By: Archana Murugan, PharmD candidate c\/o 2029<\/p>\n\n\n\n
Overview<\/strong><\/p>\n\n\n\n Thiamine metabolic dysfunction syndrome (TMDS) refers to a broad term describing a group of rare errors of metabolism in newborns caused by a defect or deficiency in thiamine (vitamin B1).<\/p>\n\n\n\n Thiamine (B1) is highly essential for cell function in our bodies, as it is utilized in several phosphorylated forms. It plays an active role as a coenzyme in the metabolism of carbohydrates, fats, proteins, mitochondrial energy production, and cellular respiration. Additionally, thiamine plays an important role in the nervous system, supporting neurotransmitter synthesis and neuronal function. When the levels are too low, mitochondrial energy production is inhibited leading to lactate and pyruvate buildup which eventually leads to focal thalamic injury. This can be presented as Wernicke\u2019s encephalopathy\/Wernicke-Korsakoff syndrome. In severe cases, thiamine deficiency can cause neurologic and cardiovascular complications, including heart failure, ataxia, paralysis, delirium, and confusion, with chronic alcohol usage being the common underlying risk factor.3<\/sup><\/p>\n\n\n\n THMD5<\/strong><\/p>\n\n\n\n Thiamine metabolism dysfunction syndrome 5 (THMD5) is a subtype of TMDS, characterized as a rare genetic disorder caused by changes in the TPK1 gene. Thiamine pyrophosphokinase 1 or TPK1 directly affects the body\u2019s ability to make thiamine pyrophosphate, which is the active form of vitamin B1 necessary for energy metabolism. Since TPP (thiamine pyrophosphate) is essential for metabolic pathways, low levels can lead to a range of neurological complications.1<\/sup><\/p>\n\n\n\n Case reports, as analyzed by Dallan et al., suggest symptoms of THMD5 can vary from patient to patient. Some children experience recurrent episodes of ataxia while others develop a form of Leigh syndrome. Symptoms under this condition include dystonia, seizures, developmental regression, and high mortality. Essentially, on the mild end, some children have partially preserved metabolic function while in severe cases, there is profound impairment of thiamine-dependent pathways.1<\/sup> Thus, more research is necessary to better understand the biomarkers and how different genetic variants influence the severity of the disease. Understanding the complexities behind THMD5 allows for the development of effective treatment options.<\/p>\n\n\n\n Mechanism of Action<\/strong><\/p>\n\n\n\n Dietary thiamine is usually found in phosphorylated forms, which are first converted to free thiamine by intestinal phosphatases before absorption. Absorption in the GI tract depends on two transporters: THTR1 and THTR2. THTR1 is responsible for higher concentrations and widely expressed across both the apical and basolateral membranes. THTR2 is limited to the apical side of the membrane. When thiamine enters the cell, it is converted to TPP by TPK1 which is then modified into TMP or TTP depending on cellular needs. At high concentrations, thiamine can enter cells via passive diffusion. After circulating in the bloodstream, thiamine is reabsorbed by THTR1 or THTR2 and differences in transporter expression may occur. TPP serves as a cofactor in multiple metabolic pathways including transketolase in the cytosol (PPP), mitochondrial dehydrogenase complexes (PDH, BCKDH, \u03b1-KGDH), and HACL1 in peroxisomal fatty-acid \u03b1-oxidation. The transport of TPP into mitochondria requires SLC25A19, while peroxisomal import depends on its binding to HACL1\/HACL2.2<\/sup><\/p>\n\n\n\n Treatment<\/strong><\/p>\n\n\n\n TPK1-deficient patients can improve with high-dose thiamine (100-500 mg\/day), and some are able to achieve normal neurodevelopment if treated early, according to literature. It is noted that flooding the system with the precursor or the raw material (B1) will allow enough TPP to be produced despite the low enzyme activity. Theoretically, direct TPP supplementation is noted to work more efficiently because the defect is found in TPK1 itself, which is the enzyme converting thiamine to TPP. However, TPP is not available as a drug (e.g., in Italy). Not all patients show progress is possible due to low enzyme activity and several children die before treatment could exhibit changes. In the two cases described, both children initially exhibited improvements after high-dose thiamine administration, but long-term prognosis remained limited. One child remained steady whereas the other patient progressed to severe disability. As previously mentioned, genetic variation plays an important role in understanding and finding effective treatment for TMDS.1<\/sup><\/p>\n\n\n\n Conclusion<\/strong><\/p>\n\n\n\n Vitamin B1 (thiamine) is essential for energy production and neurologic health. Any defect or deficiency is bound to disrupt multiple metabolic pathways. THMD5 tends to be more severe due to its broad spectrum of effects, as it is dependent upon TPK1 mutations and how early treatment begins. Continued research in genetic variation and patterns is important in treating such rare disorders.<\/p>\n\n\n\n References:<\/strong><\/p>\n\n\n\n By: Archana Murugan, PharmD candidate c\/o 2029 Overview Thiamine metabolic dysfunction syndrome (TMDS) refers to a broad term describing a group of rare errors of metabolism in newborns caused by a defect or deficiency in thiamine (vitamin B1). Thiamine (B1) is highly essential for cell function in our bodies, as it is utilized in…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[7],"tags":[],"class_list":["post-4224","post","type-post","status-publish","format-standard","hentry","category-clinical"],"views":22,"_links":{"self":[{"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/posts\/4224","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/comments?post=4224"}],"version-history":[{"count":1,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/posts\/4224\/revisions"}],"predecessor-version":[{"id":4225,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/posts\/4224\/revisions\/4225"}],"wp:attachment":[{"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/media?parent=4224"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/categories?post=4224"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/rhochistj.org\/RhoChiPost\/wp-json\/wp\/v2\/tags?post=4224"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}\n