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Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan and * Faculty of Child Nutrition, Kagawa Nutrition University, Toshima-ku, Tokyo 170-8481, Japan
3To whom correspondence should be addressed. E-mail: fendo{at}kumamoto-u.ac.jp.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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-ketoacid dehydrogenase complex. Accumulations of branched-chain amino acids (BCAAs) and branched-chain -ketoacids (BCKAs) in patients with MSUD induce ketoacidosis, neurological disorders, and developmental disturbance. BCAAs and BCKAs influence on the nervous system can be estimated by analyzing these patients. According to clinical investigations on MSUD patients, leucine levels over 400 µmol/L apparently can cause any clinical problem derived from impaired function of the central nervous system. Damage to neuronal cells found in MSUD patients are presumably because of higher concentrations of both blood BCAAs or BCKAs, especially -ketoisocapronic acids. These clinical data from MSUD patients provide a valuable basis on understanding leucine toxicity in the normal subject.
KEY WORDS: • maple syrup urine disease • leucine • branched-chain amino acid • branched-chain -ketoacid • branched-chain -ketoacid dehydrogenase
Maple syrup urine disease (MSUD)4 is an autosomal recessive disease caused by a deficiency in a subunit of the branched-chain -ketoacid dehydrogenase (BCKDH) complex. Mammalian BCKDH is a mitochondrial macromolecular multienzyme complex catalyzing the oxidative decarboxylation of branched-chain -ketoacids (BCKA), which are in turn derived from transamination of the branched-chain amino acids (BCAAs), valine, leucine, and isoleucine (Fig. 1).
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Population genetics
MSUD is very rare in most populations. Incidence of MSUD is 1 in 185,000 births throughout the world. In European and American Caucasians, it is 1 in 290,000 births. In Japan, it is 1 in 560,000 births. In a group of Mennonites in the United States, the incidence is reported to be very high, at 1 in 176 births (3).
Molecular genetics of MSUD
BCKDH consists of 3 catalytic components, the branched-chain -ketoacid decarboxylase (E1), the dihydrolipoyl transacylase (E2), and the dihydrolipoyl dehydrogenase (E3). The E1 and E2 components are specific to BCKDH, whereas E3 is common among the 3 ketoacid dehydrogenase complexes, BCKDH, pyruvate dehydrogenase, and -ketoglutarate dehydrogenase. The function of E1 is to remove CO2 from BCKA and subsequently to transfer the acyl moiety to E2. For this reaction, E1 requires thiamine pyrophosphate (TPP) as a cofactor. The E1 component binding to TPP creates the ketoacid binding site for the release of CO2. In addition, the E1 component consists of and ß subunits. The E1 subunit contains phosphores responsible for regulation of catalytic activity through interconversion of an active nonphosphorylated form to an inactive phosphorylated form of the BCKDH complex (3,4). The structure of cDNAs and genes of E1 (5–9), E1ß (10,11), E2 (12–16), and E3 (17,18) were reported by us and others. Among these, we analyzed the genes of Mennonite MSUD patients and 11 Japanese MSUD patients (Table 1). Subsequently, various mutations in the genes were identified. The relation between forms or phenotypes of MSUD and mutations in the genes are partially clarified (3,4).
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gene.
In Mennonite patients with classic MSUD, we identified a mutation in the gene encoding the E1 subunit (Y393N) (19,20). Studies by others confirmed that MSUD in Mennonites is caused by a homozygote mutation, Y393N of the E1 subunit (21). Four other mutations were also found in the E1 gene in 3 Japanese patients with classic MSUD and in 1 Japanese patient with intermediate MSUD (4,22–24). Mutations in the E1ß gene. The first report for a E1ß mutation was by Nobukuni et al. (25). They found an 11 bps deletion in exon 1 of the E1ß gene in a patient whose parents were consanguineous. The same mutation was found in another Japanese family. This mutation was also reported in Italian families with MSUD (26). These Japanese and Italian patients were not related. The 11 bps deletion was located in a recurrent sequence region in the E1ß gene. Therefore, it is believed that this mutation occurred by a slipped-strand mispairing mechanism. In addition, we identified 5 other mutations in the E1ß gene in 4 Japanese patients. All the patients had classic MSUD (4,22–24,27).
