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Communication is the Key to Successful Anesthesia in a Patient
with Asymptomatic MTHFR Deficiency
Gregory Kozlov DO, Ivan Kukhar MD, and David J. Lang DO
Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, IL 60657 USA
Abstract
The key to any successful anesthetic is open lines of
communication between all involved parties: patients,
physicians, nursing staff, and families of patients. We present a
case that could have had less than desirable outcomes if
information concerning a child with methyltetrahydrofolate
deficincy. The dentist had called the anesthesia department and
sent records for review in advance of the case. With this
information, a safe and successful anesthetic was done.
Introduction
5,10-Methylenetetrahydrofolate Reductase (MTHFR) deficiency,
also known as Type III Homocysteinuria, is an autosomal
recessive genetic disorder characterized by severe elevation in
plasma and urine homocysteine and extreme deficiency of
methionine. Prevalence of the disease in the general population
is unknown. In European, Middle Eastern, and Japanese
populations the prevalence of the homozygous mutation is 10%
to 15%. In African-Americans the prevalence is below 1.4%.
MTHFR deficiency affects about 200,000 Americans, females
more than males (2/3 of cases), with a spectrum of
manifestations including neurologic symptoms, premature
atherosclerosis, venous and arterial thrombosis. The disease
may manifest itself at any age from infancy to adulthood.
Nitrous oxide oxidizes the cobalt atom of vitamin B12, thereby
inactivating vitamin B12 as a necessary cofactor for methionine
synthase function. The subsequent accumulation of 5methyltetra-hydrofolate due to inactive methionine synthase is
called folate trapping. MTHFR catalyses the reduction of 5,10methylenetetrahydrofolate
to
5-methyltetrahydrofolate,
deficiency of this enzyme also leads to folate trapping. Selzer
et al.* postulated a double-hit hypothesis to explain the
pathophysiology of the fatal neurologic outcome in patient with
MTHFR deficiency exposed to nitrous oxide. This hypothesis
links nitrous oxide-induced hyperhomocysteinemia and inhibition
of folate metabolism with an underlying MTHFR gene defect.
Case Description
A 13-yr-old autistic boy (height-144cm, weight-30 kg) diagnosed with MTHFR deficiency was
scheduled for dental rehabilitation under general anesthesia. One day prior to the surgery,
patient’s dentist contacted the anesthesia department and advised that, because of MTHFR
deficiency, the anesthesiologist should not administer nitrous oxide during the surgery, or the
patient would die!!! With this in mind, the nitrous oxide hose disconnected from the
anesthesia machine, and the machine was flushed with oxygen for ten minutes. The patient
was premedicated with midazolam 15 mg orally, and induced via mask with oxygen and
sevoflurane. After a peripheral intravenous line was started, fentanyl 60 mcg (2mcg/kg),
rocuronium 20 mg (0.6mg/kg) and glycopyrrolate 0.1mg were administered. Following direct
laryngoscopy, the trachea was intubated with nasal RAE tube. Anesthesia was maintenaned
with sevoflurane (2.2-2.4 vol%) and 50% FIO2. The duration of the case was two hours and
12.5 mcg of fentanyl, and 15 mg of ketorolac were administered. The procedure was
uneventful. Neuromuscular blockade was reversed with neostigmine 1mg (0.03 mg/kg) and
glycopyrrolate 0.1 mg. After successful extubation, patient taken to recovery room.
The postoperative period was uneventful and patient discharged home on the same day.
Homocysteine Pathway
References
Yamada T, et al. J Clin Anesth 2005;17: 565-7.
Selzer RR, et al. N Engl J Med. 2003;349:45-50.
Global Distribution of MTHFR
Discussion
The inhibition of methionine synthase by nitrous oxide
has two consequences:
• First: homocysteinemia causes endothelial
dysfunction in blood vessels and enhanced platelet
aggregation, which may lead perioperative
thromboembolic events and myocardial ischemia
• Second: folate trapping, severely limits the de novo
synthesis of DNA resulting in apoptosis of rapidly
dividing cells. This process is the cause for the
megaloblastic changes observed in bone marrow
neurological deterioration.
Nitrous oxide-induced homocysteinemia and folate
trapping can be catastrophic when they develop in
conjunction with an inherited MTHFR enzyme
deficiency.
Because MHFTR may be undiagnosed until
adulthood, the anesthesiologist must be keenly aware
of clues as to the possibility that their patient may be
affected by MTHFR deficiency: combination of high
risk ethnic background, family history, spina bifida,
young women with coronary and carotid artery
disease, and mental retardation may suggest further
investigation.
There are several key features of the disease that are
of particular interest to anesthesia providers:
• Microcephaly leading to difficult intubation
• Hypercoagulability
• Predisposition to preeclampsia,
• Absolute contraindication to nitrous oxide.
The anesthetic plan for patients with MTHFR
deficiency should include:
• anticipation of difficult airway
• precautions for thromboembolic events
• avoiding nitrous oxide.
With some foresight and planning, general anesthesia
can be administered to these patients uneventfully.