Maple Syrup Urine Disease (MSUD) 

Updated: May 02, 2018
Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

Overview

Background

Maple syrup urine disease (MSUD), also known as branched-chain ketoaciduria, is an aminoacidopathy due to an enzyme defect in the catabolic pathway of the branched-chain amino acids leucine, isoleucine, and valine. Accumulation of these 3 amino acids and their corresponding alpha-keto acids leads to encephalopathy and progressive neurodegeneration in untreated infants. Early diagnosis and dietary intervention prevent complications and may allow for normal intellectual development. Consequently, maple syrup urine disease has been added to many newborn screening programs, and preliminary results indicate that asymptomatic newborns with maple syrup urine disease have better outcomes compared with infants who are diagnosed after they become symptomatic.

In 1954, Menkes et al reported a family in which 4 infants died within the first 3 months of life owing to a neurodegenerative disorder. The urine of these infants had an odor similar to that of maple syrup (burnt sugar).[1] Therefore, this disorder was called maple sugar urine disease and, later, maple syrup urine disease. In the following years, Dancis et al identified the pathogenetic compounds as branched-chain amino acids and their corresponding alpha-keto acids.[2] In 1960, Dancis et al demonstrated that the enzymatic defect in maple syrup urine disease was at the level of the decarboxylation of the branched-chain amino acids.[3] Snyderman et al initiated the first successful dietary treatment of maple syrup urine disease by restricting oral intake of branched-chain amino acids.[4] In 1971, Scriver et al reported the first case of thiamine-responsive maple syrup urine disease.[5] The branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex was purified and characterized in 1978.[2]

Pathophysiology

Maple syrup urine disease is caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex, which catalyses the decarboxylation of the alpha-keto acids of leucine, isoleucine, and valine to their respective branched-chain acyl-CoAs. These are further metabolized to yield acetyl-CoA, acetoacetate, and succinyl-CoA.[6, 7]

The BCKD enzyme complex, which is associated with the inner mitochondrial membrane, has 3 different catalytic components (ie, E1, E2, E3) and 2 associated regulatory enzymes (ie, BCKD phosphatase, BCKD kinase). In addition, the E1 component consists of 2 distinct subunits (ie, E1 alpha, E1 beta) that form an alpha-2 beta-2 heterotetramer. The E3 component is associated with 2 additional alpha-ketoacid dehydrogenase complexes, namely pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. Mutations in E1, E2, or E3 cause maple syrup urine disease. No clear genotype-phenotype correlation between molecular and clinical phenotypes is known, with the exemption of mutations in E2, which cause thiamine-responsive maple syrup urine disease. Mutations in E3 cause additional deficiencies of pyruvate and alpha-ketoglutarate dehydrogenases.[8] Mutations in the regulatory enzymes have not been reported.[9]

Accumulation of plasma leucine causes neurological symptoms. Leucine is rapidly transported across the blood-brain barrier and is metabolized to presumably yield glutamate and glutamine. The accumulation of plasma isoleucine is associated with the maple syrup urine odor.[10, 11]

Epidemiology

Frequency

United States

Maple syrup urine disease occurs in about 1 case per 185,000 live births. Within the Ashkenazi Jewish population, the incidence is higher, at 1 per 26,000 live births. In select inbred populations (ie, the Mennonites in Pennsylvania), it may be as common as 1 case per 176 newborns. As an autosomal recessive disorder, maple syrup urine disease is more prevalent in populations with a high occurrence of consanguinity.[6]

International

Quental et al identified a homozygous 1-bp deletion (117delC) in the BCKDHA gene (this gene codes for the alpha subunit of the BCKD enzyme complex, specifically E1) in Portuguese Gypsies and estimated the carrier frequency for this deletion to be as high as 1.4% (about 1 case per 71 live births).[12]

Mortality/Morbidity

Infants with untreated early onset (ie, classic) maple syrup urine disease have significant developmental delay and die within the first months of life. Children or juveniles with late-onset (ie, intermediate, intermittent) forms of maple syrup urine disease may have some form of developmental delay, depending on the residual enzyme activity of BCKD. All children are at increased risk for metabolic decompensation during periods of increased protein catabolism (eg, intercurrent illness, trauma, surgery). Morbidity can almost entirely be prevented with early diagnosis (in a neonate younger than 10 days), with appropriate treatment at presentation and during episodes of potential metabolic decompensation.

