1)Synonyms of Maple Syrup Urine Disease

 BCKD Deficiency
 branched-chain ketoacid dehydrogenase deficiency
 branched-chain ketoaciduria
 MSUD

Subdivisions of Maple Syrup Urine Disease

 classic MSUD
 intermediate MSUD
 intermittent MSUD
 thiamine-responsive MSUD

General Discussion
Summary
Maple syrup urine disease (MSUD) is a rare genetic disorder characterized by
deficiency of an enzyme complex (branched-chain alpha-keto acid dehydrogenase) that
is required to break down (metabolize) the three branched-chain amino acids (BCAAs)
leucine, isoleucine and valine, in the body. The result of this metabolic failure is that all
three BCAAs, along with a number of their toxic byproducts, (specifically their respective
organic acids), all accumulate abnormally. In the classic, severe form of MSUD, plasma
concentrations of the BCAAs begin to rise within a few hours of birth. If untreated,
symptoms begin to emerge, often within the first 24-48 hours of life.
The presentation starts with non-specific symptoms of increasing neurological
dysfunction and include lethargy, irritability and poor feeding, soon followed by focal
neurological signs such as abnormal movements, increasing spasticity, and shortly
thereafter, by seizures and deepening coma. If untreated, progressive brain damage is
inevitable and death occurs usually within weeks or months. The only specific finding
that is unique to MSUD is the development of a characteristic odor, reminiscent of
maple syrup that can most readily be detected in the urine and earwax and may be
smelled within a day or two of birth. The toxicity is the result of damaging effects of
leucine on the brain accompanied by severe ketoacidosis caused by accumulation of
the three branched-chain ketoacids (BCKAs).
The disorder can be successfully managed through a specialized diet in which the three
BCAAs are rigorously controlled. However, even with treatment, patients of any age
with MSUD remain at high risk for developing acute metabolic decompensation
(metabolic crises) often triggered by infection, injury, failure to eat (fasting) or even by
psychological stress. During these episodes there is a rapid, sudden rise in amino acid
levels necessitating immediate medical intervention.
There are three or possibly four types of MSUD: the classic type; intermediate type,
intermittent type, and possibly a thiamine-responsive type. Each of the various subtypes
of MSUD have different levels of residual enzyme activity which account for the variable
severity and age of onset. All forms are inherited in an autosomal recessive pattern.
Introduction
Newborn screening for MSUD is performed throughout the US and in many other
countries so that most such infants are detected through these programs. Where such
screening is not available, infants with MSUD usually present with advancing
neurological signs. Early diagnosis and treatment stabilizes the infants and, if well and
consistently performed, can largely mitigate against serious long-term complications.

Signs & Symptoms

The symptoms and severity of MSUD varies greatly from patient to patient and largely
depends upon the amount of residual enzyme activity.
Classic maple syrup urine disease is the most common and most severe form of MSUD
characterized by little to no enzyme activity. Most infants with classic MSUD show
subtle emerging non-specific symptoms within 2-3 days; these include poor feeding at
bottle or breast and increasing lethargy and irritability. As the decline continues, the
infant further disengages and then starts to show increasing focal neurologic signs
including abnormal movements together with increasing hypertonia and spasticity
progressing to seizures and coma. There may be temporary episodes of extreme
hypotonia. In the end, central neurologic function fails with respiratory failure and death.
By the time that the early symptoms have emerged, a distinctive odor of maple syrup
may be detected in cerumen, sweat, and urine. This is derived from one of the BCKA
organic acids derived from its respective BCAA that accumulate as the disorder spirals
out of control. The odor cannot usually be detected during periods of metabolic stability.
Once the disorder has been treated and stabilized, there remains a life-long threat of
sudden or gradual recurrent metabolic decompensation that results in a return of all the
symptoms typical of untreated cases. Dietary intake of the BCAAs must be strictly
controlled and monitored. But even without any change in dietary intake, metabolic
crises can occur caused by an imbalance between the inherent residual activity of the
enzyme and increased BCAAs release of protein from the tissues due to increased
breakdown (catabolism). An increasing catabolic rate can occur insidiously or may
develop rapidly during any metabolic stress, including infection, even if very mild,
psychological or physical stress, trauma or fasting. These episodes are characterized
by emergence of the symptoms that are typical in an untreated case and are due to
elevated BCAAs, especially leucine and the three associated BCKAs. Every episode
can turn into a metabolic crisis and must be treated as vigorously as any episode in a
newborn. Individuals with classic MSUD may show a degree of intellectual limitation and
may develop a variety of behavioral issues including attention deficient hyperactivity
disorder (ADHD), impulsivity, anxiety and/or depression and seizures.
Additional complications with classic MSUD include generalized loss of bone mass
(osteoporosis) that may predispose to fractures, and inflammation of the pancreas
(pancreatitis). Some individuals may develop increased pressure in the skull
(intracranial hypertension), which causes painful headaches that are sometimes
associated with nausea and vomiting.
Intermediate MSUD is characterized by greater levels of residual enzyme activity than is
seen with classic MSUD. The onset and symptoms of intermediate MSUD may be
neonatal, but the majority of children are diagnosed between the ages of five months
and seven years. Symptoms, when they occur, are similar to those of the classical form
and may include lethargy, feeding problems, poor growth, ataxia, and acute metabolic
crises that result in seizures, coma, brain damage, and, in rare cases, life-threatening
neurological complications. It should be noted that Intermediate MSUD patients are
susceptible to the same degree of neurologic complications and extreme acidosis as
those with classic MSUD. The characteristic odor of maple syrup in the earwax, sweat
and urine, is present. Some affected children may remain asymptomatic until later in
life. Disease management principles are the same for both.
Intermittent MSUD is usually characterized by normal growth and intellectual
development and affected individuals often can tolerate normal levels of protein in their
diet. Symptoms are provoked by the same stressors as in classical MSUD. Thiamine-
response MSUD responds to treatment with thiamine (vitamin B1). Thiamine plays a
role in the BCAA enzyme complex. The symptoms and clinical course of thiamine-
responsive MSUD resembles intermediate MSUD and rarely presents in the newborn
period. Affected infants respond to large doses of thiamine, which boosts residual
enzyme activity. No individuals with thiamine-responsive MSUD have been treated
solely with thiamine – most follow a combination of thiamine with a partially-restricted
protein diet.
While the majority of patients fall into the categories above, several families with
multiple affected members have been identified who do not fit the criteria for any of the
above subtypes. These unique patients are deemed unclassified MSUD.
It should be emphasized that in the presence of such apparently non-specific neurologic
findings, the diagnosis of MSUD cannot be excluded by the absence of the maple syrup
smell.

Causes
MSUD is caused by changes (mutations) in one of three different
genes: BCKDHA, BCKDHB and DBT. Mutations in these genes result in absent or
decreased activity of human branched-chain alpha-ketoacid dehydrogenase complex
(BCKAD) enzymes. These enzymes are responsible for breaking down the branched
chain amino acids leucine, isoleucine, and valine that are in all proteins. Accumulation
of these amino acids and their toxic byproducts (ketoacids) results in the serious health
problems associated with MSUD. The toxicity of these amino acids is restricted to
leucine; indeed, extra valine and isoleucine are often given during treatment.
Accumulation of their respective ketoacids results in the metabolic acidosis.
MSUD follows autosomal recessive inheritance. Recessive genetic disorders occur
when an individual inherits a non-working gene from each parent. If an individual
receives one working gene and one non-working gene for the disease, the person will
be a carrier for the disease, but usually will not show symptoms. The risk for two carrier
parents to both pass the non-working gene and, therefore, have an affected child is
25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is
50% with each pregnancy. The chance for a child to receive working genes from both
parents is 25%. The risk is the same for males and females.

