Posted by: Chris Maloney | May 24, 2011

Maple Syrup Urine Disease: Brain Effects For the Rest of Us?

Branched-chain amino acids

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Maple Syrup Urine Disease (MSUD) is not an overdose of Maine‘s favorite syrup on Maple Sunday.  It’s the inability to process branched chain amino acids (part of a complete protein).  The amino acids build up in the brain and in the body, giving the infant a smell like maple syrup.  The treatment is medical food that is bereft of these amino acids (and also evidently hasn’t caught up with baby food, because the MSUDers are short DHA). 

But what is interesting for the majority of people is what happens to MSUDers under stress.  The amino acids build up and cause acidosis, shutting things down.  Another common side effect is tremors or tics.  I immediately thought of my many patients who have difficulty with stress, and the common issue of “essential tremor,” which occurs in the older population. 

So I went looking for the spectrum of MSUD.  Sure enough, individuals may not process the amino acids, but may not even show symptoms.  They commonly show a range of symptoms, but those worsen with stress or infection. 

MSUD may not simply affect those who present with the outright illness in infancy.  It may be much more common, and be a factor in a variety of aging disorders. 

Below (apologies for those who don’t like data) are the studies I looked at.

Mov Disord. 2011 Apr 11. doi: 10.1002/mds.23629. [Epub ahead of print]

Movement disorders in adult surviving patients with maple syrup urine disease.

Carecchio M, Schneider SA, Chan H, Lachmann R, Lee PJ, Murphy E, Bhatia KP.

SourceSobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, London, United Kingdom; Department of Neurology, Amedeo Avogadro University, Novara, Italy.

Abstract

Maple syrup urine disease is a rare metabolic disorder caused by mutations in the branched-chain α-keto acid dehydrogenase complex gene. Patients generally present early in life with a toxic encephalopathy because of the accumulation of the branched-chain amino acids leucine, isoleucine, and valine and the corresponding ketoacids. Movement disorders in maple syrup urine disease have typically been described during decompensation episodes or at presentation in the context of a toxic encephalopathy, with complete resolution after appropriate dietary treatment. Movement disorders in patients surviving childhood are not well documented. We assessed 17 adult patients with maple syrup urine disease (mean age, 27.5 years) with a special focus on movement disorders. Twelve (70.6%) had a movement disorder on clinical examination, mainly tremor and dystonia or a combination of both. Parkinsonism and simple motor tics were also observed. Pyramidal signs were present in 11 patients (64.7%), and a spastic-dystonic gait was observed in 6 patients (35.2%). In summary, movement disorders are common in treated adult patients with maple syrup urine disease, and careful neurological examination is advisable to identify those who may benefit from specific therapy. © 2011 Movement Disorder Society.

Copyright © 2011 Movement Disorder Society.

Pediatrics. 2002 Jun;109(6):999-1008.

Diagnosis and treatment of maple syrup disease: a study of 36 patients.

Morton DH, Strauss KA, Robinson DL, Puffenberger EG, Kelley RI.

SourceClinic for Special Children, Strasburg Pennsylvania 17579,, USA.

Abstract

OBJECTIVE: To evaluate an approach to the diagnosis and treatment of maple syrup disease (MSD).

METHODS: Family histories and molecular testing for the Y393N mutation of the E1alpha subunit of the branched-chain alpha-ketoacid dehydrogenase allow us to identify infants who were at high risk for MSD. Amino acid concentrations were measured in blood specimens from these at-risk infants between 12 and 24 hours of age. An additional 18 infants with MSD were diagnosed between 4 and 16 days of age because of metabolic illness. A treatment protocol for MSD was designed to 1) inhibit endogenous protein catabolism, 2) sustain protein synthesis, 3) prevent deficiencies of essential amino acids, and 4) maintain normal serum osmolarity. Our protocol emphasizes the enhancement of protein anabolism and dietary correction of imbalances in plasma amino acids rather than removal of leucine by dialysis or hemofiltration. During acute illnesses, the rate of decrease of the plasma leucine level was monitored as an index of net protein synthesis. The treatment protocol for acute illnesses included the use of mannitol, furosemide, and hypertonic saline to maintain or reestablish normal serum sodium and extracellular osmolarity and thereby prevent or reverse life-threatening cerebral edema. Similar principles were followed for both sick and well outpatient management, especially during the first year, when careful matching of branched-chain amino acid intake with rapidly changing growth rates was necessary. Branched-chain ketoacid excretion was monitored frequently at home and branched-chain amino acid levels were measured within the time of a routine clinic visit, allowing immediate diagnosis and treatment of metabolic derangements.