Race

Maple syrup urine disease has been reported to occur in all ethnic groups, although the incidence and prevalence may widely vary.[6]

Sex

No sex predilection is noted, as the genetic case is autosomal recessive and not related to the sex chromosomes.

Patient Education

Educate patients and their caregivers about the principles of dietary treatment, how to calculate their dietary leucine requirement and overall daily nutritional needs, and how to obtain emergency care for episodes of metabolic decompensation. Supply a written emergency regimen and emergency contact card to families and caregivers.

Resources for patients, families, and caregivers include the following:

MSUD Family Support Group

March of Dimes

 

Presentation

History

Classic maple syrup urine disease (MSUD) is the most common type, with symptoms developing in neonates aged 3-7 days, depending on feeding regimen. Breastfeeding may delay onset of symptoms into the second week of life.

Infants with classic maple syrup urine disease appear normal at birth. Symptoms that may develop within the first week of life include fussiness, lethargy, decreased nursing/feeding, emesis, poor weight gain, increasing lethargy, hypotonia and/or hypertonia, a high-pitched cry, seizures, and the characteristic maple syrup smell of the urine. This burnt maple sugar smell is more noticeable in a diaper after the urine has dried. In infants with non-classic maple syrup urine disease (ie, intermediate maple syrup urine disease, intermittent maple syrup urine disease), symptoms tend to be milder and may not be readily apparent early in the course.

Physical

The clinical presentation of an infant/child with maple syrup urine disease varies. Five distinct clinical phenotypes can be distinguished based on age of onset, severity of clinical symptoms, and response to oral thiamine treatment. These types of maple syrup urine disease include classic, intermediate, intermittent, thiamine-responsive, and E3-deficient.[6]

Classic maple syrup urine disease is the most common type. In classic maple syrup urine disease, little or no BCKD enzyme activity (usually <2% of normal) is present. Infants show symptoms within the first week of life. They generally have poor tolerance for the branched-chain amino acids (BCAAs), so dietary protein must be severely restricted. In the classic type, neurological signs (eg, muscular hypotonia and/or hypertonia, dystonia, seizures, encephalopathy) rapidly develop. Signs of pseudotumor cerebri may be observed, and acute transient ataxia has been reported. Pancreatitis has been occasionally reported. Ketosis and the characteristic urine odor of maple syrup are usually present when the first symptoms develop. Interestingly, this characteristic urine odor has been reported in healthy infants not affected with maple syrup urine disease. The reason for this observation is not understood.[6, 9, 13, 14]

Intermediate maple syrup urine disease is a variant of classic maple syrup urine disease and is less common than classic maple syrup urine disease; approximately 20 patients have been reported with this phenotype. Patients with intermediate maple syrup urine disease have a higher level of BCKD enzyme activity (approximately 3%-8% of normal), and they can usually tolerate a greater amount of leucine. Clinical signs in these patients include neurological impairment, developmental delay of varying degree, and seizures. Presentation may occur at any age, depending on residual BCKD enzyme activity; however, if the patient is ill or fasting, he or she will react in a similar way to a child with classic maple syrup urine disease and will require immediate medical intervention and care.

Intermittent maple syrup urine disease, the second most common type of maple syrup urine disease (after the classic type), is a milder form of the disease owing to the presence of greater enzyme activity (approximately 8%-15% of normal). Patients have normal growth and intelligence. Symptoms may not present until age 12-24 months, usually in response to catabolic stress as due to illness (eg, otitis media) or a surge in protein intake. During these episodes, the characteristic maple syrup odor becomes evident, and metabolic decompensation can occur. Ataxia, lethargy, seizures, and coma may ensue. Patients with intermittent maple syrup urine disease have died during these acute episodes when not appropriately treated.

The descriptive term thiamine-responsive maple syrup urine disease reflects the treatment of this rare type of maple syrup urine disease. Giving large doses of thiamine to the thiamine-responsive child increases BCKD enzyme activity, which, in turn, breaks down the BCAAs. Only one case report described by Scriver et al has been shown to be unambiguously responsive to thiamine.[5] Positive clinical response to supplemental thiamine has been documented in patients and has shown improved metabolic control when moderate dietary restriction of BCAAs is also followed.[5]

E3-deficient maple syrup urine disease (dihydrolipoamide dehydrogenase deficiency [DLDD]) is a very rare type of maple syrup urine disease, with fewer than 10 patients reported in the medical literature (OMIM #246900). The clinical presentation is very similar to that of intermediate maple syrup urine disease, with the exception of early-onset lactic acidosis. These patients have combined deficiencies of the BCKD enzyme complex, pyruvate, and alpha-ketoglutarate dehydrogenases.[6]

Causes

See Pathophysiology.

