PKU is commonly included in the newborn screening panel of many countries, with varied detection techniques. Most babies in developed countries are screened for PKU soon after birth. Screening for PKU is done with bacterial inhibition assay (Guthrie test), immunoassays using fluorometric or photometric detection, or amino acid measurement using tandem mass spectrometry (MS/MS). Measurements done using MS/MS determine the concentration of Phe and the ratio of Phe to tyrosine, the ratio will be elevated in PKU.

Dozens of congenital metabolic diseases are now detectable by newborn screening tests, especially the expanded testing using mass spectrometry. This is an increasingly common way for the diagnosis to be made and sometimes results in earlier treatment and a better outcome. There is a revolutionary Gas chromatography–mass spectrometry-based technology with an integrated analytics system, which has now made it possible to test a newborn for over 100 mm genetic metabolic disorders.

Because of the multiplicity of conditions, many different diagnostic tests are used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis.

Common screening tests used in the last sixty years:

- Ferric chloride test (turned colors in reaction to various abnormal metabolites in urine)

- Ninhydrin paper chromatography (detected abnormal amino acid patterns)

- Guthrie bacterial inhibition assay (detected a few amino acids in excessive amounts in blood) The dried blood spot can be used for multianalyte testing using Tandem Mass Spectrometry (MS/MS). This given an indication for a disorder. The same has to be further confirmed by enzyme assays, IEX-Ninhydrin, GC/MS or DNA Testing.

- Quantitative measurement of amino acids in plasma and urine

- IEX-Ninhydrin post column derivitization liquid ion-exchange chromatography (detected abnormal amino acid patterns and quantitative analysis)

- Urine organic acid analysis by gas chromatography–mass spectrometry

- Plasma acylcarnitines analysis by mass spectrometry

- Urine purines and pyrimidines analysis by gas chromatography-mass spectrometry

Specific diagnostic tests (or focused screening for a small set of disorders):

- Tissue biopsy or necropsy: liver, muscle, brain, bone marrow

- Skin biopsy and fibroblast cultivation for specific enzyme testing

- Specific DNA testing

A 2015 review reported that even with all these diagnostic tests, there are cases when "biochemical testing, gene sequencing, and enzymatic testing can neither confirm nor rule out an IEM, resulting in the need to rely on the patient's clinical course."

Diagnosis of Fatty-acid metabolism disorder requires extensive lab testing.

Normally, in cases of hypoglycaemia, triglycerides and fatty acids are metabolised to provide glucose/energy. However, in this process, ketones are also produced and ketotic hypoglycaemia is expected. However, in cases where fatty acid metabolism is impaired, a non-ketotic hypoglycaemia may be the result, due to a break in the metabolic pathways for fatty-acid metabolism.

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 isovaleric acidemia.

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.

The urine of newborns can be screened for isovaleric acidemia using mass spectrometry, allowing for early diagnosis. Elevations of isovalerylglycine in urine and of isovalerylcarnitine in plasma are found.

It is one of the 29 conditions currently recommended for newborn screening by the American College of Medical Genetics.

For women with phenylketonuria, it is important for the health of their children to maintain low Phe levels before and during pregnancy. Though the developing fetus may only be a carrier of the PKU gene, the intrauterine environment can have very high levels of phenylalanine, which can cross the placenta. The child may develop congenital heart disease, growth retardation, microcephaly and intellectual disability as a result. PKU-affected women themselves are not at risk of additional complications during pregnancy.

In most countries, women with PKU who wish to have children are advised to lower their blood Phe levels (typically to between 2 and 6 mg/dL) before they become pregnant, and carefully control their levels throughout the pregnancy. This is achieved by performing regular blood tests and adhering very strictly to a diet, in general monitored on a day-to-day basis by a specialist metabolic dietitian. In many cases, as the fetus' liver begins to develop and produce PAH normally, the mother's blood Phe levels will drop, requiring an increased intake to remain within the safe range of 2–6 mg/dL. The mother's daily Phe intake may double or even triple by the end of the pregnancy, as a result. When maternal blood Phe levels fall below 2 mg/dL, anecdotal reports indicate that the mothers may suffer adverse effects, including headaches, nausea, hair loss, and general malaise. When low phenylalanine levels are maintained for the duration of pregnancy, there are no elevated levels of risk of birth defects compared with a baby born to a non-PKU mother.

The term homocystinuria describes an increased excretion of the thiol amino acid homocysteine in urine (and incidentally, also an increased concentration in plasma). The source of this increase may be one of many metabolic factors, only one of which is CBS deficiency. Others include the re-methylation defects (cobalamin defects, methionine sythase deficiency, MTHFR) and vitamin deficiencies (cobalamin (vitamin B12) deficiency, folate (vitamin B9) deficiency, riboflavin deficiency (vitamin B2), pyridoxal phosphate deficiency (vitamin B6)). In light of this information, a combined approach to laboratory diagnosis is required to reach a differential diagnosis.

