Branched-chain amino acid (BCAA) metabolism plays a central role in the pathophysiology of both rare inborn errors of metabolism and the more common multifactorial diseases. Although deficiency of the branched-chain ketoacid dehydrogenase (BCKDC) and associated elevations in the BCAAs and their ketoacids have been recognized as the cause of maple syrup urine disease (MSUD) for decades, treatment options for this disorder have been limited to dietary interventions. In recent years, the discovery of improved leucine tolerance after liver transplantation has resulted in a new therapeutic strategy for this disorder. Likewise, targeting the regulation of the BCKDC activity may be an alternative potential treatment strategy for MSUD. The regulation of the BCKDC by the branched-chain ketoacid dehydrogenase kinase has also been implicated in a new inborn error of metabolism characterized by autism, intellectual disability and seizures. Finally, there is a growing body of literature implicating BCAA metabolism in more common disorders such as the metabolic syndrome, cancer and hepatic disease. This review surveys the knowledge acquired on the topic over the past 50 years and focuses on recent developments in the field of BCAA metabolism.

INTRODUCTION

The branched-chain amino acids (BCAAs) namely valine, isoleucine and leucine are essential amino acids with hydrophobic side chains that comprise ∼20–40% of most dietary proteins (1,2). A large proportion of BCAAs from dietary sources is absorbed from the intestines, bypasses the liver, and is delivered to the peripheral tissues (3). Although the enzymatic machinery for BCAA metabolism is predominantly active in the liver, BCAA catabolism also occurs in other tissues including skeletal muscle, heart and adipose tissue (1,2). The complex interorgan relationships in BCAA metabolism have been summarized elsewhere (1,2).

The role of abnormal BCAA metabolism in human disease was initially recognized with the description and biochemical characterization of maple syrup urine disease (MSUD; MIM:248600), a Mendelian disorder caused by a deficiency of the rate-limiting enzyme in BCAA catabolism (46). Since then, dysregulated BCAA metabolism has been found to be causative or associated with complex neurocognitive phenotypes, insulin resistance, adverse cardiovascular outcomes and liver disease. This review will focus on Mendelian diseases characterized by both elevated and decreased levels of BCAA and dysregulation of BCAA metabolism in more common disorders like diabetes, cancer and liver disease.

BCAA METABOLISM

The initial step in BCAA catabolism is a transamination of these amino acids by branched-chain aminotransferase (BCAT) to generate their respective α-ketoacids (α-ketoisocaproic acid (KIC), α-keto-β-methylvaleric acid (KMV) and α-ketoisovaleric acid (KIV)). These branched-chain ketoacids (BCKAs) undergo oxidative decarboxylation by the branched-chain ketoacid dehydrogenase complex (BCKDC), a large (4.5 MDa) catalytic complex which consists of a heterodimeric E1 decarboxylase component (E1α and E1β subunits), an E2 transacylase component with 24 identical subunits and a homodimeric E3 component (2). BCKDC requires several cofactors, including thiamine pyrophosphate (for the E1 component), Coenzyme A (for the E2 component), lipoamide and flavin and nicotinamide adenine dinucleotides (FAD and NAD) (all for the E3 component). The products resulting from BCKDC-mediated catalysis are isovaleryl-CoA, α-methylbutyrylCoA and isobutyryl-CoA. Through a series of further enzymatic reactions, these products are converted to the end products of BCAA metabolism: acetoacetate, acetyl-CoA and succinyl-CoA (Fig. 1).

Figure 1.

BCAA catabolism. The BCAAs are transaminated by BCAT to generate α-ketoacids (KIC, KMV and KIV). These α-ketoacids undergo oxidative decarboxylation by the BCKDC.

Figure 1.

BCAA catabolism. The BCAAs are transaminated by BCAT to generate α-ketoacids (KIC, KMV and KIV). These α-ketoacids undergo oxidative decarboxylation by the BCKDC.

MENDELIAN DISORDERS OF BCAA METABOLISM

Maple syrup urine disease

MSUD is an inborn error of metabolism caused by decreased activity of the BCKDC (46). Patients with the classic form of MSUD present in the neonatal period with poor feeding and irritability that, if left untreated, may progress to lethargy, coma and death. Elevations of plasma BCAAs and urinary BCKAs are the biochemical hallmark and the presence of l-alloisoleucine in the plasma is pathognomonic for the disorder.

The prevalence of MSUD in the USA is estimated to be ∼1:200 000 live births (7) but is much higher is some populations, such as the Mennonites (1:358 live births) (8). Classic MSUD characterized by neonatal presentation is typically a result of biallelic mutations in the E1α, E1β or E2 subunits of the BCKDC. An intermediate or variant form of MSUD presents with milder symptoms or at a later age, and an intermittent form presents with episodic symptoms with normal levels of BCAA between episodes. The intermediate and intermittent forms of MSUD are also due to mutations in the E1α, E1β or E2 subunits; however, the residual activity of BCKDC is higher when compared with classic forms (9,10). A fourth type of MSUD is the thiamine-responsive form which occurs due to mutations in the E2 subunit that produce a full-length mutant form of the E2 protein (11,12). Finally, mutations in the E3 subunit (dihydrolipoyl dehydrogenase), which is shared with pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, result in a severe phenotype distinct from MSUD that is characterized by congenital lactic acidosis and progressive neurologic deterioration (13).

The goal of the initial acute treatment of MSUD is the reduction of plasma leucine levels by discontinuing protein feeds, providing calories from dextrose and intravenous lipids, hemodialysis, if necessary, and eventually introducing BCAA-free formula (1417). Neurologic status, plasma amino acids, electrolytes and serum osmolarity should be closely monitored as patients are at risk for cerebral edema, a potentially fatal complication. Because prolonged elevation of plasma leucine in the neonatal period contributes to long-term intellectual outcomes, early identification and treatment are necessary (18,19). Thus, MSUD is an ideal disorder for detection via newborn screening (7,20). However, late-onset or intermittent forms may not always be detected by newborn screening (21).

The goal of long-term treatment is to maintain the plasma BCAA levels as close to normal as possible using dietary modifications including protein restriction and BCAA-free medical formula. The plasma concentration of leucine, the most neurotoxic of the BCAA, typically guides adjustments to the dietary regimen. Long-term control of leucine levels has been associated with intellectual and neuropsychiatric outcome in this disorder (18,19,22,23). Intercurrent illnesses can result in the release of BCAAs from endogenous protein catabolism and risk for acute metabolic decompensation. Strategies, such as the judicious use of dextrose-containing intravenous fluids, insulin, BCAA-free ‘sick day’ formula and isoleucine and valine supplements may be necessary in the setting of illnesses to promote anabolism. Although a small proportion of patients respond to thiamine supplementation (12), there are currently no medications for the long-term management of MSUD. Several new therapies for MSUD are being investigated in clinical and preclinical studies.