Affected Populations
The estimated incidence in a general population is 1 in 185,000 live births. Parents who
are close relatives (consanguineous) have a higher chance than unrelated parents to
both carry the same abnormal gene, which increases the risk to have children with a
recessive genetic disorder. Due to this “founder effect”, the disorder occurs with greater
frequency among individuals in the Mennonite populations in the United States, where
the incidence is estimated to be as high as in 1 in 380. MSUD occurs in the Ashkenazi
Jewish population with an incidence estimated at 1:26,000 live births.

Related Disorders
Symptoms of the following disorders can be similar to those of MSUD. Comparisons
may be useful for a differential diagnosis.
The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series
of biochemical processes in which nitrogen is converted into urea and removed from the
body through the urine. The symptoms of all urea cycle disorders vary in severity and
result from the excessive accumulation of ammonia in the blood and body tissues
(hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness,
seizures, and/or coma. The liver may be abnormally enlarged (hepatomegaly), life-
threatening complications may result. The urea cycle disorders include ornithine
transcarbamylase (OTC) deficiency: carbamyl phosphate synthetase (CPS) deficiency;
argininosuccinate synthetase deficiency (citrullinemia); argininosuccinate lyase (ASL)
deficiency; arginase deficiency (argininemia); and N-acetylglutamate synthetase
(NAGS) deficiency. (For more information on these disorders, choose the specific
disorder name as your search terms in the Rare Disease Database.)
Propionic acidemia is a rare autosomal recessively inherited metabolic disorder caused
by a deficiency of the enzyme propionyl CoA carboxylase, one of the enzymes
necessary for breaking down certain amino acids. Symptoms most commonly become
apparent during the first weeks of life and may include hypotonia, poor feeding,
vomiting, dehydration, and seizures accompanied by worsening metabolic acidosis and
often with hyperammonemia. Without appropriate treatment, coma and life-threatening
complications are usual. In milder cases, the condition may only present later during
infancy and may then be associated with less severe symptoms and findings. (For more
information on this disorder, choose “propionic acidemia” as your search term in the
Rare Disease Database.)
Methylmalonic acidemia (MMA) is a rare inborn error of metabolism in which people
have trouble metabolizing certain proteins and fats in food. The symptoms usually arise
during early infancy, but may even remain occult until adulthood. The presentation is
similar to that of propionic acidemia. Over the course of the disease, patients can
develop intellectual disability, chronic kidney disease, pancreatitis and feeding
problems. Mutations in several different genes can cause MMA and thus different
treatments are required for each type. The mainstay of treatment is a carefully balanced
dietary restriction of certain amino acids; namely, methionine, threonine, isoleucine and
valine. Some require specific forms of cobalamin (vitamin B 12). All MMAs are
autosomal recessive genetic disorders and can caused by mutations in five different
genes: MMAA, MMAB, MMADHC, MCEE and MUT. (For more information on this
disorder, choose “methylmalonic acidemia” as your search term in the Rare Disease
Database.)
Glycine encephalopathy is an inborn error of metabolism characterized by the
accumulation of large amounts of the amino acid glycine in blood and, particularly, in
the cerebrospinal fluid (CSF). The metabolic block occurs in the conversion of glycine
into smaller molecules. There are four forms of this disorder: a relatively common
neonatal form, an infantile form, a mild-episodic form, and a late-onset form. Common
presenting symptoms of the disease include hypotonia, seizures, unexplained coma,
and developmental delay in neonates and infants. Metabolic acidosis is not a feature.
For more information on this disorder, choose “glycine encephalopathy” as your search
term in the Rare Disease Database.)

Diagnosis
Many infants with MSUD are identified through newborn screening programs. Tandem
mass spectrometry, an advanced newborn screening test that screens for more than 40
different disorders through one blood sample, has aided in the diagnosis of MSUD. As
with all inborn errors, Infants with mild or intermittent forms of the disorder may have
totally normal blood metabolites after birth and thus can be missed by newborn
screening.
For patients who present later, the diagnosis usually comes at a time of metabolic
decompensation when plasma amino acids and urine organic acids are normally tested
at which time they are wildly abnormal. The presence of the maple syrup odor is so
characteristic that this, together with appropriate symptoms, can be diagnostic enough
to initiate therapy until the patient is transferred to an ICU. Initial confirmation is done by
examination of plasma BCAAs and urine organic acids. The activity of the BCAA
complex activity can be performed in white blood cells or cultured skin fibroblasts.
Prenatal detection cannot, at present, be done on maternal blood (looking for the fetal
DNA). It is done either through chorionic villus biopsy or by amniocentesis. These
analyses must be performed in a laboratory that is experienced in the relevant
techniques. Molecular genetic testing for mutations in
the BCKDHA, BCKDHB and DBT genes is also available to confirm the diagnosis and is
necessary for purposes of carrier testing for at-risk relatives and prenatal diagnosis for
at-risk pregnancies.

Standard Therapies
Treatment
The treatment of classic, intermediate, intermittent, and thiamine-responsive MSUD has
three chief components: 1. Lifelong therapy to maintain an acceptable diet; 2. Life-long
maintenance of normal metabolic conditions including the levels of the BCAAs in the
body; 3. immediate medical intervention for metabolic crises.
Individuals with MSUD must remain on a protein-restricted diet that limits the amount of
branched-chain amino acids they can eat. Protein-restriction must start as soon as
possible after birth to promote proper growth and development. Artificially-made
(synthetic) formulas are available that provide all the nutrients necessary for proper
growth and development, but lack leucine, isoleucine and valine. Diet management is a
constant balancing act between giving enough food, protein and BCAAs to provide for
normal growth and development on the one hand and trying to ensure that the patient’s
condition and biochemistry remain in a therapeutic range on the other. It is particularly
important to limit the amount of leucine in the diet. The three amino acids are essential
nutrients. They are added to the diet separately in small amounts depending upon their
plasma levels. The amount of leucine, isoleucine and valine that can be tolerated by a
child depends upon residual enzyme activity. Affected children must be regularly
monitored to ensure that their diet is adequate and that amino acid levels remain within
acceptable normal ranges.
Some physicians recommend a trial of thiamine therapy to determine whether an
affected individual is thiamine-responsive. However, no individual with MSUD has been
treated solely with thiamine.
Even if affected individuals follow the specialized diet strictly, the risk of metabolic crisis
always remains. Episodes of metabolic crisis require immediate medical intervention to
lower the levels of branched-chain amino acids, especially leucine, in the blood. Various
techniques have been used to reduce plasma leucine levels including dialysis or a
process in which blood is removed from the body and passed through a filter before
being returned to the body (hemofiltration).
The aim of aggressive therapy for metabolic crises is to try and reduce, and then
reverse, the increased protein catabolism that is the root cause of such episodes. This
means that ANY method to increase calories, to reduce protein catabolism (for energy
needs) may be helpful. This includes a high glucose intake with intravenous glucose, if
necessary, supplemented by a “glucose-insulin drip” since insulin is known to enhance
endogenous protein synthesis. Intravenous fat is another important source of calories.
In addition, it is essential to provide all the other amino acids in amounts sufficient to
permit new protein synthesis. This is done by the judicious use of intra GI drips or more
usually, parenteral nutrition IV using solutions that lack leucine. Many hospitals may use
total parenteral nutrition solutions that lack branched-chain amino acid. In addition,
insulin may be used to stimulate a metabolic process known as anabolism. During
anabolism, amino acids and other compounds are synthesized to form new muscle and
other proteins as well as a huge variety of other compounds.
Other treatment is symptomatic and supportive.
Genetic counseling is recommended for affected individuals and their families.
Investigational Therapies
Liver transplantation has been used to treat individuals with classic MSUD. This
procedure has resulted in individuals who are symptom-free and able to eat normal
foods. The new liver supplies enough enzyme activity to breakdown the three BCAAs.
However, availability of a donor liver and the high cost are hurdles to this procedure. For
those that do undergo liver transplantation, success rates are very high. More research
is necessary to determine the long-term effects of liver transplantation on neurological
development in individuals with MSUD.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov .
All studies receiving U.S. government funding, and some supported by private industry,
are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in
Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Maple Syrup Urine Disease