CBS deficiency may be diagnosed by routine metabolic biochemistry. In the first instance, plasma or urine amino acid analysis will frequently show an elevation of methionine and the presence of homocysteine. Many neonatal screening programs include methionine as a metabolite. The disorder may be distinguished from the re-methylation defects (e.g., MTHFR, methionine synthase deficiency and the cobalamin defects) in lieu of the elevated methionine concentration. Additionally, organic acid analysis or quantitative determination of methylmalonic acid should help to exclude cobalamin (vitamin B12) defects and vitamin B12 deficiency giving a differential diagnosis.

The laboratory analysis of homocysteine itself is complicated because most homocysteine (possibly above 85%) is bound to other thiol amino acids and proteins in the form of disulphides (e.g., cysteine in cystine-homocysteine, homocysteine in homocysteine-homocysteine) via disulfide bonds. Since as an equilibrium process the proportion of free homocystene is variable a true value of total homocysteine (free + bound) is useful for confirming diagnosis and particularly for monitoring of treatment efficacy. To this end it is prudent to perform total homocyst(e)ine analysis in which all disulphide bonds are subject to reduction prior to analysis, traditionally by HPLC after derivatisation with a fluorescent agent, thus giving a true reflection of the quantity of homocysteine in a plasma sample.

Infant mortality is high for patients diagnosed with early onset; mortality can occur within less than 2 months, while children diagnosed with late-onset syndrome seem to have higher rates of survival. Patients suffering from a complete lesion of mut0 have not only the poorest outcome of those suffering from methylaonyl-CoA mutase deficiency, but also of all individuals suffering from any form of methylmalonic acidemia.

Carnitor - an L-carnitine supplement that has shown to improve the body's metabolism in individuals with low L-carnitine levels. It is only useful for Specific fatty-acid metabolism disease.

Histidenemia is characterized by increased levels of histidine, histamine and imidazole in blood, urine and cerebrospinal fluid. This also results in decreased levels of the metabolite urocanic acid in blood, urine, and skin cells. In Japan, neonatal screening was previously performed on infants within 1 month of birth; infants demonstrating a blood histidine level of 6 mg/dl or more underwent careful testing as suspected histidinemia cases. A typical characteristic of histidinemia is an increase in the blood histidine levels from normal levels (70-120 μM) to an elevated level (290-1420 μM). Further testing includes: observing histidine as well as imidazolepyruvic acid metabolites in the urine. However, neonatal urine testing has been discontinued in most places, with the exception of Quebec.

Clinically, MCADD or another fatty acid oxidation disorder is suspected in individuals who present with lethargy, seizures, coma and hypoketotic hypoglycemia, particularly if triggered by a minor illness. MCADD can also present with acute liver disease and hepatomegaly, which can lead to a misdiagnosis of Reye syndrome. In some individuals, the only manifestation of MCADD is sudden, unexplained death often preceded by a minor illness that would not usually be fatal.

In areas with expanded newborn screening using tandem mass spectrometry (MS/MS), MCADD is usually detected shortly after birth, by the analysis of blood spots collected on filter paper. Acylcarnitine profiles with MS/MS will show a very characteristic pattern of elevated hexanoylcarnitine (C6), octanoylcarnitine (C8), decanoylcarnitine (C10) or decenoylcarnitine (C10:1), with C8 being greater than C6 and C10. Secondary carnitine deficiency is sometimes seen with MCADD, and in these cases, acylcarnitine profiles may not be informative. Urine organic acid analysis by gas chromatography-mass spectrometry (GC-MS) will show a pattern of dicarboxylic aciduria with low levels of ketones. Traces of acylglycine species may also be detected. Asymptomatic individuals may have normal biochemical lab results. For these individuals, targeted analysis of acylglycine species by GC-MS, specifically hexanoylglycine and suberylglycine can be diagnostic. After biochemical suspicion of MCADD, molecular genetic analysis of "ACADM" can be used to confirm the diagnosis. The analysis of MCAD activity in cultured fibroblasts can also be used for diagnosis.

In cases of sudden death where the preceding illness would not usually have been fatal, MCADD is often suspected. The autopsy will often show fatty deposits in the liver. In cases where MCADD is suspected, acylcarnitine analysis of bile and blood can be undertaken postmortem for diagnosis. Where samples are not available, residual blood from newborn screening may be helpful. Biochemical testing of asymptomatic siblings and parents may also be informative. MCADD and other fatty acid oxidation disorders have been recognized in recent years as undiagnosed causes of sudden infant death syndrome.

