Reply to the letter: Biotinidase deficiency masquerading as multiple sclerosis?

We thank Dr Wolf for his comments. ¹ As the author indicates, biotinidase deficiency is an inherited metabolic disease that is usually described in children and that is known to improve with “pharmacological” biotin therapy (10–20 mg). Cases with delayed-onset biotinidase deficiency have also been described. A recent case was reported in a 22-year-old patient with a presentation suggesting a possible neuromyelitis optica (NMO) spectrum disease. ² Some of these cases may have initially been diagnosed as multiple sclerosis (MS); however, to our knowledge, none responded to the international criteria of MS, and the described lesions on magnetic resonance imaging (MRI) were not suggestive of MS.

Whether some of the patients included in the MS-SPI trial, ³ particularly those who responded on the primary endpoint, have biotinidase deficiency is an interesting suggestion. However, many more patients responded to MD1003 if we include patients with improved Expanded Disability Status Scale (EDSS) or TW25 who did not however reach the stringent criteria for the primary endpoint and also patients improved on other modalities as captured by clinical global impression of change scales (CGI and SGI) as well as decreased risk of progression (which was 70% reduced compared to placebo). Our results therefore indicate that a larger group of progressive MS patients benefit from MD1003, an observation that is not compatible with the known incidence and prevalence of biotinidase deficiency. Indeed, based on neonatal screening in different countries, the prevalence of biotinidase deficiency is estimated to be 1/61,000, ⁴ far below the prevalence of MS (about 1/1000). Therefore, even when focusing on a subpopulation of progressive MS patients who would benefit from MD1003, the proportion of these responders would be far above the incidence of biotinidase deficiency. In the pilot observational study, ⁵ patients with lower doses than those used in the MS-SPI trial (300 mg/day) appeared to either not benefit, or to do so to a lesser degree, from the treatment.