The most prominent missense mutation detected in TPI deficiency patients occurs at codon 104 in the TPI gene encoding aspartic acid instead of glutamic acid within the enzyme and accounts for MK-0683 approximately 80% of mutant alleles within Northern European kindreds with clinical TPI deficiency. Re-markably, this variant is the only one observed to be homozygous among TPI deficiency patients. Other amino acid exchanges in the TPI protein, such as Cys41Tyr and Ile170Val, have been predicted to interfere with both the substrate binding and the dimerization site possibly affecting the catalytic activity plus molecular stability of TPI; both pathogenic TPI variants have been identified in unrelated European kindreds. Furthermore, other missense mutations like a mutation at codon 240 in the TPI gene encoding leucine instead of phenylalanine within the enzyme could have an effect on the substrate binding site. Other mutations, for instance,Cabozantinib the pathogenic TPI variants Gly122Arg or Val154Met could not be assigned to defined domains. However, Perry and Mohrenweiser showed that the Gly122Arg TPI variant, which was identified as an electromorphic variant by screening 3,400 persons in a Caucasian population, is a thermolabile enzyme possibly indicating improper folding. Furthermore, a start codon mutation has been identified in a French family as well as a frame shift mutation at codon 28 or mutations within the upstream region of the TPI gene. To date, the best-studied family affected with TPI deficiency is a Hungarian family in which two germ-line identical compound heterozygote brothers have inherited a missense mutation at codon 240 encoding the Phe240Leu TPI variant and a nonsense mutation at codon 145 leading to a truncated TPI protein. Interestingly, these brothers are suffering from an atypical moderate form of TPI deficiency, although both have an extremely reduced activity of TPI with less than 5% of normal enzyme activity and a particularly high level of cellular DHAP. Strikingly, only one of the brothers has developed neurological symptoms indicating that the two mutations alone cannot explain the variance in clinical symptoms.