INTRODUCTION — Maple syrup urine disease (MSUD; MIM #248600) also known as branched-chain ketoaciduria, is a disorder affecting the aliphatic or branched-chain amino acids (BCAAs). It is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase complex (BCKDC), the second enzyme of the metabolic pathway of the three BCAAs, leucine, isoleucine, and valine. It is characterized by psychomotor delay, feeding problems, and a maple syrup odor of the urine.
MSUD is reviewed here. A general discussion of amino acid disorders is presented separately. (See "Inborn errors of metabolism: Classification".)
EPIDEMIOLOGY — MSUD occurs in approximately 1 in 86,800 to 185,000 live births [1,2]. The MSUD incidence is up to 1:200 live births in certain Mennonite populations in Pennsylvania and elsewhere due to a founder variant (c.1312T>A) in the branched-chain ketoacid dehydrogenase complex gene (BCKDHA) .
PATHOGENESIS — MSUD is caused by pathogenic variants of genes that encode branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) components E1-alpha, E1-beta, E2, and E3. These genes map to human chromosomes 19q13.1-q13.2 (BCKDHA), 6p22-p21 (BCKDHB), 1p31 (dihydrolipoamide branched-chain transacylase E2 [DBT]), and 7q31-q32 (dihydrolipoamide dehydrogenase [DLD]), respectively [4-8]. The mode of inheritance is autosomal recessive. The sequences of all genes are fully characterized, including regulatory elements. Homozygous or compound heterozygous variants in any of these genes can cause any of the forms of MSUD. No strict genotype-phenotype correlation exists in patients with MSUD. Founder variants are identified in populations with a particularly high prevalence of MSUD (eg, Mennonites, Amish) . There are case reports of a mild form of MSUD due to homozygous variants in the protein phosphatase, Mg2+/Mn2+ dependent 1K (PPM1K) gene encoding the BCKDC phosphatase  and variable increases of branched-chain amino acids (BCAAs) due to deficiency of one of the two branched-chain aminotransferase (BCAT) enzymes [10,11]. Pathogenic variants in the gene encoding the BCKDC kinase have not been identified.
BCKDC plays a key role in the metabolism of BCAAs for energy production and synthesis of fatty acids and cholesterol through gluconeogenesis (figure 1). Decreased activity of BCKDC results in elevation of plasma concentrations of the BCAAs (leucine, isoleucine, and valine) and their corresponding keto acids . A metabolite of isoleucine causes the urine to smell like maple syrup. Elevated levels of BCAA interfere with normal function of the immune system, skeletal muscle, and central nervous system , exerting direct and indirect neurotoxic effects through tissue swelling, impaired glutamate homeostasis, and relative deficiency of large neutral amino acids, resulting in reduced neurotransmitter synthesis including dopamine and serotonin [13,14].
Clinical phenotypes — There are five distinct clinical phenotypes of MSUD: classic, intermittent, intermediate, thiamine responsive, and E3 deficient (table 1) . In most cases, they do not correlate with specific variants or residual enzyme activity. Classic and E3-deficient MSUD present during the neonatal period and/or early infancy, while the other forms may present at any age during childhood, typically during a catabolic episode such as an intercurrent illness. However, they can be distinguished based upon age of onset and severity of clinical symptoms. Response to oral thiamine treatment may help distinguish the clinical phenotype in patients who present at a later age, but clinicians should keep in mind that response may be incomplete. All affected patients have elevated plasma levels of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine), including alloisoleucine and urine levels of branched-chain ketoacids, lactate, and pyruvate.
Classic MSUD — Classic MSUD is the most common form of the disorder. It results from pathogenic variants in the genes for E1-alpha, E1-beta, and E2, leading to less than 3 percent residual enzyme activity. Newborns typically develop ketonuria within 48 hours of birth and present with neonatal encephalopathy, which is characterized by irritability, poor feeding, vomiting, lethargy, and dystonia . By four days of age, neurologic abnormalities include alternating lethargy and irritability, dystonia, apnea, seizures, and signs of cerebral edema. Initial symptoms may not develop until the infant is four to seven days of age, depending upon the amount of protein in the feeding regimen. Breastfeeding may delay onset of symptoms to the second week.
Episodes of metabolic intoxication may occur in affected older infants or children who usually are controlled by nutritional management . These episodes often are caused by increased catabolism of endogenous protein that may be induced by intercurrent illness or by exercise, injury, surgery, or fasting. Clinical manifestations include epigastric pain, vomiting, anorexia, and muscle fatigue. Pancreatitis is an occasional finding. Neurologic signs may include hyperactivity, sleep disturbance, stupor, decreased cognitive function, dystonia, and ataxia. A clinical picture similar to Wernicke encephalopathy has been reported in cases of acute decompensation . Death may occur from cerebral edema and herniation. (See "Wernicke encephalopathy".)
