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Oroticaciduria

MedGen UID:
78642
Concept ID:
C0268128
Finding; Finding
Synonyms: OPRT AND ODC DEFICIENCY; Orotate phosphoribosyltransferase and omp decarboxylase deficiency; OROTATE PHOSPHORIBOSYLTRANSFERASE AND OROTIDYLIC DECARBOXYLASE DEFICIENCY; Orotic aciduria; OROTIC ACIDURIA I; Orotic aciduria II (formerly); Orotidylic decarboxylase deficiency; Orotidylic pyrophosphorylase and orotidylic decarboxylase deficiency; UMP SYNTHASE DEFICIENCY; UMP synthtase deficiency; UMPS deficiency; Uridine monophosphate synthase deficiency; Uridine monophosphate synthetase deficiency
SNOMED CT: Deficiency of orotidylic acid phosphorylase (124277009); Deficiency of orotate phosphoribosyltransferase (124277009); Orotic aciduria (47641009)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): UMPS (3q21.2)
 
HPO: HP:0003218
Orphanet: ORPHA30

Definition

An increased concentration of orotic acid in the urine. [from HPO]

Conditions with this feature

Hereditary orotic aciduria
MedGen UID:
472940
Concept ID:
C0220987
Disease or Syndrome
Orotic aciduria is a rare autosomal recessive disorder characterized by megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001). Bailey (2009) stated that only 2 cases of orotic aciduria without megaloblastic anemia (OAWA) had been reported.
Ornithine carbamoyltransferase deficiency
MedGen UID:
75692
Concept ID:
C0268542
Disease or Syndrome
Ornithine transcarbamylase (OTC) deficiency can occur as a severe neonatal-onset disease in males (but rarely in females) and as a post-neonatal-onset (also known as "late-onset" or partial deficiency) disease in males and females. Males with severe neonatal-onset OTC deficiency are asymptomatic at birth but become symptomatic from hyperammonemia in the first week of life, most often on day two to three of life, and are usually catastrophically ill by the time they come to medical attention. After successful treatment of neonatal hyperammonemic coma these infants can easily become hyperammonemic again despite appropriate treatment; they typically require liver transplant to improve quality of life. Males and heterozygous females with post-neonatal-onset (partial) OTC deficiency can present from infancy to later childhood, adolescence, or adulthood. No matter how mild the disease, a hyperammonemic crisis can be precipitated by stressors and become a life-threatening event at any age and in any situation in life. For all individuals with OTC deficiency, typical neuropsychological complications include developmental delay, learning disabilities, intellectual disability, attention-deficit/hyperactivity disorder, and executive function deficits.
Argininosuccinate lyase deficiency
MedGen UID:
78687
Concept ID:
C0268547
Disease or Syndrome
Deficiency of argininosuccinate lyase (ASL), the enzyme that cleaves argininosuccinic acid to produce arginine and fumarate in the fourth step of the urea cycle, may present as a severe neonatal-onset form or a late-onset form: The severe neonatal-onset form is characterized by hyperammonemia within the first few days after birth that can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, and respiratory alkalosis. Absence of treatment leads to worsening lethargy, seizures, coma, and even death. In contrast, the manifestations of late-onset form range from episodic hyperammonemia triggered by acute infection or stress to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia. Manifestations of ASL deficiency that appear to be unrelated to the severity or duration of hyperammonemic episodes: Neurocognitive deficiencies (attention-deficit/hyperactivity disorder, developmental delay, seizures, and learning disability). Liver disease (hepatitis, cirrhosis). Trichorrhexis nodosa (coarse brittle hair that breaks easily). Systemic hypertension.
Arginase deficiency
MedGen UID:
78688
Concept ID:
C0268548
Disease or Syndrome
Arginase deficiency in untreated individuals is characterized by episodic hyperammonemia of variable degree that is infrequently severe enough to be life threatening or to cause death. Most commonly, birth and early childhood are normal. Untreated individuals have slowing of linear growth at age one to three years, followed by development of spasticity, plateauing of cognitive development, and subsequent loss of developmental milestones. If untreated, arginase deficiency usually progresses to severe spasticity, loss of ambulation, complete loss of bowel and bladder control, and severe intellectual disability. Seizures are common and are usually controlled easily. Individuals treated from birth, either as a result of newborn screening or having an affected older sib, appear to have minimal symptoms.
Lysinuric protein intolerance
MedGen UID:
75704
Concept ID:
C0268647
Disease or Syndrome
Lysinuric protein intolerance (LPI) typically presents after an infant is weaned from breast milk or formula; variable findings include recurrent vomiting and episodes of diarrhea, episodes of stupor and coma after a protein-rich meal, poor feeding, aversion to protein-rich food, failure to thrive, hepatosplenomegaly, and muscular hypotonia. Over time, findings include: poor growth, osteoporosis, involvement of the lungs (progressive interstitial changes, pulmonary alveolar proteinosis) and of the kidneys (progressive glomerular and proximal tubular disease), hematologic abnormalities (normochromic or hypochromic anemia, leukopenia, thrombocytopenia, erythroblastophagocytosis in the bone marrow aspirate), and a clinical presentation resembling the hemophagocytic lymphohistiocytosis/macrophagic activation syndrome. Hypercholesterolemia, hypertriglyceridemia, and acute pancreatitis can also be seen.
Developmental and epileptic encephalopathy, 50
MedGen UID:
904125
Concept ID:
C4225320
Disease or Syndrome
Developmental and epileptic encephalopathy-50 (DEE50) is an autosomal recessive progressive neurodegenerative neurometabolic disorder characterized by delayed psychomotor development, early-onset refractory seizures, severe developmental regression, and normocytic anemia. Onset is within the first months or years of life. Evidence suggests that affected children can have a favorable response to treatment with uridine (summary by Koch et al., 2017). For a discussion of genetic heterogeneity of DEE, see 308350.
Citrullinemia type I
MedGen UID:
1648491
Concept ID:
C4721769
Disease or Syndrome
Citrullinemia type I (CTLN1) presents as a spectrum that includes a neonatal acute form (the "classic" form), a milder late-onset form (the "non-classic" form), a form in which women have onset of symptoms at pregnancy or post partum, and a form without symptoms or hyperammonemia. Distinction between the forms is based primarily on clinical findings, although emerging evidence suggests that measurement of residual argininosuccinate synthase enzyme activity may help to predict those who are likely to have a severe phenotype and those who are likely to have an attenuated phenotype. Infants with the acute neonatal form appear normal at birth. Shortly thereafter, they develop hyperammonemia and become progressively lethargic, feed poorly, often vomit, and may develop signs of increased intracranial pressure (ICP). Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in increased ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. Children with the severe form who are treated promptly may survive for an indeterminate period of time, but usually with significant neurologic deficits. Even with chronic protein restriction and scavenger therapy, long-term complications such as liver failure and other (rarely reported) organ system manifestations are possible. The late-onset form may be milder than that seen in the acute neonatal form, but commences later in life for reasons that are not completely understood. The episodes of hyperammonemia are similar to those seen in the acute neonatal form, but the initial neurologic findings may be more subtle because of the older age of the affected individuals. Women with onset of severe symptoms including acute hepatic decompensation during pregnancy or in the postpartum period have been reported. Furthermore, previously asymptomatic and non-pregnant individuals have been described who remained asymptomatic up to at least age ten years, with the possibility that they could remain asymptomatic lifelong.
Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A
MedGen UID:
1841116
Concept ID:
C5830480
Disease or Syndrome
Mitochondrial complex V deficiency nuclear type 4A (MC5DN4A) is an autosomal dominant metabolic disorder characterized by poor feeding and failure to thrive in early infancy. Laboratory studies show increased serum lactate, alanine, and ammonia, suggesting mitochondrial dysfunction. Some affected individuals show spontaneous resolution of these symptoms in early childhood and have subsequent normal growth and development, whereas others show developmental delay with impaired intellectual development and movement abnormalities, including dystonia, ataxia, or spasticity; these neurologic deficits are persistent (Lines et al., 2021, Zech et al., 2022). For a discussion of genetic heterogeneity of mitochondrial complex V deficiency, nuclear types, see MC5DN1 (604273).

