Biotin and demyelinating diseases – a new connection?

There is increasing evidence that metabolic diseases involving the central nervous system may present with an adult onset and mimic degenerative or demyelinating diseases. ¹ Another case is reported in this issue by Bottin et al. They describe the case of a 22-year-old man presenting with a subacute extensive myelopathy with bilateral optic neuropathy mimicking seronegative neuromyelitis optica. Metabolic evaluation revealed biotidinase deficiency, and treatment with high doses of biotin progressively improved the clinical condition. Very few cases of similar observations have been previously reported in adolescents or children with biotinidase deficiency and, as stated by Bottin et al., it becomes increasingly important to include biotinidase assessment in patients with seronegative neuromyelitis optica, especially because biotinidase deficiency can be efficiently treated by pharmacological doses of biotin.

Inborn errors of metabolism often represent model diseases that may shed light on more common neurological disorders. In this perspective, this particular presentation of biotinidase deficiency has to be interpreted in the context of a recent publication claiming that very high doses of biotin (100−600 mg/day) could halt or even improve disease condition in patients with progressive multiple sclerosis (MS). ² These preliminary results were based on an uncontrolled study in a small cohort of patients and have to be taken cautiously. More recently, preliminary results of a randomized placebo-controlled study evaluating the impact of 300 mg/day of biotin in patients with progressive MS have been presented orally at meetings of the American Academy of Neurology and the European Academy of Neurology. ³ Although the results are not yet published, high doses of biotin were said to significantly improve a proportion of patients with progressive MS-related myelopathy and results suggested a decrease in disease progression. The results of a second placebo-controlled trial in patients with chronic optic neuropathies due to MS are awaited later this year.

Biotinidase or biotin deficiency has not been systematically evaluated in patients with MS. It is believed that the 300 mg daily intake of biotin (which corresponds to 10,000 times the recommended daily intake) is efficacious though triggering an endogenous metabolic pathway rather than correcting any biotin deficiency.

Progression in MS (either secondary or primary) is often considered as a consequence of both demyelination and energy failure. ⁴ A large proportion of ATP produced in the nervous system is used by the Na/K ATPase to restore the membrane-resting potential. In the normal condition, myelin insulation reduces the energy demand during impulse propagation because only the nodes of Ranvier are excited. In contrast, in demyelinated fibres where the entire membrane is involved, much more ATP is needed for ion pumping. In MS, energy production may be compromised because of mitochondrial injury. The resulting mismatch between increased energy demand for nerve conduction and decreased supply by impaired mitochondria could bias demyelinated axons towards a state of ‘virtual hypoxia’ culminating in neuronal degeneration. ⁴

Biotin is a cofactor for four essential carboxylases: acetyl-CoA carboxylase (two isoforms) expressed in oligodendrocytes that produces malonyl-CoA, the two-carbon building blocks for fatty acid synthesis, and three other enzymes expressed in neurons (pyruvate carboxylase, 3-methylcrotonyl-CoA carboxylase, propionyl-CoA carboxylase) that generate intermediates for the tricarboxylic acid cycle. Biotin may thus be acting through carboxylase activation to support myelin repair (by promoting fatty acid synthesis) and to protect against hypoxia-driven axonal degeneration (by enhancing energy production). ²

The new finding by Bottin et al. that biotin deficiency (caused by mutations in the biotinidase coding gene involved in biotin recycling) can present as a severe and diffuse demyelinating disorder further supports the idea that biotin is involved in myelin metabolism.

Neuromyelitis optica is an inflammatory demyelinating disorder of the CNS associated with circulating IgG1 antibodies against the astrocyte water channel protein aquaporin 4 (AQP4). The finding that biotinidase might mimic neuromyelitis optica is somewhat surprising at first sight. However, there is an indirect interplay between energy metabolism and regulation of astrocyte volume. Indeed neurons and axons that lose potassium to the extracellular space during action potential propagation must eventually recover this potassium, which may be achieved via their Na/K ATPase. Glial cells possess a variety of mechanisms that make them transiently accumulate potassium intracellularly or redistribute it throughout the extracellular space following action potentials. ⁵

It may, therefore, be speculated that decreased ATP supply, which occurs in biotinidase deficiency because of low functioning of the Krebs cycle, may lead to astrocyte swelling (because potassium is not re-pumped efficiently into the axon) leading to neuromyelitis optica through an astrocyte edema.