Intermittent MSUD — Intermittent MSUD is the second most common type of MSUD due to pathogenic variants in the genes for E1-alpha, E1-beta, and E2 but with higher residual enzyme activity than is seen in patients with classic MSUD. Affected patients have normal growth and development. They typically present with ketoacidosis during episodes of catabolic stress, including intercurrent illnesses such as otitis media, or increased protein intake. Signs of neurotoxicity develop during these episodes, including ataxia, lethargy, seizures, and coma. Death may occur without appropriate recognition and treatment.
Intermediate MSUD — Intermediate MSUD is a rare disorder that is associated with pathogenic variants in the gene for the E1-alpha component of branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) . Residual BCKDC activity typically is 3 to 30 percent of normal. Patients may become symptomatic at any age. Presentation is later in those with greater enzyme activity [6,17].
The clinical signs are characterized by acute neurologic symptoms (irritability, dystonia) and developmental delay of variable extent. Seizures may occur in some patients. Episodes of acute metabolic decompensation are rare.
Thiamine-responsive MSUD — Thiamine-responsive MSUD is a rare phenotype that is associated with pathogenic variants in the gene for the E2 component of BCKDC [7,18]. Thiamine pyrophosphate, an intracellular product of thiamine, increases the stability of BCKDC through a conformational change. This results in an increase in biologic half-life and residual enzyme activity in certain mutant BCKDCs, explaining why some patients with MSUD respond to thiamine supplementation. Clinical presentation is similar to the intermediate form. In general, affected patients do not respond to thiamine supplementation alone, despite the term used for this phenotype, and dietary restriction of BCAAs is required to achieve metabolic control. Only one reported case has shown true thiamine responsiveness .
E3-deficient MSUD — Pathogenic variants in the gene encoding the E3 component of BCKDC result in a rare form of MSUD, with only a few reported patients . Affected patients have combined deficiencies of BCKDC and the pyruvate and alpha-ketoglutarate dehydrogenase complexes. Clinical features are similar to intermediate MSUD. However, patients with E3-deficiency typically present in the newborn period and also have lactic acidosis.
Diagnostic approach — Newborns, infants, and children who present with encephalopathy and ketoacidosis sporadically, intermittently, during episodes of intercurrent illness, or following prolonged fasting or trauma should be tested for MSUD, even in the context of negative newborn screening results. The diagnosis of MSUD is established by the measurement of plasma amino acid concentrations that demonstrate elevated levels of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) and alloisoleucine (a stereo-isomer of L-isoleucine). The identification of elevated alloisoleucine in plasma is sufficient for a diagnosis of MSUD; urine studies are not needed in this case. However, an increase in alloisoleucine levels may not appear until six days of age, even when leucine levels are elevated. Urine organic acid analysis to detect branched-chain hydro acids and branched-chain keto acids can be used to corroborate the diagnosis during this transient period. Detection of plasma alloisoleucine and 2-oxo-3-methylvaleric acid with high-pressure liquid chromatography is also diagnostic for MSUD.
Genetic testing using an MSUD gene panel to identify the underlying molecular etiology should be included as part of the diagnostic work-up whenever possible. Identification of the genotype informs the likelihood of thiamine responsiveness and can be used for prenatal and/or preimplantation diagnosis if future pregnancies are anticipated. When genetic testing is not available, the biochemical confirmation of plasma alloisoleucine in the context of elevated plasma BCAA levels is sufficient to initiate dietary therapy.
Prenatal diagnosis — Prenatal diagnosis can be performed by measuring branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) enzyme activity in cultured amniocytes or choriovillus cells or by mutation analysis if the specific gene defect is known. Preimplantation diagnosis is feasible if the pathogenic variants of the index patient are known.
Neonatal diagnosis — Mutational analysis can be performed in a newborn with a family history of MSUD if the specific gene defects are known. If pathogenic variants are not known, high-risk newborns can be evaluated with deoxyribonucleic acid (DNA) testing for BCKDHA, BCKDHB, and DBT gene variants. Plasma for amino acid analysis should be obtained between 18 to 24 hours of life in these high-risk newborns.
