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Clinical Manifestation of Mitochondrial Disorders in Childhood
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Ketogenic diet can stimulate fatty acid metabolism, provides an alternative energy source and supplements intermediates missing in PDHC (coenzyme A of Krebs cycle) (Gano et al., 2014). In patients with milder forms of the disease, some treatment effects were observed after fast carbohydrates restriction (improved muscle weakness and dystonic disorder) (Debray et al., 2006). A very small number of about 5% patients with mutations in the PDHA1 gene are thiamine-responsive, however, initial therapy with thiamine (50 mg/kg/day) may be indicated especially for those presenting with a dystonic disorder. Dichloroacetate has been used but significant side effects, such as peripheral neuropathy, may limit effectiveness. The benefit of treatment combination of high dose of thiamine and biotin has been established in some patients with thiamine transporters deficiency (SLC19A3) (Subramanian et al., 2006). Metabolic acidosis can be partially compensated using alkalinisation therapy.
A new set of clinical tools for physicians
Published in Priya Hays, Advancing Healthcare Through Personalized Medicine, 2017
There are too many examples of WES successes to list all of them here, which can be placed in different categories based on the types of genes discovered. WES is shown to be cost-effective and clinically useful. Sanger sequencing costs are about $1000 for the average gene. WES for very “genetically heterogeneous” disorders (i.e., caused by one of a potentially large number of genes), including familial amyotrophic lateral sclerosis (ALS), caused by 15 different genes; autosomal recessive deafness, caused by 39 genes; and Leigh’s encephalopathy, caused by 35 genes. Studies of multiple family members with the same phenotypes led to the discovery of mutation in known genes, thus expanding their known phenotypes: familial leukemia, germline p53 mutations found; fatal infantile encephalopathy, SLC19A3; autosomal dominant distal myopathy, tropomysin; two members of a consanguineous family with macrocephaly and epiphyseal dysplasia, KIF7; and two relatives with osteoporosis, CLCN7 (confirmed by finding cosegregation among four other family members).
Laboratory testing for mitochondrial diseases: biomarkers for diagnosis and follow-up
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Abraham J. Paredes-Fuentes, Clara Oliva, Roser Urreizti, Delia Yubero, Rafael Artuch
The active form of thiamine is thiamine diphosphate, which participates in mitochondrial metabolism as the cofactor of three mitochondrial dehydrogenases: pyruvate, ketoglutarate, and branched-chain keto acid dehydrogenases. Thiamine is phosphorylated by one specific kinase (e.g. TPK1) and is incorporated into the mitochondria by different mitochondrial thiamine carriers (e.g. those coded by SLC19A2, SLC19A3, and SLC25A19 genes). Mutations in these genes are associated with different phenotypes that lead to impaired mitochondrial metabolism. The most consistent biomarkers are the decrease in free thiamine concentrations in CSF and fibroblasts in SLC19A3 transport deficiency, and low whole blood thiamine diphosphate values in TPK1 deficiency (Table 1) [60,61]. Although it is not always observed, thiamine deficiency usually leads to increases in other surrogate biomarkers as a consequence of thiamine-dependent enzymes: lactate (caused by PDH deficiency), alpha-ketoglutarate (caused by alpha-ketoglutarate dehydrogenase deficiency), and branched-chain keto acids (caused by branched-chain keto acid dehydrogenase deficiency) (Table 1) [62].
Thiamine and phosphate esters concentrations in whole blood and serum of patients with alcohol use disorder: a relation with cognitive deficits
Published in Nutritional Neuroscience, 2021
Laurent Coulbault, Ludivine Ritz, François Vabret, Coralie Lannuzel, Céline Boudehent, Marie Nowoczyn, Hélène Beaunieux, Anne Lise Pitel
Whereas TDP is the main intracellular chemical form of thiamine in blood (95% in healthy controls), unphosphorylated thiamine (Th) is mainly extracellular. An excess of Th in blood may thus reflect an alteration of intracellular transport, and its uptake by cells. In the AUD COG− patients, we also found lower percentages of phosphate esters of Th in WB, and higher percentage of Th in serum compared to controls. Percentage of Th in serum was also significantly different between the two groups of AUD patients. Taken together, these data suggest that thiamine metabolism and/or distribution in the body is altered in AUD patients, potentially contributing to the development of brain dysfunction. Indeed, considering that thiamine is essential for ATP production in glucose-dependent tissues, an impairment of thiamine distribution in the brain could contribute to damages in specific cerebral regions. This transport seems to be essential for the brain; Kono et al. showed that a mutation in SLC19A3 thiamine-transporter gene was involved in the development of a Wernicke’s like encephalopathy [21]. In our study, a high level of thiamine in serum (or a high percentage of thiamine) could reflect this impairment of thiamine transport, producing metabolic disturbance, and then affecting cognitive functions. Our data do not challenge the paradigm that thiamine deficiency occurs in AUD patients and is responsible for cognitive deficits. Rather, they suggest that not only TD but also impairment of thiamine metabolism and/or distribution should be taken into account during treatment.
Gene variations in Autism Spectrum Disorder are associated with alternation of gut microbiota, metabolites and cytokines
Published in Gut Microbes, 2021
Zhi Liu, Xuhua Mao, Zhou Dan, Yang Pei, Rui Xu, Mengchen Guo, Kangjian Liu, Faming Zhang, Junyu Chen, Chuan Su, Yaoyao Zhuang, Junming Tang, Yankai Xia, Lianhong Qin, Zhibin Hu, Xingyin Liu
Also, APOB (Apolipoprotein B, rs13306187, c.G4163A, p.R1388H) and RARRES2 (Retinoic Acid Receptor Responder 2, rs147597725, c.G440A, p.S147N), two genes involved in the retinoid metabolic process, were related to the abundance of Lachnospiraceae bacterium 7_1_58FAA and Bacteroides eggerthii, respectively. Apolipoprotein B was an innate barrier against bacterial infection,41 and novel APOB mutations were observed in autism.42 The Bacteroides eggerthii was reported to enhance colitis in mice.43 Studies have reported that the Bacteroidetes/Bacteroidales were among the key taxa related to vitamin A in ASD children.44 Other associations include the thiamine transporters SLC19A3 (rs117864472, c.A1132G, p.I378V) and Clostridiales bacterium VE202-03, among others. The thiamine deficiency was observed in Alzheimer’s disease and contribute to synapse and neural circuit defects.45