DISORDERS OF PURINE & PYRAMIDINE METABOLISM Flashcards
1
Q
What are Purine and Pyrimidines?
A
Related compounds based on purine or pyrimidine rings. Found in the body as metabolic intermediates, dietary constituents and medications.
2
Q
What is a nucleoside?
A
Base and a pentose sugar (usually ribose or deoxyribose) in an N-glycosidic linkage.
Examples:
- Adenosine (adenine and ribose)
- Deoxyguanosine (guanine and deoxyribose)
- Cytidine (cytosine and ribose)
3
Q
What is a Nucleotide?
A
Nucleoside with added phosphate groups (can be mono-, di- or tri- phosphate esters)
Examples:
- Adenosine Triphospate (adenosine and 3 phosphates)
- Uridine monophosphate (uridine and 1 phosphate)
- Deoxyguanosine diphosphate (deoxyguanosine and 2 phosphates)
4
Q
How are Purines and Pyrimidines used within the body?
A
- DNA and RNA replication
- High energy compounds
- Cellular signalling
- Coenzyme A
- Glycosylation reactions
5
Q
What some features of Inborn Errors of Metabolism associated with Purines and Pyrimidines?
A
- 35 defects of purine and pyrimidine metabolism identified. ~20 associated with serious clinical consequences
- Usually not full enzyme blocks cause abnormal concentrations of nucleotides in cells, or nucleosides and bases in body fluids
- Diverse clinical spectrum; patients often have non-specific symptoms but some disorders can be grouped by features: Immunological (SCID), Haematological (anaemia), Neurological (various), Renal (stones)
6
Q
What are the Biosynthetic pathway associated Purine Disorders?
A
- PRPP synthetase deficiency: X linked disorder leading to superactivity. You get excess de-novo synthesis of purine leading to high excretion of uric acid so you get uric acid stones and gout
- ADSL deficiency: present neurologically with seizure and if in the neonatal, can present with encephalopathy. If it presents later in life then it can present with autism and intellectual impairment
- ATIC deficiency: Present quite simarly with ADSL but with blindness and seziure
7
Q
What are the Catabolic Pathway associated Purine Disorders?
A
- Adenosine monophosphate deaminase (AMPDA) deficiency
- Severe Combined Immunodeficiency (SCID)
- Adenosine deaminase (ADA) deficiency
- Purine nucleoside phosphorylase (PNP) deficiency
- Xanthine Oxidase dehydrogenase Deficiency
8
Q
What are features of Adenosine monophosphate deaminase (AMPDA) deficiency?
A
- AMPDA catalyses the deamination of AMP to IMP and ammonia in skeletal muscle
- Potentially pathological variant is present in 12% of Caucasian population, but vast majority of homozygotes remain asymptomatic.
9
Q
What are symptoms and diagnosis of Adenosine monophosphate deaminase (AMPDA) deficiency?
A
Symptoms
- Exercise-related muscular weakness, muscle cramps and increased CK
Diagnosis
- Forearm ischaemic exercise test: Normal rise in lactate and Absent rise in ammonia
- Muscle histology
10
Q
What is the treatment of Adenosine monophosphate deaminase (AMPDA) deficiency?
A
Ribose or xylitol before exercise can help exercise tolerance.
11
Q
What are features of Severe Combined Immunodeficiency?
A
- X-linked SCID most common form of inherited SCID, but be aware of other causes, including ADA/PNP deficiency.
- SCID is a possible candidate for newborn screening
- Purine and pyrimidine analysis useful for diagnosis of screen-positive cases
- X-linked SCID due to defects in interleukin signalling (60-75% inherited SCID)
- ADA second most common cause overall (10-15% inherited SCID) and most common cause in females
12
Q
What are features of Adenosine deaminase (ADA) deficiency?
A
- ADA catalyses the irreversible deamination of adenosine and deoxyadenosine to inosine and deoxyinosine
- dATP inhibits ribonucleotide reductase, preventing DNA synthesis
- T- and B- cells are highly mitotically active so they are severely affected by ADA deficiency
13
Q
What are symptoms and investigation of Adenosine deaminase (ADA) deficiency?
A
Symptoms
- Severe combined immunodeficiency (SCID) – marked lymphopaenia, skeletal abnormalities, deafness, below average IQ.
Diagnosis
- ↑deoxyadenosine (U,P)
- ↑dATP (RBC)
- Absent ADA activity (RBC)
14
Q
What is the treatment of Adenosine deaminase (ADA) deficiency?