Mutations in the E2 gene. We identified 5 mutations in the E2 gene in 4 Japanese patients. A patient with a classic form of MSUD had a skipping of exon 8 due to 1 base deletion in the splice donor site of intron 8 (28). The other 3 patients with an intermittent form of MSUD had various mutations, 1 base substitution, an aberrant splicing, and 1 base insertion (29).
Molecular phenotypes
Chuang and Shih (3) classified 4 molecular phenotypes based on the affected locus of the BCKDH complex. Type IA refers to mutations in the E1 gene, type IB to mutations in the E1ß gene, type II to mutations in the E2 gene, and type III to mutations in the E3 gene. More than 60 kinds of mutations have been reported in patients with MSUD. Analyzing the relation between clinical phenotypes and molecular phenotypes revealed that type IA and IB mutations had a tendency to cause the severe classic form of MSUD. A type II mutation had a tendency to cause the milder form of MSUD. Moreover, all the thiamine-responsive forms were type II.
Clinical phenotypes
The clinical phenotypes of MSUD are characterized by various degrees of mental and physical retardation, depending on the severity of the BCKDH defect. The time until presentation of clinical symptoms and clinical course depend on the degree of BCKDH activity. If BCKDH activity is low, the symptoms appear earlier and the clinical course is more severe. The blood levels of ketoacids, which elevate in parallel with blood levels of leucine, seem to determine the clinical symptoms. When leucine levels rise above a certain threshold (
400 µmol/L), the patients show clinical problems. The relation between clinical features and blood BCAAs or BCKAs concentrations suggests that development of clinical features is most closely related to blood leucine concentration. Discussion about the toxicity of the BCAAs may be possible based on these clinical observations.
MSUD is classified into several forms according to the clinical course (Table 2). Among these forms, the classic form has the earliest onset and is the most severe (3).
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The other forms, usually with milder symptoms that appear after the neonatal period, are intermediate and intermittent MSUD.
Intermediate MSUD. Patients with this form have no severe ketoacidosis attack but fail to thrive, and have mild systemic acidosis and developmental delay. The levels of plasma BCAAs and BCKAs are persistently increased. Protein restriction is an effective treatment but not thiamine administration. These patients have 3 to 30% residual BCKDH activity.
Intermittent MSUD. Patients with this form have recurrent episodic ataxia, lethargy, semicoma, and occasional elevated plasma BCAAs and BCKAs after infections or other acute illnesses. They usually have normal intellect, although in some cases with repeated ketoacidosis attacks, intellect is borderline or less. Dietary protein restriction is an effective treatment. The levels of BCKDH activity are higher than in the classic form of the disease.
Indo et al. (30) reported that the BCKDH complex enzyme activities and kinetics in MSUD patients were altered and that these biochemical features of the enzyme appeared to correspond with the MSUD phenotype. Classic, intermediate, and intermittent types of MSUD demonstrated increasing levels of complex activity and were associated with sigmoidal, near-sigmoidal, and hyperbolic kinetics, respectively.
There are 2 additional forms of MSUD: the thiamine-responsive form and the E3-deficient form.
Thiamine-responsive MSUD.
Patients with this form have hyperaminoacidemia similar to the intermediate form, but it can be successfully treated with thiamine administration. The BCKDH complex activity in the thiamine-responsive MSUD patient is 2 to 40% of normal subjects. Further studies showed that the primary defect in thiamine-responsive MSUD is reduced affinity of the mutant BCKDH for TPP because of a mutation in the E2 protein (31).
E3-Deficient MSUD.
E3-deficient MSUD, or MSUD type III, presents a combined deficiency of BCKDH, pyruvate dehydrogenase, and -ketoglutarate dehydrogenase complexes. This is the result of E3 being a common component of all 3 mitochondrial multienzyme complexes. Patients with this form show failure to thrive, hypotonia, lactic acidosis, and developmental delay. Lactate, pyruvate, and -ketoglutarate are elevated as well as BCAAs and BCKAs. The prognosis of this form varies with levels of residual enzymatic activity. Neuropathological studies showed Leigh encephalopathy. In some cases, treatments with biotin, lipoic acid, and dichloroacetate are effective (3).
Treatment
Treatment of MSUD is divided into acute (symptomatic) stage treatment and chronic (asymptomatic) stage treatment (32,33).