Liver transplantation in MSUD

The discovery that liver transplantation may be an effective treatment for MSUD was made from observations in two patients with MSUD who required liver transplantation for liver failure secondary to other causes. Both patients had improvement in BCAA levels after transplant (2426). Since then, numerous liver transplants have been performed. A recent case series described outcomes in 54 patients with MSUD who underwent liver transplantation in the USA between 2004 and 2010 (UNOS registry) with a 98% patient survival and 96% graft survival (27). Of these 54 patients, the course of 37 patients who received liver transplants at a single center has been described (27). BCAA homeostasis normalized within hours of surgery and all patients had increased leucine tolerance after transplantation (27). Interestingly, the finding of one patient with leucinosis in the setting of dehydration indicates that patients may still require careful management in the face of intercurrent illness even after transplantation (27). Pre- and posttransplantation IQ scores were not significantly different in 14 patients (28). However, liver transplantation may prevent future metabolic decompensations and further worsening of cognitive outcomes.

The effectiveness of liver transplantation in MSUD suggests that providing 9–13% of the bodies' BCKDC activity is sufficient to restore BCAA homeostasis (27,29). Furthermore, the livers from several patients with MSUD have been successfully transplanted into patients requiring liver transplant for other reasons (27,3032). The success of domino transplantation suggests that BCKDC activity in the skeletal muscle and other tissues is sufficient even in the face of deficient activity in the liver (27,3032).

Obviously, liver transplantation is not without consequences including postoperative complications and the effects of long-term immunosuppression. Nearly 40% of transplanted patients have needed management for acute rejection (27). Of 54 patients in the UNOS registry, one died and one required a second transplant (27). A larger study (n = 446) evaluating pediatric liver transplantation performed for any metabolic disease revealed a 95% survival at 1 year with 89% survival at 5 years (33). Thus, the risks and benefits of liver transplantation must be carefully considered.

Tissue and cell transplantation in preclinical models of MSUD

Although liver transplantation has been shown to be successful in MSUD, the limitations in availability of donor tissue preclude its widespread applicability. Hence, preclinical studies focusing on other sources of cells or tissues with BCKDC activity have gained prominence. Hepatocyte cell transplantation has been evaluated in the iMSUD mouse model (34,35). The iMSUD mouse model was generated by introducing a human cDNA for the E2 subunit that is expressed in the liver of cMSUD (E2 knockout) and has improved survival compared with the cMSUD model (36). Two injections of donor hepatocytes given transdermally into the liver parenchyma in the first 10 days of life resulted in engraftment of cells and BCKDC activity that was 14.36% of control activity when compared with 6.23% in PBS-treated mice (35). The mice treated with hepatocyte transfer had improved body weight, survival and partial corrections of neurotransmitter abnormalities in the brain (34,35). However, although BCAA levels were improved at weaning, they were not significantly different from controls or untreated mice at the time of sacrifice (35). It is thus unclear whether this partial increase in enzyme activity will be sufficient to promote long-term survival in this mouse model for MSUD or be sufficient to prevent metabolic decompensation in the setting of stress.

Although hepatocyte cell transplantation has given some promising results in preclinical models, the utility of such an approach in humans may be complicated by limited availability of donor hepatocytes and the need for immunosuppression. An alternative approach is the use of stem cells, such as human amnion epithelial cells, that can be differentiated into hepatocytes. The possibility of human amnion epithelial cell therapy is enticing because these cells are less immunogenic. Transdermal hepatic injections of human amnion epithelial cells in iMSUD mice, doubled the BCKDC enzyme activity and decreased the BCAA levels in the serum and brain (37,38). Furthermore, these biochemical improvements were associated with improvements in body weight, survival and bioenergetic parameters in both brain and serum (37,38).

Recent studies have also investigated adipose tissue as a source of BCAA activity in MSUD mouse (39). Subcutaneous transplantation of adipose tissue from wild-type mice into two different mouse models of MSUD (BCATm knockout or branched-chain dehydrogenase phosphatase (PPM1K) knockout models) resulted in decreased BCAAs by 52–81% compared with non-transplanted mice (40).

Targeting leucine neurotoxicity in MSUD

Despite therapy, patients with MSUD typically have intellectual and social impairments (23,41,42). However, the exact mechanisms underlying the neurotoxicity of BCAAs, particularly leucine and BCKAs are likely complex and incompletely understood. The neurotoxicity of leucine and BCKAs has been discussed elsewhere (43,44) and here, we will focus on aspects of neurotoxicity that are targets of new therapeutic strategies.

One mechanism that explains leucine toxicity is interference with neurotransmitter biosynthesis. Leucine competes with other large neutral amino acids for transport across the blood–brain barrier using the large neutral amino acid transporter (45). Given that some of these amino acids, such as phenylalanine and tyrosine, are precursors of neurotransmitters, this competition for transport likely interferes with neurotransmitter synthesis. Optimization of neutral amino acid transport across the blood–brain barrier has hence become a treatment strategy in MSUD. Strauss and colleagues designed a metabolic formula that enhances the transport of amino acids (e.g. tyrosine, tryptophan, histidine, methionine, threonine, glutamine and phenylalanine) which compete with leucine for entry into the brain (46). In patients using this formula, plasma leucine levels were improved and decreased variation in plasma leucine measurements was noted (46). However, no randomized controlled trial comparing this formula with standard MSUD formulas has been performed.

Likewise, norleucine, a BCAA analog which competes with leucine for transport across the blood–brain barrier has been explored as a therapy in preclinical models (47,48). The administration of norleucine resulted in improved survival, reduced levels of leucine and KIC, and normalization of glutamate, GABA and aspartate levels in the brain (47). However, levels of tyrosine and dopamine in the brain were still low suggesting that although norleucine restores some aspects of energy metabolism in the iMSUD mice, normal amino acid transport across the blood–brain barrier is not restored with this treatment (47).

BCAAs and BCKAs may also contribute to neurotoxicity by increased lipid peroxidation and oxidative stress (4951). Measures of oxidative stress have been found to be higher in the plasma of patients with MSUD when compared with control subjects even in the setting of low plasma leucine levels (52,53). Carnitine is a quaternary amine that is hypothesized to have antioxidant properties in addition to its well-known role in the transport of long chain fatty acids into the mitochondria. Mescka et al. showed that the plasma levels of free carnitine were lower and that measures of free-radical mediated peroxidation (e.g. malondialdehyde) were higher in patients with MSUD when compared with healthy subjects (54). Levocarnitine therapy increased the plasma free carnitine (54) and decreased malondialdehyde levels (54) which suggest that levocarnitine may have antioxidant effects in MSUD (54,55). Long-term studies are necessary to evaluate whether levocarnitine supplementation could affect neurocognitive outcomes in MSUD.

