The signs/symptoms of this condition are consistent with the following:

- Intellectual disability,

- Muscular hypotonia

- Encephalitis

- Seizures

- Aphasia

2-hydroxyglutaric aciduria is an organic aciduria, and because of the stereoisomeric property of 2-hydroxyglutarate different variants of this disorder are distinguished:

Argininosuccinic aciduria, also called argininosuccinic acidemia, is an inherited disorder that causes the accumulation of argininosuccinic acid (also known as "ASA") in the blood and urine. Some patients may also have an elevation of ammonia, a toxic chemical, which can affect the nervous system. Argininosuccinic aciduria may become evident in the first few days of life because of high blood ammonia, or later in life presenting with "sparse" or "brittle" hair, developmental delay, and tremors.

An infant with argininosuccinic aciduria may seem lethargic or be unwilling to eat, have poorly controlled breathing rate or body temperature, experience seizures or unusual body movements, or go into a coma. Complications from argininosuccinic aciduria may include developmental delay and mental retardation. Progressive liver damage, skin lesions, and brittle hair may also be seen. Immediate treatment and lifelong management (following a strict diet and using appropriate supplements) may prevent many of these complications.

Occasionally, an individual may inherit a mild form of the disorder in which ammonia accumulates in the bloodstream only during periods of illness or other stress.

Depending on the affected gene(s), this disorder may present symptoms that range from mild to life-threatening.

- Stroke

- Progressive encephalopathy

- Seizure

- Kidney failure

- Vomiting

- Dehydration

- Failure to thrive and developmental delays

- Lethargy

- Repeated Yeast infections

- Acidosis

- Hepatomegaly

- Hypotonia

- Pancreatitis

- Respiratory distress

As with several other metabolic conditions, OTC deficiency can have variable presentations, regarding age of onset and the severity of symptoms. This compounded when considering heterozygous females and the possibility of non-random X-inactivation. In the classic and most well-known presentation, a male infant appears well initially, but by the second day of life they are irritable, lethargic and stop feeding. A metabolic encephalopathy develops, and this can progress to coma and death without treatment. Ammonia is only toxic to the brain, other tissues can handle elevated ammonia concentrations without problems.

Later onset forms of OTC deficiency can have variable presentations. Although late onset forms of the disease are often considered milder than the classic infantile presentation, any affected individual is at risk for an episode of hyperammonemia that could still be life-threatening, if presented with the appropriate stressors. These patients will often present with headaches, nausea, vomiting, delayed growth and a variety of psychiatric symptoms (confusion, delirium, aggression, or self-injury). A detailed dietary history of an affected individual with undiagnosed OTC deficiency will often reveal a history of protein avoidance.

The prognosis of a patient with severe OTC deficiency is well correlated with the length of the hyperammonemic period rather than the degree of hyperammonemia or the presence of other symptoms, such as seizures. Even for patients with late onset forms of the disease, their overall clinical picture is dependent on the extent of hyperammonemia they have experienced, even if it has remained unrecognized.

Affected individuals may have difficulty moving and may experience spasms, jerking, rigidity or decreased muscle tone and muscle weakness (which may be the result of secondary carnitine deficiency). Glutaric aciduria type 1, in many cases, can be defined as a cerebral palsy of genetic origins.

Babies with glutaric acidemia type 1 often are born with unusually large heads (macrocephaly). Macrocephaly is amongst the earliest signs of GA1. It is thus important to investigate all cases of macrocephaly of unknown origins for GCDH deficiency, given the importance of the early diagnosis of GA1.

Macrocephaly is a "pivotal clinical sign" of many neurological diseases. Physicians and parents should be aware of the benefits of investigating for an underlying neurological disorder, particularly a neurometabolic one, in children with head circumferences in the highest percentiles.

Methylmalonic acidemia (MMA), also called methylmalonic aciduria, is an autosomal recessive metabolic disorder. It is a classical type of organic acidemia. The result of this condition is the inability to properly digest specific fats and proteins, which in turn leads to a buildup of a toxic level of methylmalonic acid in the blood.

Methylmalonic acidemia stems from several genotypes, all forms of the disorder usually diagnosed in the early neonatal period, presenting progressive encephalopathy, and secondary hyperammonemia. The disorder can result in death if undiagnosed or left untreated. It is estimated that this disorder has a frequency of 1 in 48,000 births, though the high mortality rate in diagnosed cases make exact determination difficult. Methylmalonic acidemias are found with an equal frequency across ethnic boundaries.

A characteristic feature of isovaleric acidemia is a distinctive odor of sweaty feet. This odor is caused by the buildup of a compound called isovaleric acid in affected individuals.

In about half of cases, the signs and symptoms of this disorder become apparent within a few days after birth and include poor feeding, vomiting, seizures, and lack of energy that can progress to coma. These medical problems are typically severe and can be life-threatening. In the other half of cases, the signs and symptoms of the disorder appear during childhood and may come and go over time. They are often triggered by an infection or by eating an increased amount of protein-rich foods.

SBCADD is included as a secondary target condition in most newborn screening programs, as the key analyte is the same as is used to identify isovaleric acidemia. Most cases have been Hmong individuals, who are asymptomatic. There are isolated case reports where individuals have been identified with SBCADD in addition to developmental delay and epilepsy. It is currently unclear what the complete clinical presentation of SBCADD looks like. There is some concern that these cases with additional symptoms may reflect an ascertainment bias rather than being a true representation of the clinical spectrum of the disease. Currently, there is no accepted treatment, as most affected individuals do not require any. Some recommend avoidance of valproic acid, as it can be a substrate for 2-methylbutyryl-CoA dehydrogenase.