Acute stage treatment.
Early diagnosis and early treatment is the principle for acute stage treatment. Accumulation of BCKAs in the body seems to cause disorder in the central nervous system. The -ketoisocaproic acid derived from leucine is strongly neurotoxic. Hence, blood level of leucine is an important index. The purpose of treatment during the acute stage is to control the accumulation of BCAAs and BCKAs and to promote anabolism with inhibition of protein catabolism. During acute onset of this disease, sufficient energy intake (0.502–0.586 MJ · kg–1 · d–1) should be given to the patient with BCAA-free milk, fat administration (40–50% of total energy), or by intravenous hyperalimentation. If large quantities of BCAAs and BCKAs are accumulated, continuous hemodialysis filtration should be performed in an intensive care unit. The rate of decrease of blood leucine levels should exceed 750 µmol · L–1 · 24 h–1. This should decrease blood leucine levels to <400 µmol/L between 2 to 4 d after diagnosis. High levels of leucine inhibit transfer of other neutral amino acids, causing deficiency of other essential amino acids in the brain. Therefore, 3–4 g · kg–1 · d–1 protein as essential and nonessential amino acid supplementation, excluding BCAAs, is necessary. Keeping blood levels of valine and isoleucine above 400–600 µmol/L is important for promoting anabolism of the high blood level of leucine. In some cases 80–120 mg · kg–1 · d–1 of valine and isoleucine each should be supplemented.
In addition, during the acute stage of MSUD, brain edema and hyponatremia are easily caused by high secretion of the atrial natriuresis hormone, high intracellular osmolality with high levels of leucine, and iatrogenic hydration. Such serious conditions should be prevented by administration of mannitol or a diuretic drug, along with control of electrolyte balance. Serum Na level and plasma osmolality should be kept between 140–145 mmol/L and 290–300 mmol/L, respectively. Treatment of the acute stage gradually shifts to chronic stage treatment with the patient’s condition.
Chronic stage treatment. The purpose of chronic stage treatment is to inhibit acute illness and achieve sufficient growth and development. In actual practice, common formula milk mixed with BCAA-free milk is used in infancy. This mixed ratio (leucine tolerance) depends on the BCKDH activity. Concentration of blood leucine should be maintained in the range of 100–300 µmol/L by changing this ratio with consequent frequent examination of blood leucine. An infant with classic MSUD typically takes 60–90 mg · kg–1 · d–1 of leucine and 40–50 mg · kg–1 · d–1 of isoleucine and valine. As other essential amino acids are important for normal growth and development, the patient requires formula milk or amino acid powder. If the patient has the possibility of the thiamine-responsive form, administration of a large quantity of thiamine should be attempted. The range of effective quantity of thiamine (10–1000 mg/d) is wide. After infancy, dietary management should be continued using BCAA-free milk or amino acid powder.
Liver transplantation. Liver transplantation is an effective therapy in MSUD. Wendel et al. (34) reported investigations of 3 patients with MSUD who received orthotopic whole liver transplantation (OLT). Liver replacement resulted in a clear increase in whole body BCKDH activity to at least the levels of very mild MSUD variants. The average blood levels of leucine in the patients with pre-OLT were 500 µmol/L, which fell to 200 µmol/L after OLT. These patients no longer required protein-restricted diets, and the risk of metabolic decompensation during catabolic events had apparently abolished (34,35).
Outcome of MSUD
Early treatment for MSUD significantly improves the intellectual outcome, but poor biochemical control may adversely affect performance. Therefore newborn screenings are performed in the United States, Europe, and Japan by blood leucine concentration. In a Japanese study, 44 patients with MSUD were identified from 1978 when newborn screening in Japan began, until 2004. Aoki and Wada (36) analyzed 31 MSUD patients found by Japanese newborn screening during the 10 y from 1978 until 1988 and reported that their neurological condition was not favorable. [Approximately half had intelligence quotient (IQ) scores lower than 80.] Among them, 8 patients had died. Four patients died during the neonatal period and 3 during infancy. One patient died at school age from acute illness of MSUD after stress from an operation and infection. Another 8 patients attended schools for handicapped children. This report suggested that these poor prognoses were because of recurrent acute MSUD and its inadequate treatment.
