Disorders of purines, pyrimidines and nucleotide metabolism

Disorders of Purines, Pyrimidines and Nucleotide Metabolism

Overview

Purines and pyrimidines are essential components of DNA and RNA. Their metabolism involves de novo synthesis, salvage pathways, interconversion, and degradation. Genetic defects in these pathways can cause metabolic, neurological, renal, hematological, immunological and developmental disorders.

Conditions Covered

Purine Metabolism Disorders

• Lesch–Nyhan syndrome — HPRT1
• Kelley–Seegmiller syndrome — HPRT1
• Adenosine deaminase deficiency — ADA
• Purine nucleoside phosphorylase deficiency — PNP
• Adenylosuccinate lyase deficiency — ADSL
• Adenosine monophosphate deaminase deficiency — AMPD1
• Xanthinuria — XDH / MOCS1
• Phosphoribosyl pyrophosphate synthetase disorders — PRPS1
• APRT deficiency — APRT
• Molybdenum cofactor-related purine degradation disorders

Pyrimidine Metabolism Disorders

• Dihydropyrimidine dehydrogenase deficiency — DPYD
• Dihydropyrimidinase deficiency — DPYS
• Beta-ureidopropionase deficiency — UPB1
• Hereditary orotic aciduria — UMPS
• CAD-associated pyrimidine synthesis disorders — CAD
• Mitochondrial pyrimidine metabolism disorders

Nucleotide Metabolism Disorders

• Thymidine phosphorylase deficiency — TYMP
• Deoxyguanosine kinase-related disorders — DGUOK
• Nucleoside phosphorylase and nucleotide salvage defects
• Disorders affecting nucleotide biosynthesis, salvage and degradation pathways

Clinical Features

Depending on the affected pathway, patients may present with:

• Developmental delay and intellectual disability
• Seizures and movement disorders
• Hypotonia or neurological abnormalities
• Recurrent infections and immunodeficiency
• Hyperuricemia and gout
• Kidney stones or nephropathy
• Metabolic acidosis
• Megaloblastic anemia
• Failure to thrive
• Exercise intolerance or muscle weakness
• Medication toxicity, particularly with 5-fluorouracil in DPYD deficiency

Sample Types

• Peripheral blood
• EDTA blood
• Saliva/buccal sample where applicable
• Other specimens depending on the specific molecular test

Testing Methodology

A comprehensive gene panel may use:

• Next-Generation Sequencing (NGS)
• Sequence analysis of coding regions and splice sites
• Copy Number Variant (CNV) analysis
• Deletion/duplication analysis
• Confirmation of clinically significant variants by an orthogonal method where appropriate

Clinical Utility

The panel can help:

• Establish a molecular diagnosis
• Identify the genetic cause of unexplained metabolic abnormalities
• Support diagnosis of inherited metabolic disorders
• Guide clinical management and surveillance
• Assess recurrence risk and facilitate genetic counselling
• Enable targeted testing of family members when a pathogenic variant is identified

Important Note

Interpretation should be performed along with clinical findings, biochemical/metabolic investigations, family history and other laboratory results. A negative panel does not completely exclude a genetic disorder if the causative gene or variant type is outside the scope of the assay.