Another mechanism of leucine and BCKA toxicity is the disruption of energy metabolism in the brain. The BCAAs, particularly leucine and BCKAs inhibit pyruvate dehydrogenase (56), α-ketoglutarate dehydrogenase (57) and mitochondrial respiration (5862). Leucine also alters creatine kinase activity in the brain with the direction of the alteration dependent on the anatomical location in the brain (63). In addition, elevations in KIC contribute to glutamate and aspartate depletion (43,64,65). Alternative mechanisms by which the BCAAs and BCKAs may contribute to neurotoxicity include the inhibition of the acetylcholine synthesis (66), induction of apoptosis of glial cells and neurons (67), alterations of various neurotrophic factors (6870) or intermediate filament phosphorylation (71,72) and decreased α- and β-adrenergic receptor binding (73).

MSUD therapy and BCKDC regulation

Whereas increasing BCKDC activity via tissue or cell transplantation is one therapeutic strategy for MSUD, an alternative strategy is to focus on targeting regulation of BCKDC by altering its phosphorylation. BCKDC activity is inhibited by phosphorylation of two serine residues of the E1α subunit by the branched-chain ketoacid dehydrogenase kinase (BCKDK) (Fig. 2). In contrast, dephosphorylation of the E1α subunit by PPM1K, which is encoded by PPM1K, activates the enzyme. Interestingly, the finding of a homozygous mutation in PPM1K in a patient with a mild form of MSUD highlights the importance of BCKDC regulation by phosphorylation (74). The regulation of BCKDC has been reviewed elsewhere (1,2,7577).

Figure 2.

BCKDC regulation. The BCKDC is regulated by phosphorylation. The BCKDK phosphorylates two serine residues of BCKDC and inactivates the enzyme complex. PPM1K (protein phosphatase, pp2c domain containing, 1k) dephosphorylates and inactivates the BCKDC.

Figure 2.

BCKDC regulation. The BCKDC is regulated by phosphorylation. The BCKDK phosphorylates two serine residues of BCKDC and inactivates the enzyme complex. PPM1K (protein phosphatase, pp2c domain containing, 1k) dephosphorylates and inactivates the BCKDC.

Sodium phenylbutyrate (NaPBA) is a nitrogen-scavenging agent that is used for the prevention of hyperammonemia in patients with urea cycle disorders (UCDs) (7881). Patients with UCDs who are treated with NaPBA have been observed to have decreased plasma BCAA levels, a phenomenon that is replicated in healthy controls (8284). Furthermore, an open-label pilot study demonstrated a decrease in BCAAs and BCKAs in three of the five patients with MSUD treated with NaPBA (84). Thus, the decrease in BCAAs associated with NaPBA is not unique to patients with UCDs. In vitro and animal studies have demonstrated that NaPBA increases the activity of the BCKDC by preventing phosphorylation of the E1α subunit by BCKDK (84). Thus, the resulting increased residual enzymatic activity of BCKDC leads to decreased plasma levels of BCAAs (84). A randomized placebo controlled study to investigate the effects of NaPBA on plasma BCAAs in a large population of patients with MSUD is currently underway (ClinicalTrials.gov Identifier: NCT01529060).

A structurally based design approach has been used to design a more potent and novel inhibitor (S-CPP) of the BCKDK that results in decreased phosphorylation of the BCKDC and thus increased activity of the enzyme complex (85). Single dose of S-CPP in mice demonstrated a decrease in plasma levels of the BCAAs (85). Long-term studies in animals are necessary to test whether these effects on the BCAAs persist with long-term treatment.

Low BCAA and neurocognitive phenotypes

Mutations in the genes encoding components of the BCKDC or PPM1K result in increased BCAA levels and MSUD. In contrast, mutations in the BCKDK, which phosphorylates and activates the BCKDC, have been recently associated with decreased BCAA levels and a phenotype of autism with seizures (86). The affected patients had lower plasma BCAA levels despite normal protein consumption (86). In a separate report, inactivating mutations in BCKDK in two unrelated children were found to cause developmental delay, microcephaly and neurobehavioral abnormalities (87). Normalizing BCAA levels in one of these patients required supplementation with high-protein diet and frequent BCAA supplement dosing throughout the day (87). The authors state that normalization of plasma BCAAs was associated with improvements in attention span, hyperactivity, communication and gross motor skills. Corroborating these findings, a mouse model of BCKDK deficiency exhibits similar features as the patients including seizures, tremors, lower plasma and brain levels of BCAAs and elevations in other large neutral amino acids (86).

ABNORMALITIES OF BCAA AND COMMON DISORDERS

Cancer

Until recently, no known human diseases had been associated with mutations in BCAT. However, recently, transcriptional studies in glioblastomas revealed a high level of expression of the BCAT1 in primary glioblastomas compared with secondary glioblastomas, diffuse astrocytomas or anaplastic astrocytoma (88). Furthermore, BCAT1 expression was higher in gliomas that have wild-type IDH1 when compared with gliomas with mutant forms of IDH1 or normal brain tissue (88). Mutations in IDH1 and IDH2 have been identified in 70% of astrocytomas, oligodendrogliomas and glioblastomas that developed from gliomas (89) and are associated with improved outcome compared with those without mutations (89). Knockdown of BCAT1 in glioblastoma cell cultures resulted in reduced cell proliferation, whereas overexpression of BCAT1 resulted in increased cell proliferation (88). When BCAT1 knockdown cells were implanted into mice, they resulted in smaller tumors than control cells (88). Thus, BCAT1 has been hypothesized to be a useful diagnostic marker but also a possible promising therapeutic target for glioblastoma. Studies in other forms of cancer must be performed to evaluate whether BCAA metabolism plays a role in other cancers.

Insulin resistance

A positive correlation between insulin resistance and BCAA levels was first recognized in the late 1960s (90,91), and interest on the topic has been recently stimulated by a series of studies that have refined this correlation with newer methods. Using liquid chromatography–tandem mass spectrometry metabolomics and principal component analysis, Newgard et al. noted that obese and insulin-resistant individuals had higher serum BCAAs and related metabolites than their lean and insulin-sensitive counterparts (92). These findings were confirmed using different study designs, methodologies and populations in independent studies (9395). Importantly, the elevated BCAAs can be used to predict long-term insulin resistance (96,97) and response to treatment (98). While the correlation is clear, whether elevated BCAAs are a cause or an effect of insulin resistance remains unclear. Leucine does lead to increased insulin secretion (99) and can activate mTOR, the master regulator of cell growth and metabolism. In rats fed a high-fat, high-BCAA diet, the diet led to insulin resistance and this effect could be curtailed by the mTOR inhibitor rapamycin (92). However, other studies have shown that supplementation with BCAAs alone does not lead to insulin resistance and that in some cases, they can be beneficial for metabolic health, a topic that has been extensively reviewed elsewhere (100).