People with maple syrup urine (MSUD) disease can’t break down three specific amino acids found in
protein-containing foods. These amino acids build up in the body, become toxic and cause severe health
problems. Without medical management, MSUD can lead to a wide range of intellectual and physical
disabilities and death

What is maple syrup urine disease (MSUD)?

Maple syrup urine disease (MSUD) is a life-threatening metabolic disorder. Metabolic disorders are
conditions in which your body can’t function normally because it can’t properly convert food to energy
to keep your body healthy.

Protein is needed by the body to function normally. Proteins are made up of 20 different types of amino
acids. Proteins must be broken down (metabolized) so they can be absorbed and used by the body.
People with MSUD don’t have the needed enzymes (either don’t have the specific enzymes at all, have
the specific enzymes but they don’t work, or don’t have enough of the specific enzyme) to break down
three particular amino acids – leucine, isoleucine and valine.

Because people with MSUD can’t break down these three amino acids, these amino acids build up in the
body, become toxic to the body and cause severe health problems. Without medical management,
maple syrup urine disease can lead to a wide range of intellectual and physical disabilities and death.

What are the types of maple syrup urine disease (MSUD)?

The four main types of MSUD are:

 Classic: Classic maple syrup urine disease is the most severe type of MSUD. It is also the most
common. Symptoms usually develop within the first three days of birth.

 Intermediate: This type of MSUD is less severe than classic MSUD. Symptoms typically appear in
children between the ages of 5 months and 7 years.

 Intermittent: Children with intermittent MSUD develop as expected until an infection or period

of stress cause symptoms to appear. People with intermittent MSUD can usually tolerate higher
levels of the three amino acids than people with classic MSUD.

 Thiamine-responsive: This type of MSUD responds to treatment using high doses of vitamin B1

(thiamine) along with a restricted diet. With treatment, people with thiamine-responsive MSUD
have higher tolerance for the three amino acids.

How common is maple syrup urine disease (MSUD)?

MSUD is very rare. It occurs in about 1 of every 185,000 births worldwide. It appears more often in
populations with a small gene pool or when cousins and other close relatives have children together.
About 2,000 people in the United States live with MSUD. It affects males and females equally.

Who is affected by maple syrup urine disease (MSUD)?

MSUD can affect anyone, but people whose parents are closely related are much more likely to have the
metabolic disease. For this reason, MSUD frequently occurs among Mennonites in the United States,
where members of the community often marry each other. MSUD occurs in 1 of every 380 births in the
Mennonite population.

How do people get maple syrup urine disease (MSUD)?

MSUD is inherited (passed on) through families. A child is born with MSUD when both parents are
carriers of three specific gene mutations (changes) and their child inherits copies of these altered genes
– one copy from each parent. These mutations result in little to no activity of enzymes needed to break
down three specific amino acids that are in protein-rich foods. These three specific amino acids are
leucine, isoleucine and valine. Without the needed enzymes, the three amino acids build up and so do
their toxic byproducts (called ketoacids). This leads to the serious health problems seen in MSUD.

MSUD occurs more often in communities that have little genetic variation (such as the Mennonite
community in the United States). These groups have a higher concentration of people who are carriers
of the mutated gene.

What are the symptoms of maple syrup urine disease (MSUD)?

Symptoms of classic MSUD appear in newborns within 48 hours of birth. In older children, signs of
intermediate, intermittent, and thiamine-responsive MSUD usually develop before age seven. All four
types of MSUD have symptoms including:

 Urine, sweat, or earwax that smells like maple syrup or burnt sugar. (This disorder got its name
from this common symptom.) This may not always be present in all types.

 Poor feeding, vomiting, loss of appetite, irritability.

 Sluggish/slow/tiredness and weakness.

 Changes in muscle tone – poor muscle tone, muscle tightness/tension

 Abnormal muscle movements, spasms that cause a backward arching of the head, neck and
spine.

 Developmental delay.

 Seizures, convulsions, respiratory failure and coma (as the condition progresses).
Overview

Maple syrup urine disease (MSUD) is a rare, inherited metabolic disorder. The disease prevents your
body from breaking down certain amino acids.

Amino acids are what remain after your body digests protein from the food you eat. Special enzymes
process amino acids so they can be used to maintain all of your body functions. If some of the necessary
enzymes are missing or defective, the amino acids and their byproducts, called keto acids, collect in your
body. As the levels of these substances increase, it can result in:

 neurological damage

 coma

 life-threatening conditions

In MSUD, the body lacks an enzyme called BCKDC (branched-chain alpha-keto acid dehydrogenase
complex). The BCKDC enzyme processes three important amino acids: leucine, isoleucine, and valine,
also called BCAAs (branched-chain amino acids). BCAAs are found in foods rich in protein, such as meat,
eggs, and milk.

When untreated, MSUD can cause significant physical and neurological problems. MSUD can be
controlled with dietary restrictions. The success of this method can be monitored with blood tests. Early
diagnosis and intervention improve the chance of long-term success.

Types of MSUD

MSUD is also known as:

 BCKDC deficiency

 branched-chain alpha-keto acid dehydrogenase deficiency

 branched-chain ketoaciduria

 branched-chain ketonuria I

There are four subtypes of MSUD. All are inherited genetic disorders. They differ by their degree of
enzyme activity, severity, and the age when the disease appears.

Classic MSUD

This is the most common and severe form of the condition. A person with this form has little, if any,
enzyme activity — about 2 percent or less of normal activity. Symptoms are present in newborns within
a few days of birth. Onset is usually triggered when the infant’s body begins to process protein from
feedings.

Intermediate MSUD

This is a rare version of MSUD. Symptoms and age of onset vary greatly. People with this type of MSUD
have a higher level of enzyme activity than classic MSUD — about 3 to 8 percent of normal activity.
Intermittent MSUD

This form doesn’t interfere with normal physical and intellectual growth and development. Symptoms
usually don’t appear until a child is between 1 and 2 years of age. It’s a milder form of classic MSUD.
Individuals have significant enzyme activity — about 8 to 15 percent of normal activity. The initial
reaction of the disease often occurs when the child experiences stress, illness, or an unusual increase in
protein.

Thiamine-responsive MSUD

This rare form of the condition often improves with large doses of thiamine, or vitamin B-1. Symptoms
usually occur after infancy. Even though thiamine can be beneficial, dietary restrictions also are
necessary.

