Clinical symptoms of Defects in pyrimidine metabolism - ERNDIM
Clinical symptoms of Defects in pyrimidine metabolism - ERNDIM
Clinical symptoms of Defects in pyrimidine metabolism - ERNDIM
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<strong>Cl<strong>in</strong>ical</strong> <strong>symptoms</strong> <strong>of</strong><br />
<strong>Defects</strong> <strong>in</strong> pyrimid<strong>in</strong>e <strong>metabolism</strong><br />
Birgit Assmann<br />
Department <strong>of</strong> General Pediatrics<br />
Universtiy Children‘s Hospital<br />
Düsseldorf, Germany
Overview<br />
• Biosynthesis: UMP Synthase<br />
• Degradation:<br />
– Pyrimid<strong>in</strong>e 5‘-Nucleotidase(UMP<br />
Nucleotidase(UMP-Hydrolase) Hydrolase)<br />
– [Thymid<strong>in</strong>e-Phosphorylase, mitochondrial]<br />
– Dihydropyrimid<strong>in</strong>e Dehydrogenase<br />
– Dihydropyrimid<strong>in</strong>ase<br />
– Ureidopropionase
HCO 3 +gluNH 2<br />
carbamoyl-P<br />
UMP OD<br />
OMP<br />
orotic acid<br />
OPRT<br />
UMPS<br />
UMPS = urid<strong>in</strong>emonophosphate synthase<br />
Bifunctional enzyme (one gene):<br />
a) Orotate phosphoribosyl transferase (OPRT)<br />
b) Orotid<strong>in</strong>e decarboxylase (OD)
UMPS deficiency<br />
• = Hereditary orotic aciduria<br />
Hallmarks:<br />
- Megaloblastic anemia <strong>in</strong> <strong>in</strong>fants<br />
>> If untreated: untreated:<br />
Failure to thrive<br />
Psychomotor retardation<br />
• Therapy: urid<strong>in</strong>e (≥100-150 mg/kg/d)
<strong>Defects</strong> <strong>of</strong> pyrimid<strong>in</strong>e degradation<br />
• Pyrimid<strong>in</strong>e 5‘-Nucleotidase deficiency<br />
- chronic hemolytic anemia + basophilic<br />
stippl<strong>in</strong>g <strong>of</strong> erythrocytes<br />
• Thymid<strong>in</strong>e phosphorylase deficiency<br />
= MNGIE=Mitoch. NeuroGastroIntest<strong>in</strong>al<br />
Encephalomyopathy<br />
Mitochondrial disorder with elevated<br />
ur<strong>in</strong>ary thymid<strong>in</strong>e excretion
HCO 3 +gluNH 2<br />
TMP<br />
Thym. Thym<br />
thymid<strong>in</strong>e<br />
phosphor<br />
ylase<br />
thym<strong>in</strong>e<br />
carbamoyl-P<br />
cytosolic 5‘-<br />
Nucleotidase<br />
UMP<br />
urid<strong>in</strong>e<br />
uracil<br />
OMP<br />
orotic acid<br />
UMPS
Pyrimid<strong>in</strong>e 5‘-Nucleotidase-<br />
Superactivity<br />
• Existence now doubted<br />
• Psychomotor retardation, seizures,<br />
extreme hyperactivity, slurred speech<br />
• Responded well to high dose urid<strong>in</strong>e<br />
• Only metabolic marker >> reduced<br />
excretion <strong>of</strong> uric acid to approx. 50%
HCO 3 +gluNH 2<br />
carbamoyl-P<br />
UMP<br />
urid<strong>in</strong>e<br />
uracil<br />
OMP<br />
dihydrouracil<br />
orotic acid<br />
β-ureidopropionate<br />
β -alan<strong>in</strong>e<br />
UMPS
HCO 3 +gluNH 2<br />
TMP<br />
thymid<strong>in</strong>e<br />
thym<strong>in</strong>e<br />
dihydrothym<strong>in</strong>e<br />