Hepatic disease

As liver is a central organ involved in amino acid metabolism, it is not surprising that patients with chronic liver disease (CLD) have abnormalities in BCAA metabolism. However, there is a growing body of evidence that suggests low plasma levels of BCAA in patients with CLD is more than a mere epiphenomenon and may have a role in progression of disease. Patients with CLD have decreased ratio of BCAA to aromatic amino acids (Fischer ratio) that has been associated with decreased albumin synthesis and progression of CLD (101). Whereas the mechanisms by which low BCAA contribute to the overall outcome in CLD are not known, many controlled clinical studies have shown that supplementation with BCAA can lead to increase in serum albumin, decrease in hepatic failure, improvements in manifestations associated with hepatic encephalopathy, and better quality of life (102106). Whereas not all studies have shown beneficial effects of BCAA supplementation in CLD, they are now considered in treatment of subsets of patients with CLD, a topic reviewed elsewhere (107).

CONCLUSIONS

Recent advances in the understanding of BCAA metabolism have shown that these amino acids are not mere constituents for protein synthesis but have a central role in regulation of pivotal pathways. Dysregulation of BCAA metabolism not only results in well-characterized Mendelian disorders but also contributes to pathogenesis of more common disorders. Thus, lessons learned from therapeutic modulation of BCAA metabolism in inborn errors of metabolism could have significant impact on the treatment of common multifactorial diseases. At the same time, treatment approaches whether cell, gene or small molecule based, may offer improved outcomes for Mendelian disorders of BCAA metabolism but also may impact common diseases such as cancer, diabetes and liver failure. An increasingly in depth appreciation of how apparently simple Mendelian diseases can inform pathogenesis in complex disease will be important in the development of mechanism-based therapies.

FUNDING

L.C.B. is supported by the ACMG Foundation/Genzyme Biochemical Genetics Fellowship. S.C.S.N. is supported by the Clinical Scientist Development Award by the Doris Duke Charitable Foundation. P.M.C. was supported by the O'Malley Foundation Research Fellowship. This work was supported by the NIH (DK92921 to B.L.), Baylor College of Medicine General Clinical Research Center (RR00188), the BCM Intellectual and Developmental Disabilities Research Center (HD024064) from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development and the Urea Cycle Disorders Research Consortium (U54 HD061221, a part of the National Institutes of Health (NIH) Rare Diseases Clinical Research Network (RDCRN), supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS) and the NICHD. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of Interest statement. None declared.

REFERENCES

1
Brosnan
J.T.
Brosnan
M.E.
Branched-chain amino acids: enzyme and substrate regulation
J. Nutr.
 
2006
136
207S
211S
2
Harper
A.E.
Miller
R.H.
Block
K.P.
Branched-chain amino acid metabolism
Annu. Rev. Nutr.
 
1984
4
409
454
3
Wahren
J.
Felig
P.
Hagenfeldt
L.
Effect of protein ingestion on splanchnic and leg metabolism in normal man and in patients with diabetes mellitus
J. Clin. Invest.
 
1976
57
987
999
4
Dancis
J.
Levitz
M.
Miller
S.
Westall
R.G.
Maple syrup urine disease
Br. Med. J.
 
1959
1
91
93
5
Menkes
J.H.
Maple syrup disease; isolation and identification of organic acids in the urine
Pediatrics
 
1959
23
348
353
6
Menkes
J.H.
Hurst
P.L.
Craig
J.M.
A new syndrome: progressive familial infantile cerebral dysfunction associated with an unusual urinary substance
Pediatrics
 
1954
14
462
467
7
Naylor
E.W.
Guthrie
R.
Newborn screening for maple syrup urine disease (branched-chain ketoaciduria)
Pediatrics
 
1978
61
262
266
8
Puffenberger
E.G.
Genetic heritage of the Old Order Mennonites of southeastern Pennsylvania
Am. J. Med. Genet. C Sem. Med. Genet.
 
2003
121C
18
31
9
Chuang
D.T.
Shih
V.E.
Max Wynn
R.R.
2013
Maple Syrup Urine Disease (Branched-Chain Ketoaciduria). In: Valle D., Beaudet A.L., Vogelstein B., Kinzler K.W., Antonarakis S.E., Ballabio A., Gibson K., Mitchell G. eds. OMMBID–The Online Metabolic and Molecular Bases of Inherited Diseases. McGraw-Hill, New York. http://ommbid.mhmedical.com.ezproxyhost.library.tmc.edu/content.aspx?bookid=474&Sectionid=45374075. Last accessed on 17 February 2014
10
Indo
Y.
Akaboshi
I.
Nobukuni
Y.
Endo
F.
Matsuda
I.
Maple syrup urine disease: a possible biochemical basis for the clinical heterogeneity
Hum. Genet.
 
1988
80
6
10
11
Chuang
J.L.
Wynn
R.M.
Moss
C.C.
Song
J.L.
Li
J.
Awad
N.
Mandel
H.
Chuang
D.T.
Structural and biochemical basis for novel mutations in homozygous Israeli maple syrup urine disease patients: a proposed mechanism for the thiamin-responsive phenotype
J. Biol. Chem.
 
2004
279
17792
17800
12
Scriver
C.R.
Mackenzie
S.
Clow
C.L.
Delvin
E.
Thiamine-responsive maple-syrup-urine disease
Lancet
 
1971
1
310
312
13
Robinson
B.H.
Taylor
J.
Sherwood
W.G.
Deficiency of dihydrolipoyl dehydrogenase (a component of the pyruvate and alpha-ketoglutarate dehydrogenase complexes): a cause of congenital chronic lactic acidosis in infancy
Pediatr. Res.
 
1977
11
1198
1202
14
Clow
C.L.
Reade
T.M.
Scriver
C.R.
Outcome of early and long-term management of classical maple syrup urine disease
Pediatrics
 
1981
68
856
862
15
Puliyanda
D.P.
Harmon
W.E.
Peterschmitt
M.J.
Irons
M.
Somers
M.J.
Utility of hemodialysis in maple syrup urine disease
Pediatr. Nephrol.
 
2002
17
239
242
16
Rutledge
S.L.
Havens
P.L.
Haymond
M.W.
McLean
R.H.
Kan
J.S.
Brusilow
S.W.
Neonatal hemodialysis: effective therapy for the encephalopathy of inborn errors of metabolism
J. Pediatr.
 