Symptoms of MSUD

Some initial symptoms characteristic of classic MSUD are:

 lethargy

 poor appetite

 weight loss

 weak sucking ability

 irritability

 a distinctive maple sugar odor in earwax, sweat, and urine

 irregular sleep patterns

 alternating episodes of hypertonia (muscle rigidity) and hypotonia (muscle limpness)

 high-pitched cry

Signs of intermediate and thiamine-response MSUD include:

 seizures

 neurological deficiencies

 developmental delays

 feeding problems

 poor growth

 a distinctive maple sugar odor in earwax, sweat, and urine

Risk factors for MSUD

The National Organization for Rare Disorders (NORD) reports that MSUD occurs at the same rate in
males and females (about 1 in 185,000 people).
Your risk for having any form of MSUD depends on whether your parents are carriers of the disease. If
both parents are carriers, their child has a:

 25 percent chance of receiving two mutated genes and having MSUD

 50 percent chance for receiving only one defective gene and being a carrier

 25 percent chance of receiving one normal gene from each parent

If you have two normal genes for BCKDC, you can’t pass the disease to your children.

When two parents carry the recessive gene for BCKDC, it’s possible for one of their children to have the
disease and other children to not have it. However, these children have a 50 percent chance of being
carriers. They also may carry a risk later in life of having a child with MSUD.

Causes of MSUD

MSUD is a recessive genetic disorder. All forms of the disease inherited from your parents. The four
varieties of MSUD are caused by mutations, or changes, in the genes that are related to the BCKDC
enzymes. When those genes are defective, the BCKDC enzymes aren’t produced or don’t work properly.
These gene mutations are inherited on the chromosomes you receive from your parents.

Typically, parents of children with MSUD don’t have the disease and they possess one mutated gene and
one normal gene for MSUD. Though they carry the defective recessive gene, they aren’t affected by it.
Having MSUD means that you inherited one flawed gene for BCKDC from each parent.

Diagnosis of MSUD

Data from the National Newborn Screening and Genetics Resource Center (NNSGRC) indicates that
every state in the United States tests infants for MSUD as part of their newborn screening program,
which is a blood test that also screens for more than 30 different disorders.

Identifying the presence of MSUD at birth is critical to preventing long-term damage. In cases when both
parents are carriers and their child’s test is negative for MSUD, additional tests may be advised to
confirm the findings and prevent the onset of symptoms.

When symptoms show up after the newborn period, diagnosis of MSUD can be made by a urine analysis
or blood test. A urine analysis can detect a high concentration of keto acids, and a blood test can detect
a high level of amino acids. The diagnosis of MSUD also can be confirmed with an enzyme analysis of
white blood cells or skin cells.

If you are concerned that you might be a carrier of MSUD, genetic testing can confirm if you possess one
of the malformed genes that cause the disease. During pregnancy, your physician can use samples
obtained by chorionic villus sampling (CVS) or amniocentesis to diagnose your baby.

Complications of MSUD

Complications from undiagnosed and untreated MSUD can be severe and even fatal. Even babies in a
treatment plan can experience incidents of extreme sickness, called metabolic crises.
Metabolic crises occur when there is a sudden and intense increase of BCAAs in the system. If untreated,
the situation can lead to serious physical and neurological damage. A metabolic crisis usually is indicated
by:

 extreme fatigue or lethargy

 loss of alertness

 irritability

 vomiting

When MSUD is undiagnosed, or metabolic crises are untreated, the following severe complications can
occur:

 seizures

 swelling of the brain

 lack of blood flow to the brain

 metabolic acidosis — a situation in which the blood contains high levels of acidic substances

 coma

When these conditions occur, they can result in:

 severe neurological damage

 intellectual disability

 blindness

 spasticity, or uncontrolled muscle tightness

Eventually, life-threatening complications can develop and lead to death, especially if they go untreated.

Treatment of MSUD

If your infant is diagnosed with MSUD, prompt medical treatment can avoid serious medical problems
and intellectual disability. Initial treatment involves reducing the levels of BCAAs in your baby’s blood.

Typically, this involves intravenous (IV) administration of amino acids that don’t contain BCAAs,
combined with glucose for extra calories. The treatment will promote the utilization of existing leucine,
isoleucine, and valine in the body. At the same time it will reduce the BCAA level and provide necessary
protein.

Your physician will create a long-term treatment plan for your child with MSUD in conjunction with a
metabolic specialist and a dietitian. The goal of the treatment plan is to provide your child with all the
protein and nutrients needed for healthy growth and development. The plan will also avoid allowing too
many BCAAS to collect in their blood.

How to prevent MSUD

Since MSUD is an inherited disease, there is no method for prevention. A genetic counselor can help you
determine your risk for having a baby with MSUD. Genetic testing can tell you if you or your partner is a
carrier of the disease. DNA testing can identify the disease in a fetus before birth.

Long-term outlook for MSUD

Children with MSUD can lead active, normal lives. Regular medical monitoring and careful attention to
dietary restrictions can help your child avoid potential complications. However, even with careful
monitoring, a metabolic crisis can erupt. Tell your physician if your child develops any MSUD symptoms.
You can achieve the best results if treatment is started and maintained as early as possible.

PUBMET:

Introduction

Maple syrup urine disease (MSUD) was first described as a rapid onset of Menkes' neurodegenerative
disease in 1954.[1] It is a defect of metabolism due to abnormal activity of the branched-chain alpha-
ketoacid dehydrogenase (BCKAD) complex. This complex is responsible for the breakdown of branched-
chain amino acids:

 Leucine

 Isoleucine

 Valine

The underlying defect in the BCKAD complex disrupts the metabolism of branched-chain amino acids,
which leads to an accumulation of branched-chain amino acids (BCAAs) in the plasma and their
respective branched-chain ketoacids in the urine.[2] It classically manifests in the neonatal period with
failure to thrive, delayed developmental milestones, feeding difficulties, and a maple syrup odor in the
urine or cerumen.[2] Treatment consists of close metabolic monitoring and dietary restriction of
branched-chain amino acids. If left untreated, irreversible neurological damage and metabolic
catastrophe ensue. Good clinical outcomes can be expected if management is initiated early.

Go to:

Etiology

Four subunits comprise the BCKAD multienzyme complex. These subunits include dihydrolipoamide
dehydrogenase (E3 subunit) and BCKAD decarboxylase (E1 subunit) bound to dihydrolipoyl
acyltransferase (E2 subunit).[1] Two regulatory subunits (BCKAD kinase and BCKAD phosphatase) are
also associated with the E2 subunit's core.[1] Furthermore, the E1 subunit is composed of E1alpha and
two E1beta subunits. The metabolic disorder occurs due to a decreased activity of the branched-chain
alpha-ketoacid dehydrogenase (BCKAD) complex which is located within the mitochondria. The defect is
transmitted in an autosomal recessive pattern. There are five main clinical phenotypes of maple syrup
urine disease.[3]

Go to:
Epidemiology

Maple syrup urine disease involves males and females equally. It has an estimated worldwide incidence
of 1 case per 185,000 live births.[1] Higher occurrences have been noted in populations with a higher
rate of consanguinity. In the Ashkenazi Jewish population, the incidence is estimated at 1 in 26,000 live
births. In Mennonites, maple syrup urine disease occurs with an incidence of 1 in 380 newborns. This is
often termed as a founder's effect in the BCKDHA (E1a) gene (c.1312T>A). In Portuguese gypsies, 1.4% of
cases occur due to the homozygous deletion (117delC) of the BCKDHA gene. It can be estimated as 1
case per 71 births.[4]

Go to:

