She denies any problems with her two previous C Sections, both performed with an epidural.
Since her deliveries, she reports that she was genotyped by a direct to consumer genomic service and is a carrier for Pseudocholinesterase Deficiency, specifically something called rs28933389.
“I looked it up and it said I might have a problems with anesthesia,” she says.
What Can I Learn From This Patient?
Direct to consumer genomic services are becoming more common. Information contained in these reports may encourage you to increase your understanding of genomics.
Genomics is a rapidly developing discipline that has seen incredible progress over the last two decades. Since the completion of the human genome project in 2003, the price of sequencing a single genome has decreased from $3 billion to between $5,000 and $10,000, coming close to the $1,000 per genome goal. In fact, whole genome sequencing can now be performed in less than a week . Today, a little over a decade after the first human genome has been sequenced, anyone can access their genetic information – it is just a click and swab away.
There is widespread public interest in personal genetic testing, both due to the risk prediction value and the explanatory aspect regarding existing medical conditions. Several companies already offer their genotyping services. 23andMe is a company that performs partial SNP (single nucleotide polymorphism) genotyping, and as of June 2015, has genotyped over 1,000,000 individuals. More than half a million people have their genetic information stored in the Icelandic deCODE Genetics’ database. A new project – Helix was kicked off by Illumina in August 2015, offering a novel “sequence once, query often” approach. This approach focuses on the development of specialized apps that will answer one consumer need at a time. The biggest issue at this time remains figuring out a way to make use of this personal genomic information in day-to-day clinical practice.
Wait, What Is Pseudocholinesterase Deficiency?
Anesthetics like succinylcholine and tetracaine act longer in patients who have pseudocholinesterase deficiency because pseudocholinesterase breaks them down.
Pseudocholinesterase, also known as butyrylcholinesterase (BCHE), is an enzyme that is produced in the liver and is present in most tissue throughout the body and the plasma. Although its endogenous physiological role is unknown, it degrades the muscle relaxants succinylcholine and mivacurium as well as ester local anesthetics (chloroprocaine, procaine, benzocaine, tetracaine). Muscle relaxants are generally used to intubate a patient during surgery or during an emergency situation when a secured airway must be obtained.
These muscle relaxants are usually fast acting and broken down by pseudocholinesterase in the plasma in a few minutes, however if a patient has pseudocholinesterase deficiency the patient can experience prolonged muscle paralysis and apnea requiring continued ventilatory support and monitoring for up to several hours.
Pseudocholinesterase deficiency is inherited in an autosomal recessive fashion. It has been estimated that approximately 24% of people carry at least one variant of this allele. Approximately 70 mutations have been documented with most mutations having an adverse effect on pseudocholinesterase activity. In the normal homozygous (EuEu) succinylcholine muscle relaxation usually last approximately 5 minutes, in the heterozygous (EuEa) it lasts approximately 15 minutes, and in the abnormal homozygous it lasts anywhere from 120 to 300 minutes.
SNPs – Misense or Nonsense?
A SNP can change the structure of a protein by changing an amino acid, which in this case prolongs the effects of certain anesthetics because they can longer be metabolized.
rs28933389 is a single nucleotide polymorphisms (SNP) in the gene for pseudocholinesterase and is located on chromosome 3q26.1. This particular SNP is a “missense” mutation because the presence of a certain base modification leads to substitution of a specific amino acid in the enzyme encoded by this gene. The presence of the base “T” is recessive and it causes substitution of the amino acid threonine at 243 position to a methionine (thr243met). This patient is a carrier which means she only has one copy of the gene. This missense mutation leads to low activity of the pseudocholinesterase enzyme which translates into longer clinical effect.
Can I Trust This Information?
Although the accuracy of direct to consumer genetic tests have been reported as >99%, false positives do occur.
23andme, one of the largest direct to consumer genomic services companies as of 2016, uses the Illumina HumanOmniExpress-24 chip to call SNPs on its samples. Per Illumina’s data sheet, it has a reproducibility of 99.99%. As 23andme reports on approximately 600,000 SNPs, an error rate of approximately 0.1% implies that roughly 60 SNP calls may be inaccurate per individual. Therefore, error does exists but it is extremely rare. For this reason, the raw genetic data produced by 23andme comes with a disclaimer that it “is suitable only for research, educational, and informational use and not for medical or other use.” One such case report of a false positive result has been described with Long QT Syndrome.
Should This Information Change My Approach?
It’s hard to ignore this information, even if the source of the information might be wrong. However, you might be able to test the activity of pseudocholinesterase by sending a dibucaine number and cholinesterase activity level.
Usually in clinical practice, one does not consider pseudocholinesterase deficiency until a patient has prolonged response to succinylcholine. However, with genomic services becoming less expensive and more convenient, this paradigm may change.
One should perform, as they do for any patient, a thorough history before the procedure. Has this patient had surgery before? If so, what was the procedure? Did it involve general anesthesia? If so, did the patient have any abnormal or adverse reactions to medications used? The patient should be asked about any blood related relatives that have had “prolonged awakening” from anesthesia. If possible, anesthetic records from previous surgeries should be obtained. A strong family history of prolonged awakening from anesthesia along with a known mutation in pseuducholinesterase might lead one to reconsider succinylcholine.
The conventional way of establishing abnormal pseudocholinesterase activity is with the dibucaine number after a patient has had prolonged apnea following anesthesia or a family history that initiates testing. However, if this genotype is known ahead of time, the patient can be sent for testing to help quantify the range of pseudocholinesterase deficiency. The dibucaine number is a laboratory test that can give the quality, not quantity, of typical pseudocholinestase in approximately 1-5 days. A dibucaine number of 70-80 denotes a homozygous typical phenotype. A number of 50-60 denotes heterozygous atypical pseudocholinesterase, with a response time to succinylcholine lengthened by 50-100%. A number of 20-30 denotes the homozygous atypical phenotype and succinylcholine activity prolongation of 2-5 hours. This test is limited by only being able to identify some of the pseudocholinesterase variants.
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