1990
116
125
128
17
Schaefer
F.
Straube
E.
Oh
J.
Mehls
O.
Mayatepek
E.
Dialysis in neonates with inborn errors of metabolism
Nephrol. Dial. Transpl.
 
1999
14
910
918
18
Hilliges
C.
Awiszus
D.
Wendel
U.
Intellectual performance of children with maple syrup urine disease
Eur. J. Pediatr.
 
1993
152
144
147
19
Kaplan
P.
Mazur
A.
Field
M.
Berlin
J.A.
Berry
G.T.
Heidenreich
R.
Yudkoff
M.
Segal
S.
Intellectual outcome in children with maple syrup urine disease
J. Pediatr.
 
1991
119
46
50
20
American College of Medical Geneticsa Newburn Screening Express Group
Newborn screening: toward a uniform screening panel and system
Genet. Med.
 
2006
8
Suppl. 1
1S
252S
21
Bhattacharya
K.
Khalili
V.
Wiley
V.
Carpenter
K.
Wilcken
B.
Newborn screening may fail to identify intermediate forms of maple syrup urine disease
J. Inherited Metabolic Dis.
 
2006
29
586
22
Muelly
E.R.
Moore
G.J.
Bunce
S.C.
Mack
J.
Bigler
D.C.
Morton
D.H.
Strauss
K.A.
Biochemical correlates of neuropsychiatric illness in maple syrup urine disease
J. Clin. Invest.
 
2013
123
1809
1820
23
Hoffmann
B.
Helbling
C.
Schadewaldt
P.
Wendel
U.
Impact of longitudinal plasma leucine levels on the intellectual outcome in patients with classic MSUD
Pediatr. Res.
 
2006
59
17
20
24
Bodner-Leidecker
A.
Wendel
U.
Saudubray
J.M.
Schadewaldt
P.
Branched-chain L-amino acid metabolism in classical maple syrup urine disease after orthotopic liver transplantation
J. Inherited Metabolic Dis.
 
2000
23
805
818
25
Wendel
U.
Saudubray
J.M.
Bodner
A.
Schadewaldt
P.
Liver transplantation in maple syrup urine disease
Eur. J. Pediatr.
 
1999
158
Suppl 2
S60
S64
26
Strauss
K.A.
Mazariegos
G.V.
Sindhi
R.
Squires
R.
Finegold
D.N.
Vockley
G.
Robinson
D.L.
Hendrickson
C.
Virji
M.
Cropcho
L.
et al.  
Elective liver transplantation for the treatment of classical maple syrup urine disease
Am. J. Transpl.
 
2006
6
557
564
27
Mazariegos
G.V.
Morton
D.H.
Sindhi
R.
Soltys
K.
Nayyar
N.
Bond
G.
Shellmer
D.
Shneider
B.
Vockley
J.
Strauss
K.A.
Liver transplantation for classical maple syrup urine disease: long-term follow-up in 37 patients and comparative United Network for Organ Sharing experience
J. Pediatr.
 
2012
160
116
121 e111
28
Shellmer
D.A.
DeVito Dabbs
A.
Dew
M.A.
Noll
R.B.
Feldman
H.
Strauss
K.A.
Morton
D.H.
Vockley
J.
Mazariegos
G.V.
Cognitive and adaptive functioning after liver transplantation for maple syrup urine disease: a case series
Pediatr. Transpl.
 
2011
15
58
64
29
Suryawan
A.
Hawes
J.W.
Harris
R.A.
Shimomura
Y.
Jenkins
A.E.
Hutson
S.M.
A molecular model of human branched-chain amino acid metabolism
Am. J. Clin. Nutr.
 
1998
68
72
81
30
Badell
I.R.
Hanish
S.I.
Hughes
C.B.
Hewitt
W.R.
Chung
R.T.
Spivey
J.R.
Knechtle
S.J.
Domino liver transplantation in maple syrup urine disease: a case report and review of the literature
Transpl. Proc.
 
2013
45
806
809
31
Barshop
B.A.
Khanna
A.
Domino hepatic transplantation in maple syrup urine disease
New England J. Med.
 
2005
353
2410
2411
32
Khanna
A.
Hart
M.
Nyhan
W.L.
Hassanein
T.
Panyard-Davis
J.
Barshop
B.A.
Domino liver transplantation in maple syrup urine disease
Liver Transpl.
 
2006
12
876
882
33
Arnon
R.
Kerkar
N.
Davis
M.K.
Anand
R.
Yin
W.
Gonzalez-Peralta
R.P.
Liver transplantation in children with metabolic diseases: the studies of pediatric liver transplantation experience
Pediatr. Transpl.
 
2010
14
796
805
34
Skvorak
K.J.
Hager
E.J.
Arning
E.
Bottiglieri
T.
Paul
H.S.
Strom
S.C.
Homanics
G.E.
Sun
Q.
Jansen
E.E.
Jakobs
C.
et al.  
Hepatocyte transplantation (HTx) corrects selected neurometabolic abnormalities in murine intermediate maple syrup urine disease (iMSUD)
Biochim. Biophys. Acta
 
2009
1792
1004
1010
35
Skvorak
K.J.
Paul
H.S.
Dorko
K.
Marongiu
F.
Ellis
E.
Chace
D.
Ferguson
C.
Gibson
K.M.
Homanics
G.E.
Strom
S.C.
Hepatocyte transplantation improves phenotype and extends survival in a murine model of intermediate maple syrup urine disease
Mol. Ther.
 
2009
17
1266
1273
36
Homanics
G.E.
Skvorak
K.
Ferguson
C.
Watkins
S.
Paul
H.S.
Production and characterization of murine models of classic and intermediate maple syrup urine disease
BMC Med. Genet.
 
2006
7
33
37
Skvorak
K.J.
Dorko
K.
Marongiu
F.
Tahan
V.
Hansel
M.C.
Gramignoli
R.
Arning
E.
Bottiglieri
T.
Gibson
K.M.
Strom
S.C.
Improved amino acid, bioenergetic metabolite and neurotransmitter profiles following human amnion epithelial cell transplant in intermediate maple syrup urine disease mice
Mol. Genet. Metab.
 
2013
109
132
138
38
Skvorak
K.J.
Dorko
K.
Marongiu
F.
Tahan
V.
Hansel
M.C.
Gramignoli
R.
Gibson
K.M.
Strom
S.C.
Placental stem cell correction of murine intermediate maple syrup urine disease
Hepatology
 
2013
57
1017
1023
39
Herman
M.A.
She
P.
Peroni
O.D.
Lynch
C.J.
Kahn
B.B.
Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels
J. Biol. Chem.
 
2010
285
11348
11356
40
Zimmerman
H.A.
Olson
K.C.
Chen
G.
Lynch
C.J.
Adipose transplant for inborn errors of branched chain amino acid metabolism in mice
Mol. Genet. Metab.
 