Pathophysiology

Branched-chain ketoacid dehydrogenase (BCKAD) is located within the inner mitochondrial membrane
of various tissues such as skeletal muscle, liver, kidney, and the brain. It is composed of three catalytic
subunits (E1, E2, and E3). Together with branched-chain amino acid transaminase, it helps mediate
catabolism of branched-chain amino acids (BCAA). In the presence of thiamin pyrophosphate, E1
decarboxylates the alpha ketoacids. The lipoic acid residue in E2 transfers the acyl group from E1 to CoA.
The E3 subunit helps reoxidize the lipoic acid residue in E2. The activity of branched-chain ketoacid
dehydrogenase is further regulated by BCKAD phosphatase and BCKAD kinase. Therefore, within the
mitochondria, branched-chain amino acids are first converted into their respective alpha-ketoacids by
the enzyme branched-chain amino acid transaminase. Their respective yielded alpha-ketoacids include
alpha-ketoisocaproic acid, alpha-keto-beta-methyl valeric acid, and alpha-ketoisovaleric acid. Alpha-
ketoacids are then oxidatively decarboxylated by the branched-chain ketoacid dehydrogenase complex.
Consequently, alpha-ketoacids are further metabolized into intermediates such as isovaleryl-coenzyme
A, alpha-methylbutyryl-CoA, and isobutyrl-CoA. These intermediates are then converted into succinyl-
CoA, acetoacetate, and acetyl-CoA.[2] The branched-chain amino acids are essential amino acids with
hydrophobic side chains and are found in protein-rich food. The catabolism of these amino acids is
necessary to maintain various physiologic functions such as :

 Protein synthesis 

 Gluconeogenesis

 Fatty acid synthesis

 Cholesterol synthesis

 Cellular signaling

In the brain, BCKAD helps metabolize BCAA to facilitate cerebral GABA and glutamate synthesis. The
liver and kidney are responsible for the catabolism of 10% to 15% of BCAA.[5] Most BCAA
transamination and oxidation occur in the skeletal muscle.[6] Maple syrup urine disease occurs due to a
pathogenic defect in any BCKAD subunit resulting in elevated branched-chain amino acids and their
corresponding alpha keto-acids. Accumulated BCAA and alpha-ketoacids manifests as a constellation of
clinical symptoms due to dysfunction of the central nervous system, immune system, and skeletal
muscle. Elevated leucine and alpha-ketoisocaproic acid levels notoriously cause neurochemical
disturbances resulting in clinically apparent neurotoxicity. The transport of large neutral amino acids
across the blood-brain barrier is drastically reduced due to interference from elevated leucine levels. As
a result, the supply of tyrosine, phenylalanine, methionine, tryptophan, histidine, and valine to the
brain.[3] As a consequence, brain growth and myelin synthesis are negatively impacted. The restricted
supply of the amino acids leads to decreased neurotransmitters, such as dopamine, serotonin,
norepinephrine, epinephrine, GABA, and glutamate. Alpha-ketoisocaproic acid levels of greater than 60
micromol/L negatively regulate transamination reactions within astrocytes.[3] This reversal accounts for
low cerebral glutamate levels, which results in cognitive dysfunctions such as learning disabilities and
memory loss. Furthermore, elevated leucine concentrations impair cell volume regulation. This results in
decreased blood osmolarity, sodium concentrations, and increased intracellular water leading to
cerebral edema.[7] In infants and children, decreased blood osmolarity can further precipitate brain
herniation. Clinical evidence suggests that the neurotoxin alpha-ketoisocaproic acid contributes to the
encephalopathic syndrome.[2] In patients with classic MSUD, decreased levels of glutamate and
increased cerebral lactate levels indicate inhibition of the respiratory chain by alpha-ketoisocaproic acid.
[3] The metabolic decompensations in MSUD lead to the activation of matrix metalloproteinases,
resulting in the blood-brain barrier's breakdown.[8] Isoleucine metabolites are responsible for the maple
syrup odor of the urine.

NCBI

Abstract
Go to:

Introduction
Maple syrup urine disease (MSUD, MIM #248600) is an autosomal recessive disease
characterized by disruption of the normal activity of the branched-chain α-ketoacid
dehydrogenase (BCKAD) complex, the second step in the catabolic pathway for the branched-
chain amino acids (BCAAs) that include leucine, isoleucine, and valine. Pathogenic homozygous
or compound heterozygous variants in BCKDHA (MIM #608348), BCKDHB (MIM
#248611), DBT (MIM #248610), or DLD (MIM #238331), which form the catalytic subunits of
BCKAD, can result in MSUD, which is characterized by neurological and developmental delay,
encephalopathy, feeding problems, and a maple syrup odor to the urine. Patients with this
disorder have elevations of branch chain ketoacids in the urine in addition to elevated BCAAs in
the plasma. MSUD is amenable to treatment through dietary restriction of BCAAs, and with
early treatment, patients typically have good clinical outcomes. MSUD is therefore included on
the Recommended Uniform Screening Panel (RUSP), a list of actionable, early onset disorders
for which screening is recommended for all newborns in the United States. The use of tandem
mass spectrometry (MS/MS) in newborn screening (NBS) has helped facilitate early detection of
and timely medical intervention for patients with MSUD, thus improving clinical outcomes in
affected individuals. In this review, we will discuss the pathophysiology, clinical presentation,
screening and diagnosis, as well as treatment of patients with MSUD with a particular focus on
the management of adult patients.
 Go to:

Pathophysiology of MSUD
MSUD is a metabolic disorder caused by decreased function of the BCKAD enzyme complex.
Biallelic pathogenic variants in the catalytic components of BCKAD decrease its activity thereby
increasing BCAA levels and causing toxicity within skeletal muscle and brain tissue.1,2 BCAA
catabolism is essential for normal physiological functions.3 The first step involves the
conversion of leucine, isoleucine, and valine into their relevant α-ketoacids by branch-chain
aminotransferase within the mitochondria (Figure 1). Unlike most other amino acid metabolism,
the majority of this process does not take place in the liver but rather in skeletal muscle.3–
5 BCAAs can be found in protein-rich diets and are among the nine amino acids essential for
human life, playing important roles in protein synthesis and function, cellular signaling, and
glucose metabolism.6,7

