Congenital non-progressive encephalopathy and deafness with intermittent episodes of coma and hyperkynureninuria (original) (raw)
Related papers
Quinolinic acid in children with congenital hyperammonemia
Annals of Neurology, 1993
Levels of the excitotoxin quinolinic acid (QUIN) were measured in the cerebrospinal fluid of infants and children with congenital hyperanimonemia. Twofold to tenfold elevations of QUIN were found in 4 neonates in hyperammonemic coma (QUIN range, 250-990 nM; control mean, 110 f 30 nM; p < 0.005). Similar elevations of neopterin were found (range, 24-75 nM; control mean, 9.0 * 4.9 nM; p < 0.005). In addition, significant elevations of QUIN were found in 14 older children with congenital hyperammonemia (mean, 50 2 20 vs 17 2 6 nM; p < 0.05). Neopterin levels were not elevated in these children. The QUIN may originate from an increase in tryptophan transport across the blood-brain barrier or from induction of indolamine-2,3-dioxygenase activity. These findings support a role for QUIN in the neuropathology of congenital hyperammonemia. They also suggest the potential utility of N-methyl+aspartate receptor-blocking agents or inhibitors of QUIN synthesis in the treatment of hyperammonemic coma.
The role of kynurenine metabolism in the development of the central nervous system
2014
List of abbreviations ALS Amyotrophic lateral sclerosis AMPA 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid ANOVA Analysis of variance ASD Autistic spectrum disorder α7NCR α-7 nicotinic acethylcholine receptor BDNF Brain-derived neurotrophic factor BSA Bovine serum albumin CA1 Cornu Ammonis area 1 CA3 Cornu Ammonis area 3 Ca 2+ Calcium CBM Cerebellum CNS Central nervous system
Kynurenine Metabolism in Central Nervous System in Experimental Chronic Renal Failure
Advances in Experimental Medicine and Biology, 2003
Tryptophan metablolism via kynureninc pathway leads to the formation of several neuroactive substances including kynurenine, anthranilic acid and quinolinic acid, which are involved in numerous neurodegenerative diseases. Also chronic renal insufficiency is associated with neurological disturbances but it is still not clear which substances are responsible for those disorders. Thus, the aim of our study was to evaluate the concentration of tryptophan, kynurenine and anthranilic acid in plasma as well as in different brain regions in uremic rats. We have shown that tryptophan concentrations in plasma and in brain were decreased, whereas kynurenine and anthranilic acid levels were elevated, both in plasma and in central nervous system. Only in cerebellum and hippocampus were no difference in concentration of antranilic acid between contro.1 and uremic rats. Accumulation of tryptophan metabolites in nervous tissue may be involved in pathogenesis of several neurological disorders in uremia.
Phenylketonuria in Pediatric Neurology Practice: A Series of 146 Cases
Journal of Child Neurology, 2006
The neurologic manifestations of patients with phenylketonuria treated at different ages are illustrated in this series of 146 cases, including 9 sib pairs. In addition to well-known findings such as mental retardation, autistic features, microcephaly, and tremor, motor retardation was common and responded promptly to dietary treatment. Hypotonia and diminished reflexes were more frequent findings than hypertonia. Four sib pairs showed divergent features, such as the later-treated sibling having higher function than the early-treated one. Because siblings have a similar genotype and similar environmental and dietary conditions, this observation can be explained by differences in phenylalanine transport to the brain or additional metabolic or perinatal factors influencing the neurologic outcome. (J Child
Neonatal Asphyxia in Rats: Acute Effects on Cerebral Kynurenine Metabolism
Pediatric Research, 2001