2013
109
345
353
41
Simon
E.
Schwarz
M.
Wendel
U.
Social outcome in adults with maple syrup urine disease (MSUD)
J. Inherited Metabolic Dis.
 
2007
30
264
42
Packman
W.
Mehta
I.
Rafie
S.
Mehta
J.
Naldi
M.
Mooney
K.H.
Young adults with MSUD and their transition to adulthood: psychosocial issues
J. Genet. Couns.
 
2012
21
692
703
43
Yudkoff
M.
Daikhin
Y.
Nissim
I.
Horyn
O.
Luhovyy
B.
Lazarow
A.
Brain amino acid requirements and toxicity: the example of leucine
J. Nutr.
 
2005
135
1531S
1538S
44
Sitta
A.
Ribas
G.S.
Mescka
C.P.
Barschak
A.G.
Wajner
M.
Vargas
C.R.
Neurological damage in MSUD: the role of oxidative stress
Cell. Mol. Neurobiol.
 
2013
34
157
165
45
Oldendorf
W.H.
Szabo
J.
Amino acid assignment to one of three blood-brain barrier amino acid carriers
Am. J. Physiol.
 
1976
230
94
98
46
Strauss
K.A.
Wardley
B.
Robinson
D.
Hendrickson
C.
Rider
N.L.
Puffenberger
E.G.
Shellmer
D.
Moser
A.B.
Morton
D.H.
Classical maple syrup urine disease and brain development: principles of management and formula design
Mol. Genet. Metab.
 
2010
99
333
345
47
Zinnanti
W.J.
Lazovic
J.
Griffin
K.
Skvorak
K.J.
Paul
H.S.
Homanics
G.E.
Bewley
M.C.
Cheng
K.C.
Lanoue
K.F.
Flanagan
J.M.
Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease
Brain
 
2009
132
903
918
48
Tews
J.K.
Repa
J.J.
Harper
A.E.
Branched-chain and other amino acids in tissues of rats fed leucine-limiting amino acid diets containing norleucine
J. Nutr.
 
1991
121
364
378
49
Fontella
F.U.
Gassen
E.
Pulrolnik
V.
Wannmacher
C.M.
Klein
A.B.
Wajner
M.
Dutra-Filho
C.S.
Stimulation of lipid peroxidation in vitro in rat brain by the metabolites accumulating in maple syrup urine disease
Metabolic Brain Dis.
 
2002
17
47
54
50
Bridi
R.
Araldi
J.
Sgarbi
M.B.
Testa
C.G.
Durigon
K.
Wajner
M.
Dutra-Filho
C.S.
Induction of oxidative stress in rat brain by the metabolites accumulating in maple syrup urine disease
Int. J. Dev. Neurosci.
 
2003
21
327
332
51
Funchal
C.
Latini
A.
Jacques-Silva
M.C.
Dos Santos
A.Q.
Buzin
L.
Gottfried
C.
Wajner
M.
Pessoa-Pureur
R.
Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease
Neurochem. Int.
 
2006
49
640
650
52
Barschak
A.G.
Sitta
A.
Deon
M.
de Oliveira
M.H.
Haeser
A.
Dutra-Filho
C.S.
Wajner
M.
Vargas
C.R.
Evidence that oxidative stress is increased in plasma from patients with maple syrup urine disease
Metabolic Brain Dis.
 
2006
21
279
286
53
Barschak
A.G.
Sitta
A.
Deon
M.
Barden
A.T.
Dutra-Filho
C.S.
Wajner
M.
Vargas
C.R.
Oxidative stress in plasma from maple syrup urine disease patients during treatment
Metabolic Brain Dis.
 
2008
23
71
80
54
Mescka
C.P.
Wayhs
C.A.
Vanzin
C.S.
Biancini
G.B.
Guerreiro
G.
Manfredini
V.
Souza
C.
Wajner
M.
Dutra-Filho
C.S.
Vargas
C.R.
Protein and lipid damage in maple syrup urine disease patients: l-carnitine effect
Int. J. Dev. Neurosci.
 
2013
31
21
24
55
Mescka
C.
Moraes
T.
Rosa
A.
Mazzola
P.
Piccoli
B.
Jacques
C.
Dalazen
G.
Coelho
J.
Cortes
M.
Terra
M.
et al.  
In vivo neuroprotective effect of L-carnitine against oxidative stress in maple syrup urine disease
Metabolic Brain Dis.
 
2011
26
21
28
56
Patel
M.S.
Auerbach
V.H.
Grover
W.D.
Wilbur
D.O.
Effect of the branched-chain alpha-keto acids on pyruvate metabolism by homogenates of human brain
J. Neurochem.
 
1973
20
1793
1796
57
Patel
M.S.
Inhibition by the branched-chain 2-oxo acids of the 2-oxoglutarate dehydrogenase complex in developing rat and human brain
Biochem. J.
 
1974
144
91
97
58
Amaral
A.U.
Leipnitz
G.
Fernandes
C.G.
Seminotti
B.
Schuck
P.F.
Wajner
M.
Alpha-ketoisocaproic acid and leucine provoke mitochondrial bioenergetic dysfunction in rat brain
Brain Res.
 
2010
1324
75
84
59
Ribeiro
C.A.
Sgaravatti
A.M.
Rosa
R.B.
Schuck
P.F.
Grando
V.
Schmidt
A.L.
Ferreira
G.C.
Perry
M.L.
Dutra-Filho
C.S.
Wajner
M.
Inhibition of brain energy metabolism by the branched-chain amino acids accumulating in maple syrup urine disease
Neurochem. Res.
 
2008
33
114
124
60
Sgaravatti
A.M.
Rosa
R.B.
Schuck
P.F.
Ribeiro
C.A.
Wannmacher
C.M.
Wyse
A.T.
Dutra-Filho
C.S.
Wajner
M.
Inhibition of brain energy metabolism by the alpha-keto acids accumulating in maple syrup urine disease
Biochim. Biophys. Acta
 
2003
1639
232
238
61
Shestopalov
A.I.
Kristal
B.S.
Branched chain keto-acids exert biphasic effects on alpha-ketoglutarate-stimulated respiration in intact rat liver mitochondria
Neurochem. Res.
 
2007
32
947
951
62
Howell
R.K.
Lee
M.
Influence of alpha-ketoacids on the respiration of brain in vitro
Proc. Soc. Exp. Biol. Med.
 
1963
113
660
663
63
Pilla
C.
de Oliveira Cardozo
R.F.
Dutra-Filho
C.S.
Wyse
A.T.
Wajner
M.
Wannmacher
C.M.
Effect of leucine administration on creatine kinase activity in rat brain
Metabolic Brain Dis.
 