Open in a separate window

Figure 1
Overview of BCAA catabolic pathway. The BCAAs undergo transamination that is catalyzed by the
branched-chain aminotransferase (BCAT) and requires α- ketoglutarate, leading to the production of the
α-ketoacids KIC, KMV, and KIV. These intermediates then undergo oxidative decarboxylation, catalyzed
by the BCKAD complex.
Abbreviations: KIC, α-ketoisocaproic acid; KIV, α-ketoisovaleric acid; KMV, α-keto-β-methylvaleric
acid; Glu, glutamate; BCAAs, branched-chain amino acids; BCKAD, branched-chain α-ketoacid
dehydrogenase.
During the second step in BCAA catabolism, the BCKAD complex initiates oxidative
decarboxylation of α-ketoacids.4 This process results in the conversion of α-ketoacids into
acetoacetate, acetyl-CoA, and succinyl-CoA as illustrated in Figure 1. The BCKAD complex is
made up of several components, including subunits E1α and E1β, E2, and E3. Increased BCAA
levels within the body due to pathogenic defects in these components cause MSUD, leading to a
variety of symptoms mentioned above, including dysfunction of the immune system, skeletal
muscle, and central nervous system (CNS).2–4 The generation of various mouse models has
been used to study MSUD and the effects of dietary BCAA restriction.8,9 In these models, as
well as MSUD patients, excessive amounts of BCAAs build up and can cause severe tissue
damage if left untreated.10 Within the brain, BCAA metabolism functions to maintain glutamate
levels.2,11,12 Glutamate serves as a neurotransmitter within the CNS and plays important roles
in brain development and cognitive functions such as learning and memory. Disorders of BCAA
metabolism can cause abnormalities in glutamate synthesis leading to various neurological
problems in patients.13 Controlling plasma concentrations of BCAA levels is key to preventing
these symptoms. Furthermore, the accumulation of leucine is highly neurotoxic.2 Elevated levels
of leucine can affect water homeostasis within the subcortical gray matter causing swelling
within the brain, alter nitrogen homeostasis further depleting glutamate levels, increase oxidative
stress, and compete with other important amino acids within the CNS such as tyrosine, which is
involved in protein signaling. In addition, there is evidence that α-ketoisocaproic acid, an
intermediate in the metabolism of leucine, is a major neuro-toxin contributing to the
encephalopathic syndrome.
Although the specific outcomes of BCAA abnormalities have not been fully characterized, it is
apparent that proper metabolism is critical for human health.4 While genetic variants in certain
components of this pathway lead to MSUD, several other disorders have been associated with
abnormal BCAA metabolism, including insulin resistance and type 2 diabetes mellitus, liver
disease, and certain types of cancer, broadening its respective roles in human health.3,4
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In: Swaiman KF, Ashwal S, Ferriero DM, et al, eds. Swaiman's Pediatric Neurology: Principles and
Practice. 6th ed. Philadelphia, PA: Elsevier; 2017:chap 37.

Kliegman RM, St. Geme JW, Blum NJ, Shah SS, Tasker RC, Wilson KM. Defects in metabolism of amino
acids. In: Kliegman RM, St. Geme JW, Blum NJ, Shah SS, Tasker RC, Wilson KM, eds. Nelson Textbook of
Pediatrics. 21st ed. Philadelphia, PA: Elsevier; 2020:chap 103.

Merritt JL, Gallagher RC. Inborn errors of carbohydrate, ammonia, amino acid, and organic acid
metabolism. In: Gleason CA, Juul SE, eds. Avery's Diseases of the Newborn. 10th ed. Philadelphia, PA:
Elsevier; 2018:chap 22.

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Introduction
Maple syrup urine disease (MSUD) was first described as a rapid onset
of Menkes' neurodegenerative disease in 1954.[1] It is a defect of
metabolism due to abnormal activity of the branched-chain alpha-
ketoacid dehydrogenase (BCKAD) complex. This complex is responsible
for the breakdown of branched-chain amino acids:
 Leucine
 Isoleucine
 Valine
The underlying defect in the BCKAD complex disrupts the metabolism of
branched-chain amino acids, which leads to an accumulation of
branched-chain amino acids (BCAAs) in the plasma and their respective
branched-chain ketoacids in the urine.[2] It classically manifests in the
neonatal period with failure to thrive, delayed developmental milestones,
feeding difficulties, and a maple syrup odor in the urine or cerumen.
[2] Treatment consists of close metabolic monitoring and dietary
restriction of branched-chain amino acids. If left untreated, irreversible
neurological damage and metabolic catastrophe ensue. Good clinical
outcomes can be expected if management is initiated early.

Etiology
Four subunits comprise the BCKAD multienzyme complex. These
subunits include dihydrolipoamide dehydrogenase (E3 subunit) and
BCKAD decarboxylase (E1 subunit) bound to dihydrolipoyl
acyltransferase (E2 subunit).[1] Two regulatory subunits (BCKAD kinase
and BCKAD phosphatase) are also associated with the E2 subunit's
core.[1] Furthermore, the E1 subunit is composed of E1alpha and two
E1beta subunits. The metabolic disorder occurs due to a decreased
activity of the branched-chain alpha-ketoacid dehydrogenase (BCKAD)
complex which is located within the mitochondria. The defect is
transmitted in an autosomal recessive pattern. There are five main
clinical phenotypes of maple syrup urine disease.[3]

Epidemiology
Maple syrup urine disease involves males and females equally. It has an
estimated worldwide incidence of 1 case per 185,000 live births.
[1] Higher occurrences have been noted in populations with a higher rate
of consanguinity. In the Ashkenazi Jewish population, the incidence is
estimated at 1 in 26,000 live births. In Mennonites, maple syrup urine
disease occurs with an incidence of 1 in 380 newborns. This is often
termed as a founder's effect in the BCKDHA (E1a) gene (c.1312T>A). In
Portuguese gypsies, 1.4% of cases occur due to the homozygous
deletion (117delC) of the BCKDHA gene. It can be estimated as 1 case
per 71 births.[4]

Pathophysiology
Branched-chain ketoacid dehydrogenase (BCKAD) is located within the
inner mitochondrial membrane of various tissues such as skeletal
muscle, liver, kidney, and the brain. It is composed of three catalytic
subunits (E1, E2, and E3). Together with branched-chain amino acid
transaminase, it helps mediate catabolism of branched-chain amino
acids (BCAA). In the presence of thiamin pyrophosphate, E1
decarboxylates the alpha ketoacids. The lipoic acid residue in E2
transfers the acyl group from E1 to CoA. The E3 subunit helps reoxidize
the lipoic acid residue in E2. The activity of branched-chain ketoacid
dehydrogenase is further regulated by BCKAD phosphatase and BCKAD
kinase. Therefore, within the mitochondria, branched-chain amino acids
are first converted into their respective alpha-ketoacids by the enzyme
branched-chain amino acid transaminase. Their respective yielded
alpha-ketoacids include alpha-ketoisocaproic acid, alpha-keto-beta-
methyl valeric acid, and alpha-ketoisovaleric acid. Alpha-ketoacids are
then oxidatively decarboxylated by the branched-chain ketoacid
dehydrogenase complex. Consequently, alpha-ketoacids are further
metabolized into intermediates such as isovaleryl-coenzyme A, alpha-
methylbutyryl-CoA, and isobutyrl-CoA. These intermediates are then
converted into succinyl-CoA, acetoacetate, and acetyl-CoA.[2] The
branched-chain amino acids are essential amino acids with hydrophobic
side chains and are found in protein-rich food. The catabolism of these
amino acids is necessary to maintain various physiologic functions such
as :
 Protein synthesis 
 Gluconeogenesis
 Fatty acid synthesis
 Cholesterol synthesis
 Cellular signaling
In the brain, BCKAD helps metabolize BCAA to facilitate cerebral GABA
and glutamate synthesis. The liver and kidney are responsible for the
catabolism of 10% to 15% of BCAA.[5] Most BCAA transamination and
oxidation occur in the skeletal muscle.[6] Maple syrup urine disease
occurs due to a pathogenic defect in any BCKAD subunit resulting in
elevated branched-chain amino acids and their corresponding alpha
keto-acids. Accumulated BCAA and alpha-ketoacids manifests as a
constellation of clinical symptoms due to dysfunction of the central
nervous system, immune system, and skeletal muscle. Elevated leucine
and alpha-ketoisocaproic acid levels notoriously cause neurochemical
disturbances resulting in clinically apparent neurotoxicity. The transport
of large neutral amino acids across the blood-brain barrier is drastically
reduced due to interference from elevated leucine levels. As a result, the
supply of tyrosine, phenylalanine, methionine, tryptophan, histidine, and
valine to the brain.[3] As a consequence, brain growth and myelin
synthesis are negatively impacted. The restricted supply of the amino
acids leads to decreased neurotransmitters, such as dopamine,
serotonin, norepinephrine, epinephrine, GABA, and glutamate. Alpha-
ketoisocaproic acid levels of greater than 60 micromol/L negatively
regulate transamination reactions within astrocytes.[3] This reversal
accounts for low cerebral glutamate levels, which results in cognitive
dysfunctions such as learning disabilities and memory loss. Furthermore,
elevated leucine concentrations impair cell volume regulation. This
results in decreased blood osmolarity, sodium concentrations, and
increased intracellular water leading to cerebral edema.[7] In infants and
children, decreased blood osmolarity can further precipitate brain
herniation. Clinical evidence suggests that the neurotoxin alpha-
ketoisocaproic acid contributes to the encephalopathic syndrome.[2] In
patients with classic MSUD, decreased levels of glutamate and
increased cerebral lactate levels indicate inhibition of the respiratory
chain by alpha-ketoisocaproic acid.[3] The metabolic decompensations
in MSUD lead to the activation of matrix metalloproteinases, resulting in
the blood-brain barrier's breakdown.[8] Isoleucine metabolites are
responsible for the maple syrup odor of the urine.