Positive newborn screening — Classic MSUD in newborn infants is readily detected only by screening using tandem mass spectrometry. Recall rates may be reduced by use of a second-tier method to analyze alloisoleucine in dry blood spots . However, affected newborns may be symptomatic before the results are available. Confirmatory testing should include, at a minimum, plasma amino acids, urine organic acids, and urine ketones. Newborn screening may not detect milder or variant forms of the disorder [21,22].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis for classic MSUD includes other disorders that can present with neonatal encephalopathy, including urea cycle defects, glycine encephalopathy, and organic acidopathies (methylmalonic acidemia, propionic acidemia, and others); 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) lyase deficiency; and beta-ketothiolase deficiency. Basic laboratory testing that is performed in patients with a suspected inborn error of metabolism will distinguish between most of the disorders in the differential diagnosis. These tests include blood gas analysis, electrolytes (anion gap), lactic acid, ammonia, beta-hydroxybutyrate, and urine ketone analysis. Specialized metabolic testing including urine organic acid and acylglycine, plasma amino acid, and acylcarnitine analysis is needed to finalize the diagnosis. The diagnosis of inborn errors of metabolism is discussed in greater detail separately. (See "Inborn errors of metabolism: Identifying the specific disorder" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management" and "Inborn errors of metabolism: Classification".)
Detection of alloisoleucine is also helpful to differentiate MSUD from ketotic hypoglycemia. Branched-chain amino acid (BCAA) concentrations may be transiently elevated in ketotic hypoglycemia or in the postabsorptive state, but alloisoleucine will not be present. (See "Approach to hypoglycemia in infants and children".)
The differential diagnoses for intermittent and intermediate forms of MSUD presenting during later childhood or adulthood with an encephalopathic picture is broad and includes urea cycle disorders, mitochondrial disorders, organic acidurias, intoxications with solvents or methanol, and ketoacidosis due to type 1 diabetes mellitus. (See "Urea cycle disorders: Clinical features and diagnosis" and "Mitochondrial myopathies: Clinical features and diagnosis" and "Diabetic ketoacidosis in children: Clinical features and diagnosis" and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis".)
MANAGEMENT — Management of MSUD has two primary aspects:
●Dietary therapy to promote normal growth and development
●Aggressive treatment of episodes of acute metabolic decompensation to prevent short- and long-term sequelae
An experienced metabolic disease specialist and a dietitian should be involved in the management of MSUD patients.
Liver transplantation offers an additional therapeutic avenue for difficult-to-treat patients with MSUD.
Dietary therapy — The goals of dietary therapy are to:
●Reduce toxic metabolites
●Achieve plasma concentrations of branched-chain amino acids (BCAAs), especially leucine, that are within the target range
●Support normal growth
●Preserve intellectual function and development
These goals are accomplished by restricting intake of BCAAs using commercially available formulas and medical food. Patients are started on a low-protein diet providing sufficient protein, calories, and fluids to maintain metabolic homeostasis. Additional valine and isoleucine supplementation may be required to prevent low plasma concentrations, which would be rate limiting for protein synthesis, and to promote anabolism . Dietary restriction is maintained throughout life .
Plasma leucine concentrations should be maintained between 75 to 200 micromol/L in children under five years of age and between 75 to 300 micromol/L for patients over five years of age to achieve favorable intellectual outcome . Plasma valine and isoleucine concentrations should be maintained between 200 to 400 micromol/L . A retrospective study of 35 patients with MSUD (mean age of 16.3, range 2.1 to 49 years) found that metabolic decompensations (plasma leucine >380 micromol/L) were more common during the first year of life and after 15 years of age, primarily due to infection and dietary nonadherence .
Monitoring consists of measurement of plasma amino acid concentrations every one to two weeks for the first 6 to 12 months of age. The intake of leucine, valine, and isoleucine can be adjusted for the individual patient according to these measurements. Monitoring can be performed less frequently with increasing age, based upon individual circumstances such as metabolic stability and dietary adherence. We typically test weekly in patients <3 months of age, every other week to monthly from 3 to 12 months of age, and then monthly thereafter. For patients presenting after infancy, we usually check levels weekly to monthly until stabilized and then every three to six months thereafter.
Thiamine supplementation — In addition to dietary therapy, we suggest a four-week trial of thiamine supplementation, at a dose of 50 to 200 mg/day, in all patients with MSUD except those with loss-of-function variants expected to result in insignificant (<3 percent) residual enzyme activity. The latter variants result in a truncated branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) that is not amenable to stabilization through thiamine pyrophosphate and therefore do not respond to thiamine. Thiamine supplementation can be started once genetic test results are available. Plasma BCAAs and tolerance for dietary BCAAs should be monitored to evaluate thiamine responsiveness, which is expected to reduce plasma BCAAs and increase dietary tolerance. Thiamine supplementation should be continued in addition to dietary therapy in patients with confirmed thiamine-responsive MSUD. (See 'Thiamine-responsive MSUD' above.)