RESULTS: 1) Eighteen neonates with MSD were identified in the high-risk group (n = 39) between 12 and 24 hours of age using amino acid analysis of plasma or whole blood collected on filter paper. The molar ratio of leucine to alanine in plasma ranged from 1.3 to 12.4, compared with a control range of 0.12 to 0.53. None of the infants identified before 3 days of age and managed by our treatment protocol became ill during the neonatal period, and 16 of the 18 were managed without hospitalization. 2) Using our treatment protocol, 18 additional infants who were biochemically intoxicated at the time of diagnosis recovered rapidly. In all infants, plasma leucine levels decreased to <400 micromol/L between 2 to 4 days after diagnosis. Rates of decrease of the plasma leucine level using a combination of enteral and parenteral nutrition were consistently higher than those reported for dialysis or hemoperfusion. Prevention of acute isoleucine, valine, and other plasma amino acid deficiencies by appropriate supplements allowed a sustained decrease of plasma leucine levels to the therapeutic range of 100 to 300 micromol/L, at which point dietary leucine was introduced. 3) Follow-up of the 36 infants over >219 patient years showed that, although common infections frequently cause loss of metabolic control, the overall rate of hospitalization after the neonatal period was only 0.56 days per patient per year of follow-up, and developmental outcomes were uniformly good. Four patients developed life-threatening cerebral edema as a consequence of metabolic intoxication induced by infection, but all recovered. These 4 patients each showed evidence that acutely decreased serum sodium concentration and decreased serum osmolarity were associated with rapid progression of cerebral edema during their acute illnesses.

CONCLUSIONS: Classical MSD can be managed to allow a benign neonatal course, normal growth and development, and low hospitalization rates. However, neurologic function may deteriorate rapidly at any age because of metabolic intoxication provoked by common infections and injuries. Effective management of the complex pathophysiology of this biochemical disorder requires integrated management of general medical care and nutrition, as well as control of several variables that influence endogenous protein anabolism and catabolism, plasma amino acid concentrations, and serum osmolarity.

PMID:12042535

Anaesthesist. 2010 Oct;59(10):914-7. Epub 2010 Sep 9.

[Anaesthesia in patients with maple syrup urine disease. Case report and perioperative anaesthetic management].

[Article in German]

Haberstich P, Kindler CH, Schürch M.

SourceKlinik für Anästhesie und Operative Intensivmedizin, Bereich Perioperative Medizin, Kantonsspital Aarau, 5001 Aarau, Schweiz. phaberstich75@hotmail.com

Abstract

Maple syrup urine disease is a rare autosomal-recessive metabolic disorder caused by a deficit of oxidative decarboxylation of branched-chain amino acids. First symptoms appear in the neonatal period. Without treatment the disease is characterized by rapid progression of neurological symptoms. During stressful situations, such as infection or surgery, patients may experience severe ketoacidosis, rapid neurological deterioration and hypoglycemia. The perioperative management of a 26-year-old man with maple syrup urine disease is described, a review of the disease is given and anaesthesia-related implications are discussed.

PMID:20827453

J Inherit Metab Dis. 2010 Apr;33(2):121-7. Epub 2010 Mar 9.

Docosahexaenoic acid status in females of reproductive age with maple syrup urine disease.

Mazer LM, Yi SH, Singh RH.

SourceEmory University School of Medicine, Atlanta, GA, USA.

