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 Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of 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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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Phenylketonuria

Overview

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.

Pathophysiology

  • Mutations in the phenylalanine hydroxylase ( PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration) gene, which encodes PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration, an enzyme that converts phenylalanine to tyrosine
  • A defect in PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration 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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the phenylalanine hydroxylase ( PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration) gene

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

Classification

  • Classical PKU: very little PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration gene activity and significant accumulation of phenylalanine
  • Mild PKU: less severe phenylalanine accumulation, some PAH PAH The glycine amide of 4-aminobenzoic acid. Its sodium salt is used as a diagnostic aid to measure effective renal plasma flow (ERPF) and excretory capacity. Glomerular Filtration gene activity present

Symptoms

  • Newborns do not present with symptoms; it takes time for phenylalanine to accumulate.
  • Neurologic:
    • Developmental delays
    • Intellectual disability
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Microcephaly
  • Behavioral and psychiatric:
    • Social issues
    • Behavioral and emotional problems
    • Mental health issues
    • Hyperactivity
  • Orthopedic: low bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones density
  • Dermatologic
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin rashes Rashes Rashes are a group of diseases that cause abnormal coloration and texture to the skin. The etiologies are numerous but can include irritation, allergens, infections, or inflammatory conditions. Rashes that present in only 1 area of the body are called localized rashes. Generalized rashes occur diffusely throughout the body. Generalized and Localized Rashes ( eczema Eczema Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema))
    • Fair skin (due to lack of melanin)
  • Other: a musty odor in breath or urine

Diagnosis

  • 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

Management

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

Overview

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

Pathophysiology

  • MSUD: 
    • Caused by a deficiency in branched-chain alpha-keto acid dehydrogenase
  • Isovaleric acidemia: 
    • Autosomal recessive 
    • Caused by mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations 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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations at either methylmalonyl-CoA mutase or methylmalonyl-CoA epimerase.

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

Symptoms

  • MSUD
    • Symptoms present within the first 2 days of life.
    • Neurologic: 
      • Developmental delay
      • Poor feeding
      • Lethargy
      • Irritability
      • Hypertonia
      • Spasticity
      • Convulsions
      • Coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma
    • Orthopedic: osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
    • GI: pancreatitis
    • GU: sweet-smelling urine
  • Isovaleric acidemia
    • Characterized by a distinct odor described as “sweaty feet”
    • GI: 
      • Nausea
      • Vomiting
    • Neurologic: 
      • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
      • Apathy
      • Coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma 
      • Hypotonia
  • Methylmalonic acidemia
    • Symptoms appear within the 1st year of life.
    • Neurologic: 
      • Encephalopathy
      • Seizure
      • Stroke
      • Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive
      • Hypotonia 
    • GU: kidney failure 
    • GI: 
      • Nausea
      • Vomiting 
    • Respiratory: respiratory distress
  • Propionic acidemia
    • Neurologic: 
      • Poor feeding
      • Hypotonia
      • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • GI: 
      • Nausea
      • Vomiting
      • Dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration
    • Genitourinary:  CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease 
    • Cardiovascular: 
      • Cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies (dilated and hypertrophic)
      • Conduction disorders

Diagnosis

  • MSUD:
    • Newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the 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 Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the 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 Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the 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

Management

  • 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 Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin injections promoting anabolism
    • Surgical therapy: Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Vitamin B12 Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and 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 Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancecondition due to a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the HGD gene. Alkaptonuria leads to accumulation of homogentisic acid. Patients present with dark urine. Complications include osteoarthritis Osteoarthritis Osteoarthritis (OA) is the most common form of arthritis, and is due to cartilage destruction and changes of the subchondral bone. The risk of developing this disorder increases with age, obesity, and repetitive joint use or trauma. Patients develop gradual joint pain, stiffness lasting < 30 minutes, and decreased range of motion. Osteoarthritis, nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. 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.

References

  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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