Overview

Characterised by elevated levels of the toxic intermediary non-essential amino acid homocysteine.

The currently described genetic causes for homocystinuria all show autosomal recessive inheritance.

Accumulation of homocysteine leads to complications involving multiple body systems:

• Aggressive vascular disease and thrombosis
• Developmental delay and seizures
• Connective tissue disease with Marfanoid body habitus
• Ophthalmic complications

While homocystinuria strictly refers to the high levels of homocysteine caused by a defect in the cystathione β-synthase enzyme, high homocysteine levels have a number of other potential causes - inherited and acquired.

Epidemiology

Homocystinuria is rare, with a prevalence of around 1/200,000 births worldwide.

There is an increased incidence in certain populations; particularly in Qatar, where the incidence is reported at 1/1,800. [El-Said et al, 2006]

Pathophysiology

Some degree of hyperhomocysteinaemia is relatively common, occurring in about 5-10% of the population.

Homocysteine levels high enough to cause disease are generally due to an inborn error of metabolism, or severe vitamin B12/folate deficiency

Inborn errors of metabolism

Classical homocysteinuria

'Classical' homocysteinuria refers to impaired function of the cystathione β-synthase (CBS) enzyme, which is involved in the conversion of homocysteine to the amino acid cysteine. Homocysteinuria due to CBS deficiency is often treated with high doses of vitamin B6 (pyridoxine), which is a co-factor of CBS.

Remethylation defects

Impaired remethylation of homocysteine also leads to high homocysteine levels - though these are typically not classified as homocysteinuria.

Methyltetrahydrofolate reductase (MTHFR) deficiency results in a reduced ability to synthesise methionine from homocysteine, leading to both high homocysteine levels and low methionine levels.

Disorders of cobalamin metabolism also impact the processing of homocysteine. These disorders reduce the availability of vitamin B12, which is used in the conversion of homocysteine to methionine.

Acquired hyperhomocysteinaemia

Deficiencies of vitamin B6, folate, and vitamin B12 are common causes of high homocysteine levels. Other causes include chronic renal failure, hypothyoidism, malignancy and certain drugs. [Kim et al, 2018]

Impacts on anaesthesia

Nitrous Oxide

Proposed mechanism: nitrous oxide inhibition of methionine synthase activity

Nitrous oxide is known to cause irreversible inhibition of methionine synthase by oxidation of the cobalt atom in vitamin B12 - a necessary cofactor. Enzyme activity has been shown experimentally to be reduced to zero after 200 minutes of exposure, with de-novo synthesis of the methionine synthase enzyme required to restore activity. [Royston et al, 1988]

Case Reports The death of a patient with an undiagnosed MTHFR (i.e. homocysteine remethylation) defect has been attributed to nitrous oxide exposure.

The case report details that a family history of high homocysteine levels was noted in retrospect, and the patient was found post-mortem to have an MTHFR mutation resulting in low methionine synthase activity. The patient developed severe neurological deterioration over the course of a month and ultimately died from respiratory failure. [Selzer et al, 2003]

At least two similar cases are reported in the literature. [McNeely et al, 2000] [Felmet et al, 2000]

Expert Opinion While nitrous oxide does not cause the same catastrophic neurological impact on patients with classical homocystinuria, its impact on vitamin B12 activity does increase plasma homocysteine levels [Gerarrd et al, 2022] and should therefore be avoided.