Pharmacogenetics in Neurology
5 sections · 20 min
Principles of Pharmacogenetics
Pharmacogenetics is the study of how genetic variation influences drug response — affecting absorption, distribution, metabolism, excretion (ADME), and pharmacodynamic drug targets. Genetic variants in drug-metabolizing enzymes alter plasma drug concentrations, creating a spectrum from toxicity (impaired metabolism → drug accumulation) to therapeutic failure (ultra-rapid metabolism → subtherapeutic levels). The major clinical phenotypes are: poor metabolizer (PM), intermediate metabolizer (IM), normal/extensive metabolizer (NM/EM), and ultra-rapid metabolizer (UM).
Key Points
- Phase I metabolism: CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5) — oxidation, reduction, hydrolysis; most critical for neurological drug metabolism
- Phase II metabolism: UGT enzymes (glucuronidation), TPMT (thiopurine methylation), NAT2 (acetylation) — less critical for most neurological drugs but important for valproate (UGT1A6/UGT2B7)
- Star (*) allele nomenclature: reference allele = *1 (normal function); loss-of-function alleles (e.g., CYP2C9*2, *3); gain-of-function alleles (CYP2D6*1xN gene duplication = ultra-rapid)
- Copy number variation: CYP2D6 gene can be deleted (PM), duplicated (UM), or multiplied (UM with >2 functional copies); CYP2D6*1xN duplication causes UM phenotype
- CPIC guidelines (cpicpgx.org): Clinical Pharmacogenetics Implementation Consortium — evidence-based prescribing recommendations based on genotype; freely available and regularly updated
✦ Check Your Understanding
A woman with epilepsy well-controlled on lamotrigine 300 mg/day becomes pregnant. Her seizure control begins to deteriorate in the second trimester. The pharmacogenetic principle underlying this is:
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CYP450 Enzymes Most Relevant to Neurology
Four CYP450 enzymes are most important for neurological drugs: CYP2C9 (phenytoin, valproate, losartan), CYP2C19 (clopidogrel, clobazam, diazepam, omeprazole), CYP2D6 (tricyclics, opioids, atomoxetine, antipsychotics), and CYP3A4/5 (carbamazepine, oxcarbazepine, statins). Polymorphisms in these enzymes are common — CYP2D6 PM phenotype affects ~7–10% of Europeans; CYP2C19 PM affects ~2–5% of Europeans but up to 15–20% of Asians.
Key Points
- CYP2C9 and phenytoin: poor metabolizers (CYP2C9*2/*3 compound heterozygous) have dramatically reduced phenytoin clearance → toxicity at standard doses; CPIC recommends 25–50% dose reduction and monitoring in PMs; phenytoin has narrow therapeutic index
- CYP2C19 and clopidogrel: clopidogrel is a prodrug requiring CYP2C19 activation; PMs (CYP2C19*2/*3) cannot convert to active thienopyridine → increased stroke/MI risk; CYP2C19 loss-of-function alleles common in Asians (~50% have at least one); alternative antiplatelet therapy (prasugrel, ticagrelor) for PMs
- CYP2C19 and clobazam: clobazam is metabolized to active N-desmethylclobazam by CYP2C19; PMs have 5-fold higher N-desmethylclobazam levels → increased sedation risk; dose reduction recommended
- CYP2D6 and tricyclic antidepressants (amitriptyline, nortriptyline): PMs have very high plasma levels → cardiac arrhythmia, anticholinergic toxicity; UMs have subtherapeutic levels; CPIC recommends alternative antidepressants for PMs/UMs
- CYP3A4/5 and carbamazepine: CYP3A4/5 metabolizes carbamazepine; also induces its own metabolism (autoinduction); drug interactions with CYP3A4 inhibitors/inducers are complex; CYP3A5*3 reduces activity but clinical impact of genotype is less than for CYP2D6/2C19
✦ Check Your Understanding
A patient is found to be a CYP2D6 ultra-rapid metabolizer (UM). She is started on nortriptyline for chronic pain. The pharmacogenetic concern is:
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HLA Alleles and Serious Drug Hypersensitivity in Neurology
Certain HLA alleles confer high risk of severe immune-mediated drug hypersensitivity reactions — Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). Neurologists prescribe several drugs with well-characterized HLA associations. Pre-prescription HLA testing prevents severe, potentially fatal adverse reactions.
