Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital carbamyl phosphate synthetase deficiency was diagnosed by liver biopsy in a 13-year-old girl, alpha-Keto analogues of essential amino acids have been shown to spare nitrogen by reducing urea formation; hence, they were given to this patient in the hope of reducing hyperammonemia and improving protein tolerance. After intravenous infusion of the keto analogues of valine, leucine, isoleucine, methionine and phenylalanine, the corresponding plasma amino acids, including alloisoleucine and tyrosine, rose sharply. Twenty-four hours later, fasting plasma ammonia had fallen from the preinfusion value of 0.050 to 0.028 mM. Protein intake was kept at 0.5 g per kilogram for two weeks. Addition of keto acids by mouth reduced plasma ammonia and alanine to normal or near normal levels. Seizures and episodes of vomiting and lethargy decreased in frequency. Urinary nitrogen decreased, suggesting that nitrogen balance improved. These data indicate that keto acids may be useful in the treatment of congenital hyperammonemia.
 ...
PMID:Treatment of carbamyl phosphate synthetase deficiency with keto analogues of essential amino acids. 16 4

Rats with a portacaval anastomosis and ligation of the hepatic artery 2 days later were infused for 6 hr with a 10% glucose solution (group I) or the same solution combined with 0.24 M/liter branched-chain amino acids (BCAA, group II). Control animals with portacaval anastomosis and sham-operation (group III) or two sham-operations (group IV) were infused with a 10% glucose solution. The rats were killed by decapitation and indoleamines and amino acids were determined in the brain. Rats with liver ischemia were stuporous at the end of the experiment irrespective of treatment. The concentrations in the cortex of lysine, methionine, phenylalanine, threonine, alanine, glutamine, glycine, histidine, and tyrosine were significantly increased in group I compared to group IV. Infusion of BCAA to rats with liver-ischemia (group II) resulted in significantly lower concentrations of lysine, methionine, phenylalanine, threonine, histidine and tyrosine and increased concentrations of isoleucine, leucine, valine, and arginine compared to group I. The content of serotonin in the cortex and brain stem was significantly increased in group I compared with the BCAA-treated animals (group II) and the control groups III and IV. The concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in the cortex and brain stem were higher in group I than in group IV. Infusion of BCAA to rats with liver ischemia normalized the concentrations of 5-HIAA in the cortex and brain stem.
 ...
PMID:Amino acids and indoleamines in the brain after infusion of branched-chain amino acids to rats with liver ischemia. 242 87

Classical Maple Syrup Urine Disease (MSUD) is a disease of infancy which is an inherited disorder of metabolism of branched-chain amino acids (BCAA). The BCAA are normally transaminated to branched-chain keto acids (BCKA). However, the enzyme required to metabolize the BCKA is deficient, resulting in elevation of both, the BCAA and the BCKA. One of the BCAA (isoleucine) produces a metabolite that causes the urine to smell like maple syrup. The elevations of the BCAA and BCKA are associated with an acute, critical neurotoxic condition often prior to the age of two weeks. The clinical state, the electroencephalogram-(EEG), and plasma BCAA levels were evaluated in 26 patients with classical and variant MSUD. Patients were seen from the time of diagnosis, often within a week after birth, and some were followed clinically for more than 20 years while on specific diet therapy. They were monitored by plasma BCAA (leucine, isoleucine and valine) levels and a total of 101 EEGs were performed during different phases of their illness. During periods of acute metabolic decompensation, there were marked clinical symptoms of neurotoxicity including opisthotonos, seizures, and coma with elevated BCAA plasma levels. The EEGs revealed spikes, polyspikes, spike-wave complexes, triphasic waves, severe slowing and bursts of periodic suppression. Occasionally paradoxical EEG arousal was noted while the patient was lethargic. During asymptomatic periods when the plasma BCAA were at low or normal levels, EEG abnormalities occurred in patients with and without residual neurological deficit. These observations included rolandic sharp waves (comb-like rhythm) which were observed in 7 of 15 patients less than two months of age. Additionally, paroxysmal spike and spike-wave response to photic stimuli were observed in 9 of 17 patients. Loading tests were performed on three patients. Clinical and EEG changes were most marked after leucine. Less dramatic EEG changes also occurred with the other two BCAA loads but without clinical manifestations. Elevation of the appropriate BCAA plasma level occurred after each load. These studies and a review of the literature suggest that one component of the pathophysiological mechanism for the acute neurotoxic effects in this disorder is related to a defect in glutamate, glutamine and gamma-aminobutyric acid (GABA) production. The BCAAs are transaminated to BCKAs. Further metabolism of the BCKAs are blocked because of enzyme deficiency required for decarboxylation.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Maple syrup urine disease: clinical, EEG, and plasma amino acid correlations with a theoretical mechanism of acute neurotoxicity. 774 49

