Orotic Aciduria via the UMPS Gene

Hereditary orotic aciduria (MIM #258900) is a rare disorder of pyrimidine metabolism characterized by increased excretion of orotic acid in the urine, failure to thrive, and megaloblastic anemia. Hemoglobin levels often are in the 7-8 g/dL range, with hematocrit around 25% (Nyhan et al., 2012). This anemia is unresponsive to supplementation with iron, folate, or vitamin B12 (Huguley et al., 1959). Neutropenia is also present in most patients, with associated increased risk for infections. In the classical presentation, hair is sparse, fine, and very short; nail growth may also be poor. Some patients have been reported to have congenital anomalies, including cardiac malformations and strabismus (Van Kuilenburg et al., 2012).

Orotic acid crystals may be visualized in the urine via microscopy, and crystalluria may lead to gross or microscopic hematuria (Nyhan et al., 2012). The amount of orotic acid excreted by affected infants may be as high as 1000 times the normal adult mean, while orotidine excretion may also be elevated, but markedly less so (Sumi et al., 1997). Activities of aspartate transcarbamylase and dihydroorotase, two enzymes which occur earlier in the biochemical pathway, are also usually elevated.

Orotic aciduria represents pyrimidine nucleotide starvation in man. Impaired intellectual development has been observed in some patients. However, treatment in the form of oral uridine supplementation allows for remission (Nyhan et al., 2012; Van Kuilenburg et al., 2012). Dietary therapy leads to hematologic response, weight gain, increased activity levels, and improvement in overall well-being.

Hereditary orotic aciduria is caused by deficiency of uridine monophosphate (UMP) synthase. This enzyme is bifunctional in nature and catalyzes the last two steps in the de novo pyrimidine biosynthetic pathway. The enzyme’s two independent catalytic activities include orotate phosphoribosyltransferase (OPRT), which converts orotic acid to orotidine-5’-monophospate (OMP), and orotidine-5’-monophospate decarboxylase (ODC), which decraboxylates OMP to uridine monophosphate (UMP).

Hereditary orotic aciduria is extremely rare, with approximately 20 reported cases to date. The disorder shows autosomal recessive inheritance and is not confined to any particular ethnic group. The vast majority of affected patients have deficiency of both OPRT and ODC catalytic activities and were formerly classified as having Type I hereditary orotic aciduria (OMIM #258900). However, there is at least one reported individual who was found to have deficiency of ODC catalytic activity with normal to increased expression of OPRT. This individual was categorized as having Type II hereditary orotic aciduria (formerly reported under OMIM #258920). At present, all cases of hereditary orotic aciduria, regardless of type, are reported under OMIM #258900.

Mutations within the UMPS gene (OMIM 613891) are the only known cause of orotic aciduria. The gene is located on chromosome 3q13, consists of 6 exons, and encodes a protein that is 480 amino acids in length (Suchi et al., 1997). While the first 214 amino acids found in the N-terminus contain OPRT, the last 258 amino acids at the C-terminus contain OMP decarboxylase (Suttle et al., 1988). Missense mutations which lead to amino acid substitutions are a common cause of disease; such mutations are known to decrease steady-state levels of the enzyme, impair substrate binding, and reduce catalytic efficiency (Perry et al., 1989; Winkler et al, 1988; Suchi et al., 1997).

The sensitivity of this test is currently unknown, as comprehensive assessments of sensitivity using direct sequencing methods have not been cited in the published literature for this extremely rare disorder.

The sensitivity of duplication/deletion testing for this extremely rare disorder is currently unknown. However, it should be noted that no gross duplications or deletions in the UMPS gene have been published to date (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the UMPS gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).