A
- Bone marrow transplant
- Pegylated ADA (enzyme replacement)
- Strimvelis (stem cell therapy)
15
Q
What are features of Purine Nucleoside Phosphorylase (PNP) deficiency?
A
- PNP catalyses the reversible cleavage of inosine and guanosine and their deoxy counterparts to hypoxanthine and guanine
- Deficiency leads to profound hypouricaemia and accumulation of dGTP
- Excess dGTP toxic to T-cells with a variable degree of B-cell dysfunction
16
Q
What are symptoms and investigation of Purine Nucleoside Phosphorylase (PNP) deficiency?
A
Symptoms
- Severe combined immunodeficiency (SCID) – marked lymphopaenia, neurological abnormalities, haemolytic anaemia
Diagnosis
- ↑ deoxyguanosine (U,P)
- ↑ dGTP (RBC)
- ↓ urate (U,P)
- Absent PNP activity (RBC or fibroblasts)
17
Q
What are treatments of Purine Nucleoside Phosphorylase (PNP) deficiency?
A
Bone marrow Transplant
18
Q
How does Xanthine Oxidase dehydrogenase Deficiency present?
A
Present with xanthine stones and can precipitate urinary failure
19
Q
What are some Salvage Pathway associated Purine Disorders?
A
- Hypoxanthine-guanine phosphoribosyl transferase (HPRT) deficiency
- Adenine phosphoribosyltransferase (APRT) deficiency (2,8-dihydroxyadeninuria)
20
Q
What are features of Hypoxanthine-guanine phosphoribosyl transferase (HPRT) deficiency?
A
- Also known as Lesch-Nyhan syndrome
- X-linked disorder
- HPRT catalyses recycling of purine bases hypoxanthine and guanine to nucleotides
- Full spectrum of residual enzyme activity, from mild to severe
21
Q
What are symptoms and diagnosis of Hypoxanthine-guanine phosphoribosyl transferase (HPRT) deficiency?
A
Symptoms
- Self-mutilation, Impulsive aggression, Dystonia, Motor retardation, Gout, Renal stones and Megaloblastic anaemia.
Diagnosis
- ↑ uric acid (U,P)
- ↑ hypoxanthine (U,P)
- ↑ xanthine (U,P)
22
Q
What are treatments of Hypoxanthine-guanine phosphoribosyl transferase (HPRT) deficiency?
A
- Allopurinol
- High fluid intake
- Low purine diet
- Urine alkalinisation
23
Q
What are features of Adenine phosphoribosyltransferase (APRT) deficiency (2,8-dihydroxyadeninuria)?
A
- In the absence of APRT, xanthine oxidase oxidises adenine to form 2,8-dihydroxyadenine which is highly insoluble, leads to renal stone formation
- Important to diagnose correctly, as 2,8-dihydroxyadenine is insoluble at alkaline pH (urine alkalinisation used to treat uric acid stones)
24
Q
What are signs and symptoms of Adenine phosphoribosyltransferase (APRT) deficiency (2,8-dihydroxyadeninuria)?
A
Symptoms
- Renal stones, UTIs, renal failure
Diagnosis
- ↑ 2,8-dihydroxyadenine (U)
25
What is the treatment of Adenine phosphoribosyltransferase (APRT) deficiency (2,8-dihydroxyadeninuria)?
* Allopurinol
* High fluid intake
* Low purine diet
* Urine acidification
26
What are biosynthetic pathway associated Pyrimidine disorders?
Uridine monophosphate synthase deficiency (hereditary orotic aciduria)
27
What is Uridine monophosphate synthase?
UMPS is a bifunctional enzyme with two parts:
* Orotate phosphoribosyltransferase (OPRT) – converts orotic acid to orotidine monophosphate (OMP)
* Orotidine monophosphate decarboxylase (OMPDC) – converts OMP to UMP
28
What are the 3 types of Uridine monophosphate synthase deficiency?
* **Type I:** Severe loss of activity, inactivation of both OPRT and OMPDC
* **Type II:** Inactivation of OMPDC only, but clinically indistinguishable from type I due to end-product repression of synthesis of OPRT
* **Type III:** Orotic aciduria without megaloblastic anaemia, due to inhibition of OMPDC
29
What are symptoms, investigations and treatment for Uridine monophosphate synthase deficiency?
**Symptoms**
* Megaloblastic anaemia
* Orotic acid crystalluria (very rarely renal stones)
**Diagnosis**
* ↑↑ orotic acid (U)
* Normal ammonia
**Treatment**
* Uridine
30
What are catabolic pathway associated Pyrimidine disorders?
