mitochondrial dysfunction.. In the case of mood disorders, specifically bipolar disorder, it is hypothesized that N-acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q10 (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and melatonin could be potential treatment options.