The action of this enzyme can also be crippled by mutations in the MMAA, MMAB, and MMADHC genes, each of which encodes a protein required for normal functioning of methylmalonyl-CoA mutase. Methylmalonyl-CoA epimerase
Mutations in the MCEE gene, which encodes the methylmalonyl-CoA epimerase protein, also referred to as methylmalonyl racemase, will cause a much more mild form of the disorder than the related methylmalonyl-CoA mutase variant. Like the mutase, the epimerase also functions in breaking down the same substances, but to a significantly lesser extent than the mutase does. The phenotypic differences caused by a deficiency of the epimerase as opposed to the mutase are so mild that there is debate within the medical community as to whether or not this genetic deficiency can be considered a disorder or clinical syndrome. Adenosylcobalamin
Also known as vitamin B12, this form of cobalamin is a required cofactor of methylmalonyl-CoA mutase. Even with a functional version of the enzyme at physiologically normal levels, if B12 cannot be converted to this active form, the mutase will be unable to function. Progression
Though there are not distinct stages of the disease, methylmalonic acidemia is a progressive condition; the symptoms of this disorder are compounded as the concentration of methylmalonic acid increases. If the triggering proteins and fats are not removed from the diet, this buildup can lead to irreparable kidney or liver damage and eventually death.
In the second and third trimester, this risk is diminished and methimazole is preferred to avoid the risk of liver complications from PTU in the mother.The primary effect on the fetus from transplacental passage of PTU is the production of a mild hypothyroidism when the drug is used close to term. This usually resolves within a few days without treatment. The hypothyroid state may be observed as a goiter in the newborn, and is the result of increased levels of fetal pituitary thyrotropin. The incidence of fetal goiter after PTU treatment in reported cases is approximately 12%. Mechanism of action
Thyroid
PTU inhibits the enzyme thyroperoxidase, which normally acts in thyroid hormone synthesis by oxidizing the anion iodide (I−) to iodine (I0), facilitating iodines addition to tyrosine residues on the hormone precursor thyroglobulin. This is one of the essential steps in the formation of thyroxine (T4).PTU does not inhibit the action of the sodium-dependent iodide transporter located on follicular cells basolateral membranes. Inhibition of this step requires competitive inhibitors, such as perchlorate and thiocyanate. T3/T4 target tissues
PTU also acts by inhibiting the enzyme 5-deiodinase (tetraiodothyronine 5 deiodinase), which converts T4 to the more active form T3. (This is in contrast to methimazole, which shares propylthiouracils central mechanism, but not its peripheral one.) It is important to recognize that these enzymes only work on the conjugated tyrosine molecules of T3 and T4: a completely different enzyme family is responsible for the deiodinase activity of iodized single tyrosine molecules within the thyroid follicular cells.