2003
18
17
25
64
Yudkoff
M.
Daikhin
Y.
Lin
Z.P.
Nissim
I.
Stern
J.
Pleasure
D.
Interrelationships of leucine and glutamate metabolism in cultured astrocytes
J. Neurochem.
 
1994
62
1192
1202
65
Zielke
H.R.
Huang
Y.
Baab
P.J.
Collins
R.M.
Jr
Zielke
C.L.
Tildon
J.T.
Effect of alpha-ketoisocaproate and leucine on the in vivo oxidation of glutamate and glutamine in the rat brain
Neurochem. Res.
 
1997
22
1159
1164
66
Gibson
G.E.
Blass
J.P.
Inhibition of acetylcholine synthesis and of carbohydrate utilization by maple-syrup-urine disease metabolites
J. Neurochem.
 
1976
26
1073
1078
67
Jouvet
P.
Rustin
P.
Taylor
D.L.
Pocock
J.M.
Felderhoff-Mueser
U.
Mazarakis
N.D.
Sarraf
C.
Joashi
U.
Kozma
M.
Greenwood
K.
et al.  
Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane depolarization or cytochrome c release: implications for neurological impairment associated with maple syrup urine disease
Mol. Biol. Cell
 
2000
11
1919
1932
68
Scaini
G.
Mello-Santos
L.M.
Furlanetto
C.B.
Jeremias
I.C.
Mina
F.
Schuck
P.F.
Ferreira
G.C.
Kist
L.W.
Pereira
T.C.
Bogo
M.R.
et al.  
Acute and chronic administration of the branched-chain amino acids decreases nerve growth factor in rat hippocampus
Mol. Neurobiol.
 
2013
48
581
589
69
Scaini
G.
Comim
C.M.
Oliveira
G.M.
Pasquali
M.A.
Quevedo
J.
Gelain
D.P.
Moreira
J.C.
Schuck
P.F.
Ferreira
G.C.
Bogo
M.R.
et al.  
Chronic administration of branched-chain amino acids impairs spatial memory and increases brain-derived neurotrophic factor in a rat model
J. Inherited Metabolic Dis.
 
2013
36
721
730
70
Funchal
C.
Tramontina
F.
Quincozes dos Santos
A.
Fraga de Souza
D.
Goncalves
C.A.
Pessoa-Pureur
R.
Wajner
M.
Effect of the branched-chain alpha-keto acids accumulating in maple syrup urine disease on S100B release from glial cells
J. Neurol. Sci.
 
2007
260
87
94
71
Funchal
C.
de Lima Pelaez
P.
Loureiro
S.O.
Vivian
L.
Dall Bello Pessutto
F.
de Almeida
L.M.
Tchernin Wofchuk
S.
Wajner
M.
Pessoa Pureur
R.
Alpha-Ketoisocaproic acid regulates phosphorylation of intermediate filaments in postnatal rat cortical slices through ionotropic glutamatergic receptors
Brain Res.
 
2002
139
267
276
72
Funchal
C.
Dall Bello Pessutto
F.
de Almeida
L.M.
de Lima Pelaez
P.
Loureiro
S.O.
Vivian
L.
Wajner
M.
Pessoa-Pureur
R.
Alpha-keto-beta-methylvaleric acid increases the in vitro phosphorylation of intermediate filaments in cerebral cortex of young rats through the gabaergic system
J. Neurol. Sci.
 
2004
217
17
24
73
Dwivedi
C.
James
E.C.
Parmar
S.S.
Effects of abnormal metabolites of maple syrup urine disease on neurotransmitter receptor binding
Biochem. Med. Metabolic Biol.
 
1986
35
275
278
74
Oyarzabal
A.
Martinez-Pardo
M.
Merinero
B.
Navarrete
R.
Desviat
L.R.
Ugarte
M.
Rodriguez-Pombo
P.
A novel regulatory defect in the branched-chain alpha-keto acid dehydrogenase complex due to a mutation in the PPM1K gene causes a mild variant phenotype of maple syrup urine disease
Hum. Mutat.
 
2013
34
355
362
75
Harris
R.A.
Joshi
M.
Jeoung
N.H.
Obayashi
M.
Overview of the molecular and biochemical basis of branched-chain amino acid catabolism
J. Nutr.
 
2005
135
1527S
1530S
76
Harris
R.A.
Popov
K.M.
Zhao
Y.
Shimomura
Y.
Regulation of branched-chain amino acid catabolism
J. Nutr.
 
1994
124
1499S
1502S
77
Harris
R.A.
Joshi
M.
Jeoung
N.H.
Mechanisms responsible for regulation of branched-chain amino acid catabolism
Biochem. Biophys. Res. Commun.
 
2004
313
391
396
78
Batshaw
M.L.
MacArthur
R.B.
Tuchman
M.
Alternative pathway therapy for urea cycle disorders: twenty years later
J. Pediatr.
 
2001
138
S46
S54
discussion S54–45
79
Brusilow
S.
Tinker
J.
Batshaw
M.L.
Amino acid acylation: a mechanism of nitrogen excretion in inborn errors of urea synthesis
Science
 
1980
207
659
661
80
Brusilow
S.W.
Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion
Pediatr. Res.
 
1991
29
147
150
81
Burlina
A.B.
Ogier
H.
Korall
H.
Trefz
F.K.
Long-term treatment with sodium phenylbutyrate in ornithine transcarbamylase-deficient patients
Mol. Genet. Metab.
 
2001
72
351
355
82
Scaglia
F.
Brunetti-Pierri
N.
Kleppe
S.
Marini
J.
Carter
S.
Garlick
P.
Jahoor
F.
O'Brien
W.
Lee
B.
Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism
J. Nutr.
 
2004
134
2775S
2782S
discussion 2796S–2797S
83
Tuchman
M.
Lee
B.
Lichter-Konecki
U.
Summar
M.L.
Yudkoff
M.
Cederbaum
S.D.
Kerr
D.S.
Diaz
G.A.
Seashore
M.R.
Lee
H.S.
et al.  
Cross-sectional multicenter study of patients with urea cycle disorders in the United States
Mol. Genet. Metab.
 
2008
94
397
402
84
Brunetti-Pierri
N.
Lanpher
B.
Erez
A.
Ananieva
E.A.
Islam
M.
Marini
J.C.
Sun
Q.
Yu
C.
Hegde
M.
Li
J.
et al.  
Phenylbutyrate therapy for maple syrup urine disease
Hum. Mol. Genet.
 