Complications

Patients with maple syrup urine disease are at risk for metabolic decompensation during periods of increased catabolism. Dietary compliance is necessary to prevent developmental delay and neurological symptoms.

 

Workup

Laboratory Studies

Routine newborn metabolic screening for maple syrup urine disease (MSUD) has been available since 1964. This screening is performed in all 50 United States and in various parts of the world. The test is performed within 24-48 hours following birth. Newborn screening for maple syrup urine disease is performed with tandem mass spectrometry (MS/MS) using concentrations of leucine and isoleucine and the Fisher ratio (branch-chain amino acids/phenylalanine and tyrosine) as diagnostic measures. Immediate treatment should follow the identification of affected newborn infants.

Plasma amino acids testing

Plasma amino acids (PAA) testing should be performed to assess for elevated levels of branched-chain amino acids (BCAAs) and to detect l-alloisoleucine (derived from l-isoleucine).

The detection of l-alloisoleucine (also termed alloisoleucine) is diagnostic for  maple syrup urine disease. Alloisoleucine reference values in plasma were established in healthy adults (1.9 ± 0.6 μmol/L [mean ± SD]; n = 35), children aged 3-11 years (1.6 ± 0.4 μmol/L; n = 17), and infants younger than 3 years (1.3 ± 0.5 μmol/L; n = 37). The effect of dietary isoleucine was assessed in oral loading tests. A plasma l-alloisoleucine level greater than 5 μmol/L is the most specific and most sensitive diagnostic marker for all forms of maple syrup urine disease.[15]

Plasma alloisoleucine may not appear until the sixth day of life, even when leucine levels are elevated. Transient elevations of BCAAs (without the presence of alloisoleucine) may develop in patients with ketotic hypoglycemia. Infants in the neonatal intensive care unit receiving total parental nutrition (TPN) may have artificially elevated plasma amino acid levels.

Urine organic acids

Urine organic acids (UOA) should be analyzed using gas chromatography-mass spectrometry (GC-MS) to detect alpha-hydroxyisovalerate, lactate, pyruvate, and alpha-ketoglutarate. A random urine specimen is usually sufficient for this study.

BCKD enzyme activity

BCKD enzyme activity can be measured in lymphocytes, cultured fibroblasts, or both, although this test is not required for diagnosis.

Molecular testing

Molecular testing confirmation should be pursued in all patients diagnosed with maple syrup urine disease to confirm the diagnosis, to provide additional information about prognosis, to provide the knowledge for in-depth genetic counseling for the family, and to provide criteria for prenatal testing. Molecular testing is available for the three genes that have been reported in patients with maple syrup urine disease, as follows: ​

  • BCKDHA gene located at 19q13.2, which encodes BCKA decarboxylase (E1) alpha subunit gene (maple syrup urine disease type 1A)
  • BCKDHB gene located at 6q14.1, which encodes BCKA decarboxylase (E1) beta subunit gene (maple syrup urine disease type 1B)
  • DBT gene located at 1p21.2, which encodes dihydrolipoyl transacylase (E2) subunit gene (maple syrup urine disease type 2) (see also OMIM #248600, GeneTests)

Prenatal diagnosis

Prenatal diagnosis can be performed by measuring BCKD enzyme activity in cultured amniocytes or chorionic villus cells, by performing mutation analysis, or by measuring branched-chain amino acid concentrations in amniotic fluid. However, molecular analysis is the most reliable and therefore preferred method for prenatal diagnosis. Prenatal diagnostic studies require identification of two pathogenic mutations in the index patient.

 

Treatment

Medical Care

The two main approaches to the treatment of maple syrup urine disease (MSUD) include (1) long-term daily dietary management and (2) treatment of episodes of acute metabolic decompensation.

The mainstay in the treatment of maple syrup urine disease is dietary restriction of branched-chain amino acids (BCAAs).[16, 7, 14] Consultation with a neonatal/pediatric nutritionist with expertise in dietary management of metabolic disorders is required to address medical nutrition therapy immediately.

