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Paediatric Biochemistry > DISORDERS OF PURINE & PYRAMIDINE METABOLISM > Flashcards

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.

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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)
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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)
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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
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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)
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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
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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
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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.
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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
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10
Q

What is the treatment of Adenosine monophosphate deaminase (AMPDA) deficiency?

A

Ribose or xylitol before exercise can help exercise tolerance.

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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
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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
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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)
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14
Q

What is the treatment of Adenosine deaminase (ADA) deficiency?

A
  • Bone marrow transplant
  • Pegylated ADA (enzyme replacement)
  • Strimvelis (stem cell therapy)
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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
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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)
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17
Q

What are treatments of Purine Nucleoside Phosphorylase (PNP) deficiency?

A

Bone marrow Transplant

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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
Q

What is the treatment of Adenine phosphoribosyltransferase (APRT) deficiency (2,8-dihydroxyadeninuria)?

A
  • Allopurinol
  • High fluid intake
  • Low purine diet
  • Urine acidification
26
Q

What are biosynthetic pathway associated Pyrimidine disorders?

A

Uridine monophosphate synthase deficiency (hereditary orotic aciduria)

27
Q

What is Uridine monophosphate synthase?

A

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
Q

What are the 3 types of Uridine monophosphate synthase deficiency?

A
  • 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
Q

What are symptoms, investigations and treatment for Uridine monophosphate synthase deficiency?

A

Symptoms

  • Megaloblastic anaemia
  • Orotic acid crystalluria (very rarely renal stones)

Diagnosis

  • ↑↑ orotic acid (U)
  • Normal ammonia

Treatment

  • Uridine
30
Q

What are catabolic pathway associated Pyrimidine disorders?

A
  • Thymidine Phosphorylase (TP) deficiency
  • Dihydropyrimidine Dehydrogenase (DPD) deficiency
  • Dihydropyrimidinase (DHP) deficiency
  • Ureidopropionase (UP) deficiency
31
Q

What are features of Thymidine Phosphorylase (TP) deficiency?

A
  • 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
Q

What are symptoms and investigations of Thymidine Phosphorylase (TP) deficiency?

A

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
Q

What is the management of Thymidine Phosphorylase (TP) deficiency?

A
  • Dialysis and platelet transfusion can reduce thymidine temporarily.
  • Trials of stem cell and enzyme replacement ongoing.
34
Q

What are symptoms and investigations of Dihydropyrimidine Dehydrogenase (DPD) deficiency?

A

Symptoms

  • Diverse presentation but frequently asymptomatic. Epilepsy, psychomotor retardation, microcephaly, skeletal abnormalities

Diagnosis

  • ↑ Uracil (U,P)
  • ↑ Thymine (U,P)
35
Q

What is the management of Dihydropyrimidine Dehydrogenase (DPD) deficiency?

A
  • Symptomatic relief
  • Avoidance of 5-fluorouracil
36
Q

What are symptoms and investigations of Dihydropyrimidinase (DHP) deficiency?

A

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
Q

What is the management of Dihydropyrimidinase (DHP) deficiency?

A
  • Symptomatic relief
  • Avoidance of 5-fluorouracil
38
Q

What are symptoms and investigations of Ureidopropionase (UP) deficiency?

A

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
Q

What is the management of Ureidopropionase (UP) deficiency?

A
  • Symptomatic relief
  • Avoidance of 5-fluorouracil
40
Q

What are features of 5-Fluorouracil toxicity?

A
  • 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
Q

What are symptoms of 5-Fluorouracil toxicity?

A
  • Neutropaenia
  • Paralysis
  • Death
42
Q

What diagnostic techniques for 5-Fluorouracil toxicity?

A

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
Q

What specialist assays for 5-Fluorouracil toxicity?

A

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
Q

What are salvage pathway associated Pyrimidine Disorders?

A

Thymidine Kinase deficiency: No way to currently find it as no biochemistry available

Paediatric Biochemistry (31 decks)

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