Key Points
- HLA-B*15:02 and carbamazepine SJS/TEN: HLA-B*15:02 is present in ~8–10% of Han Chinese, Thai, and other Southeast Asian populations (rare in Europeans <0.1%); carbamazepine-SJS risk is >10-fold higher in carriers; FDA mandates HLA-B*15:02 testing before carbamazepine use in high-risk Asian ancestry patients
- HLA-A*31:01 and carbamazepine: common in Northern Europeans (~5%), Japanese; associated with carbamazepine DRESS and maculopapular exanthem; less severe than SJS/TEN but still clinically significant
- HLA-B*57:01 and abacavir (antiretroviral): hypersensitivity syndrome in ~5% of HIV+ patients; mandated pre-prescription testing in many countries; 100% negative predictive value if absent
- HLA-B*58:01 and allopurinol: common in Han Chinese (~6–8%); strong association with allopurinol SJS/TEN in Asian populations; screening recommended in high-risk ethnic groups before starting allopurinol for gout
- Oxcarbazepine cross-reactivity: patients with HLA-B*15:02 who have SJS with carbamazepine are at risk with oxcarbazepine and structurally related AEDs; avoid in B*15:02 carriers; lacosamide and levetiracetam have no known HLA association; lamotrigine is also associated with HLA-B*15:02-related SJS/TEN risk, though the association is weaker than with carbamazepine
✦ Check Your Understanding
A Han Chinese patient with new-onset epilepsy is being considered for carbamazepine. The FDA-recommended screening test before prescribing is:
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Antiepileptic Drug Pharmacogenomics
Antiepileptic drug (AED) pharmacogenomics encompasses both pharmacokinetic (drug metabolism) and pharmacodynamic (drug target) genetic variation. SCN1A variants that reduce sodium channel sensitivity may explain resistance to sodium channel-blocking AEDs. UGT enzymes metabolize lamotrigine and valproate. POLG mutations contraindicate valproate use. These interactions have direct clinical management implications.
Key Points
- SCN1A and sodium channel AED response: Dravet syndrome is caused by SCN1A loss-of-function; sodium channel-blocking AEDs (oxcarbazepine, lamotrigine, carbamazepine, phenytoin) may paradoxically worsen seizures in Dravet by further reducing Nav1.1; oxcarbazepine and lamotrigine are the most important to avoid as they are commonly prescribed before a genetic diagnosis — valproate, clobazam, and stiripentol are preferred
- POLG (mitochondrial DNA polymerase gamma) mutations and valproate hepatotoxicity: POLG-related disorders (Alpers syndrome, POLG-spectrum disorder) — valproate causes fulminant hepatotoxicity and neurological deterioration; MUST screen for POLG mutations or suggestive features before starting valproate in children with developmental regression or mitochondrial features
- UGT1A4 and lamotrigine: UGT1A4 metabolizes lamotrigine; female sex hormones (pregnancy, oral contraceptives) induce UGT1A4, dramatically increasing lamotrigine clearance; serum level monitoring essential; lamotrigine dose often needs to double during pregnancy
- Valproate and NAGS/CPS1 (urea cycle): valproate inhibits urea cycle → hyperammonemia in partial UCD carriers; valproate-induced hyperammonemic encephalopathy; consider UCD evaluation before valproate in patients with unexplained hyperammonemia or protein aversion
- CYP2C9 and phenytoin toxicity: ~1% of Europeans are CYP2C9 poor metabolizers; phenytoin toxicity (nystagmus, ataxia, lethargy) at standard doses should prompt CYP2C9 genotyping and dose reduction
✦ Check Your Understanding
A child with Dravet syndrome (heterozygous SCN1A loss-of-function variant) continues to have breakthrough seizures. The parent asks about lamotrigine, which helped a friend's child with epilepsy. The appropriate response is:
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Clinical Implementation of Pharmacogenetic Testing
Pharmacogenetic testing is increasingly available as preemptive panels that genotype multiple clinically actionable variants before drug prescribing is needed. Implementation requires understanding how to interpret multi-gene reports, recognizing the limitations of current evidence, and integrating results with clinical context. Several health systems have implemented preemptive pharmacogenomics as part of precision medicine initiatives.
Key Points
- Preemptive vs. reactive testing: reactive testing (at the time of prescribing) requires fast turnaround (days to weeks) which may delay treatment; preemptive panel testing (at first clinical encounter) stores results in EHR for all future prescribing decisions — more cost-effective over time
- Test report interpretation: reports gene name, diplotype (e.g., CYP2D6*1/*4), predicted phenotype (PM/IM/NM/UM), and drug-specific recommendations; metabolizer phenotypes are substrate-specific (same gene, different recommendations per drug)
- Evidence tiers: CPIC grades recommendations as A (action required), B (consider modification), C (inform/optional) — not all variants require prescribing changes; distinguish strong associations from weak signals
- Limitations: most panels cover common variants in European populations; sensitivity lower for non-European ancestries; structural variants (CYP2D6 CNV, CYP2D6-CYP2D7 hybrids) may be missed by simple SNP arrays
- EHR integration: pharmacogenomic clinical decision support (CDS) alerts at the point of prescribing are most effective; passive reporting without alerts has minimal impact on practice; CPIC guidelines are designed for implementation in EHR-based CDS systems
✦ Check Your Understanding
A 2-year-old with developmental regression and suspected mitochondrial disease is being considered for valproate for new seizures. Which assessment is most critical before prescribing?
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