In the middle of the 20th century the principal treatment for some of the amino acid disorders was restriction of dietary protein and all other care was simply management of complications. In the past twenty years, enzyme replacement, gene therapy, and organ transplantation have become available and beneficial for many previously untreatable disorders. Some of the more common or promising therapies are listed:

One of, if not the most common form of organic acidemia, methylmalonic acidemia is not apparent at birth as symptoms usually do not present themselves until proteins are added to the infant's diet. Because of this, symptoms typically manifest anytime within the first year of life. Due to the severity and rapidity in which this disorder can cause complications when left undiagnosed, screening for methylmalonic acidemia is often included in the newborn screening exam.

Because of the inability to properly break down amino acids completely, the byproduct of protein digestion, the compound methylmalonic acid, is found in a disproportionate concentration in the blood and urine of those afflicted. These abnormal levels are used as the main diagnostic criteria for diagnosing the disorder. This disorder is typically determined through the use of a urine analysis or blood panel. The presence of methylmalonic acidemia can also be suspected through the use of a CT or MRI scan or ammonia test, however these tests are by no means specific and require clinical and metabolic/correlation. Elevated levels of ammonia, glycine, and ketone bodies may also be present in the blood and urine.

Treatment or management of organic acidemias vary; eg see methylmalonic acidemia, propionic acidemia, isovaleric acidemia, and maple syrup urine disease.

As of 1984 there were no effective treatments for all of the conditions, though treatment for some included a limited protein/high carbohydrate diet, intravenous fluids, amino acid substitution, vitamin supplementation, carnitine, induced anabolism, and in some cases, tube-feeding.

As of 1993 ketothiolase deficiency and other OAs were managed by trying to restore biochemical and physiologic homeostasis; common therapies included restricting diet to avoid the precursor amino acids and use of compounds to either dispose of toxic metabolites or increase enzyme activity.

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.

Methylmalonic acidemia has varying diagnoses, treatment requirements and prognoses, which are determined by the specific genetic mutation causing the inherited form of the disorder. The following are the known genotypes responsible for methylmalonic acidemia:

The mut type can further be divided in mut0 and mut- subtypes, with mut0 characterized by a complete lack of methylmalonyl CoA mutase and more severe symptoms and mut- characterized by a decreased amount of mutase activity.

Mut-, cblB, and cblA versions of methylmalonic acidemia have been found to be cobalamin responsive. Mut0 is a nonresponsive variant.

Symptoms can be reduced through avoidance of leucine, an amino acid. Leucine is a component of most protein-rich foods; therefore, a low-protein diet is recommended. Some isolated cases of this disorder have responded to supplemental biotin; this is not altogether surprising, consider that other biotin-related genetic disorders (such as biotinidase deficiency and holocarboxylase synthetase deficiency) can be treated solely with biotin. Individuals with these multiple carboxylase disorders have the same problem with leucine catabolism as those with 3-methylcrotonyl-CoA carboxylase deficiency.

A 1994 study of the entire population of New South Wales (Australia) found 20 patients. Of these, 5 (25%) had died at or before 30 months of age. Of the survivors, 1 (5%) was severely disabled and the remainder had either suffered mild disability or were making normal progress in school. A 2006 Dutch study followed 155 cases and found that 27 individuals (17%) had died at an early age. Of the survivors, 24 (19%) suffered from some degree of disability, of which most were mild. All the 18 patients diagnosed neonatally were alive at the time of the follow-up.

Several tests can be done to discover the dysfunction of methylmalonyl-CoA mutase. Ammonia test, blood count, CT scan, MRI scan, electrolyte levels, genetic testing, methylmalonic acid blood test, and blood plasma amino acid tests all can be conducted to determine deficiency.

There is no treatment for complete lesion of the mut0 gene, though several treatments can help those with slight genetic dysfunction. Liver and kidney transplants, and a low-protein diet all help regulate the effects of the diseases.

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

It has been suggested that a possible method of treatment for histidinemia is through the adoption of a diet that is low in histidine intake. However, the requirement for such dietary restrictions is typically unnecessary for 99% of all cases of histidinemia.

Upon clinical suspicion, diagnostic testing will often consist of measurement of amino acid concentrations in plasma, in search of a significantly elevated ornithine concentration. Measurement of urine amino acid concentrations is sometimes necessary, particularly in neonatal onset cases to identify the presence or absence of homocitrulline for ruling out ornithine translocase deficiency (hyperornithinemia, hyperammonemia, homocitrullinuria syndrome, HHH syndrome). Ornithine concentrations can be an unreliable indicator in the newborn period, thus newborn screening may not detect this condition, even if ornithine is included in the screening panel. Enzyme assays to measure the activity of ornithine aminotransferase can be performed from fibroblasts or lymphoblasts for confirmation or during the neonatal period when the results of biochemical testing is unclear. Molecular genetic testing is also an option.