It typically presents as a severe encephalopathy with myoclonic seizures, is rapidly progressive and eventually results in respiratory arrest.Standard evaluation for inborn errors of metabolism and other causes of this presentation does not reveal any abnormality (no acidosis, no hypoglycaemia, or hyperammonaemia and no other organ affected). Pronounced and sustained hiccups in an encephalopathic infant have been described as a typical observation in non-ketotic hyperglycinaemia.

Propionic acidemia is characterized almost immediately in newborns. Symptoms include poor feeding, vomiting, dehydration, acidosis, low muscle tone (hypotonia), seizures, and lethargy. The effects of propionic acidemia quickly become life-threatening.

2-Methylbutyryl-CoA dehydrogenase deficiency, also called 2-Methylbutyryl glycinuria or short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD), is an autosomal recessive metabolic disorder. It causes the body to be unable to process the amino acid isoleucine properly. Initial case reports identified individuals with developmental delay and epilepsy, however most cases identified through newborn screening have been asymptomatic.

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.

Glycine encephalopathy (also known as non-ketotic hyperglycinemia or NKH) is a rare autosomal recessive disorder of glycine metabolism. After phenylketonuria, glycine encephalopathy is the second most common disorder of amino acid metabolism. The disease is caused by defects in the glycine cleavage system, an enzyme responsible for glycine catabolism. There are several forms of the disease, with varying severity of symptoms and time of onset. The symptoms are exclusively neurological in nature, and clinically this disorder is characterized by abnormally high levels of the amino acid glycine in bodily fluids and tissues, especially the cerebral spinal fluid.

Glycine encephalopathy is sometimes referred to as "nonketotic hyperglycinemia" (NKH), as a reference to the biochemical findings seen in patients with the disorder, and to distinguish it from the disorders that cause "ketotic hyperglycinemia" (seen in propionic acidemia and several other inherited metabolic disorders). To avoid confusion, the term "glycine encephalopathy" is often used, as this term more accurately describes the clinical symptoms of the disorder.

Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia.

Infants with this disease seem healthy at birth but quickly deteriorate, often with severe brain damage, which may be permanent. Death often occurs within the first five months in severe cases of the disease, when left untreated.

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.

The disease is named for the presence of sweet-smelling urine, an odor similar to that of maple syrup, when the person goes into metabolic crisis. The smell is also present and sometimes stronger in the ear wax of an affected individual at these times. In populations to whom maple syrup is unfamiliar, the aroma can be likened to fenugreek, and fenugreek ingestion may impart the aroma to urine.

It is difficult to determine the prevalence of hyperprolinemia type I, as many people with the condition are asymptomatic.

People with hyperprolinemia type I have proline levels in their blood between 3 and 10 times the normal level. Some individuals with type I exhibit seizures, intellectual disability, or other neurological problems.

Hyperprolinemia type II results in proline levels in the blood between 10 and 15 times higher than normal, and high levels of a related compound called pyrroline-5-carboxylate. This rare form of the disorder may appear benign at times, but often involves seizures, convulsions, and intellectual disability.

Hyperprolinemia can also occur with other conditions, such as malnutrition or liver disease. In particular, individuals with conditions that cause elevated levels of lactic acid in the blood, such as lactic acidemia, are likely to have elevated proline levels, because lactic acid inhibits the breakdown of proline.

People with methylmalonyl CoA mutase deficiency exhibit many symptoms similar to other diseases involving inborn errors of metabolism. Sometimes the symptoms appear shortly after birth, but other times the onset of symptoms is later.

Newborn babies experience with vomiting, acidosis, hyperammonemia, hepatomegaly (enlarged livers), hyperglycinemia (high glycine levels), and hypoglycemia (low blood sugar). Later, cases of thrombocytopenia and neutropenia can occur.

In some cases intellectual and developmental disabilities, such as autism, were noted with increased frequency in populations with methylmalonyl-CoA mutase deficiency.

Diagnostic methods

Diagnosis is based mainly on clinical findings and laboratory test results. Plasma concentrations of ammonia (>150 µmol/L) and citrulline (200-300 µmol/L) are elevated. Elevated levels of argininosuccinic acid (5-110 µmol/L) in the plasma or urine are diagnostic. Molecular genetic testing confirms diagnosis. Newborn screening for ASA is available in the U.S. and parts of Australia, and is considered in several European countries<

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.

Organic acidemias are usually diagnosed in infancy, characterized by urinary excretion of abnormal amounts or types of organic acids. The diagnosis is usually made by detecting an abnormal pattern of organic acids in a urine sample by gas chromatography-mass spectrometry. In some conditions, the urine is always abnormal, in others the characteristic substances are only present intermittently. Many of the organic acidemias are detectable by newborn screening with tandem mass spectrometry.

These disorders vary in their prognosis, from manageable to fatal, and usually affect more than one organ system, especially the central nervous system.

Neurological damage and developmental delay are common factors in diagnosis, with associated symptoms ranging from poor feeding to slow growth, lethargy, vomiting,

dehydration, malnutrition, hypoglycemia, hypotonia, metabolic acidosis, ketoacidosis, hyperammonemia, and if left untreated, death.