Metabolic decompensation — Episodes of metabolic decompensation must be treated aggressively. Plasma and tissue concentrations of leucine should be lowered rapidly by inhibition of protein catabolism and enhancement of protein synthesis through aggressive therapy including glucose infusions (eg, dextrose 10% and sodium chloride 0.9% [D10NS] at 1 to 1.5 times maintenance) with or without the addition of insulin (add if glucose levels are >130 mg/dL) and supplementation with precursor-free amino acid mixture. The latter may be provided as an intravenous infusion in situations where the gastrointestinal tract cannot be used (eg, comatose patients) . Protein intake is typically discontinued for 24 to 48 hours [2,24,28]. The target range for plasma leucine is within the upper range of normal (target: 200 to 300 micromol/L) . Retrospective analysis of data from 29 episodes of hyperleucinemia in 15 patients with MSUD treated with leucine-free formula showed an approximately 50 percent drop in plasma leucine concentration every 24 hours . (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Immediate management'.)
At least 1.25 times the weight or body surface-adjusted estimated energy requirement must be provided. The total nutritional goal can be met by combined enteral and parenteral administration. Isoleucine and valine supplementation, at a dose of 20 to 120 mg/kg/day each, should be provided to maintain plasma concentrations of 400 to 600 micromol/L during the acute decompensation period. Intravenous fluid resuscitation is indicated during presumed episodes of metabolic decompensation because forced diuresis may assist in detoxification. Hypotonic fluid is generally not used to avoid osmolarity fluctuation, and sodium concentration should be maintained within physiologic concentrations of 138 to 145 mEq/L . Supplementation with sodium chloride may be necessary to help maintain serum sodium concentration in the normal range and to reduce the risk for cerebral edema . During acute admissions, plasma sodium concentrations are followed at least every 12 to 24 hours or more frequently if clinically indicated.
Hyponatremic cerebral edema should be treated with hypertonic saline, mannitol, and furosemide. In rare circumstances, hemodialysis or peritoneal dialysis may be needed to remove BCAAs and ketoacids and to prevent recurrent clinical intoxication but should be closely managed along with nutritional support to reduce catabolism [30-33].
Treatment of urea cycle disorders with sodium phenylacetate/benzoate or sodium phenylbutyrate results in a reduction of BCAAs. Phenylbutyrate therapy reduced plasma levels of BCAAs in patients with intermediate MSUD , although additional studies are underway to evaluate the efficacy of this approach .
Liver transplantation — Approximately 10 percent of BCKDC enzyme activity is expressed in the liver . Thus, liver transplantation has been used to treat classic MSUD [37-43]. However, dietary therapy is considered the more appropriate option in most patients because of the higher risks and potential long-term complications of liver transplantation . Indications for liver transplantation include poor metabolic control and poor quality of life as indicated by significant psychomotor disabilities and more frequent acute metabolic decompensations and related hospitalizations.
After transplantation, BCKDC activity is similar to mild types of MSUD, and patients no longer require dietary restriction. Transplantation appears to abolish the risk for metabolic decompensation during catabolic events or with protein loading. Results suggest that patients are protected from further brain damage after transplantation, although previous damage is not reversed .
OUTCOME — Normal outcome is possible in MSUD . The best outcomes occur in patients who begin therapy before they become symptomatic or are treated rapidly after symptoms develop. Cognitive outcome appears to be related to plasma leucine concentration. In one retrospective review of patients with classic MSUD, median plasma leucine concentrations during the first six years of life indirectly correlated with intelligence quotient (IQ) at six years of age . Some school-age patients with classic MSUD may show lower performance than verbal IQ scores, although a clear correlation between metabolic control and neurocognitive test performance has not been established .
A review of medical records from 35 MSUD patients with a mean age of 16.3 years (2.1 to 49) found that 61 percent of adult patients lived independently with good integration into society, although 56 percent continued to receive infrequent or regular psychological or psychiatric care .
Acute metabolic decompensation can result in brain injury and requires prompt and aggressive treatment to avoid neurologic sequelae and maintain good health outcomes .
PATIENT RESOURCES — A self-reported patient registry and resource for patients with inherited metabolic disorders was launched in 2012 by Emory University. The Newborn Screening Connect (NBS Connect) had 442 registered participants in 2017, including 68 with MSUD .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Maple syrup urine disease".)