β-ureidoisobutyrate<br />
β-am<strong>in</strong>oisobutyrate<br />
carbamoyl-P<br />
UMP<br />
urid<strong>in</strong>e<br />
uracil<br />
OMP<br />
dihydrouracil<br />
orotic acid<br />
β-ureidopropionate<br />
β -alan<strong>in</strong>e<br />
UMPS
HCO 3 +gluNH 2<br />
TMP<br />
thymid<strong>in</strong>e<br />
thym<strong>in</strong>e<br />
dihydrothym<strong>in</strong>e<br />
β-ureidoisobutyrate<br />
β-am<strong>in</strong>oisobutyrate<br />
carbamoyl-P<br />
DPD<br />
DHP<br />
UP<br />
UMP<br />
urid<strong>in</strong>e<br />
uracil<br />
OMP<br />
dihydrouracil<br />
orotic acid<br />
β-ureidopropionate<br />
β -alan<strong>in</strong>e<br />
UMPS
Pyr.bases‘ degradation disorders<br />
• DPD = Dihydropyrimid<strong>in</strong>e Dehydrogenase<br />
deficiency (? Hundreds <strong>of</strong> cases?)<br />
• DHP = Dihydropyrimid<strong>in</strong>ase Deficiency<br />
(1 dozen cases)<br />
• UP = Ureidopropionase deficiency<br />
(4 cases)<br />
• <strong>Cl<strong>in</strong>ical</strong> pictures not dist<strong>in</strong>guishable
Symptomatology<br />
Asymptomatic (cave 5‘-Fluoro-Uracil!)<br />
>> severe neurological disorder<br />
• No degenerative course (exceptional)<br />
Hallmarks:<br />
- Seizures<br />
- Mental retardation<br />
- Motor retardation
Pathophysioloy<br />
• Deficit <strong>of</strong> β-alan<strong>in</strong>e ??<br />
• β-alan<strong>in</strong>e b<strong>in</strong>ds to<br />
- glyc<strong>in</strong>e receptor<br />
- glyc<strong>in</strong>e b<strong>in</strong>d<strong>in</strong>g site <strong>of</strong> NMDA-glut. receptor<br />
- GABA transporter<br />
- GABA A receptor<br />
• Inhibitory neuromodulator,<br />
neuromodulator,<br />
neurotransmitter for nocireception
BUT<br />
Study Van Kuilenburg et al.<br />
• CSF concentration <strong>of</strong> β-alan<strong>in</strong>e not<br />
reduced <strong>in</strong> DPD patients<br />
Instead:<br />
• CSF concentrations <strong>of</strong> βam<strong>in</strong>oisobutyrate<br />
(β-AIB) reduced<br />
pathomechanism<br />
pathomechanism and therapy<br />
unresolved
Take-home messages<br />
• Hereditary orotic aciduria should not be<br />
missed because it is treatable<br />
• Pyrimid<strong>in</strong>e bases‘ bases degradation defects<br />
show unspecific cl<strong>in</strong>ical syndromes,<br />
syndromes<br />
- screen<strong>in</strong>g useful because <strong>of</strong> 5‘-FU<br />
toxicity
HCO 3 +gluNH 2<br />
Thy-phosphor<br />
Thy phosphor<br />
ylase<br />
TMP<br />
thymid<strong>in</strong>e<br />
thym<strong>in</strong>e<br />
dihydrothym<strong>in</strong>e<br />
β-ureidoisobutyrate<br />
β-am<strong>in</strong>oisobutyrate<br />
carbamoyl-P<br />
cytosolic 5‘-<br />
Nucleotidase<br />
DPD<br />
DHP<br />
UP<br />
UMP<br />
urid<strong>in</strong>e<br />
uracil<br />
OMP<br />
dihydrouracil<br />
orotic acid<br />
β-ureidopropionate<br />
β -alan<strong>in</strong>e<br />
UMPS
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