Development of personalized medicine, including treatments of hereditary diseases, requires translation of biochemistry advances into medical practice. Our work is dedicated to solving this problem in a clinical case of hereditary Charcot-Marie-Tooth neuropathy 2K (CMT2K) due to compound-heterozygous mutations in GDAPI gene, leading to the protein variants with the most common in Europe substitution L239F (from the father) or with a previously uncharacterized substitution A175P (from the mother). The ganglioside-induced, differentiation-associated protein GDAPI encoded by the GDAPI gene, is localized to the outer mitochondrial membrane and belongs to the glutathione-S-transferase superfamily. Our structure-function analysis of GDAPI shows that dimerization of the monomers with either L239F or A175P substitutions, along with the half-of-the-sites reactivity of GDAPI to hydrophobic ligands, may synergistically impair the binding. This mechanism explains the early onset and progress of the disease in a child, whereas the heterozygous parents are asymptomatic. Published phenotypes of the amino acid substitutions in the GDAPI region comprising the binding site for hydrophobic compounds, including the phenotypes of the homozygous L239F substitution and its compound-heterozygous combinations with other substitutions in this region are analyzed. Association of the regional substitutions with axonal form of CMT and disturbances in the thiamine diphosphate (ThDP)- and NAD-dependent mitochondrial metabolism is revealed. Hence, the therapeutic effect of the precursors of these coenzymes, thiamine and nicotinamide riboside (NR), is studied. Oral administration of the precursors to the patient leads to increased levels of ThDP and NAD in the whole blood, an improvement in the hand grip strength, and, after the long-term administration, to normalization of ThDP-dependent metabolism. That is, after the therapy, the disease-altered levels of the translketolase (TKT) activity and its apoform, as well as the relationships between the levels of the holoenzyme TKT, ThDP and NAD in the patients blood, approach those of healthy women. Our results demonstrate the therapeutic potential of thiamine and NR in correcting metabolic dysregulation in CMT caused by GDAPI mutations, suggesting the underlying molecular mechanisms. Genetic diagnostics and biochemical characterization of the mechanisms of mutation pathogenicity may increase efficiency of the therapy in clinically asymptomatic or early stages of the disease, as it is easier to protect from the accumulating metabolic damage than to reverse the damage.
Borisova et al. (Wed,) studied this question.