A review is presented of 22 published cases of verified or probable mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency, a disorder of isoleucine and ketone body metabolism. The clinical expression, characterized by ketoacidosis, vomiting and lethargy, is highly variable. Typical age of onset is between 6 and 24 months. The disorder, which has been observed in several ethnic groups, is apparently inherited as an autosomal, recessive trait. The prognosis is relatively good if acute episodes of ketoacidosis and dehydration are adequately treated. There is abnormal urinary excretion of 2-methyl-3-hydroxybutyric acid, tiglylglycine, and in some instances also 2-methyl-acetoacetic acid. However, such a pattern of organic aciduria has also been found in cases with normal thiolase activity. Genetic complementation analyses have demonstrated considerable heterogeneity. The cDNA for human methyl-acetoacetyl-CoA thiolase has been cloned and sequenced. Studies in one patient showed a G-to-A substitution at position 1138 of the mRNA, causing 347Ala to Thr change in the mature enzyme. Studies in other patients have shown variable enzyme amount and/or stability.
 ...
PMID:Mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency: an inborn error of isoleucine and ketone body metabolism. 848 3

A 22-day-old female infant was referred to our hospital due to unusual urine odor suspecting inborn error of metabolism. Physical examination revealed a stuporous and hypotonic infant with poor reflexes. Intravenous thiamine and high glucose along with appropriate protein were given under the suspicion of maple syrup urine disease (MSUD), which was confirmed by blood and cerebrospinal fluid amino acid assays, and urinary organic acid assay. Progressive neurological deterioration was observed despite the non-invasive treatment. So, we performed pump assisted continuous arteriovenous haemofiltration (CAVHF). Dramatic improvement in neurological function was observed hours after initiation of CAVHF, along with decrease in the level of isoleucine, leucine and valine. In our experience, CAVHF is a well-tolerated procedure for managing the acute phase of neonatal MSUD. Further study on indications, duration of treatment, and preventing complications is needed.
 ...
PMID:Management of acute decompensation of neonatal maple syrup urine disease with continuous arteriovenous haemofiltration: report of one case. 1260 85

A 12-month-old boy diagnosed with propionic acidemia underwent gastrostomy. The patient's general state was good and he was alert, but with reduced muscular tone (unstable when seated with support, floppy head) and with dystonic movements in all extremities. An electroencephalogram showed slightly slowed brain activity. The patient was being treated with a low protein diet, phenobarbital, L-carnitine, L-isoleucine, and biotin. Surgery was carried out in satisfactory conditions with general anesthesia without opioids combined with infiltration of the surgical wound with local anesthetic. Recovery from anesthesia was rapid and free of complications. Propionic acidemia is caused by mitochondrial propionyl coenzyme carboxylase deficiency. Most patients have episodes of severe metabolic ketoacidosis as a result of excessive protein intake, delayed development, vomiting, gastroesophageal reflux, lethargy, hypotonia, and convulsions. The anesthetic approach involves avoiding triggers of metabolic acidosis (such as fasting, dehydration, hypoxemia, and hypotension) and preventing airway complications. Agents that metabolize propionic acid (such as succinylcholine, benzylisoquinoline neuromuscular blocking agents, and propofol) are not used, as they can exacerbate acidemia. We also believe that using local or regional anesthesia in combination with general anesthesia without opiates is safe and effective for controlling pain during surgery and postoperative recovery, as that combination avoids respiratory depression in these patients, who are highly sensitive to opiates.
 ...
PMID:[Infant boy with propionic acidemia: anesthetic implications]. 1620 Sep 24

