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Orotic Aciduria

Orotic aciduria is an extremely rare genetic disorder that can result in crystalluria, megaloblastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, developmental delay, and 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. The disorder is caused by an enzyme deficiency in the pyrimidine synthesis Synthesis Polymerase Chain Reaction (PCR) pathway resulting in the accumulation of orotic acid. Depletion of nucleotides Nucleotides The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. Nucleic Acids leads to the symptoms of the disease. Diagnosis is made with genetic sequencing as well as 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 studies. Options for treatment include uridine monophosphate Uridine monophosphate 5'-uridylic acid. A uracil nucleotide containing one phosphate group esterified to the sugar moiety in the 2. Purine and Pyrimidine Metabolism and uridine triacetate.

Last updated: Jun 1, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Epidemiology

  • Rare disorder affecting men and women equally
  • Birth prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: < 1 in 1 million live births

Classification

Type I: 

  • Deficiency in both uridine monophosphate Uridine monophosphate 5′-uridylic acid. A uracil nucleotide containing one phosphate group esterified to the sugar moiety in the 2. Purine and Pyrimidine Metabolism synthetase (UMPS) genes Genes 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. DNA Types and Structure
  • More common than type II 

Type II:

  • Deficiency in orotidine 5’-phosphate decarboxylase (ODC) activity with increased activity of orotate phosphoribosyltransferase Orotate phosphoribosyltransferase The enzyme catalyzing the formation of orotidine-5′-phosphoric acid (orotidylic acid) from orotic acid and 5-phosphoribosyl-1-pyrophosphate in the course of pyrimidine nucleotide biosynthesis. Purine and Pyrimidine Metabolism (OPRT)
  • Extremely rare

Etiology

  • Autosomal recessive inheritance Autosomal recessive inheritance Autosomal Recessive and Autosomal Dominant Inheritance
  • Mutations in uridine UMPS 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:
    • Found on the long arm Arm The arm, or “upper arm” in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm: Anatomy of chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 3 (3q13)
    • Uridine monophosphate Uridine monophosphate 5′-uridylic acid. A uracil nucleotide containing one phosphate group esterified to the sugar moiety in the 2. Purine and Pyrimidine Metabolism synthetase is a bifunctional protein product Product A molecule created by the enzymatic reaction. Basics of Enzymes that has both OPRT and ODC actions.

Pathophysiology

  • UMPS 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 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
    • Normal function of this 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 product Product A molecule created by the enzymatic reaction. Basics of Enzymes is an enzyme that catalyzes 2 consecutive metabolic reactions necessary for de novo pyrimidine biosynthesis Biosynthesis The biosynthesis of peptides and proteins on ribosomes, directed by messenger RNA, via transfer RNA that is charged with standard proteinogenic amino acids. Virology.
    • Nonfunctional 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 means that there is a low level of this enzyme and a buildup of orotic acid.
  • Excessive orotic acid is excreted 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, which leads to crystalluria.
  • Depletion of pyrimidine nucleotide leads to clinical symptoms.

Clinical Presentation

  • Hematologic: 
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types unresponsive to iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements/folic acid therapy
  • Neurologic: 
    • Developmental delays
    • Mild 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 ( epilepsy Epilepsy Epilepsy is a chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition. Clinical presentation correlates to the classification of the epileptic disorder. Epilepsy)
  • Systemic:
    • 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
  • Genitourinary: 
    • Cloudy 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 due to orotic acid crystals (crystalluria)
    • May lead to obstructive uropathy
  • Other reported symptoms:
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Congenital malformations Congenital malformations Congenital malformations or teratogenic birth defects are developmental disorders that arise before birth during the embryonic or fetal period. The rate of incidence for children born alive is approximately 3%. Teratogenic Birth Defects
    • Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the mouth and lips Lips The lips are the soft and movable most external parts of the oral cavity. The blood supply of the lips originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy ( stomatitis Stomatitis Stomatitis is a general term referring to inflammation of the mucous membranes of the mouth, which may include sores. Stomatitis can be caused by infections, autoimmune disorders, allergic reactions, or exposure to irritants. The typical presentation may be either solitary or a group of painful oral lesions. Stomatitis)
    • Misalignment of the eyes ( strabismus Strabismus Strabismus is the misalignment of the eyes while fixating the gaze on an object. Strabismus can be idiopathic, but it may also be caused by cerebral palsy, uncorrected refractive errors, and extraocular muscle or cranial nerve dysfunction. Strabismus)
    • Congenital Congenital Chorioretinitis heart disease
Blood smear of megaloblastic anemia orotic aciduria

Blood smear Blood smear Myeloperoxidase Deficiency of megaloblastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types:
Megaloblastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types is seen on blood smear Blood smear Myeloperoxidase Deficiency in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with orotic aciduria because of decreased pyrimidine synthesis Synthesis Polymerase Chain Reaction (PCR), which reduces the amount of nucleotide-lipid cofactors necessary for RBC membrane synthesis Synthesis Polymerase Chain Reaction (PCR).