Owada (37) compared clinical symptoms with blood leucine levels during acute illness in Japanese patients with neonatal MSUD. Poor feeding appeared when blood levels of leucine exceeded 800 µmol/L. Other symptoms, such as unconsciousness, convulsion, opisthotonus, and apnea, apparently occurred with blood levels of leucine over 1000 µmol/L (Fig. 2). In addition, the relations between the IQ and DQ (development quotient) of the MSUD patients, and the blood levels of leucine at the time of diagnosis were analyzed. The result showed a inverse relation (Fig. 3). This report suggested that the patients with classic MSUD already had some degree of brain damage at the time of the diagnosis by newborn screening (diagnosis by newborn screening was still too late for efficient treatment of MSUD). Moreover, they reported that the MSUD patients who seemed to have the milder form (200–300 µmol/L blood levels of leucine) easily fell into extremely severe conditions after infections, and they pointed out the difficulty of managing MSUD.
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In general, approximately one-third of the classic MSUD patients had normal IQ scores, and one-third had IQ scores between 70 and 90. The remaining one-third had even lower IQ scores. The subsequent course of the disease was closely related with the age of diagnosis and initial treatment. Treatment initiated before 10 d of age gave the best results, but patients treated after 14 d of age subsequently suffered neurological disorders (3). This shows that early diagnosis and treatment during the neonatal period are extremely important.
Recently, Morton et al. (32) reported diagnosis and treatment of classic MSUD in 36 Mennonite patients. In this investigation, amino acid concentrations were measured in at-risk infants between 12 and 24 h of age. An additional 18 patients with MSUD were diagnosed between 4 and 16 d of age because of metabolic illness. A treatment protocol for MSUD was designed in this report. Inhibition of endogenous protein catabolism, promotion of protein synthesis, prevention of deficiencies of essential amino acids, and maintenance of normal serum osmolarity were emphasized for the treatment, and, with this protocol, classic MSUD can be managed to allow a benign neonatal course, normal growth, and low hospitalization rates. They concluded that early treatment provided favorable prognosis (32,33).
These MSUD studies suggest that upper limits of plasma leucine for minimum clinical problems are 1000–1200 µmol/L for acute exposure and 400–500 µmol/L for chronic exposure. Higher leucine levels cause brain edema during acute illness, and moderate leucine levels cause dysmyelination in chronic illness. Schonberger et al. (39) reported dysmyelination in the brain of adolescents and young adults with MSUD by means of cerebral MRI. In this report, no significant changes in MRI were associated with plasma total BCAA concentrations < 1300 µmol/L. Safe plasma leucine levels also seemed to be < 400–500 µmol/L.
Conclusion
According to the clinical investigations of MSUD patients, leucine levels > 400 µmol/L apparently cause clinical problems derived from impaired function of the central nervous system. Because BCKDH is ubiquitously expressed in cells, including neuronal cells, damage of neuronal cells found in MSUD patients are presumably because of both higher concentrations of blood BCAAs and BCKAs, especially leucine, and response of individuals with normal enzyme activity might differ when provided large amounts of leucine or other BCAA (40). However, clinical data from MSUD patients will provide a valuable basis for understanding leucine toxicity in the normal subject.
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FOOTNOTES |
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2 This work was supported by grants from Research for the Future Program of Japan Society for the Promotion of Science; grant-in-aid for scientific research; grant-in-aid for 21th century COE research from the Ministry of Education, Culture, Sports, Science and Technology "cell fate regulation research and education unit" and a research grant from the Ministry of Health, Labor and Welfare, Japan.
4 Abbreviations used: BCKA, branched-chain -ketoacid; BCKDH, branched-chain -ketoacid dehydrogenase; DQ, development quotient; E1, branched-chain -ketoacid decarboxylase; E2, dihydrolipoyl transacylase; E3, dihydrolipoyl dehydrogenase; IQ, intelligence quotient; MSUD, maple syrup urine disease; OLT, orthotopic whole liver transplantation; TPP, thiamine pyrophosphate.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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. In the second (irreversible) step, BCKAs are catalyzed by BCKDH, which is a rate-limiting enzyme in this pathway 
. The transamination of BCAAs and decarboxylation of BCKAs form CoA compounds.