History and Physical

There are five clinical subtypes of MSUD. These include:
 The classic
 Intermediate
 Intermittent
 Thiamine responsive
  E3 deficient subtypes
They are clinically distinguished based on their clinical presentation, age
of onset, and residual BCKAD enzyme activity.[1] There is no good
correlation between genotype and phenotype. The clinical presentation
relies on the BCKAD residual function.[2] However, phenotypic
classification depends on the response to metabolic decompensation
and leucine tolerance. The specific characteristics and the differences
between the different types are shown in table 1.[2][3] 
 

Evaluation
Evaluation of maple syrup urine disease requires prompt identification of
clinical characteristics by a physician. In addition to the clinical features,
biochemical testing and molecular testing play a significant role in
disease phenotype evaluation.
Clinical Characteristics
Clinical characteristics depend on the underlying metabolic phenotype of
MSUD. It is important to note the following manifestations:
 Maple syrup odor in cerumen is the first detectable clinical sign within
the first 12 hours after birth.
 2 to 3 days of age: Irritability, ketonuria, and poor feeding 
 A worsening course of encephalopathy presenting as apnea,
opisthotonus, and lethargy. Furthermore, fencing and bicycling
movements can also develop by the age of 4 to 5 days.
 Coma and respiratory failure by the age of 7-10 days.
 Milder forms of the disease can present later in infancy/childhood as
anorexia, stunted growth, and delayed milestones. Such cases will only
develop encephalopathy and ketonuria during metabolic decompensation
during an acute illness.
Diagnosis
Children and newborns should be tested for MSUD if the following are
present:
 Sporadic encephalopathy and ketoacidosis 
 Intermittent encephalopathy and ketoacidosis
 Encephalopathy and ketoacidosis during an underlying illness
 Encephalopathy and ketoacidosis following trauma or fasting
 Encephalopathy and ketoacidosis with a negative newborn screening
result
Prenatal Diagnosis
Diagnosis requires the measurement of BCKAD enzyme activity in
cultured chorion villus cells or amniocytes using mutational analysis.
Branched-chain amino acid concentrations can also be measured in
amniotic fluid. Pre-implantation diagnosis requires the identification of
familial pathogenic variants. The preferred diagnostic method is
molecular analysis. 
Newborn Screening and Biochemical Evaluation
Since 1964, routine newborn screening has been performed for MSUD.
The screening is performed in all 50 United States and is best performed
within 24-48 hours after birth. It is performed with tandem mass
spectrometry amino acid profiling (MS/MS). The process examines the
fisher ratio and concentrations of leucine-isoleucine as a standard
measure.[2] Additional laboratory studies need to be performed if
elevated branched-chain amino acids are detected.[2] Tandem mass
spectrometry readily detects classic MSUD. However, it may not detect
milder forms of MSUD due to normal leucine levels. MS/MS does not
possess the capability to distinguish amino acids with the same mass,
such as hydroxyproline, leucine, isoleucine, and allo-isoleucine.[2] In
such cases, a second-tier test such as liquid chromatography must be
conducted to analyze allo-isoleucine on dry blood spots. Second-tier
testing can help distinguish MSUD from hydroxyprolinemia. Additional
laboratory studies include dinitrophenylhydrazine test, gas
chromatography, liquid chromatography, BCKAD enzyme activity, and
molecular testing.[2] 
Plasma amino acid testing is the most important diagnostic test for
MSUD. It is used to assess elevated levels of BCAAs and allo-
isoleucine. Elevated allo-isoleucine levels (> 5 micromols/L) confer high
specificity and sensitivity for diagnosis. Even with elevated leucine
levels, allo-isoleucine levels are not detectable until the age of six days.
The urinary organic acids can be detected using gas chromatography-
mass spectrometry, dinitrophenylhydrazine tests, and urine test strips.
Gas chromatography-mass spectrometry detects branched-chain
ketoacids, which further support the diagnosis of MSUD. Branched-chain
ketoacids usually follow after BCAA elevation and are detected 48-72
hours after birth.[2] The dinitrophenylhydrazine (DNPH) test can also be
used to detect branched-chain ketoacids in the urine. DNPH reagent and
urine are mixed in equal volumes. The sample is then observed for 10
minutes for any precipitation and color changes. Clear urine with no
precipitate indicates a score of zero. Whereas, a yellow-white precipitate
with opaque urine indicates a score of 4. The advantage of using the
DNPH test stems from its ability to detect urinary branched-chain
ketoacids in an outpatient setting. Standard urine test strips enable the
detection of ketonuria. It offers an alternative source of testing in settings
of restricted access to other diagnostic tests. Ketonuria is termed as a
surrogate marker of underlying metabolic instability.[3] BCKAD enzyme
activity can be measured in cells such as lymphoblasts, skin fibroblasts,
and liver biopsy. In vivo measurements of BCKAD activity are not
clinically useful because the activity levels do not correlate with leucine
tolerance and oxidation.[3]
Molecular testing:
Molecular testing is available for three biallelic pathogenic gene variants.
These include:
 BCKDHA gene: Encodes the E1-alpha subunit of the BCKAD enzyme
complex (MSUD Type 1A).[3]
 BCKDHB gene: Encodes the E1-beta subunit of the BCKAD enzyme
complex (MSUD Type 1B).[3]
 DBT gene: Encodes the E2 subunit of the BCKAD enzyme complex
(MSUD Type 2).[3]
Genetic testing allows for a better understanding of the prognosis and
genetic counseling of the family. Furthermore, it allows for accurate
assessment of the deficient BCKAD subunit. This helps determine the
individualized therapies. There are over 190 pathogenic variations in
BCKAD enzyme subunits. All detected variants are homozygous or
compound heterozygous
Diagnostic Strategies
Adult with symptoms of MSUD:
 DNPH testing can be used to alpha-ketoacids in the urine.[3]
 The most informative test is the identification of allo-isoleucine using
plasma amino acid analysis.
 Branched-chain ketoacids and other organic acids can be detected
using gas chromatography-mass spectrometry.
Newborn with signs and symptoms and a positive screening test
for leucine, isoleucine, and valine or unexplained ketonuria:
 If infants are older than 48 to 72 hours, screening tests such as DNPH
and urine ketone test strips can be used.
 Plasma amino acid analysis to detect elevated BCAA and allo-
isoleucine.
 Gas chromatography-mass spectrometry is used to analyze the urine
for ketoacids.
 Newborns and infants should not be challenged with higher than normal
protein intake.[3]
Newborn with an affected sibling:
 If familial pathogenic variants are known, isolated blood from the
umbilical cord can be used for a pathogenic variant detection by
polymerase chain reaction (PCR), advanced sequencing, and melting
analysis.
 If pathogenic variants are unknown, obtain blood from the umbilical cord
to allow for pathogenic variant detection. The first diagnostic sign is the
presence of maple syrup odor in the cerumen of a newborn. Therefore,
inquire for a maple syrup smell 12 to 24 hours after birth. Allow protein
intake to measure serum amino acid levels between 18 to 24 hours of life.
If the results are vague, repeat the test between 24 to 36 hours of life.
 Amino acid profile indicative of MSUD should initiate dietary therapy.
Furthermore, molecular testing and urine organic acid analysis should
follow. It is important to remember that DNPH can't be used as a
screening test until the age of 48 to 72 hours.
 

