Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease

Zinnanti, William J.; Lazović, Jelena; Griffin, Kathleen; Skvorak, Kristen J.; Paul, Harbhajan S.; Homanics, Gregg E.; Bewley, Maria C.; Cheng, Keith C.; LaNoue, Kathryn F.; Flanagan, John M.

doi:10.1093/brain/awp024

Cited by 120 publications

(144 citation statements)

References 38 publications

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“…Additionally, Linck and colleagues (2012) have demonstrated that AMPA receptors play a key role in the mechanism of the antidepressant-like action of NAC by indirectly modulating the serotonin and noradrenaline pathways. Consistent with these mechanisms, reduced cerebral dopamine and glutamate levels have been observed in experimental MSUD animals (Dodd et al 1992;Zinnanti et al 2009) and postmortem brain tissue from a child who died of leucine intoxication (Prensky and Moser 1996).…”

Section: Discussionmentioning

confidence: 75%

“…The worldwide frequency is approximately 1:185,000 based on routine screening data from 26.8 million newborns (Chuang and Shih 2001). Individuals with MSUD usually present with poor feeding, convulsions, ketoacidosis, hypoglycemia, coma, ataxia, psychomotor delay, and mental retardation, as well as generalized edema and hypomyelination/ demyelination shown by magnetic resonance imaging studies of the central nervous system (Chuang and Shih 2001;Cavalleri et al 2002;Ha et al 2004;Sch€ onberger et al 2004;Zinnanti et al 2009). …”

Section: Introductionmentioning

confidence: 99%

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Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

et al. 2013

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Maple syrup urine disease (MSUD) is an inborn metabolism error caused by a deficiency of branched-chain a-keto acid dehydrogenase complex activity. This blockage leads to an accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, as well as their corresponding a-keto and a-hydroxy acids. Previous reports suggest that MSUD patients are at high risk for chronic neuropsychiatric problems. Therefore, in this study, we assessed variables that suggest depressive-like symptoms (anhedonia as measured by sucrose intake, immobility during the forced swimming test and body and adrenal gland weight) in rats submitted to chronic administration of BCAA during development. Furthermore, we determined if these parameters were sensitive to imipramine and N-acetylcysteine/deferoxamine (NAC/DFX). Our results demonstrated that animals subjected to chronic administration of branched-chain amino acids showed a decrease in sucrose intake without significant changes in body weight. We also observed an increase in adrenal gland weight and immobility time during the forced swimming test. However, treatment with imipramine and NAC/DFX reversed these changes in the behavioral tasks. In conclusion, this study demonstrates a link between MSUD and depression in rats. Moreover, this investigation reveals that the antidepressant action of NAC/DFX and imipramine might be associated with their capability to maintain pro-/anti-oxidative homeostasis.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

et al. 2013

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“…10 Foi demonstrado que a rápida acumulação cerebral de leucina desloca outros aminoácidos essenciais, conduzindo à depleção de neurotransmissores e à interrupção do crescimento e desenvolvimento normal do cérebro. 10 Os valores normais de leucina sérica variam entre 80 e 200 µmol/L. 7 Valores de leucina superiores a 1000 µmol/L de forma sistemática relacionam-se com desenvolvimento intelectual negativo.…”

Section: Discussionunclassified

Hemodiafiltração venovenosa contínua nas descompensações graves de doenças metabólicas

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Gaspar

et al. 2017

Acta Pediátrica Port

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Introduction: Continuous venovenous haemodiafiltration is an extracorporeal blood purification technique that can be used in the treatment of metabolic diseases. The aim of this study was to evaluate its effectiveness and complications in the treatment of metabolic decompensation in patients with inborn errors of metabolism. Methods: Cases in which heaemodiafiltration was used in a paediatric intensive care unit over 10 years were reviewed. Results: We performed 18 sessions of continuous venovenous haemodiafiltration in 15 patients (10 with maple syrup urine disease, five with hyperammonaemia); 11 of the sessions were in newborns. The technique was initiated because of severe metabolic decompensation with neurological signs in 10/18 cases, within the first six hours of hospitalization. The median technique duration was 18 hours. There was a significant reduction in levels of leucine (1940 µmol/l to 400 µmol/l) and ammonia values (1433 µmol/l to 255 µmol/l) (p ≤ 0.01). In three cases, haemodiafiltration was suspended because of serious bleeding complications. Three types of vascular access (jugular, femoral and umbilical) were used. Jugular access resulted in longer filter life (p = 0.002). The mean length of hospital stay was 4.9 days; patients required invasive ventilation in 13 episodes. The survival rate was 66.7%. Discussion: The success of continuous venovenous haemodiafiltration in the treatment of acute metabolic decompensation is reported. The technique was very effective in reducing toxic metabolites, but the complexity of these patients and the possibility of fatal complications demonstrates the need for careful patient selection and experience in implementation. Jugular access appears to be best for this technique.

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“…With respect to the latter, mouse model experiments have shown lower CSF levels of glutamate, dopamine, and GABA, as well as lower plasma levels of tryptophan, the precursor to serotonin (Zinnanti et al 2009). The BCKAs appear to exert effects, at least partially through disruption of pyruvate metabolism (Patel et al 1973) and respiratory chain function (Sgaravatti et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Cerebral Edema in Maple Syrup Urine Disease Despite Newborn Screening Diagnosis and Early Initiation of Treatment

et al. 2011

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A 7-day-old girl had an elevated leucine level on newborn screen drawn at 2 days of age and was suspected of having maple syrup urine disease (MSUD). When reported, the patient was immediately admitted to hospital, and started on a modified diet involving high calories with reduced branched chain amino acid (BCAA) formula. Clinical exam was normal at initial assessment. Despite rapid initiation of treatment, the baby became lethargic and somnolent over the next day. Diet was stopped and infusions of 12.5% dextrose and 20% intravenous lipids at 2 g/kg per day were immediately started. Lethargy improved within 3 h of intravenous therapy initiation. Brain magnetic resonance imaging demonstrated diffuse cerebral edema, and symmetric restricted diffusion in bilateral cerebellar white matter, dorsal brainstem, thalami, globi pallidi, posterior limbs of internal capsules, and corona radiata. Plasma leucine was 1.98 mmol/L on admission (normal 0.05-0.17 mmol/L), decreasing to 1.34 mmol/L with diet, however clinical deterioration occurred despite improving leucine levels.Cerebral edema in MSUD is thought secondary to a combination of increased cerebral BCAA levels, and depleted levels of other essential amino acids, as well as neurotransmitters. Our case illustrates that newborns can develop encephalopathy with cerebral edema despite treatment with special formula initiated while asymptomatic. These findings suggest decompensation may begin early on, so that early introduction of high dextrose infusion and intravenous lipids, in combination with reduced BCAA formula, should be initiated for any patient with a positive newborn screen for MSUD.

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Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease

Cited by 120 publications

References 38 publications

Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

Hemodiafiltração venovenosa contínua nas descompensações graves de doenças metabólicas

Cerebral Edema in Maple Syrup Urine Disease Despite Newborn Screening Diagnosis and Early Initiation of Treatment

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