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Disorders of Amino Acid Metabolism

Amino acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance are the building blocks of proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis, 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 Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids metabolism are often serious and present early in life. Congenital Congenital Chorioretinitis errors in amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids metabolism are due to either impaired synthesis Synthesis Polymerase Chain Reaction (PCR) or degradation. In the United States, neonates are routinely screened at birth for common disorders of amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids metabolism, which include phenylketonuria (PKU), maple syrup urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat disease (MSUD), homocystinuria, tyrosinemia Tyrosinemia A group of disorders which have in common elevations of tyrosine in the blood and urine secondary to an enzyme deficiency. Type I tyrosinemia features episodic weakness, self-mutilation, hepatic necrosis, renal tubular injury, and seizures and is caused by a deficiency of the enzyme fumarylacetoacetase. Type II tyrosinemia features intellectual disability, painful corneal ulcers, and keratosis of the palms and plantar surfaces and is caused by a deficiency of the enzyme tyrosine transaminase. Type III tyrosinemia features intellectual disability and is caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase. Renal Tubular Acidosis, 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.

Last updated: 12 Apr, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Phenylketonuria

Overview

Phenylketonuria (PKU) is an inherited disease that causes an increase in phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids levels in the body due to the inability to metabolize this amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids.

Pathophysiology

  • Mutations in the phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids 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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, 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 Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids to tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids
  • 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 Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids (in most cases tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids levels are normal or slightly low).
  • Elevated phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids levels cause damage to white matter White Matter The region of central nervous system that appears lighter in color than the other type, gray matter. It mainly consists of myelinated nerve fibers and contains few neuronal cell bodies or dendrites. Brown-Séquard Syndrome tracts and myelin (mechanism unknown), leading to neurological deficits.
Classic phenylketonuria

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 Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids 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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics.
Phe: phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids
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: phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids hydroxylase
Tyr: tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids
HT-2: tyrosinemia Tyrosinemia A group of disorders which have in common elevations of tyrosine in the blood and urine secondary to an enzyme deficiency. Type I tyrosinemia features episodic weakness, self-mutilation, hepatic necrosis, renal tubular injury, and seizures and is caused by a deficiency of the enzyme fumarylacetoacetase. Type II tyrosinemia features intellectual disability, painful corneal ulcers, and keratosis of the palms and plantar surfaces and is caused by a deficiency of the enzyme tyrosine transaminase. Type III tyrosinemia features intellectual disability and is caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase. Renal Tubular Acidosis II
TAT: tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids transaminase Transaminase A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Catabolism of Amino Acids
pHPP: p-hydroxyphenylpyruvate
HPD HPD Trichotillomania (hair-pulling disorder (HPD)) is defined as repetitive pulling of one’s hair resulting in hair loss that may be visible to others. This disorder is classified under obsessive-compulsive and related disorders, as there is tension prior to the act that is relieved after the hair-pulling. Trichotillomania: p-hydroxyphenylpyruvate dioxygenase
HT-3: tyrosinemia Tyrosinemia A group of disorders which have in common elevations of tyrosine in the blood and urine secondary to an enzyme deficiency. Type I tyrosinemia features episodic weakness, self-mutilation, hepatic necrosis, renal tubular injury, and seizures and is caused by a deficiency of the enzyme fumarylacetoacetase. Type II tyrosinemia features intellectual disability, painful corneal ulcers, and keratosis of the palms and plantar surfaces and is caused by a deficiency of the enzyme tyrosine transaminase. Type III tyrosinemia features intellectual disability and is caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase. Renal Tubular Acidosis III
HGA HGA Ehrlichiosis and Anaplasmosis: homogentisate
HGD: homogentisate oxidase Oxidase Neisseria
AKU: alcaptonuria
MAA: 4-maleylacetoacetate
MAAI: 4-maleylacetoacetate isomerase
FAA: 4-fumarylacetoacetate
FAH: 4-fumarylacetoacetase
HT-1: tyrosinemia Tyrosinemia A group of disorders which have in common elevations of tyrosine in the blood and urine secondary to an enzyme deficiency. Type I tyrosinemia features episodic weakness, self-mutilation, hepatic necrosis, renal tubular injury, and seizures and is caused by a deficiency of the enzyme fumarylacetoacetase. Type II tyrosinemia features intellectual disability, painful corneal ulcers, and keratosis of the palms and plantar surfaces and is caused by a deficiency of the enzyme tyrosine transaminase. Type III tyrosinemia features intellectual disability and is caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase. Renal Tubular Acidosis I

