Disorders of Amino Acid Metabolism

Amino acids are the building blocks of proteins, whose production is a tightly regulated enzymatic cascade. Disorders of the enzymes involved in amino acid metabolism are often serious and present early in life. Congenital errors in amino acid metabolism are due to either impaired synthesis or degradation. In the United States, neonates are routinely screened at birth for common disorders of amino acid metabolism, which include phenylketonuria (PKU), maple syrup urine disease (MSUD), homocystinuria, tyrosinemia, and alkaptonuria. Symptoms of these conditions often present early in life. Although treatment varies, most of these conditions require dietary changes, and some require protein supplementation or other medication regimens.

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Phenylketonuria (PKU) is an inherited disease that causes an increase in phenylalanine levels in the body due to the inability to metabolize this amino acid.


  • Mutations in the phenylalanine hydroxylase (PAH) gene, which encodes PAH, an enzyme that converts phenylalanine to tyrosine
  • A defect in PAH leads to accumulation of phenylalanine (in most cases tyrosine levels are normal or slightly low).
  • Elevated phenylalanine levels cause damage to white matter tracts and myelin (mechanism unknown), leading to neurological deficits.
Classic PKU Disorders of amino acid metabolism

Classic phenylketonuria (PKU) is caused by a mutation in the phenylalanine hydroxylase (PAH) gene

Image: “Errors of Metabolism” by Bradford Morris. License: CC BY-SA 4.0


  • Classical PKU: very little PAH gene activity and significant accumulation of phenylalanine
  • Mild PKU: less severe phenylalanine accumulation, some PAH gene activity present


  • Newborns do not present with symptoms; it takes time for phenylalanine to accumulate.
  • Neurologic:
    • Developmental delays
    • Intellectual disability
    • Seizures
    • Microcephaly
  • Behavioral and psychiatric:
    • Social issues
    • Behavioral and emotional problems
    • Mental health issues
    • Hyperactivity
  • Orthopedic: low bone density
  • Dermatologic
    • Skin rashes (eczema)
    • Fair skin (due to lack of melanin)
  • Other: a musty odor in breath or urine


  • PKU screening via heel prick within the 1st week of life
    • Measurement of amino acid levels showing high phenylalanine and low/normal tyrosine 
    • Positive results must be confirmed with follow-up testing.
  • Genetic testing
    • Carrier testing in parents for prenatal counseling
    • Prenatal testing
Phenylketonuria Testing

The blood of a 2-week-old infant is collected for a phenylketonuria (PKU) screening.

Image: “Phenylketonuria testing” by USAF Photographic Archives. License: Public Domain


This condition cannot be cured and must be managed with dietary modification and medication/supplementation.

  • Regular blood testing to evaluate the level of phenylalanine in the blood
  • Low-phenylalanine diet, eliminating foods such as soybean, chicken, shrimp, nuts, turkey, and legumes
  • Avoid aspartame-containing products, as these are converted to phenylalanine.
  • Protein supplementation formula:
    • Includes the amino acid tyrosine
    • Includes large neutral amino acids (e.g., valine)
  • For adults with poor control of their phenylalanine, the drug pegvaliase is available and acts as an enzyme that can metabolize phenylalanine.

Organic Acidemia


A group of genetic disorders of amino acid metabolism involving branched-chain amino acids such as leucine, isoleucine, and valine. These disorders are caused by disruption of metabolism of these amino acids, resulting in accumulation of toxic metabolites that often spill into urine. 

There are 4 main types of organic acidemia:

  • Maple syrup urine disease (MSUD)
  • Isovaleric acidemia
  • Methylmalonic acidemia
  • Propionic acidemia


  • MSUD: 
    • Caused by a deficiency in branched-chain alpha-keto acid dehydrogenase
  • Isovaleric acidemia: 
    • Autosomal recessive 
    • Caused by mutation to isovaleric acid-CoA dehydrogenase 
    • Prevents leucine breakdown
  • Methylmalonic acidemia
    • Deficiency in either methylmalonyl-CoA mutase, methylmalonyl-CoA epimerase, or an enzyme involved in adenosylcobalamin synthesis
    • Results in methylmalonic acid buildup 
  • Propionic acidemia
    • Caused by defective propionyl-CoA carboxylase
    • Leads to buildup of propionyl-CoA
pathophysiology of methylmalonic acidemia

The pathophysiology of methylmalonic acidemia is most often due to mutation at either methylmalonyl-CoA mutase or methylmalonyl-CoA epimerase.

Image: “Schematic of enzymatic pathways involved in organic acidemias” by Timwryan. License: CC0 1.0


  • MSUD
    • Symptoms present within the first 2 days of life.
    • Neurologic: 
      • Developmental delay
      • Poor feeding
      • Lethargy
      • Irritability
      • Hypertonia
      • Spasticity
      • Convulsions
      • Coma
    • Orthopedic: osteoporosis
    • GI: pancreatitis
    • GU: sweet-smelling urine
  • Isovaleric acidemia
    • Characterized by a distinct odor described as “sweaty feet”
    • GI: 
      • Nausea
      • Vomiting
    • Neurologic: 
      • Seizures
      • Apathy
      • Coma 
      • Hypotonia
  • Methylmalonic acidemia
    • Symptoms appear within the 1st year of life.
    • Neurologic: 
      • Encephalopathy
      • Seizure
      • Stroke
      • Failure to thrive
      • Hypotonia 
    • GU: kidney failure 
    • GI: 
      • Nausea
      • Vomiting 
    • Respiratory: respiratory distress
  • Propionic acidemia
    • Neurologic: 
      • Poor feeding
      • Hypotonia
      • Seizures
    • GI: 
      • Nausea
      • Vomiting
      • Dehydration
    • Genitourinary: CKD 
    • Cardiovascular: 
      • Cardiomyopathy (dilated and hypertrophic)
      • Conduction disorders


