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Dihydropyrimidinase deficiency(DPYSD)

MedGen UID:
83353
Concept ID:
C0342803
Disease or Syndrome
Synonyms: DIHYDROPYRIMIDINURIA; DPH DEFICIENCY; DPYS DEFICIENCY; DPYSD
SNOMED CT: Dihydrouracil amidohydrolase deficiency (238014002); Dihydropyrimidinase deficiency (238014002)
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): DPYS (8q22.3)
 
Monarch Initiative: MONDO:0009111
OMIM®: 222748
Orphanet: ORPHA38874

Definition

DPYS deficiency is an autosomal recessive disease characterized by the presence of dihydropyrimidinuria. The clinical phenotype is highly variable, ranging from early infantile onset of severe neurologic involvement, dysmorphic features, and feeding problems to late onset of mild intellectual disability and even asymptomatic individuals. Patients with a complete or partial deficiency have an increased risk of developing severe toxicity after administration of the anticancer drug 5-fluorouracil (5-FU) (summary by Nakajima et al., 2017). See also dihydropyrimidine dehydrogenase deficiency (274270), a similar disorder. [from OMIM]

Additional description

From MedlinePlus Genetics
Dihydropyrimidinase deficiency is a disorder that can cause neurological and gastrointestinal problems in some affected individuals. Other people with dihydropyrimidinase deficiency have no signs or symptoms related to the disorder, and in these individuals the condition can be diagnosed only by laboratory testing.

The neurological abnormalities that occur most often in people with dihydropyrimidinase deficiency are intellectual disability, seizures, and weak muscle tone (hypotonia). An abnormally small head size (microcephaly) and autistic behaviors that affect communication and social interaction also occur in some individuals with this condition.

Gastrointestinal problems that occur in dihydropyrimidinase deficiency include backflow of acidic stomach contents into the esophagus (gastroesophageal reflux) and recurrent episodes of vomiting (cyclic vomiting). Affected individuals can also have deterioration (atrophy) of the small, finger-like projections (villi) that line the small intestine and provide a large surface area with which to absorb nutrients. This condition, called villous atrophy, can lead to difficulty absorbing nutrients from foods (malabsorption), resulting in a failure to grow and gain weight at the expected rate (failure to thrive).

People with dihydropyrimidinase deficiency, including those who otherwise exhibit no symptoms, may be vulnerable to severe, potentially life-threatening toxic reactions to certain drugs called fluoropyrimidines that are used to treat cancer. Common examples of these drugs are 5-fluorouracil and capecitabine. These drugs may not be broken down efficiently and can build up to toxic levels in the body (fluoropyrimidine toxicity), leading to drug reactions including gastrointestinal problems, blood abnormalities, and other signs and symptoms.  https://medlineplus.gov/genetics/condition/dihydropyrimidinase-deficiency

Clinical features

From HPO
Uraciluria
MedGen UID:
867456
Concept ID:
C4021833
Finding
Increased concentration of uracil in the urine.
Talipes equinovarus
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Short phalanx of finger
MedGen UID:
163753
Concept ID:
C0877165
Finding
Short (hypoplastic) phalanx of finger, affecting one or more phalanges.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Anal atresia
MedGen UID:
1997
Concept ID:
C0003466
Congenital Abnormality
Congenital absence of the anus, i.e., the opening at the bottom end of the intestinal tract.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterestedness, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Abnormal pyramidal sign
MedGen UID:
68582
Concept ID:
C0234132
Sign or Symptom
Functional neurological abnormalities related to dysfunction of the pyramidal tract.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Abnormal cerebral white matter morphology
MedGen UID:
181756
Concept ID:
C0948163
Pathologic Function
An abnormality of the cerebral white matter.
Extrapyramidal dyskinesia
MedGen UID:
376380
Concept ID:
C1848528
Disease or Syndrome
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Morphological abnormality of the pyramidal tract
MedGen UID:
892809
Concept ID:
C4021761
Anatomical Abnormality
Any structural abnormality of the pyramidal tract, whose chief element, the corticospinal tract, is the only direct connection between the brain and the spinal cord. In addition to the corticospinal tract, the pyramidal system includes the corticobulbar, corticomesencephalic, and corticopontine tracts.
Excessive daytime somnolence
MedGen UID:
1635612
Concept ID:
C4551761
Sign or Symptom
A state of abnormally strong desire for sleep during the daytime.
Plagiocephaly
MedGen UID:
78562
Concept ID:
C0265529
Congenital Abnormality
Asymmetric head shape, which is usually a combination of unilateral occipital flattening with ipsilateral frontal prominence, leading to rhomboid cranial shape.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Reduced dihydropyrimidine dehydrogenase level
MedGen UID:
892350
Concept ID:
C4025582
Finding
An abnormal reduction in dihydropyrimidine dehydrogenase (NADP+) level.
Elevated circulating uracil concentration
MedGen UID:
1762024
Concept ID:
C5421635
Finding
Concentration of uracil in the blood circulation is above the normal range.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVDihydropyrimidinase deficiency

Professional guidelines

PubMed

van Kuilenburg AB, Dobritzsch D, Meijer J, Meinsma R, Benoist JF, Assmann B, Schubert S, Hoffmann GF, Duran M, de Vries MC, Kurlemann G, Eyskens FJ, Greed L, Sass JO, Schwab KO, Sewell AC, Walter J, Hahn A, Zoetekouw L, Ribes A, Lind S, Hennekam RC
Biochim Biophys Acta 2010 Jul-Aug;1802(7-8):639-48. Epub 2010 Apr 1 doi: 10.1016/j.bbadis.2010.03.013. PMID: 20362666