Abstract

Individuals with maple syrup urine disease (MSUD) have impaired metabolism of branched-chain amino acids (BCAA) valine, isoleucine, and leucine. Life-long dietary therapy is recommended to restrict BCAA intake and thus prevent poor neurological outcomes and death. To maintain adequate nutritional status, the majority of protein and nutrients are derived from synthetic BCAA-free medical foods with variable fatty acid content. Given the restrictive diet and the importance of omega-3 fatty acids, particularly docosahexaenoic acid (DHA), in neurological development, this study evaluated the dietary and fatty acid status of females of reproductive age with MSUD attending a metabolic camp. Healthy controls of similar age and sex were selected from existing normal laboratory data. Total lipid fatty acid concentration in plasma and erythrocytes was analyzed using gas chromatography-mass spectroscopy. Participants with MSUD had normal to increased concentrations of plasma and erythrocyte alpha linolenic acid (ALA) but significantly lower concentrations of plasma and erythrocyte docosahexaenoic acid (DHA) as percent of total lipid fatty acids compared with controls (plasma DHA: MSUD 1.03 +/- 0.35, controls 2.87 +/- 1.08; P = 0.001; erythrocyte DHA: MSUD 2.58 +/- 0.58, controls 3.66 +/- 0.80; P = 0.011). Dietary records reflected negligible or no DHA intake over the 3-day period prior to the blood draw (range 0-2 mg). These results suggest females of reproductive age with MSUD have lower blood DHA concentrations than age-matched controls. In addition, the presence of ALA in medical foods and the background diet may not counter the lack of preformed DHA in the diet. The implications of these results warrant further investigation.

PMID:20217236

J Inherit Metab Dis. 2006 Dec;29(6):716-24. Epub 2006 Oct 25.

Variant maple syrup urine disease (MSUD)–the entire spectrum.

Simon E, Flaschker N, Schadewaldt P, Langenbeck U, Wendel U.

SourceDepartment of General Paediatrics, University Children’s Hospital, Heinrich-Heine University, Moorenstr. 5, D-40225, Düsseldorf, Germany. simon@med.uni-duesseldorf.de

Abstract

BACKGROUND: In the rare inborn autosomal recessive disorder maple syrup urine disease (MSUD) the accumulation of the branched-chain amino acids (BCAAs) and their metabolic products results in acute and chronic brain dysfunction. About 20% of the patients suffer from non-classic variant forms of MSUD of different clinical severity. Aim: Up to now variant cases have mostly been published as individual case reports; the aim of this study was to give a comparative description of 16 individuals (aged 6-30 years) with different forms of variant MSUD.

METHODS: Laboratory data, information on clinical course and treatment as well as aspects of developmental, intellectual and social outcome were obtained retrospectively. Data from in vitro and in vivo methods measuring the degree of enzyme deficiency were included.

RESULTS: In addition to a mild phenotype, which fits well into the so-called intermittent variant, and a more severe phenotype with a wider range from a mild variant to an almost classic form, which fits well into the so-called intermediate variant, we assume the existence of an asymptomatic, non-disease variant of MSUD. These clinical phenotypes are not unambiguously differentiable on the basis of biochemical parameters.

CONCLUSION: A continuum of clinical severity from asymptomatic to very severe (border to classic) exists in variant MSUD. Apart from newborns with classic MSUD, also those with variant forms benefit from early diagnosis and start of adequate treatment.

PMID:17063375

J Nutr. 2005 Jun;135(6 Suppl):1539S-46S.

Branched-chain amino acids and brain function.

Fernstrom JD.

SourceDepartment of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, PA 15213, USA. fernstromjd@upmc.edu

Abstract

Branched-chain amino acids (BCAAs) influence brain function by modifying large, neutral amino acid (LNAA) transport at the blood-brain barrier. Transport is shared by several LNAAs, notably the BCAAs and the aromatic amino acids (ArAAs), and is competitive. Consequently, when plasma BCAA concentrations rise, which can occur in response to food ingestion or BCAA administration, or with the onset of certain metabolic diseases (e.g., uncontrolled diabetes), brain BCAA concentrations rise, and ArAA concentrations decline. Such effects occur acutely and chronically. Such reductions in brain ArAA concentrations have functional consequences: biochemically, they reduce the synthesis and the release of neurotransmitters derived from ArAAs, notably serotonin (from tryptophan) and catecholamines (from tyrosine and phenylalanine). The functional effects of such neurochemical changes include altered hormonal function, blood pressure, and affective state. Although the BCAAs thus have biochemical and functional effects in the brain, few attempts have been made to characterize time-course or dose-response relations for such effects. And, no studies have attempted to identify levels of BCAA intake that might produce adverse effects on the brain. The only “model” of very high BCAA exposure is a very rare genetic disorder, maple syrup urine disease, a feature of which is substantial brain dysfunction but that probably cannot serve as a useful model for excessive BCAA intake by normal individuals. Given the known biochemical and functional effects of the BCAAs, it should be a straightforward exercise to design studies to assess dose-response relations for biochemical and functional effects and, in this context, to explore for adverse effect thresholds.

PMID:15930466

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