Tyrosine Metabolism

Inherited disorders of tyrosine catabolism have been identified at five of the six enzymatic steps. Under normal conditions tyrosine concentrations are regulated by its synthetic enzyme (phenylalanine hydroxylase) and especially the first catabolic enzyme (tyrosine aminotransferase). Acquired or inherited deficiency of the second catabolic enzyme (4-hydroxyphenylpyruvate dioxygenase) also results in hypertyrosinemia. Tyrosine is mainly degraded in the liver but to a minor extent also in the kidney. In tyrosinemia type I, the primary defect is in the last enzyme of the pathway, accumulation of toxic metabolites are seen, and the hypertyrosinemia results from secondary deficiency of 4-hydroxyphenylpyruvate dioxygenase, which also is found in severe liver disease in general and in the immature liver. Generally, there is no common phenotype to the different disorders of tyrosine degradation. The occurrence of corneal and skin lesions, as seen in tyrosinemia type II, is a direct effect of high tissue tyrosine. Cognitive impairment is common in tyrosinemia type II, probably common in type III, and increasingly reported in type I. The liver and kidney diseases of tyrosinemia type I are caused by accumulation of toxic metabolites (fumarylacetoacetate and its derivatives) and can be prevented by an inhibitor (nitisinone) of tyrosine degradation at the level of 4-hydroxyphenylpyruvate dioxygenase. Whether maleylacetoacetate hydrolase that essentially gives the same metabolic features as tyrosinemia type I results in clinical features is unclear. In alkaptonuria there is no increase in tyrosine level, and the degradation of tyrosine proceeds at a normal rate to produce homogentisate. Upon oxidation, homogentisate forms reactive intermediates and pigment, which is deposited in various tissues particularly in joints and connective tissue. In hawkinsinuria, a very rare condition, data suggest that an aberrant metabolism of 4-hydroxyphenylpyruvate in some cases may lead to failure to thrive, acidosis, and excretion of a characteristic metabolite pattern.</p

Tyrosine Metabolism

Inherited disorders of tyrosine catabolism have been identified at five of the six enzymatic steps. Under normal conditions tyrosine concentrations are regulated by its synthetic enzyme (phenylalanine hydroxylase) and especially the first catabolic enzyme (tyrosine aminotransferase). Acquired or inherited deficiency of the second catabolic enzyme (4-hydroxyphenylpyruvate dioxygenase) also results in hypertyrosinemia. Tyrosine is mainly degraded in the liver but to a minor extent also in the kidney. In tyrosinemia type I, the primary defect is in the last enzyme of the pathway, accumulation of toxic metabolites are seen, and the hypertyrosinemia results from secondary deficiency of 4-hydroxyphenylpyruvate dioxygenase, which also is found in severe liver disease in general and in the immature liver. Generally, there is no common phenotype to the different disorders of tyrosine degradation. The occurrence of corneal and skin lesions, as seen in tyrosinemia type II, is a direct effect of high tissue tyrosine. Cognitive impairment is common in tyrosinemia type II, probably common in type III, and increasingly reported in type I. The liver and kidney diseases of tyrosinemia type I are caused by accumulation of toxic metabolites (fumarylacetoacetate and its derivatives) and can be prevented by an inhibitor (nitisinone) of tyrosine degradation at the level of 4-hydroxyphenylpyruvate dioxygenase. Whether maleylacetoacetate hydrolase that essentially gives the same metabolic features as tyrosinemia type I results in clinical features is unclear. In alkaptonuria there is no increase in tyrosine level, and the degradation of tyrosine proceeds at a normal rate to produce homogentisate. Upon oxidation, homogentisate forms reactive intermediates and pigment, which is deposited in various tissues particularly in joints and connective tissue. In hawkinsinuria, a very rare condition, data suggest that an aberrant metabolism of 4-hydroxyphenylpyruvate in some cases may lead to failure to thrive, acidosis, and excretion of a characteristic metabolite pattern.</p