The goals of medical nutrition therapy in maple syrup urine disease are multifaceted, as follows:[17]

  • To rapidly reduce toxic metabolites by restricting dietary BCAAs to amounts allowing patients to achieve and maintain plasma BCAA concentrations within the targeted treatment ranges
  • To reduce catabolism
  • To promote anabolism
  • To monitor nutritional status and alter intake to promote and sustain normal growth
  • To enable normal development and health maintenance
  • To evaluate thiamine responsiveness if the patient has residual BCKD activity and to administer thiamine supplements if the patient is responsive

Aggressively treat episodes of metabolic decompensation. Initiate intravenous glucose infusions (5-8 mg/kg/min for infants) as rapidly as possible. Insulin infusions may be added to promote anabolism. Stop intake of BCAAs but resume intake as soon as plasma BCAAs normalize. Whenever possible, continue additional dietary support, including lipids and/or nutrition free of BCAAs. In rare circumstances, hemodialysis or peritoneal dialysis is required to remove BCAAs and keto acids.

Initial studies using retroviral vectors to infect maple syrup urine disease lymphocytes have shown stable correction of the enzyme deficiency. However, human gene therapy trials for maple syrup urine disease have yet to be performed.

Several successful pregnancies in patients with maple syrup urine disease have been reported. The most critical period for metabolic management is during the immediate postpartum period. Take particular care to counteract catabolism during this time.

Surgical Care

Orthotopic liver transplantation performed at an experienced medical center has changed the outlook for patients with classic maple syrup urine disease, who are frequently challenged with episodes of metabolic decompensation. It appears that, while liver transplantation cannot reverse the neurological damage that has already occurred, it can prevent additional episodes of decompensation and preserve the remaining neurological function.

Three successful liver transplantations in patients diagnosed with classic maple syrup urine disease have been reported.[18] A 2012 study reported that patients who were mentally impaired prior to transplantation had no change in their neurocognitive function one year later. These results suggest that liver transplantation may be an effective treatment for classic maple syrup urine disease, and, although it may arrest further brain damage, it cannot reverse it.[19]

Liver transplantation may guarantee normal or near-normal neurological outcomes if performed early following diagnosis.[19] Certainly, the objective is to prevent the need for liver transplantation in newborns diagnosed with maple syrup urine disease by immediately fostering early dietary intervention of BCAAs restriction.

Diet

The goal of dietary therapy is normalization of branched-chain amino acids (BCAAs), leucine in particular, by restricting intake of BCAAs without impairing growth and intellectual development. Dietary therapy must be lifelong. Several commercially available infant formulas (ie, BCAD 1) and foods for all ages (ie, Nutricia products, MSUD Express) are available without BCAAs or with reduced levels of BCAAs. Lifelong nutritional guidance is imperative.

For patients with maple syrup urine disease, the intake of leucine is calculated on an individual basis following measurement of plasma BCAAs. Measure plasma BCAAs levels on a regular basis at appropriate intervals for the first 6-12 months of life. In addition to dietary therapy, consider thiamine (10-20 mg/d) for 4 weeks to determine thiamine responsiveness.

Activity

Do not restrict activity.

Prevention

Patients should avoid consuming branched-chain amino acids (ie, natural protein) in excess of their daily allowance.

Long-Term Monitoring

Follow up with the patient at regular intervals (ie, at least once every 6-12 mo) with a biochemical geneticist familiar with the management of maple syrup urine disease. Seek dietary guidance with a nutritionist knowledgeable in dietary management of metabolic disorders. Emphasize the importance of continuity of care with a pediatrician/developmental pediatrician to closely follow developmental milestones and neurocognitive function.

 

Medication

Medication Summary

Some patients with maple syrup urine disease (MSUD) have been responsive to thiamine.

Vitamins

Class Summary

Vitamins are organic substances required by the body in small amounts for various metabolic processes. Vitamins may be synthesized in small or insufficient amounts in the body or not synthesized at all, thus requiring supplementation. Administer thiamine in cases of thiamine-responsiveness.

Thiamine (Thiamilate)

An essential coenzyme in carbohydrate and amino acid metabolism. Combines with ATP to form thiamine pyrophosphate. PO absorption is poor, but parenteral route may be associated with severe adverse reactions.