2011
20
631
640
85
Tso
S.C.
Qi
X.
Gui
W.J.
Chuang
J.L.
Morlock
L.K.
Wallace
A.L.
Ahmed
K.
Laxman
S.
Campeau
P.M.
Lee
B.H.
et al.  
Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain alpha-ketoacid dehydrogenase kinase
Proc. Natl. Acad. Sci. USA
 
2013
110
9728
9733
86
Novarino
G.
El-Fishawy
P.
Kayserili
H.
Meguid
N.A.
Scott
E.M.
Schroth
J.
Silhavy
J.L.
Kara
M.
Khalil
R.O.
Ben-Omran
T.
et al.  
Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy
Science
 
2012
338
394
397
87
Garcia-Cazorla
A.
Oyarzabal
A.
Fort
J.
Robles
C.
Castejon
E.
Ruiz-Sala
P.
Bodoy
S.
Merinero
B.
Lopez-Sala
A.
Dopazo
J.
et al.  
Two novel mutations in the BCKDK gene (branched-chain keto-acid dehydrogenase kinase) are responsible of a neurobehavioral deficit in two pediatric unrelated patients
Hum. Mut.
 
2014
35
470
477
88
Tonjes
M.
Barbus
S.
Park
Y.J.
Wang
W.
Schlotter
M.
Lindroth
A.M.
Pleier
S.V.
Bai
A.H.
Karra
D.
Piro
R.M.
et al.  
BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1
Nat. Med.
 
2013
19
901
908
89
Yan
H.
Parsons
D.W.
Jin
G.
McLendon
R.
Rasheed
B.A.
Yuan
W.
Kos
I.
Batinic-Haberle
I.
Jones
S.
Riggins
G.J.
et al.  
IDH1 and IDH2 mutations in gliomas
New Engl. J. Med.
 
2009
360
765
773
90
Adibi
S.A.
Influence of dietary deprivations on plasma concentration of free amino acids of man
J. Appl. Physiol.
 
1968
25
52
57
91
Felig
P.
Marliss
E.
Cahill
G.F.
Jr
Plasma amino acid levels and insulin secretion in obesity
New Engl. J. Med.
 
1969
281
811
816
92
Newgard
C.B.
An
J.
Bain
J.R.
Muehlbauer
M.J.
Stevens
R.D.
Lien
L.F.
Haqq
A.M.
Shah
S.H.
Arlotto
M.
Slentz
C.A.
et al.  
A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance
Cell Metab.
 
2009
9
311
326
93
Huffman
K.M.
Shah
S.H.
Stevens
R.D.
Bain
J.R.
Muehlbauer
M.
Slentz
C.A.
Tanner
C.J.
Kuchibhatla
M.
Houmard
J.A.
Newgard
C.B.
et al.  
Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women
Diab. Care
 
2009
32
1678
1683
94
Tai
E.S.
Tan
M.L.
Stevens
R.D.
Low
Y.L.
Muehlbauer
M.J.
Goh
D.L.
Ilkayeva
O.R.
Wenner
B.R.
Bain
J.R.
Lee
J.J.
et al.  
Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men
Diabetologia
 
2010
53
757
767
95
Shah
S.H.
Bain
J.R.
Muehlbauer
M.J.
Stevens
R.D.
Crosslin
D.R.
Haynes
C.
Dungan
J.
Newby
L.K.
Hauser
E.R.
Ginsburg
G.S.
et al.  
Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events
Circ. Cardiovasc. Genet.
 
2010
3
207
214
96
Svetkey
L.P.
Stevens
V.J.
Brantley
P.J.
Appel
L.J.
Hollis
J.F.
Loria
C.M.
Vollmer
W.M.
Gullion
C.M.
Funk
K.
Smith
P.
et al.  
Comparison of strategies for sustaining weight loss: the weight loss maintenance randomized controlled trial
JAMA
 
2008
299
1139
1148
97
Wang
T.J.
Larson
M.G.
Vasan
R.S.
Cheng
S.
Rhee
E.P.
McCabe
E.
Lewis
G.D.
Fox
C.S.
Jacques
P.F.
Fernandez
C.
et al.  
Metabolite profiles and the risk of developing diabetes
Nat. Med.
 
2011
17
448
453
98
Laferrere
B.
Reilly
D.
Arias
S.
Swerdlow
N.
Gorroochurn
P.
Bawa
B.
Bose
M.
Teixeira
J.
Stevens
R.D.
Wenner
B.R.
et al.  
Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss
Sci. Transl. Med.
 
2011
3
80–82
99
Hutton
J.C.
Sener
A.
Malaisse
W.J.
Interaction of branched chain amino acids and keto acids upon pancreatic islet metabolism and insulin secretion
J. Biol. Chem.
 
1980
255
7340
7346
100
Adams
S.H.
Emerging perspectives on essential amino acid metabolism in obesity and the insulin-resistant state
Adv. Nutr.
 
2011
2
445
456
101
Steigmann
F.
Szanto
P.B.
Poulos
A.
Lim
P.E.
Dubin
A.
Significance of serum aminograms in diagnosis and prognosis of liver diseases
J. Clin. Gastroenterol.
 
1984
6
453
460
102
The San-in Group of Liver surgery
Long-term oral administration of branched chain amino acids after curative resection of hepatocellular carcinoma: a prospective randomized trial. The San-in Group of Liver Surgery
Br. J. Surg.
 
1997
84
1525
1531
103
Habu
D.
Nishiguchi
S.
Nakatani
S.
Kawamura
E.
Lee
C.
Enomoto
M.
Tamori
A.
Takeda
T.
Tanaka
T.
Shiomi
S.
Effect of oral supplementation with branched-chain amino acid granules on serum albumin level in the early stage of cirrhosis: a randomized pilot trial
Hepatol. Res.
 
2003
25
312
318
104
Muto
Y.
Sato
S.
Watanabe
A.
Moriwaki
H.
Suzuki
K.
Kato
A.
Kato
M.
Nakamura
T.
Higuchi
K.
Nishiguchi
S.
et al.  
Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis
Clin. Gastroenterol. Hepatol.
 
2005
3
705
713
105
Gluud
L.L.
Dam
G.
Borre
M.
Les
I.
Cordoba
J.
Marchesini
G.
Aagaard
N.K.
Risum
N.
Vilstrup
H.
Oral branched-chain amino acids have a beneficial effect on manifestations of hepatic encephalopathy in a systematic review with meta-analyses of randomized controlled trials
J. Nutr.
 
2013
143
1263
1268
106
Marchesini
G.
Bianchi
G.
Merli
M.
Amodio
P.
Panella
C.
Loguercio
C.
Rossi Fanelli
F.
Abbiati
R.
Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial
Gastroenterology
 
2003
124
1792
1801
107
Kawaguchi
T.
Izumi
N.
Charlton
M.R.
Sata
M.
Branched-chain amino acids as pharmacological nutrients in chronic liver disease
Hepatology
 
2011
54
1063
1070