A 1999 retrospective study of 74 cases of neonatal onset found that 32 (43%) patients died during their first hyperammonemic episode. Of those who survived, less than 20% survived to age 14. Few of these patients received liver transplants.

That MMA can have disastrous effects on the nervous system has been long reported; however, the mechanism by which this occurs has never been determined. Published on June 15th 2015, research performed on the effects of methylmalonic acid on neurons isolated from fetal rats in an in vitro setting using a control group of neurons treated with an alternate acid of similar pH. These tests have suggested that methylmalonic acid causes decreases in cellular size and increase in the rate of cellular apoptosis in a concentration dependent manner with more extreme effects being seen at higher concentrations. Furthermore, micro-array analysis of these treated neurons have also suggested that on a epigenetic-level methylmalonic acid alters the transcription rate of 564 genes, notably including those involved in the apoptosis, p53, and MAPK signaling pathways.

This disorder, epidemiologically speaking, is thought to affect approximately 1 in 50,000 newborns according to Jethva, et al. While in the U.S. state of California there seems to be a ratio of 1 in 35,000.

Urocanic aciduria is thought to be relatively benign. Although aggressive behavior and mental retardation have been reported with the disorder, no definitive neurometabolic connection has yet been established.

Urocanic aciduria, also called urocanate hydratase deficiency or urocanase deficiency, is an autosomal recessive metabolic disorder caused by a deficiency of the enzyme urocanase. It is a secondary disorder of histidine metabolism.

The inherited forms of methylmalonic acidemia cause defects in the metabolic pathway where methylmalonyl-coenzyme A (CoA) is converted into succinyl-CoA by the enzyme methylmalonyl-CoA mutase.

Vitamin B is also needed for the conversion of methylmalonyl-CoA to Succinyl-CoA. Mutations leading to defects in vitamin B metabolism or in its transport frequently result in the development of methylmalonic acidemia.

This disorder has an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome, and two copies of the gene—one from each parent—must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder.

Propionic acidemia is inherited in an autosomal recessive pattern and is found in about 1 in 35,000 live births in the United States. The condition appears to be more common in Saudi Arabia, with a frequency of about 1 in 3,000. The condition also appears to be common in Amish, Mennonite and other populations where inbreeding is common.

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.

There is a deficiency of malate in patients because fumarase enzyme can't convert fumarate into it therefore treatment is with oral malic acid which will allow the krebs cycle to continue, and eventually make ATP.

Ornithine transcarbamylase deficiency also known as OTC deficiency is the most common urea cycle disorder in humans. Ornithine transcarbamylase, the defective enzyme in this disorder is the final enzyme in the proximal portion of the urea cycle, responsible for converting carbamoyl phosphate and ornithine into citrulline. OTC deficiency is inherited in an X-linked recessive manner, meaning males are more commonly affected than females.

In severely affected individuals, ammonia concentrations increase rapidly causing ataxia, lethargy and death without rapid intervention. OTC deficiency is diagnosed using a combination of clinical findings and biochemical testing, while confirmation is often done using molecular genetics techniques.

Once an individual has been diagnosed, the treatment goal is to avoid precipitating episodes that can cause an increased ammonia concentration. The most common treatment combines a low protein diet with nitrogen scavenging agents. Liver transplant is considered curative for this disease. Experimental trials of gene therapy using adenoviral vectors resulted in the death of one participant, Jesse Gelsinger, and have been discontinued.

Propionic acidemia, also known as propionic aciduria, propionyl-CoA carboxylase deficiency and ketotic glycinemia, is an autosomal recessive metabolic disorder, classified as a branched-chain organic acidemia.

The disorder presents in the early neonatal period with progressive encephalopathy. Death can occur quickly, due to secondary hyperammonemia, infection, cardiomyopathy, or basal ganglial stroke.

Propionic acidemia is a rare disorder that is inherited from both parents. Being autosomal recessive, neither parent shows symptoms, but both carry a defective gene responsible for this disease. It takes two faulty genes to cause PA, so there is a 1 in 4 chance for these parents to have a child with PA.

Short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD), also called ACADS deficiency and SCAD deficiency, is an autosomal recessive fatty acid oxidation disorder which affects enzymes required to break down a certain group of fats called short chain fatty acids.

Canine phosphofructokinase deficiency is found mostly in English Springer Spaniels and American Cocker Spaniels, but has also been reported in Whippets and Wachtelhunds. Mixed-breed dogs descended from any of these breeds are also at risk to inherit PFK deficiency.

Fumarase deficiency is caused by a mutation in the fumarate hydratase (FH) gene in humans, which encodes the enzyme that converts fumarate to malate in the mitochondria. Other mutant alleles of the FH gene, located on human Chromosome 1 at position 1q42.1, cause multiple cutaneous and uterine leiomyomata, hereditary leiomyomatosis and renal cell cancer. Fumarase deficiency is one of the few known deficiencies of the Krebs cycle or tricarboxylic acid cycle, the main enzymatic pathway of cellular aerobic respiration.