Recent clinical studies

Diagnosis

Vakili H, Umaña LA, Patel K
Clin Chem 2020 Feb 1;66(2):396-397. doi: 10.1093/clinchem/hvz012. PMID: 32040582
Wortmann SB, Chen MA, Colombo R, Pontoglio A, Alhaddad B, Botto LD, Yuzyuk T, Coughlin CR, Descartes M, Grűnewald S, Maranda B, Mills PB, Pitt J, Potente C, Rodenburg R, Kluijtmans LA, Sampath S, Pai EF, Wevers RA, Tiller GE; additional individual contributors
J Inherit Metab Dis 2017 May;40(3):423-431. Epub 2017 Feb 15 doi: 10.1007/s10545-017-0015-9. PMID: 28205048Free PMC Article
Debnath SK, Aggarwal A, Mittal H
Indian J Pediatr 2011 Oct;78(10):1293-5. Epub 2011 Jun 1 doi: 10.1007/s12098-011-0461-6. PMID: 21630071
Fairbanks LD, Simmonds HA, Webster DR
J Inherit Metab Dis 1987;10(2):174-86. doi: 10.1007/BF01800045. PMID: 2443757

Therapy

Vakili H, Umaña LA, Patel K
Clin Chem 2020 Feb 1;66(2):396-397. doi: 10.1093/clinchem/hvz012. PMID: 32040582
Khoja S, Nitzahn M, Hermann K, Truong B, Borzone R, Willis B, Rudd M, Palmer DJ, Ng P, Brunetti-Pierri N, Lipshutz GS
Mol Genet Metab 2018 Aug;124(4):243-253. Epub 2018 Apr 12 doi: 10.1016/j.ymgme.2018.04.001. PMID: 29801986Free PMC Article

Prognosis

Wortmann SB, Chen MA, Colombo R, Pontoglio A, Alhaddad B, Botto LD, Yuzyuk T, Coughlin CR, Descartes M, Grűnewald S, Maranda B, Mills PB, Pitt J, Potente C, Rodenburg R, Kluijtmans LA, Sampath S, Pai EF, Wevers RA, Tiller GE; additional individual contributors
J Inherit Metab Dis 2017 May;40(3):423-431. Epub 2017 Feb 15 doi: 10.1007/s10545-017-0015-9. PMID: 28205048Free PMC Article

Clinical prediction guides

Wortmann SB, Chen MA, Colombo R, Pontoglio A, Alhaddad B, Botto LD, Yuzyuk T, Coughlin CR, Descartes M, Grűnewald S, Maranda B, Mills PB, Pitt J, Potente C, Rodenburg R, Kluijtmans LA, Sampath S, Pai EF, Wevers RA, Tiller GE; additional individual contributors
J Inherit Metab Dis 2017 May;40(3):423-431. Epub 2017 Feb 15 doi: 10.1007/s10545-017-0015-9. PMID: 28205048Free PMC Article
Simmonds HA, Potter CF, Sahota A, Cameron JS, Webster DR, Becroft DM
Clin Exp Immunol 1978 Oct;34(1):42-5. PMID: 108039Free PMC Article

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