Tyrosine Metabolism

Inherited disorders of tyrosine catabolism have been identified at five of the six enzymatic steps. Under normal conditions tyrosine concentrations are regulated by its synthetic enzyme (phenylalanine hydroxylase) and especially the first catabolic enzyme (tyrosine aminotransferase). Acquired or inherited deficiency of the second catabolic enzyme (4-hydroxyphenylpyruvate dioxygenase) also results in hypertyrosinemia. Tyrosine is mainly degraded in the liver but to a minor extent also in the kidney. In tyrosinemia type I, the primary defect is in the last enzyme of the pathway, accumulation of toxic metabolites are seen, and the hypertyrosinemia results from secondary deficiency of 4-hydroxyphenylpyruvate dioxygenase, which also is found in severe liver disease in general and in the immature liver. Generally, there is no common phenotype to the different disorders of tyrosine degradation. The occurrence of corneal and skin lesions, as seen in tyrosinemia type II, is a direct effect of high tissue tyrosine. Cognitive impairment is common in tyrosinemia type II, probably common in type III, and increasingly reported in type I. The liver and kidney diseases of tyrosinemia type I are caused by accumulation of toxic metabolites (fumarylacetoacetate and its derivatives) and can be prevented by an inhibitor (nitisinone) of tyrosine degradation at the level of 4-hydroxyphenylpyruvate dioxygenase. Whether maleylacetoacetate hydrolase that essentially gives the same metabolic features as tyrosinemia type I results in clinical features is unclear. In alkaptonuria there is no increase in tyrosine level, and the degradation of tyrosine proceeds at a normal rate to produce homogentisate. Upon oxidation, homogentisate forms reactive intermediates and pigment, which is deposited in various tissues particularly in joints and connective tissue. In hawkinsinuria, a very rare condition, data suggest that an aberrant metabolism of 4-hydroxyphenylpyruvate in some cases may lead to failure to thrive, acidosis, and excretion of a characteristic metabolite pattern.</p

Renal Mitochondrial Cytopathies

Renal diseases in mitochondrial cytopathies are a group of rare diseases that are characterized by frequent multisystemic involvement and extreme variability of phenotype. Most frequently patients present a tubular defect that is consistent with complete De Toni-Debré-Fanconi syndrome in most severe forms. More rarely, patients present with chronic tubulointerstitial nephritis, cystic renal diseases, or primary glomerular involvement. In recent years, two clearly defined entities, namely 3243 A > G tRNALEU mutations and coenzyme Q10 biosynthesis defects, have been described. The latter group is particularly important because it represents the only treatable renal mitochondrial defect. In this paper, the physiopathologic bases of mitochondrial cytopathies, the diagnostic approaches, and main characteristics of related renal diseases are summarized

Tyrosine Metabolism

Inherited disorders of tyrosine catabolism have been identified at five of the six enzymatic steps. Under normal conditions tyrosine concentrations are regulated by its synthetic enzyme (phenylalanine hydroxylase) and especially the first catabolic enzyme (tyrosine aminotransferase). Acquired or inherited deficiency of the second catabolic enzyme (4-hydroxyphenylpyruvate dioxygenase) also results in hypertyrosinemia. Tyrosine is mainly degraded in the liver but to a minor extent also in the kidney. In tyrosinemia type I, the primary defect is in the last enzyme of the pathway, accumulation of toxic metabolites are seen, and the hypertyrosinemia results from secondary deficiency of 4-hydroxyphenylpyruvate dioxygenase, which also is found in severe liver disease in general and in the immature liver. Generally, there is no common phenotype to the different disorders of tyrosine degradation. The occurrence of corneal and skin lesions, as seen in tyrosinemia type II, is a direct effect of high tissue tyrosine. Cognitive impairment is common in tyrosinemia type II, probably common in type III, and increasingly reported in type I. The liver and kidney diseases of tyrosinemia type I are caused by accumulation of toxic metabolites (fumarylacetoacetate and its derivatives) and can be prevented by an inhibitor (nitisinone) of tyrosine degradation at the level of 4-hydroxyphenylpyruvate dioxygenase. Whether maleylacetoacetate hydrolase that essentially gives the same metabolic features as tyrosinemia type I results in clinical features is unclear. In alkaptonuria there is no increase in tyrosine level, and the degradation of tyrosine proceeds at a normal rate to produce homogentisate. Upon oxidation, homogentisate forms reactive intermediates and pigment, which is deposited in various tissues particularly in joints and connective tissue. In hawkinsinuria, a very rare condition, data suggest that an aberrant metabolism of 4-hydroxyphenylpyruvate in some cases may lead to failure to thrive, acidosis, and excretion of a characteristic metabolite pattern.</p

Hereditary spastic paraplegia is a common phenotypic finding in ARG1 deficiency, P5CS deficiency and HHH syndrome: Three inborn errors of metabolism caused by alteration of an interconnected pathway of glutamate and urea cycle metabolism

