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karen perlas

on 14 March 2013

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Transcript of cps1d

Urea Cycle Disorder (UCD)

genetic disorder caused by a mutation
that results in a deficiency of one of the
six enzymes in the urea cycle

nitrogen accumulates in the form of ammonia, resulting in hyperammonemia http://bodyshapeshiftersonline.com/wp-content/uploads/2011/08/590metabolism.gif high levels of ammonia in the blood induces toxic effects with alterations in the function of the central nervous system less toxic than ammonia,
kidneys transfer urea from blood to urine, which is then excreted http://ureacycle.cnmcresearch.org/otc/files/page0_1.png Transporter defects: elevated blood ammonia
ammonia then reaches the brain through the blood, where it can cause irreversible brain damage, coma and/or death http://www.nucdf.org/ucd_kinds.htm Kinds of UCDs: Carbamoyl Phosphate Synthetase 1 deficiency (CPS1D)
OMIM No. 237300

- most severe UCD (besides OTCD)
- primarily due to mutations in the CPS1 gene leading to a decrease or complete lack of enzyme catalytic activity, or enzyme instability
- caused secondarily by lack of its allosteric activator NAG
- 2 distinct phenotypes: lethal neonatal or less severe late onset
- autosomal recessive (homozygous or heterozygous)
- rare, overall incidence unknown; estimated in some populations: 1/62,000 (USA), 1/800,000 (Japan), 1/539,000 (Finland) Carbamoyl Phosphate Synthetase I (CPSI) Gene
- located on chromosome 2q34
- expands more than 120 kb, encompassing 38 exons and 37 introns
- has an open reading frame of 4503 nucleotides
- encodes a polypeptide of 1500 amino acids

- mitochondrial multi-domain (6) enzyme
- catalyzes the 1st and rate-limiting step of the urea cycle
- requires the allosteric cofactor N-acetyl-L-glutamate (NAG) to become active no valuable alternative to the cycle exist, failure of this pathway will cause diseases mutations 2MgATP+HCO3 ¯ +NH3→NH2CO2PO32¯+2MgADP+Pi

- requires cofactor NAG
- 3 sequential steps
- two molecules of ATP used in the reaction occupy separate binding sites in the enzyme
-coupling of the reactions at the two phosphorylating sites via conformational changes Steps

1 bicarbonate is phosphorylated by ATP, yielding carboxyphosphate

2 carbamate is synthesized from carboxyphosphate and ammonia

3 carbamate is phosphorylated by another ATP molecule forming the final product carbamoyl phosphate Signs and Symptoms

- hyperammonemia - memory impairment
- lethargy that may lead to coma - hypothermia
- seizures - persistent vomiting
- enlarged liver - poor feeding
-hypotonia - lack of appetite
- ataxia / loss of coordination - dizziness
- space and time disorientation - heavy or rapid breathing / respiratory distress
- confused status - irritability
- visual and speech impairment - diarrhea
- migraine - fever Diagnosis

blood tests for ammonia
liver biopsy
prenatal Treatment

liver transplant
high caloric low protein diet/nutrition
amino acid supplementation
nitrogen disposal medication (sodium benzoate, sodium phenylbutyrate) Thank you! References:

Genetic, structural and biochemical basis of carbamoyl phosphate synthetase 1 deficiency http://www.sciencedirect.com/science/article/pii/S1096719210002982#

Carbamoyl Phosphate Synthetase 1 deficiency in Italy: Clinical and genetic findings in a heterogeneous cohort http://www.sciencedirect.com/science/article/pii/S0378111911007220#

Molecular and clinical analyses of Japanese patients with carbamoylphosphate synthetase 1 (CPS1) deficiency http://ehis.ebscohost.com/eds/detail?sid=69e04aa4-938b-4ff2-a2e1-e8ffe36d800%40sessionmgr4&vid=1&hid=16&bdata=#db=mnh&AN=17310273

A case of carbamoyl phosphate synthetase 1 deficiency presenting symptoms at one month of age http://www.sciencedirect.com/science/article/pii/S0387760408002994

Carbamoyl phosphate synthetase I deficiency

Carbamoyl Phosphate Synthetase One Deficiency

Carbamoyl phosphate synthetase deficiency clinical presentation

What is a urea cycle disorder?

Hyperammonemia pathophysiology

What is urea?

http://www.omim.org/entry/237300?search=cps1%20deficiency&highlight=deficiency%20cps1 Carbamoyl Phosphate Synthetase 1 deficiency in Italy: Clinical and genetic findings in a heterogeneous cohort http://bcs.whfreeman.com/lehninger/pages/bcs-main.asp?s=18000&n=00010&i=18010.04&v=chapter&o=|00510|00520|00530|00540|00550|00PRS|00010|00020|00030|00040|00050|00060|00070|00080|00090|00100|00110|00120|01000|02000|03000|04000|05000|06000|07000|08000|09000|10000|11000|12000|13000|14000|15000|16000|17000|18000|19000|20000|21000|22000|23000|24000|25000|26000|27000|28000|99000|&ns=0&t=&uid=0&rau=0 S. Funghini, J. Thusberg, M. Spada, S. Gasperini, R. Parini, L. Ventura, C. Meli, L. De Cosmo, M. Sibilio, S.D. Mooney, R. Guerrini, M.A. Donati, A. Morrone
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