Image: “ Bone marrow aspiration Bone marrow aspiration Removal of bone marrow and evaluation of its histologic picture. Severe Congenital Neutropenia” by Turk J Haematol. License: CC BY 2.5

Diagnosis

  • Detailed patient and family history Family History Adult Health Maintenance
  • Laboratory studies:
    • Blood chemistry:
      • Normal ammonia Ammonia A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. Note that the aqueous form of ammonia is referred to as ammonium hydroxide. Acid-Base Balance and BUN levels distinguish this condition from ornithine Ornithine An amino acid produced in the urea cycle by the splitting off of urea from arginine. Urea Cycle transcarbamylase (OTC) deficiency.
    • CBC:
      • Macrocytic hypochromic megaloblastic anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types due to marrow producing unusually large, structurally abnormal, immature RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology (megaloblasts)
      • May have leukopenia 
    • Examination of 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:
      • Elevated levels of orotic acid
  • Further confirmation through molecular 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 of the UMPS 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

Management

  • Uridine monophosphate Uridine monophosphate 5′-uridylic acid. A uracil nucleotide containing one phosphate group esterified to the sugar moiety in the 2. Purine and Pyrimidine Metabolism supplementation 
  • Uridine triacetate (Xuriden): restores uridine monophosphate Uridine monophosphate 5′-uridylic acid. A uracil nucleotide containing one phosphate group esterified to the sugar moiety in the 2. Purine and Pyrimidine Metabolism
  • Additional treatment targets specific symptoms that are present in each individual 
  • Genetic counseling Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies can be beneficial
Uridine triacetate structure orotic aciduria

Structure of uridine triacetate, an orally active prodrug Prodrug Nitroimidazoles of uridine that is used in the treatment of orotic aciduria

Image: “Uridine triacetate structure” by Vaccinationist. License: Public Domain

Differential Diagnosis

  • OTC deficiency OTC deficiency An inherited urea cycle disorder associated with deficiency of the enzyme ornithine carbamoyltransferase, transmitted as an X-linked trait and featuring elevations of amino acids and ammonia in the serum. Clinical features, which are more prominent in males, include seizures, behavioral alterations, episodic vomiting, lethargy, and coma. Urea Cycle Disorders: X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) recessive condition that causes dysfunction within the urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation leading to inability to eliminate urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle. This condition is rapidly fatal and causes a 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 within the 1st days of life. OTC deficiency OTC deficiency An inherited urea cycle disorder associated with deficiency of the enzyme ornithine carbamoyltransferase, transmitted as an X-linked trait and featuring elevations of amino acids and ammonia in the serum. Clinical features, which are more prominent in males, include seizures, behavioral alterations, episodic vomiting, lethargy, and coma. Urea Cycle Disorders is similar to orotic aciduria, as both will elevate the level of orotic acid in the blood. Unlike orotic aciduria, OTC deficiency OTC deficiency An inherited urea cycle disorder associated with deficiency of the enzyme ornithine carbamoyltransferase, transmitted as an X-linked trait and featuring elevations of amino acids and ammonia in the serum. Clinical features, which are more prominent in males, include seizures, behavioral alterations, episodic vomiting, lethargy, and coma. Urea Cycle Disorders causes an elevation in ammonia Ammonia A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. Note that the aqueous form of ammonia is referred to as ammonium hydroxide. Acid-Base Balance and reduces the BUN. 
  • Lysinuric protein intolerance: 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 Inheritance disorder that causes dysfunction 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 transit. Infants present with 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, GI disturbances (e.g., vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea), hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus, and 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. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are diagnosed on the basis of increased concentrations of lysine, arginine Arginine An essential amino acid that is physiologically active in the l-form. Urea Cycle, and ornithine Ornithine An amino acid produced in the urea cycle by the splitting off of urea from arginine. Urea Cycle 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, with low concentrations 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 in the blood. Appropriate treatment is with protein restriction and dietary supplementation. Unlike orotic aciduria, these patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship will not have elevated orotic acid 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 and 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 will not show UMPS 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 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.
  • Galactosemia Galactosemia Galactosemia is a disorder caused by defects in galactose metabolism. Galactosemia is an inherited, autosomal-recessive condition, which results in inadequate galactose processing and high blood levels of monosaccharide. The rare disorder often presents in infants with symptoms of lethargy, nausea, vomiting, diarrhea, and jaundice. Galactosemia: 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 Inheritance disorder caused by defects in galactose Galactose An aldohexose that occurs naturally in the d-form in lactose, cerebrosides, gangliosides, and mucoproteins. Deficiency of galactosyl-1-phosphate uridyltransferase causes an error in galactose metabolism called galactosemia, resulting in elevations of galactose in the blood. Lactose Intolerance metabolism. Infants present with 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, 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, and jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice. The diagnosis is confirmed through blood testing for genes Genes 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. DNA Types and Structure that are required for galactose Galactose An aldohexose that occurs naturally in the d-form in lactose, cerebrosides, gangliosides, and mucoproteins. Deficiency of galactosyl-1-phosphate uridyltransferase causes an error in galactose metabolism called galactosemia, resulting in elevations of galactose in the blood. Lactose Intolerance metabolism. Treatment is avoidance of lactose and galactose Galactose An aldohexose that occurs naturally in the d-form in lactose, cerebrosides, gangliosides, and mucoproteins. Deficiency of galactosyl-1-phosphate uridyltransferase causes an error in galactose metabolism called galactosemia, resulting in elevations of galactose in the blood. Lactose Intolerance. Unlike orotic aciduria, patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship will not have elevated levels of orotic acid 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.

References:

  1. Nyhan, W.L. (2018). Hereditary orotic aciduria. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/hereditary-orotic-aciduria/
  2. Fox, R.F., Wood, M.H., Royse-Smith, D., O’Sullivan, W.J. (1973). Hereditary orotic aciduria: types I and II. American Journal of Medicine 55:791–798. https://pubmed.ncbi.nlm.nih.gov/4753642/
  3. Debnath, S., Aggarwal, A., Mittal, H. (2011). Megaloblastic anemia—a rare cause. Indian Journal of Pediatrics 78:1293–1295. https://pubmed.ncbi.nlm.nih.gov/21630071/

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