Two tryptophan metabolites, the anti-excitotoxic N-methyl-D-aspartate (NMDA) receptor antagonist kynurenic acid (KYNA) and the free radical generator 3-hydroxykynurenine (3-HK), have been proposed to influence neuronal viability in the mammalian brain. In rats, the brain content of both KYNA and 3-HK decreases immediately after birth, possibly to ensure normal postnatal functioning of NMDA receptors. Because complications of birth asphyxia have been suggested to be associated with anomalous NMDA receptor function, we examined the acute effects of an asphyctic insult on the brain levels of KYNA and 3-HK in neonatal rats. Asphyxia was induced in animals delivered by cesarean section on the last day of gestation, using the procedure introduced by Bjelke et al. (Brain Res 543: 1-9, 1991). KYNA and 3-HK levels were determined in the brain at seven time points between 10 min and 24 h after asphyxia. Up to 6 h, asphyxia caused 160-267% increases in KYNA levels. In the same tissues, 3-HK levels decreased (significantly at five of the seven time points), demonstrating an asphyxia-induced shift in kynurenine pathway metabolism toward the neuroprotectant KYNA. This shift might constitute the brain's attempt to counter the ill effects of birth asphyxia. Furthermore, the transient increase in the brain KYNA/3-HK ratio in these animals might be causally related to the well-documented detrimental long-term effects of asphyxia. (Pediatr Res 50: 231-235, 2001) Abbreviations 3-HK, 3-hydroxykynurenine KYNA, kynurenic acid NMDA, N-methyl-D-aspartate
Mutation Research/Reviews in Mutation Research, 2018
Tryptophan is metabolized primarily via the kynurenine pathway (KP), which involves several enzymes, including indoleamine 2,3-dioxygenase, tryptophan 2,3 dioxygenase (TDO), kynurenine aminotransferases (KATs), kynurenine monooxygenase (KMO) etc. The majority of metabolites are neuroactive: some of them, such as kynurenic acid, show neuroprotective effects, while others contribute to free radical production, leading to neurodegeneration. Imbalance of the pathway is assumed to contribute to the development of several neurodegenerative diseases, psychiatric disorders, migraine and multiple sclerosis. Our aim was to summarize published data on genetic alterations of enzymes involved in the KP leading to disturbances of the pathway that can be related to different diseases. To achieve this, a PubMed literature search was performed for publications on genetic alterations of the KP enzymes upto April 2017. Several genetic alterations of the KP have been identified and have been proposed to be associated with diseases. Here we must emphasize that despite the large number of recognized genetic alterations, the number of firmly established causal relations with specific diseases is still small. The realization of this by those interested in the field is very important and finding such connections should be a major focus of related research. Polymorphisms of the genes encoding the enzymes of the KP have been associated with autism, multiple sclerosis and schizophrenia, and were shown to affect the immune response of patients with bacterial meningitis, just to mention a few. To our knowledge, this is the first comprehensive review of the genetic alterations of the KP enzymes. We believe that the identification of genetic alterations underlying diseases has great value regarding both treatment and diagnostics in precision medicine, as this work can promote the understanding of pathological mechanisms, and might facilitate medicinal chemistry approaches to substitute missing components or correct the disturbed metabolite balance of KP.
Neurological Deterioration in Three Siblings: Exploring the Spectrum of Argininemia
Indian Journal of Pediatrics, 2020
Argininemia or hyperargininemia is a urea cycle disorder caused by deficiency of the enzyme arginase 1. It is inherited in an autosomal recessive fashion. It commonly leads to spastic diplegia in childhood, but other important features include cognitive deterioration and epilepsy. Unlike other disorders of the urea cycle, hyperammonemia is not prominent. The authors report three siblings with genetically proven argininemia who presented with diverse phenotypes but with spasticity being a common feature. Sibling 1 developed motor regression in early childhood, sibling 2 developed delayed motor milestones from early infancy, whereas sibling 3 had global developmental delay in late infancy after a period of normal development. All siblings had mild hyperammonemia only. Early recognition is imperative, not only to initiate ammonia scavenging therapy which may lead to definite clinical improvement, but also to provide genetic counselling.