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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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics activity and significant accumulation of phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids
  • Mild PKU: less severe phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids 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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics activity present

Symptoms

  • Newborns do not present with symptoms; it takes time for phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids to accumulate.
  • Neurologic:
    • Developmental delays
    • Intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment
    • 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 Microcephaly A congenital abnormality in which the cerebrum is underdeveloped, the fontanels close prematurely, and, as a result, the head is small. (desk reference for neuroscience, 2nd ed. ). Fetal Alcohol Spectrum Disorder
  • Behavioral and psychiatric:
  • 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. Bones: Structure and Types 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. Skin: Structure and Functions 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 Melanin Insoluble polymers of tyrosine derivatives found in and causing darkness in skin (skin pigmentation), hair, and feathers providing protection against sunburn induced by sunlight. Carotenes contribute yellow and red coloration. Seborrheic Keratosis)
  • Other: a musty odor in breath or urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat

Diagnosis

  • PKU screening Screening Preoperative Care via heel prick within the 1st week of life
    • Measurement of amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids levels showing high phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids and low/normal tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids 
    • Positive results must be confirmed with follow-up testing.
  • Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies
Phenylketonuria testing

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

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 Regular Insulin blood testing to evaluate the level of phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids in the blood
  • Low- phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids diet, eliminating foods such as soybean, chicken, shrimp, nuts, turkey, and legumes
  • Avoid aspartame-containing products, as these are converted to phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids.
  • Protein supplementation formula:
    • Includes the amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids
    • Includes large neutral amino acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance (e.g., valine)
  • For adults with poor control of their phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids, the drug pegvaliase is available and acts as an enzyme that can metabolize phenylalanine Phenylalanine An essential aromatic amino acid that is a precursor of melanin; dopamine; noradrenalin (norepinephrine), and thyroxine. Synthesis of Nonessential Amino Acids.

Organic Acidemia

Overview

A group of genetic disorders of amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids metabolism involving branched-chain amino acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance such as leucine, isoleucine, and valine. These disorders are caused by disruption of metabolism of these amino acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance, resulting in accumulation of toxic metabolites that often spill into urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat

There are 4 main types of organic acidemia Acidemia Respiratory Acidosis:

Pathophysiology

Organic acidemia

The pathophysiology of methylmalonic acidemia Acidemia Respiratory Acidosis 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 by Lecturio.

Symptoms

  • MSUD
    • Symptoms present within the first 2 days of life.
    • Neurologic: 
      • Developmental delay
      • Poor feeding
      • Lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia
      • Irritability
      • Hypertonia Hypertonia Abnormal increase in skeletal or smooth muscle tone. Skeletal muscle hypertonicity may be associated with pyramidal tract lesions or basal ganglia diseases. Neurological Examination
      • Spasticity Spasticity Spinal Disk Herniation
      • Convulsions Convulsions Seizures
      • 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 Pancreatitis Inflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis. Acute Pancreatitis
    • GU: sweet-smelling urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat
  • Isovaleric acidemia Acidemia Respiratory Acidosis
    • Characterized by a distinct odor described as “sweaty feet”
    • GI: 
      • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
      • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
    • 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 Apathy Lack of emotion or emotional expression; a disorder of motivation that persists over time. Wernicke Encephalopathy and Korsakoff Syndrome
      • 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 Hypotonia Duchenne Muscular Dystrophy
  • Methylmalonic acidemia Acidemia Respiratory Acidosis
    • GI: 
      • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
      • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia 
    • Respiratory: respiratory distress
  • Propionic acidemia Acidemia Respiratory Acidosis
    • Neurologic: 
      • Poor feeding
      • Hypotonia Hypotonia Duchenne Muscular Dystrophy
      • 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 Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
      • Vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
      • Dehydration Dehydration The condition that results from excessive loss of water from a living organism. 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). Cardiomyopathy: Overview and Types (dilated and hypertrophic)
      • Conduction disorders