Recent clinical studies

Etiology

Nakajima Y, Meijer J, Dobritzsch D, Ito T, Zhang C, Wang X, Watanabe Y, Tashiro K, Meinsma R, Roelofsen J, Zoetekouw L, van Kuilenburg ABP
Mol Genet Metab 2017 Dec;122(4):216-222. Epub 2017 Oct 12 doi: 10.1016/j.ymgme.2017.10.003. PMID: 29054612
van Kuilenburg AB, Meinsma R, van Gennip AH
Nucleosides Nucleotides Nucleic Acids 2004 Oct;23(8-9):1371-5. doi: 10.1081/NCN-200027624. PMID: 15571261
van Kuilenburg AB, Meinsma R, Zonnenberg BA, Zoetekouw L, Baas F, Matsuda K, Tamaki N, van Gennip AH
Clin Cancer Res 2003 Oct 1;9(12):4363-7. PMID: 14555507
Hamajima N, Kouwaki M, Vreken P, Matsuda K, Sumi S, Imaeda M, Ohba S, Kidouchi K, Nonaka M, Sasaki M, Tamaki N, Endo Y, De Abreu R, Rotteveel J, van Kuilenburg A, van Gennip A, Togari H, Wada Y
Am J Hum Genet 1998 Sep;63(3):717-26. doi: 10.1086/302022. PMID: 9718352Free PMC Article
Putman CW, Rotteveel JJ, Wevers RA, van Gennip AH, Bakkeren JA, De Abreu RA
Neuropediatrics 1997 Apr;28(2):106-10. doi: 10.1055/s-2007-973681. PMID: 9208410

Diagnosis

Nakajima Y, Meijer J, Dobritzsch D, Ito T, Zhang C, Wang X, Watanabe Y, Tashiro K, Meinsma R, Roelofsen J, Zoetekouw L, van Kuilenburg ABP
Mol Genet Metab 2017 Dec;122(4):216-222. Epub 2017 Oct 12 doi: 10.1016/j.ymgme.2017.10.003. PMID: 29054612
Yeung CW, Yau MM, Ma CK, Siu TS, Tam S, Lam CW
Hong Kong Med J 2013 Jun;19(3):272-5. doi: 10.12809/hkmj133598. PMID: 23732435
la Marca G, Malvagia S, Casetta B, Pasquini E, Pela I, Hirano M, Donati MA, Zammarchi E
J Mass Spectrom 2006 May;41(5):586-92. doi: 10.1002/jms.1013. PMID: 16498612
Kuhara T, Ohdoi C, Ohse M, van Kuilenburg AB, van Gennip AH, Sumi S, Ito T, Wada Y, Matsumoto I
J Chromatogr B Analyt Technol Biomed Life Sci 2003 Jul 15;792(1):107-15. doi: 10.1016/s1570-0232(03)00044-8. PMID: 12829003
Van Gennip AH, De Abreu RA, Vreken P, Van Kuilenburg AB
Adv Exp Med Biol 1998;431:125-8. doi: 10.1007/978-1-4615-5381-6_24. PMID: 9598044

Therapy

Hayashi K, Kidouchi K, Sumi S, Mizokami M, Orito E, Kumada K, Ueda R, Wada Y
Clin Cancer Res 1996 Dec;2(12):1937-41. PMID: 9816152

Prognosis

la Marca G, Malvagia S, Casetta B, Pasquini E, Pela I, Hirano M, Donati MA, Zammarchi E
J Mass Spectrom 2006 May;41(5):586-92. doi: 10.1002/jms.1013. PMID: 16498612
Putman CW, Rotteveel JJ, Wevers RA, van Gennip AH, Bakkeren JA, De Abreu RA
Neuropediatrics 1997 Apr;28(2):106-10. doi: 10.1055/s-2007-973681. PMID: 9208410
Hayashi K, Kidouchi K, Sumi S, Mizokami M, Orito E, Kumada K, Ueda R, Wada Y
Clin Cancer Res 1996 Dec;2(12):1937-41. PMID: 9816152

Clinical prediction guides

Nakajima Y, Meijer J, Dobritzsch D, Ito T, Zhang C, Wang X, Watanabe Y, Tashiro K, Meinsma R, Roelofsen J, Zoetekouw L, van Kuilenburg ABP
Mol Genet Metab 2017 Dec;122(4):216-222. Epub 2017 Oct 12 doi: 10.1016/j.ymgme.2017.10.003. PMID: 29054612
van Kuilenburg AB, Stroomer AE, Bosch AM, Duran M
Nucleosides Nucleotides Nucleic Acids 2008 Jun;27(6):825-9. doi: 10.1080/15257770802146445. PMID: 18600547
la Marca G, Malvagia S, Casetta B, Pasquini E, Pela I, Hirano M, Donati MA, Zammarchi E
J Mass Spectrom 2006 May;41(5):586-92. doi: 10.1002/jms.1013. PMID: 16498612
Hamajima N, Kouwaki M, Vreken P, Matsuda K, Sumi S, Imaeda M, Ohba S, Kidouchi K, Nonaka M, Sasaki M, Tamaki N, Endo Y, De Abreu R, Rotteveel J, van Kuilenburg A, van Gennip A, Togari H, Wada Y
Am J Hum Genet 1998 Sep;63(3):717-26. doi: 10.1086/302022. PMID: 9718352Free PMC Article
Hayashi K, Kidouchi K, Sumi S, Mizokami M, Orito E, Kumada K, Ueda R, Wada Y
Clin Cancer Res 1996 Dec;2(12):1937-41. PMID: 9816152

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