Pyruvate dehydrogenase deficiency can be diagnosed via the following methods:

- Blood test (Lactate and pyruvate levels)

- Urine analysis

- Magnetic resonance spectroscopy

- MRI

The differential diagnosis of pyruvate dehydrogenase deficiency can consist of either D-Lactic acidosis or abnormalities associated with gluconeogenesis.

There are no methods for preventing the manifestation of the pathology of MSUD in infants with two defective copies of the BCKD gene. However, genetic counselors may consult with couples to screen for the disease via DNA testing. DNA testing is also available to identify the disease in an unborn child in the womb.

On 9 May 2014, the UK National Screening Committee (UK NSC) announced its recommendation to screen every newborn baby in the UK for four further genetic disorders as part of its NHS Newborn Blood Spot Screening programme, including maple syrup urine disease.

Newborn screening for maple syrup urine disease involves analyzing the blood of 1–2 day-old newborns through tandem mass spectrometry. The blood concentration of leucine and isoleucine is measured relative to other amino acids to determine if the newborn has a high level of branched-chain amino acids. Once the newborn is 2–3 days old the blood concentration of branched-chain amino acids like leucine is greater than 1000 µmol/L and alternative screening methods are used. Instead, the newborn’s urine is analyzed for levels of branched-chain alpha-hydroxyacids and alpha-ketoacids.

Liver biopsy for microscopic analysis and enzyme assay is required for definitive diagnosis. Diagnosis may include linkage analysis in families with affected members and sequencing of the entire coding region of the GSY2 gene for mutations.

Histologic analysis of liver tissue demonstrates moderately decreased amounts of periodic acid-Schiff (PAS)–positive, diastase-sensitive glycogen stores.

Evidence of increased fat accumulation in the liver may be observed, as in other glycogen-storage diseases.

Electron microscopic analysis of liver sections shows normal glycogen structure.

Muscle glycogen stores are normal.

Congenital lactic acidosis can be suspected based on blood or cerebrospinal fluid tests showing high levels of lactate; the underlying genetic mutation can only be diagnosed with genetic testing.

MDDS is diagnosed based on systemic symptoms presenting in infants, followed by a clinical examination and laboratory tests (for example, high lactate levels are common) medical imaging, and usually is finally confirmed and formally identified by genetic testing.

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 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.

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]

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.

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.

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.

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.

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.

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.

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

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.

Mitochondrial diseases are usually detected by analysing muscle samples, where the presence of these organelles is higher. The most common tests for the detection of these diseases are:

1. Southern blot to detect big deletions or duplications

2. PCR and specific mutation analysis

3. Sequencing

Other diseases can have a similar clinical presentation to Leigh syndrome; excluding other causes of similar clinical symptoms is often a first step to diagnosing Leigh disease. Conditions that can appear similar to Leigh disease include perinatal asphyxia, kernicterus, carbon monoxide poisoning, methanol toxicity, thiamine deficiency, Wilson's disease, biotin-responsive basal ganglia disease, and some forms of encephalitis. Perinatal asphyxia can cause bilateral ganglial lesions and damage to the thalamus, which are similar to the signs seen with Leigh syndrome. When hyperbilirubinemia is not treated with phototherapy, the bilirubin can accumulate in the basal ganglia and cause lesions similar to those seen in Leigh syndrome. This is not common since the advent of phototherapy.

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.

Different genetic causes and types of Leigh syndrome have different prognoses, though all are poor. The most severe forms of the disease, caused by a full deficiency in one of the affected proteins, cause death at a few years of age. If the deficiency is not complete, the prognosis is somewhat better and an affected child is expected to survive 6–7 years, and in rare cases, to their teenage years.

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.