Diagnosis

  • MSUD:
    • Newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn screening Screening Preoperative Care to measure the amount of branched-chain amino acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance 
    • Urine organic acid levels to confirm
    • Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies for further confirmation and prenatal counseling
  • Isovaleric acidemia Acidemia Respiratory Acidosis:
  • Methylmalonic acidemia Acidemia Respiratory Acidosis:
    • Newborn Newborn An infant during the first 28 days after birth. Physical Examination of the Newborn screening Screening Preoperative Care showing elevation of propionylcarnitine
    • Screening looks for a high level of methylmalonic acid: Urine organic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance, plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products amino acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance, plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products acylcarnitine, and plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products total homocysteine should be obtained.
  • Propionic acidemia Acidemia Respiratory Acidosis: diagnosed by detection of elevated levels of propionic acid metabolites (e.g., 3-hydroxypropionate) in urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat and serum

Management

  • MSUD:
    • Dietary modification
      • Protein-free diet 
      • Use of a diet that is low in the amino acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance leucine, valine, and isoleucine, which aren’t broken down in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
    • Acute metabolic decompensation: 
      • Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance 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 transplantation Liver transplantation The transference of a part of or an entire liver from one human or animal to another. Hepatocellular Carcinoma (HCC) and Liver Metastases is successful in classic MSUD with no neurologic symptoms.
  • Isovaleric acidemia Acidemia Respiratory Acidosis:
    • Dietary changes to reduce the amount of leucine
    • Patients with acute manifestations of disease are given glycine Glycine A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. Synthesis of Nonessential Amino Acids or carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism
  • Methylmalonic acidemia Acidemia Respiratory Acidosis:
    • Low-protein diet 
    • Carnitine supplementation
    • Cyanocobalamin supplementation
    • In some severe cases, kidney or liver transplantation is considered.
  • Propionic acidemia Acidemia Respiratory Acidosis:
    • Low-protein diet 
    • Protein supplementation with methionine, threonine, valine, isoleucine, and carnitine Carnitine A constituent of striated muscle and liver. It is an amino acid derivative and an essential cofactor for fatty acid metabolism. Fatty Acid Metabolism
    • 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 B6 Vitamin B 6 refers to several picolines (especially pyridoxine; pyridoxal; & pyridoxamine) that are efficiently converted by the body to pyridoxal phosphate which is a coenzyme for synthesis of amino acids, neurotransmitters (serotonin, norepinephrine), sphingolipids, and aminolevulinic acid. During transamination of amino acids, pyridoxal phosphate is transiently converted into pyridoxamine phosphate. Although pyridoxine and vitamin B 6 are still frequently used as synonyms, especially by medical researchers, this practice is erroneous and sometimes misleading. Most of vitamin b6 is eventually degraded to pyridoxic acid and excreted in the urine. Water-soluble Vitamins and their Deficiencies, vitamin B12 Vitamin B12 A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12, or folate Folate 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. Diagnosis is made by detecting elevated levels of methionine or homocysteine in the urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat or blood. Patients are treated with vitamin B6 Vitamin B6 Vitamin B 6 refers to several picolines (especially pyridoxine; pyridoxal; & pyridoxamine) that are efficiently converted by the body to pyridoxal phosphate which is a coenzyme for synthesis of amino acids, neurotransmitters (serotonin, norepinephrine), sphingolipids, and aminolevulinic acid. During transamination of amino acids, pyridoxal phosphate is transiently converted into pyridoxamine phosphate. Although pyridoxine and vitamin B 6 are still frequently used as synonyms, especially by medical researchers, this practice is erroneous and sometimes misleading. Most of vitamin b6 is eventually degraded to pyridoxic acid and excreted in the urine. Water-soluble Vitamins and their Deficiencies, and some patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship 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 Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids.
  • Tyrosinemia: a genetic disorder characterized by disruptions in breakdown of tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids. Buildup of tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids 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 Tyrosinemia A group of disorders which have in common elevations of tyrosine in the blood and urine secondary to an enzyme deficiency. Type I tyrosinemia features episodic weakness, self-mutilation, hepatic necrosis, renal tubular injury, and seizures and is caused by a deficiency of the enzyme fumarylacetoacetase. Type II tyrosinemia features intellectual disability, painful corneal ulcers, and keratosis of the palms and plantar surfaces and is caused by a deficiency of the enzyme tyrosine transaminase. Type III tyrosinemia features intellectual disability and is caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase. Renal Tubular Acidosis. Patients are often diagnosed through a newborn screening Screening Preoperative Care 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 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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics. Alkaptonuria leads to accumulation of homogentisic acid. Patients present with dark urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat. 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 Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat collection. Patients are managed with vitamin C Vitamin C A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. Water-soluble Vitamins and their Deficiencies supplementation, dietary restriction of certain proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis, and nitisinone. Although alkaptonuria is a serious condition, patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship 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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