Maple syrup urine disease (MSUD) is a rare inborn error of metabolism, caused by a deficiency in activity of the branched chain alpha-keto acid dehydrogenase impairing the degradation of the branched-chain amino acids (leucine, isoleucine and valine). Classic MSUD usually manifests in the neonatal period with poor feeding, vomiting, lethargy, muscular hypertonicity, seizure, coma and death. Thirteen cases of classic MSUD were diagnosed from 1997-2007 at the Queen Sirikit National Institute of Child Health. All cases presented in the neonatal period. The onset of symptoms ranged from 3 to 20 days (median 8 days). The time taken to make the diagnosis ranged from 18 to 356 days (median 55 days). The diagnosis was accomplished by clinical diagnosis and confirmed by detecting abnormal levels of amino acids in the blood and organic acids in the urine. Clinical manifestations were non-specific such as poor suck, weak cry, drowsiness and seizures. Majority of cases were initially diagnosed as sepsis and/or meningitis. All patients had neurological sequelae and psychomotor retardation. This results show the need for increase awareness of metabolic disorder such as MSUD and the requirement for early detection and treatment to ensure a better outcome.
 ...
PMID:Maple syrup urine disease in Thai infants. 1925 91

Beta-ketothiolase deficiency is a rare autosomal recessive disorder of isoleucine and ketone body metabolism. This disorder is clinically characterized by ketoacidotic attacks. Ketoacidosis, vomiting, and dehydration, lethargy and coma may be seen during attacks. A 9-month-old girl was admitted to our hospital with acidosis and dehydration. The patient was lethargic. Ketoacidosis was suspected because of acetone odor on her breath. Her blood glucose level was 262 mg/dL and urine ketone was (++++). Branched chain amino acid levels were elevated in her blood sample. Organic acid analysis of urine revealed 2-methylacetoacetyl-CoA thiolase deficiency. This was reported because of rarity of the disease and we should consider it in the differential diagnosis of ketoacidotic episodes.
 ...
PMID:Beta-ketothiolase deficiency brought with lethargy: case report. 2124 97

Maple syrup urine disease (MSUD) is an autosomal recessive disorder associated with impaired metabolism of branched-chain amino acids (BCAA) leucine, isoleucine, and valine. Children with MSUD suffer from bouts of metabolic decompensation, which may lead to neurological damage. Liver transplantation from unrelated deceased donors has been considered curative. The natural history of the disease following transplantation using a haploidentical (obligate heterozygous) living donor is still unclear, although previously described as favorable. We describe acute metabolic crises in a 20-month-old child with MSUD type II. The first well-documented one occurred 5 months after a successful liver transplantation from his mother. The patient developed encephalopathy with progressive lethargy and seizures after an episode of gastroenteritis with dehydration. Plasma levels of leucine, isoleucine, and valine were markedly elevated and alloisoleucine was detected. He promptly responded to dialysis and BCAA-free dietetic management and subsequently could resume a normal diet. Since then he has had another symptomatic metabolic crisis with seizures. This case strongly suggests that some recipients of liver transplantation from a haploidentical parent possess limited capacity to oxidize BCAA at the time of catabolic stress and dehydration and remain at risk of severe metabolic crises. Thus, careful metabolic monitoring and prompt treatment post liver transplantation are still required to avoid neurological sequelae of MSUD, particularly if the donor is heterozygous for MSUD.
 ...
PMID:Acute Metabolic Crises in Maple Syrup Urine Disease After Liver Transplantation from a Related Heterozygous Living Donor. 2711 95

Beta-ketothiolase deficiency is a rare autosomal recessive disorder characterized by an inborn error of isoleucine catabolism and affecting ketone body metabolism. Clinical features characterized by intermittent keto acidotic episodes are associated with clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients, with an onset during infancy or toddler-hood. A two months old girl presented to pediatric ward of Imam Reza Hospital in Mashhad City, Northwestern Iran in October 2016, with acute episode of fever and toxic encephalopathy with attack of vomiting, hypotonia, lethargy, tonic-clonic seizures and then a day in coma, few days after vaccination. After then similar episodes happened until 7 months age. Bio chemical tests that suggested diagnose of beta ketothiolase deficiency were attacks of ketoacidosis with urinary exertion of 2-methyl-3-hydroxybutyric acid 2-methyl aceto acetic acid tiglylglycine. In genetic assessment, we detected a novel homozygous mutation c.664A> C (p. Ser 222 Arg) in ACAT gene. This is the first report of beta ketothiolase deficiency confirmed by molecular analysis from Iran. We report on a homozygous variant in the ACAT1 gene and that is a novel mutation. We recommended carrier testing for all informative family members to recognize mutations in asymptomatic family members.
 ...
PMID:A Novel Mutation of Beta-ketothiolase Deficiency: The First Report from Iran and Review of Literature. 3002 75


1