Current global vitamin and cofactor prescribing practices for primary mitochondrial diseases: Results of a European reference network survey

Abstract

Primary mitochondrial diseases (PMD) account for a group of approximately 400 different genetic disorders with diverse clinical presentations and pathomechanisms. Although each individual disorder is rare, collectively they represent one of the largest groups in the field of inherited metabolic disorders. The complexity of PMD results in a continued lack of therapeutic options, necessitating a predominantly symptomatic treatment approach for affected patients. While a subset of diseases responds exceptionally well to treatment with specific vitamins or cofactors, for most PMD systematic reviews were not able to show significant benefit. This is in discrepancy to their continued frequent use among specialists. To gain further insight into the current clinical practice of vitamin and cofactor supplementation among clinicians treating children and adults affected by PMD, we conducted a worldwide cross-sectional questionnaire study exploring the choice of substances and the specific diseases where they are applied. To our knowledge, this is the first global study exploring this topic and featuring a high response rate from paediatricians. The vast majority (95%, 106/112) of responding specialists recommended the use of vitamins and cofactors, either in an agnostic approach irrespective of the specific PMD or directed to the treatment of specific diseases or phenotypes. Our study highlights significant regional and specialty-specific differences in supplementation practices. We provide some preliminary insights into specialist-based opinions regarding the use of vitamins and cofactors in PMD and highlight the need for more rigorous clinical and preclinical investigations and/or clear consensus statements.

Keywords: cofactors; cross sectional study; inherited metabolic disease; primary mitochondrial disease; survey; treatment; vitamins.

FIGURE 1

World map displaying the geographic distribution of responding clinicians and the number of responses from each country. In total, 112 respondents from 35 countries contributed their experience. The majority of respondents are from Europe (78%), while areas with potentially substantial incidence such as Asia and South America are underrepresented, and there were no respondents from Sub‐Saharan Africa.

FIGURE 2

(A) Proportion of professionals treating paediatric patients with PMD, adult patients or both age groups. This figure provides an overview of the proportion of professionals that exclusively follow paediatric patients with PMD, exclusively follow adult patients, or care for both age groups. In contrast to previous studies, this survey received a notably higher response rate from paediatricians, with 48.2% of respondents only managing patients under 18 years old, and 17% managing both paediatric and adult patients with PMD. (B) Distribution of actively followed PMD patients between clinicians treating only paediatric patients, only adult patients or both age groups. This figure illustrates the distribution of patients with PMD actively followed by each respondent. Notably, 21.4% of respondents manage more than 100 patients with PMD. Most paediatricians follow between 11 and 50 patients with genetically confirmed PMD. While the majority of respondents are paediatricians, most clinicians who follow more than 100 patients primarily treat adult patients (83%, 19/23) (p = 0.003), either alongside paediatric patients or exclusively.

FIGURE 3

Prescribing differences for the various vitamins and cofactors. This figure displays the prescribing practices for each vitamin/cofactor addressed in the survey, indicating the proportion of professionals that use the specific vitamin or cofactor universally for every patient with PMD irrespective of the geno‐ or phenotype, as well as those who prescribe based on specific geno‐ or phenotypes.

FIGURE 4

Regional differences in vitamin/cofactor use. This colour‐enhanced table illustrates the variation in the use or prescription of various vitamins and cofactors by professionals across different regions. Each row corresponds to a specific geographic region, listing the proportion of professionals in each region who report prescription of this vitamin or cofactor.

FIGURE 5

Association between geographic location (North America vs. Europe) of specialists and prescribing practices of vitamins/cofactors. Multiple correspondence analysis (MCA) was utilised to investigate the association between the geographic location (North America vs. Europe) of specialists and their prescribing practices for various vitamins and cofactors. Each vitamin and cofactor is treated as a categorical variable, with responses categorised into whether or not a substance is used, and whether its use is universal or specific for certain geno‐/phenotypes. The MCA revealed a distinct pattern between specialists from Europe and North America regarding the spectrum of substances and their targeted application in specific diseases. An MCA plot involving the other regions can be found in Appendix S1.

FIGURE 6

Regional differences in reimbursement rates for the different vitamins and cofactors. Regional disparities in reimbursement rates for the different vitamins and cofactors are depicted in this colour‐enhanced table. Each row represents a specific geographic region and indicates the proportion of professionals who reported reimbursement for each respective vitamin or cofactor in their region.