Biotinidase deficiency: Genotype-biochemical phenotype association in Brazilian patients.

INTRODUCTION: The association between the BTD genotype and biochemical phenotype [profound biotinidase deficiency (BD), partial BD or heterozygous activity] is not always consistent. This study aimed to investigate the genotype-biochemical phenotype association in patients with low biotinidase activity. METHODS: All exons, the 5'UTR and the promoter of the BTD gene were sequenced in 72 Brazilian individuals who exhibited low biotinidase activity. For each patient, the expected biochemical phenotype based on the known genotype was compared with the observed biochemical phenotype. Additional non-genetic factors that could affect the biotinidase activity were also analysed. RESULTS: Most individuals were identified by neonatal screening (n = 66/72). When consecutive results for the same patient were compared, age, prematurity and neonatal jaundice appeared to affect the level of biotinidase activity. The biochemical phenotype at the time of the second blood collection changed in 11/22 patients compared to results from the first sample. Three novel variants were found: c.1337T>C (p.L446P), c.1466A>G (p.N489S) and c.962G>A (p.W321*). Some patients with the same genotype presented different biochemical phenotypes. The expected and observed biochemical phenotypes agreed in 68.5% of cases (concordant patients). The non-coding variants c.-183G>A, c.-315A>G and c.-514C>T were present in heterozygosis in 5/17 discordant patients. In addition, c.-183G>A and c.-514C>T were also present in 10/37 concordant patients. CONCLUSIONS: The variants found in the promoter region do not appear to have a strong impact on biotinidase activity. Since there is a disparity between the BTD genotype and biochemical phenotype, and biotinidase activity may be affected by both genetic and non-genetic factors, we suggest that the diagnosis of BD should be based on more than one measurement of plasma biotinidase activity. DNA analysis can be of additional relevance to differentiate between partial BD and heterozygosity.

Thiamine Deprivation Produces a Liver ATP Deficit and Metabolic and Genomic Effects in Mice: Findings Are Parallel to Those of Biotin Deficiency and Have Implications for Energy Disorders.

Thiamine is one of several essential cofactors for ATP generation. Its deficiency, like in beriberi and in the Wernicke-Korsakoff syndrome, has been studied for many decades. However, its mechanism of action is still not completely understood at the cellular and molecular levels. Since it acts as a coenzyme for dehydrogenases of pyruvate, branched-chain keto acids, and ketoglutarate, its nutritional privation is partly a phenocopy of inborn errors of metabolism, among them maple syrup urine disease. In the present paper, we report metabolic and genomic findings in mice deprived of thiamine. They are similar to the ones we have previously found in biotin deficiency, another ATP generation cofactor. Here we show that thiamine deficiency substantially reduced the energy state in the liver and activated the energy sensor AMP-activated kinase. With this vitamin deficiency, several metabolic parameters changed: blood glucose was diminished and serum lactate was increased, but insulin, triglycerides, and cholesterol, as well as liver glycogen, were reduced. These results indicate a severe change in the energy status of the whole organism. Our findings were associated with modified hepatic levels of the mRNAs of several carbon metabolism genes: a reduction of transcripts for liver glucokinase and fatty acid synthase and augmentation of those for carnitine palmitoyl transferase 1 and phosphoenolpyruvate carboxykinase as markers for glycolysis, fatty acid synthesis, beta-oxidation, and gluconeogenesis, respectively. Glucose tolerance was initially increased, suggesting augmented insulin sensitivity, as we had found in biotin deficiency; however, in the case of thiamine, it was diminished from the 3rd week on, when the deficient animals became undernourished, and paralleled the changes in AKT and mTOR, 2 main proteins in the insulin signaling pathway. Since many of the metabolic and gene expression effects on mice deprived of thiamine are similar to those in biotin deficiency, it may be that they result from a more general impairment of oxidative phosphorylation due to a shortage of ATP generation cofactors. These findings may be relevant to energy-related disorders, among them several inborn errors of metabolism, as well as common energy disorders like obesity, diabetes, and neurodegenerative illnesses.

Hipoglicemia neonatal refractaria como presentacion de deficit parcial de biotinidasa / Neonatal refractary hypoglicemia as clinical presentation of partial deficit of biotinidase

La hipoglicemia es el problema metabólico más común en el neonato, sin embargo, en la gran mayoría de los casos es transitoria, y solo en un pequeño porcentaje se hace refractaria a concentraciones elevadas de glucosa. se describe el caso de un neonato con clínica caracterizada por hipoglicemia desde las primeras horas de vida ameritando aporte de glucosa por vía endovenosa a dosis elevadas. Se inicia una investigación diagnóstica que concluye, al analizar la combinación de síntomas junto a las alteraciones análíticas, error innato del metabolismo tipo déficit parcial de biotinidasa, el cual constituye un trastorno perteneciente al grupo de las acidurias orgánicas, de herencia autosómica recesiva, poco frecuente, que depende de un déficit en la actividad de la enzima biotinidasa. Se evidencia mejoría al iniciar el aporte exógeno de biotina con corrección sostenida de la hipoglicemia.

Hypoglycemia is the most common metabolic problem in the neonate, however, in most cases is transient, and only a small percentage is refractory to high concentrations of glucose. We describe the case of a neonate with clinically characterized by hypoglycemia during the first hours of life merit contribution of glucose by intravenous route at high doses. Begins a diagnostic investigation concludes that, when considering the combination of symptoms with alterations analytical, inborn error of metabolism rate of partial biotinidase deficiency, which is a disorder belonging to the group of organic acidurias, inherited as an autosomal recessive rare that depends on a deficit in the activity of the enzyme biotinidase. improvement is evident when you start providing exogenous biotin with sustained correction of hypoglycemia.

Biotin-dependent regulation of gene expression in human cells.

The role of biotin as cofactor of carboxylases and its importance in metabolic homeostasis are well known. In recent years, different researchers have suggested the participation of biotin as a regulator molecule in the control of gene expression. Biotin-dependent gene expression requires of the transformation of biotin into biotinyl-5'-AMP by holocarboxylase synthetase and the activation of soluble guanylate cyclase and a cGMP-dependent protein kinase. The regulatory role of biotin is responsible for the correct expression of enzymes involved in biotin utilization in human cells. We propose that this mechanism protects the brain from biotin deficiency.