* Thymidine Phosphorylase (TP) deficiency
* Dihydropyrimidine Dehydrogenase (DPD) deficiency
* Dihydropyrimidinase (DHP) deficiency
* Ureidopropionase (UP) deficiency
31
What are features of Thymidine Phosphorylase (TP) deficiency?
* TP converts thymidine and deoxyuridine to their bases thymine and uracil.
* In the absence of TP, the nucleotides of these compounds accumulate. These interfere with mitochondrial DNA replication leading to a mitochondrial depletion syndrome.
32
What are symptoms and investigations of Thymidine Phosphorylase (TP) deficiency?
**Symptoms**
* Ptosis, GI dysmotility, leukoencephalopathy, peripheral neuropathy, myopathy. Average life expectancy 37 years.
Diagnosis
* ↑ Thymidine (U,P)
* ↑ Deoxyuridine (U,P)
* White matter changes on MRI
33
What is the management of Thymidine Phosphorylase (TP) deficiency?
* Dialysis and platelet transfusion can reduce thymidine temporarily.
* Trials of stem cell and enzyme replacement ongoing.
34
What are symptoms and investigations of Dihydropyrimidine Dehydrogenase (DPD) deficiency?
**Symptoms**
* Diverse presentation but frequently asymptomatic. Epilepsy, psychomotor retardation, microcephaly, skeletal abnormalities
**Diagnosis**
* ↑ Uracil (U,P)
* ↑ Thymine (U,P)
35
What is the management of Dihydropyrimidine Dehydrogenase (DPD) deficiency?
* Symptomatic relief
* Avoidance of 5-fluorouracil
36
What are symptoms and investigations of Dihydropyrimidinase (DHP) deficiency?
**Symptoms**
* Diverse presentation but frequently asymptomatic. Epilepsy, psychomotor retardation, microcephaly, skeletal abnormalities
* plus hypotonia and GI problems
**Diagnosis**
* ↑ Uracil (U,P)
* ↑ Thymine (U,P)
* ↑ Dihydrouracil (U,P)
* ↑ Dihydrothymine (U,P)
37
What is the management of Dihydropyrimidinase (DHP) deficiency?
* Symptomatic relief
* Avoidance of 5-fluorouracil
38
What are symptoms and investigations of Ureidopropionase (UP) deficiency?
**Symptoms**
* Diverse presentation but frequently asymptomatic. Epilepsy, psychomotor retardation, microcephaly, skeletal abnormalities
* As DPD plus ocular defects (optic atrophy, retinopathy), urogenital and colorectal abnormalities
**Diagnosis**
* ↑ Uracil (U,P)
* ↑ Thymine (U,P)
* ↑ Dihydrouracil (U,P)
* ↑ Dihydrothymine (U,P)
* ↑ B-ureidopropionate (U,P)
* ↑ B-ureidoisobutyrate (U,P)
39
What is the management of Ureidopropionase (UP) deficiency?
* Symptomatic relief
* Avoidance of 5-fluorouracil
40
What are features of 5-Fluorouracil toxicity?
* DPD and related disorders (DHP and UP) are strongly associated with 5-FU toxicity
* Treatment for solid tumours e.g. breast, ovarian and colon cancers.
* Prevalence of low activity variants is very similar to TPMT. Low activity leads to 5-FU accumulation and toxicity.
41
What are symptoms of 5-Fluorouracil toxicity?
* Neutropaenia
* Paralysis
* Death
42
What diagnostic techniques for 5-Fluorouracil toxicity?
Routine laboratory tests
* Plasma/urine uric acid (purine disorders only), but may not detect milder forms
* Some disorders lead to increased uric acid production, e.g.: HPRT deficiency (Lesch-Nyhan syndrome), PRPP synthetase superactivity
* Others lead to decreased uric acid production, e.g.: PNP deficiency, XOD deficiency
43
What specialist assays for 5-Fluorouracil toxicity?
**Urinary organic acids**
* Uracil, thymine (e.g. DPD deficiency)
* Dihydrouracil, dihydrothymine (e.g. DHP/UP deficiency)
* Orotic acid (e.g. hereditary orotic aciduria)
**Purine & pyrimidine analysis by HPLC-MS/MS or HPLC-UV (urine or plasma)**
44
What are salvage pathway associated Pyrimidine Disorders?
**Thymidine Kinase deficiency:** No way to currently find it as no biochemistry available