  • MSUD:
    • Newborn screening to measure the amount of branched-chain amino acids 
    • Urine organic acid levels to confirm
    • Genetic testing for further confirmation and prenatal counseling
  • Isovaleric acidemia:
    • Newborn urinary screening
    • Organic acid level measurements in older patients
    • Assay of isovaleryl-CoA dehydrogenase activity in cultured skin fibroblasts as confirmatory testing
  • Methylmalonic acidemia:
    • Newborn screening showing elevation of propionylcarnitine
    • Screening looks for a high level of methylmalonic acid: Urine organic acids, plasma amino acids, plasma acylcarnitine, and plasma total homocysteine should be obtained.
  • Propionic acidemia: diagnosed by detection of elevated levels of propionic acid metabolites (e.g., 3-hydroxypropionate) in urine and serum


  • MSUD:
    • Dietary modification
      • Protein-free diet 
      • Use of a diet that is low in the amino acids leucine, valine, and isoleucine, which aren’t broken down in patients
    • Acute metabolic decompensation: 
      • Glucose infusions are needed.
      • Insulin injections promoting anabolism
    • Surgical therapy: Liver transplantation is successful in classic MSUD with no neurologic symptoms.
  • Isovaleric acidemia:
    • Dietary changes to reduce the amount of leucine
    • Patients with acute manifestations of disease are given glycine or carnitine. 
  • Methylmalonic acidemia:
    • Low-protein diet 
    • Carnitine supplementation
    • Cyanocobalamin supplementation
    • In some severe cases, kidney or liver transplantation is considered.
  • Propionic acidemia:
    • Low-protein diet 
    • Protein supplementation with methionine, threonine, valine, isoleucine, and carnitine
    • Antibiotics for ⅓ of each month (removes flora that may increase protein levels)

Clinical Relevance

  • Homocystinuria: an inherited metabolic disorder of methionine due to a deficiency of cystathionine beta synthase or methionine synthase, which leads to a deficiency in vitamin B6, vitamin B12, or folate. Diagnosis is made by detecting elevated levels of methionine or homocysteine in the urine or blood. Patients are treated with vitamin B6, and some patients may change their diet to reduce the amount of sulfur they ingest. Patients who adhere to treatment do not have any reduction in life expectancy.
  • Tyrosinemia: a genetic disorder characterized by disruptions in breakdown of tyrosine. Buildup of tyrosine and its by-products in tissues and organs can lead to serious health problems. Patients may have liver or kidney dysfunction as a result of tyrosinemia. Patients are often diagnosed through a newborn screening test. Treatment is with a low-protein diet and supplemental protein formula. An inhibitor of 4-hydroxyphenylpyruvate dioxygenase, nitisinone, is often prescribed in addition to dietary changes and protein supplementation.
  • Alkaptonuria: an autosomal recessive condition due to a mutation in the HGD gene. Alkaptonuria leads to accumulation of homogentisic acid. Patients present with dark urine. Complications include osteoarthritis, nephrolithiasis, and valvular heart disease. Diagnosis is made via 24-hour urine collection. Patients are managed with vitamin C supplementation, dietary restriction of certain proteins, and nitisinone. Although alkaptonuria is a serious condition, patients do not die early due to this disease.


  1. Williams, RA, Mamotte, CD, & Burnett, JR. (2008). Phenylketonuria: An inborn error of phenylalanine metabolism. The Clinical Biochemist. Reviews, 29(1), 31–41.
  2. Blackburn, P.R, Gass, JM, Vairo, F, Farnham, KM, Atwal, HK, Macklin, S, Klee, EW, & Atwal, PS. (2017). Maple syrup urine disease: Mechanisms and management. The Application of Clinical Genetics, 10, 57–66.
  3. Loots DT. (2009). Isovaleric acidemia. In: Lang F. (eds) Encyclopedia of Molecular Mechanisms of Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-29676-8_983.
  4. Fraser, JL, & Venditti, CP. (2016). Methylmalonic and propionic acidemias: Clinical management update. Current Opinion in Pediatrics, 28(6), 682–693. https://doi.org/10.1097/MOP.0000000000000422.
  5. Grünert, SC, Müllerleile, S, De Silva, L, Barth, M, Walter, M, Walter, K, Meissner, T, Lindner, M, Ensenauer, R, Santer, R, Bodamer, OA, Baumgartner, MR, Brunner-Krainz, M, Karall, D, Haase, C, Knerr, I, Marquardt, T, Hennermann, JB, Steinfeld, & R, Beblo. (2013). Propionic acidemia: Clinical course and outcome in 55 pediatric and adolescent patients. Orphanet Journal of Rare Diseases, 8, 6. https://doi.org/10.1186/1750-1172-8-6.

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