The condition is an autosomal recessive disorder, and it is therefore usually necessary for an affected individual to receive the mutant allele from both parents. A number of children diagnosed with the disorder have been born to parents who were first cousins. It can also be associated with uniparental isodisomy.

In order to get Tarui’s disease, both parents must be carriers of the genetic defect so that the child is born with the full form of the recessive trait. The best indicator of risk is a family member with PFK deficiency.

Ethylmalonic encephalopathy (EE) is a rare autosomal recessive inborn error of metabolism. Patients affected with EE are typically identified shortly after birth, with symptoms including diarrhea, petechiae and seizures. The genetic defect in EE is thought to involve an impairment in the degradation of sulfide intermediates in the body. Hydrogen sulfide then builds up to toxic levels. EE was initially described in 1994. Most cases of EE have been described in individuals of Mediterranean or Arabic origin.

The prognosis is very poor. Two studies reported typical age of deaths in infancy or early childhood, with the first reporting a median age of death of 2.6 for boys and less than 1 month for girls.

Mutations in the "ETHE1" gene cause ethylmalonic encephalopathy. The "ETHE1" gene makes an enzyme that plays an important role in energy production. It is active in mitochondria, which are the energy-producing centers within cells. Little is known about its exact function, however.

Mutations in the "ETHE1" gene lead to the production of a defective version of the enzyme or prevents the enzyme from being made. A lack of the ETHE1 enzyme impairs the ability to make energy in mitochondria. Additionally, a loss of this enzyme allows potentially toxic compounds, including ethylmalonic acid and lactic acid, to build up in the body. Excess amounts of these compounds can be detected in urine. It remains unclear how a loss of the ETHE1 enzyme leads to progressive brain dysfunction and the other features of ethylmalonic encephalopathy.

Ethylmalonic encephalopathy is an autosomal recessive disorder, which means the defective gene is located on an autosome, and both parents must carry one copy of the defective gene in order to have a child born with the disorder. The parents of a child with an autosomal recessive disorder are usually not affected by the disorder.

The following list includes such examples:

- - hyperammonemia due to ornithine transcarbamylase deficiency

- - hyperinsulinism-hyperammonemia syndrome (glutamate dehydrogenase 1)

- - hyperornithinemia-hyperammonemia-homocitrullinuria

- - hyperammonemia due to N-acetylglutamate synthetase deficiency

- - hyperammonemia due to carbamoyl phosphate synthetase I deficiency (carbamoyl phosphate synthetase I)

- - hyperlysinuria with hyperammonemia (genetics unknown)

- Methylmalonic acidemia

- Isovaleric acidemia

- Propionic acidemia

- Carnitine palmitoyltransferase II deficiency

- Transient hyperammonemia of the newborn, specifically in the preterm

Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).

Hyperammonemia (or hyperammonaemia) is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.

Ammonia is a substance that contains nitrogen. It is a product of the catabolism of protein. It is converted to the less toxic substance urea prior to excretion in urine by the kidneys. The metabolic pathways that synthesize urea involve reactions that start in the mitochondria and then move into the cytosol. The process is known as the urea cycle, which comprises several enzymes acting in sequence.

One 10-year-old girl with Crigler–Najjar syndrome type I was successfully treated by liver cell transplantation.

The homozygous Gunn rat, which lacks the enzyme uridine diphosphate glucuronyltransferase (UDPGT), is an animal model for the study of Crigler–Najjar syndrome. Since only one enzyme is working improperly, gene therapy for Crigler-Najjar is a theoretical option which is being investigated.

It is caused due to deficient Glucuronidation of bilirubin, Glucuronidation increases the molecular weight of the drug which favours its excretion in bile.

Deficient Glucuronidation is caused by congenital deficiency of hepatic bilirubin glucuronosyltransferase(BGT)

Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is a rare autosomal recessive mitochondrial disease. It has been previously referred to as polyneuropathy, ophthalmoplegia, leukoencephalopathy, and POLIP syndrome. The disease presents in childhood, but often goes unnoticed for decades. Unlike typical mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations, MNGIE is caused by mutations in the TYMP gene, which encodes the enzyme thymidine phosphorylase. Mutations in this gene result in impaired mitochondrial function, leading to intestinal symptoms as well as neuro-ophthalmologic abnormalities. "A secondary form of MNGIE, called MNGIE without leukoencephalopathy, can be caused by mutations in the POLG gene".

A variety of mutations in the TYMP gene have been discovered that lead to the onset of mitochondrial neurogastrointestinal encephalopathy syndrome. The TYMP gene is a nuclear gene, however, mutations in the TYMP gene affect mitochrondrial DNA and function. Mutations in this gene result in a loss of thymidine phosphorylase activity. Thymidine phosphorylase is the enzymatic product of the TYMP gene and is responsible for breaking down thymidine nucleosides into thymine and 2-deoxyribose 1-phosphate. Without normal thymidine phosphorylase activity, thymidine nucleosides begin to build up in cells. High nucleoside levels are toxic to mitochondrial DNA and cause mutations that lead to dysfunction of the respiratory chain, and thus, inadequate energy production in the cells. These mitochondrial effects are responsible for the symptomatology associated with the disease.