SUMMARY AND RECOMMENDATIONS
●Genetics – Maple syrup urine disease (MSUD; MIM #248600) also known as branched-chain ketoaciduria, is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase complex (BCKDC). MSUD has autosomal recessive inheritance. The genes encoding the four components of BCKDC have been mapped to human chromosomes 19q13.1-q13.2, 6p22-p21, 1p31, and 7q31-q32. (See 'Pathogenesis' above.)
●Clinical phenotypes – There are five distinct clinical phenotypes of MSUD: classic, intermittent, intermediate, thiamine responsive, and E3 deficient . In most cases, these do not correlate with specific pathogenic variants. However, they can be distinguished based upon age of onset, severity of clinical symptoms, and, in some cases, response to thiamine treatment (table 1). (See 'Clinical phenotypes' above.)
•Classic MSUD – Patients with classic MSUD typically develop ketonuria, irritability, poor feeding, vomiting, lethargy, and dystonia within 48 hours of birth. However, depending upon the feeding regimen, the onset of symptoms may be delayed to the second week of life. (See 'Classic MSUD' above.)
•Intermediate MSUD – Patients with intermediate MSUD have residual BCKDC activity and may become symptomatic at any age. Manifestations include neurologic impairment and developmental delay of variable extent. Seizures may occur in some patients. Episodes of acute metabolic decompensation are rare. (See 'Intermediate MSUD' above.)
•Intermittent MSUD – Patients with intermittent MSUD typically present with ketoacidosis during episodes of catabolic stress. Death may occur without appropriate recognition and treatment. (See 'Intermittent MSUD' above.)
•Thiamine-responsive MSUD – The clinical presentation of thiamine-responsive MSUD and E3-deficiency MSUD is similar to the intermediate form, except that onset of E3-deficient MSUD is in the newborn period. (See 'Thiamine-responsive MSUD' above and 'E3-deficient MSUD' above.)
●Diagnosis – The diagnosis of MSUD is established by elevated plasma levels of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine), elevated alloisoleucine, and elevated urine levels of branched-chain ketoacids, lactate, and pyruvate. Detection of alloisoleucine (a stereo-isomer of L-isoleucine ) and 2-oxo-3-methylvaleric acid with high-pressure liquid chromatography is also diagnostic for MSUD. Mutation analysis can confirm the diagnosis, predict disease severity, predict thiamine responsiveness, and aid in prenatal diagnosis if future pregnancies are anticipated. (See 'Diagnostic approach' above.)
•Prenatal diagnosis – When there is a family history of MSUD, prenatal diagnosis can be performed by measuring enzyme activity in cultured amniocytes or choriovillus cells in a laboratory with the appropriate expertise or by genetic testing. Genetic testing and plasma amino acid analysis can also be performed in the immediate neonatal period. (See 'Prenatal diagnosis' above and 'Neonatal diagnosis' above.)
•Newborn screening – Newborn screening using tandem mass spectrometry readily detects classic MSUD. However, affected newborns may develop symptoms before the results are available. Confirmatory testing is required to make the diagnosis. Newborn screening may not detect milder forms of the disorder. (See 'Positive newborn screening' above.)
●Management – Management of MSUD has two primary aspects: dietary therapy to promote normal growth and development and aggressive treatment of episodes of acute metabolic decompensation. (See 'Management' above.)
•Dietary therapy – The goal of dietary therapy is to achieve normal plasma concentrations of BCAAs. Dietary restriction of BCAAs using commercially available formulas and medical food is maintained throughout life. (See 'Dietary therapy' above.)
•Thiamine – We suggest a four-week trial of thiamine supplementation, at a dose of 50 to 200 mg/day, in most patients with MSUD, in addition to dietary therapy (Grade 2C). The exception is patients with loss-of-function variants expected to result in insignificant (<3 percent) residual enzyme activity. The latter variants result in a truncated BCKDC that is not amenable to stabilization through thiamine pyrophosphate. Thiamine supplementation is continued in addition to dietary therapy in patients with confirmed thiamine-responsive MSUD. (See 'Thiamine supplementation' above.)
•Treatment of metabolic decompensation – Episodes of metabolic decompensation must be treated aggressively. Plasma and tissue concentrations of leucine should be lowered rapidly by inhibition of protein catabolism and enhancement of protein synthesis. (See 'Metabolic decompensation' above and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)
●Outcomes – Normal outcome is possible in MSUD. The best outcomes occur in patients who begin therapy before they become symptomatic or are treated rapidly after symptoms develop. Cognitive outcome appears to be related to plasma leucine concentration. (See 'Outcome' above.)
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