Hereditary Spastic Paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by a progressive rigidity and weakness of the lower limbs, caused by pyramidal tract lesions. As of today, 80 different forms of HSP have been mapped, 64 genes have been cloned, and new forms are constantly being described. HSPs represent an intensively studied field, and the functional understanding of the biochemical and molecular pathogenetic pathways are starting to be elucidated. Recently, dominant and recessive mutations in the ALDH18A1 gene resulting in the deficiency of the encoded enzyme (delta-1-pyrroline-5-carboxylate synthase, P5CS) have been pathogenetically linked to HSP. P5CS is a critical enzyme in the conversion of glutamate to pyrroline-5-carboxylate, an intermediate that enters in the proline biosynthesis and that is connected with the urea cycle. Interestingly, two urea cycle disorders, Argininemia and Hyperornithinemia-Hyperammonemia-Homocitrullinuria syndrome, are clinically characterized by highly penetrant spastic paraplegia. These three diseases represent a peculiar group of HSPs caused by Inborn Errors of Metabolism. Here we comment on these forms, on the common features among them and on the hypotheses for possible shared pathogenetic mechanisms causing the HSP phenotype

Hereditary Spastic Paraplegia Is a Common Phenotypic Finding in ARG1 Deficiency, P5CS Deficiency and HHH Syndrome: Three Inborn Errors of Metabolism Caused by Alteration of an Interconnected Pathway of Glutamate and Urea Cycle Metabolism

Hereditary Spastic Paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by a progressive rigidity and weakness of the lower limbs, caused by pyramidal tract lesions. As of today, 80 different forms of HSP have been mapped, 64 genes have been cloned, and new forms are constantly being described. HSPs represent an intensively studied field, and the functional understanding of the biochemical and molecular pathogenetic pathways are starting to be elucidated. Recently, dominant and recessive mutations in the ALDH18A1 gene resulting in the deficiency of the encoded enzyme (delta-1-pyrroline-5-carboxylate synthase, P5CS) have been pathogenetically linked to HSP. P5CS is a critical enzyme in the conversion of glutamate to pyrroline-5-carboxylate, an intermediate that enters in the proline biosynthesis and that is connected with the urea cycle. Interestingly, two urea cycle disorders, Argininemia and Hyperornithinemia-Hyperammonemia-Homocitrullinuria syndrome, are clinically characterized by highly penetrant spastic paraplegia. These three diseases represent a peculiar group of HSPs caused by Inborn Errors of Metabolism. Here we comment on these forms, on the common features among them and on the hypotheses for possible shared pathogenetic mechanisms causing the HSP phenotype

Therapeutic Drug Monitoring of Quinidine in Pediatric Patients with KCNT1 Genetic Variants

Quinidine (QND) is an old antimalarial drug that was used in the early 20th century as an antiarrhythmic agent. Currently, QND is receiving attention for its use in epilepsy of infancy with migrating focal seizures (EIMFS) due to potassium sodium-activated channel subfamily T member 1 (KCNT1) genetic variants. Here, we report the application of Therapeutic Drug Monitoring (TDM) in pediatric patients carrying KCNT1 genetic variants and orally treated with QND for developmental and epileptic encephalopathies (DEE). We measured plasma levels of QND and its metabolite hydroquinidine (H-QND) by using a validated method based on liquid chromatography coupled with mass spectrometry (LC-MS/MS). Three pediatric patients (median age 4.125 years, IQR 2.375-4.125) received increasing doses of QND. Cardiac toxicity was monitored at every dose change. Reduction in seizure frequency ranged from 50 to 90%. Our results show that QND is a promising drug for pediatric patients with DEE due to KCNT1 genetic variants. Although QND blood levels were significantly lower than the therapeutic range as an anti-arrhythmic drug, patients showed a significant improvement in seizure burden. These data underlie the utility of TDM for QND not only to monitor its toxic effects but also to evaluate possible drug-drug interactions

Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia.

Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100\u27000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity

The Mitochondrial Ornithine Transporter BACTERIAL EXPRESSION, RECONSTITUTION, FUNCTIONAL CHARACTERIZATION, AND TISSUE DISTRIBUTION OF TWO HUMAN ISOFORMS

Two isoforms of the human ornithine carrier, ORC1 and ORC2, have been identified by overexpression of the proteins in bacteria and by study of the transport properties of the purified proteins reconstituted into liposomes. Both transport L-isomers of ornithine, lysine, arginine, and citrulline by exchange and by unidirectional mechanisms, and they are inactivated by the same inhibitors. ORC2 has a broader specificity than ORC1, and L- and D-histidine, L-homoarginine, and D-isomers of ornithine, lysine, and ornithine are all substrates. Both proteins are expressed in a wide range of human tissues, but ORC1 is the predominant form. The highest levels of expression of both isoforms are in the liver. Five mutant forms of ORC1 associated with the human disease hyperornithinemia-hyperammonemia-homocitrullinuria were also made. The mutations abolish the transport properties of the protein. In patients with hyperornithinemia-hyperammonemia-homocitrullinuria, isoform ORC2 is unmodified, and its presence compensates partially for defective ORC1