Dangerous hyperkalemia in a newborn: Answers
Answers 1. The first differential considered was late onset sepsis with acute kidney injury (AKI) and dyselectrolytemia. Since this newborn had hyperkalemia with hyponatremia, out of proportion to his AKI and sepsis, congenital adrenal hyperplasia (CAH-salt wasting type) was also considered. CAH due to 21-hydroxylase deficiency leads to decreased cortisol and aldosterone which may present clinically like aldosterone resistance. In girls, virilization may be seen while in boys only increased pigmentation may be noted, which was absent in this child. Other inborn errors of metabolism and pseudo-hypoaldosteronism (PHA) [primary or secondary] were also considered as rare differentials, which could be confirmed on investigations. Secondary/transient PHA occurs in the setting of obstructive urinary tract malformation or a urinary tract infection and usually gets corrected after adequate fluid resuscitation and management of infections [1], while other types of PHA are genetically mediated disorders of tubular transport of potassium and sodium. Type 4 renal tubular acidosis (RTA) and was also considered in view of deranged renal functions and hyperkalemia, but it occurs in setting of obstructive uropathy or diabetic nephropathy, which were absent in the child. 2. Sepsis induced AKI as a primary cause for his illness was ruled out as the child continued to have severe hyperkalemia despite improvement in sepsis and initial resuscitation. His cortisol level was 15.94 μg/dl (normal 2-11 μg/ dl); 17-OH progesterone was 8.13 ng/dl (3-90 ng/dl) which ruled out CAH. Serum ammonia, lactate, and blood sugar were normal which ruled against inborn errors of metabolism. RTA type 4 and secondary or transient PHA was ruled out as renal dysfunction improved after correcting the initial shock and fluid bolus, and ultra-sound of kidneys and urinary tract did not reveal any obstructive pathology. Serum aldosterone was 171.1 ng/dl (normal range 2.52-39.2 ng/dl) and serum renin was 6.11 ng/ml (nor-mal range 0.15-2.33 ng/ml), favoring a diagnosis of PHA, likely of genetic etiology as secondary and transient forms were ruled out. Among the various types of PHA that are described, the PHA type 1 may be (a) systemic/multiple site form or (b) renal limited. The former occurs due to defects in epithelial sodium channel (ENaC) or defective miner-alocorticoid receptor at multiple sites. Since the ENaC is expressed in all epithelial tissues, it is associated with widespread systemic manifestations, like recurrent pulmonary infections [1, 2]. One may find a high sweat or salivary sodium level which provides a clue to multisystem involvement. This helps to differentiate it from the renal limited form, which occurs due to defects in receptors for mineralocorticoid on tubular epithelial cells. Since our patient had involvement of skin as well as respiratory system, such as recurrent chest and skin infections , the possibility of type 1 autosomal recessive variant of PHA was considered, which could be confirmed further by performing a genetic analysis [3]. 3. PHA occurs due to renal tubular unresponsiveness to the action of aldosterone. Aldosterone acts on the aldosterone receptor and then through nuclear transcription pathways, and increases the activity of basolateral Na/K ATPase, luminal expression of epi-thelial sodium channel (ENaC) and the activity of luminal renal outer medullary potassium (ROMK) channels (Fig. 1). A defective mineralocorticoid This refers to the article that can be found at https://doi.
Perinatal kynurenine 3-hydroxylase inhibition in rodents: Pathophysiological implications
Journal of Neuroscience Research, 2007
The kynurenine pathway (KP) of tryptophan degradation contains three neuroactive metabolites: the neuroinhibitory agent kynurenic acid (KYNA) and, in a competing branch, the free radical generator 3-hydroxykynurenine (3-HK) and the excitotoxin quinolinic acid (QUIN). These three \kynurenines" derive from a common precursor, L-kynurenine, and are recognized for their role in brain physiology and pathophysiology. Inhibition of kynurenine 3-hydroxylase, the enzyme responsible for 3-HK formation, shifts KP metabolism in the mature brain toward enhanced KYNA formation. We now tested the cerebral effects of kynurenine 3-hydroxylase inhibition in immature rodents. Rat pups treated with the kynurenine 3-hydroxylase inhibitor UPF 648 (30 mg/kg, i.p.) 10 min after birth showed substantial increases in cerebral and liver kynurenine and KYNA levels up to 24 hr later, whereas 3-HK and QUIN levels were simultaneously decreased. Administered to pregnant rats or mice on the last day of gestation, UPF 648 (50 mg/kg, i.p.) produced qualitatively similar changes (i.e., large increases in kynurenine and KYNA and reductions in 3-HK and QUIN) in the brain and liver of the offspring. Rat pups delivered by UPF 648-treated mothers and immediately exposed to neonatal asphyxia showed further enhanced brain KYNA levels. These studies demonstrate that acute kynurenine 3-hydroxylase inhibition effectively shifts cerebral KP metabolism in neonatal rodents toward increased KYNA formation. Selective inhibitors of this enzyme may therefore provide neuroprotection in newborns and will also be useful for the experimental evaluation of the long-term effects of perinatal KP impairment. V