Treatment / Management
Effective treatment of maple syrup urine disease requires addressing the
nutritional needs and optimally managing acute metabolic
decompensations.[9] A pediatric nutritionist and metabolic disease
specialist should be involved in the management of MSUD patients.
Medical Nutritional Therapy
The initiation of nutritional therapy requires clinical confirmation and a
positive newborn screening result. The mainstay of treatment remains
the dietary restriction of branched-chain amino acids. These dietary
modifications need to be maintained throughout life. The goals of
nutritional therapy are as follows [10]:
 Promote anabolism
 Prevent catabolism 
 Promote normal growth and weight gain
 Preserve intellectual function
 Enable restriction of branched-chain amino acid in the diet, which helps
reduce toxic metabolites
 Maintain plasma BCAA levels within the required treatment ranges
 Evaluate thiamine responsiveness
The allowed amounts of dietary BCAA are titrated into the diet using
biochemical lab values and growth measurements during respective life
periods. Long-term treatment warrants accurate assessment of caloric
needs, BCAA restriction, BCAA-free amino acid supplementation, and
valine and isoleucine supplementation.[2] BCAA-free medical foods can
provide up to 80%-90% of protein needs. Valine and isoleucine help
promote anabolism. They are supplemented because they are low in
content in medical nutrition. Leucine supplementation is usually not
required because they are found in ample amounts in breast milk or
formula. Favorable intellectual outcomes can be achieved if leucine
concentrations are maintained between 75 to 300 micromol/L.[11] It is
also recommended that plasma valine and isoleucine levels are
maintained between 200 to 400 micromol/L.[10] Thiamine should be
supplemented at a dose of 50 to 200 mg/day in all patients with MSUD
for four weeks. In thiamine responsive patients, thiamine
supplementation should be continued. Thiamine should not be
supplemented in patients diagnosed with the homozygous 1312T>A
mutation or with mutations leading to less than 3% of BCKAD activity.
Administration of sodium chloride may help maintain serum sodium
concentrations and plasma osmolarity. It can help prevent the
development of cerebral edema or fatal herniation. 
Treatment of Acute Metabolic Decompensation
Metabolic decompensations (plasma leucine >380 micromol/L) usually
occur due to dietary non-compliance and infections. Dietary non-
compliance raises the BCAA levels and rarely progresses to
decompensation and encephalopathy. However, trauma and infections
can trigger large protein catabolism leading to a metabolic crisis.
Decompensations arise more commonly in the first year of life and after
the age of 15.[12] Strauss et al. indicated that vomiting and viral
gastroenteritis are the most common cause of hospitalization during
acute decompensation.[13] Other common causes of hospitalization
include viral bronchiolitis, sinusitis, neonatal encephalopathy, and urinary
tract infections.[13] Residual BCKAD activity and liberation of leucine
from catabolism determine the risk of metabolic crisis.[3] Patients with a
higher residual BCKAD activity have a better leucine tolerance when
well. Furthermore, during an illness, these patients face less severe
elevations in leucine. The main aim of therapy is to suppress protein
catabolism and promote protein synthesis.[2] Management strategies in
more severe cases include:
 Effectively treating the underlying stressor causing the metabolic crisis 
 Restrict protein intake for 24 to 72 hours
 Provide ample caloric support
 Provide adequate hydration to maintain metabolic homeostasis
 Provide supplementation with cofactors
 Eliminate toxic metabolites
 Treat associated clinical sequelae
 Correct metabolic abnormalities
Home Therapy 
Providers can be instructed to use a dinitrophenylhydrazine reagent to
detect high urine branched-chain ketoacids. This allows for the timely
detection and home management of mild to moderate cases of acute
metabolic decompensation. In such cases, experienced providers can
help manage with restriction of dietary leucine, sick day formulas, and
outpatient monitoring.[3] More specifically, sick day protocols require a
120% increase in the intake of BCAA-free amino acid formula, fluid
administration of 150 mL/kg, 50% to 100% decrease in leucine intake,
and frequent small feedings.[2] It is important to ensure that nutritional
treatment is aggressive and provides sufficient energy. 
In-Hospital Therapy[3]
Goals and treatment strategies of in-hospital therapy include:
 Effectively treating the underlying stressor (e.g., fever, dehydration,
infection, and inflammation).
 To control nausea and vomiting, antiemetics such as ondansetron
should be administered.
 Reduction in leucine concentration at 750 micromol/L or more per 24
hrs. This reduction in leucine can be achieved via insulin and glucose
infusions. Ideally, leucine levels should be maintained from 200 to 300
micromol/L. Upon clinical improvement, total parenteral nutrition can be
used to reintroduce protein back into the diet (25%-50% of normal intake).
This intake can be increased depending on the clinical situation over the
next few days.
 EER must be provided at least 1.25 times the weight or surface area.
Lipid should constitute 40% to 50% of total calories. Nutritional goals can
be achieved by combined parenteral and enteral feeding. 
 Isoleucine and valine should be supplemented at 20-120 mg/kg/day
each. The intake of supplements is adjusted to maintain a steady plasma
concentration of 400-600 micromol/L.
 Enteral supplementation of tyrosine (100-400 mg/kg/day) to treat focal
or generalized dystonias.
 Glutamine and alanine supplementation at 150-400 mg/kg/day each.
 Supplement BCAA-free amino acids.
 Maintain sodium levels within the physiological range.
 Correct underlying acid-base disturbances.
 Avoid osmolarity fluctuations > 5 mosm/L per day and maintain urine
output.
 Prevent and treat hypokalemia and hypophosphatemia associated with
IV glucose and insulin therapy.
Role of Sodium Phenylbutyrate (NaPBA)
Sodium phenylbutyrate is a nitrogen scavenger. It is primarily used in the
treatment of urea cycle disorders. NaPBA can also reduce branched-
chain amino acid levels. It can be used in patients with intermediate
MSUD.[14] Hemodialysis and peritoneal dialysis can also be used to
rapidly correct BCAA and ketoacids during an acute decompensation.
Orthotopic Liver Transplantation
Indications:
 Psychomotor disabilities
 Poor metabolic control
 Frequent metabolic decompensations
The liver is responsible for expressing 10% of BCKAD activity.
Therefore, liver transplantation is recommended for classic MSUD
patients who are difficult to manage. More commonly, the liver from an
undeceased and unrelated individual is used.[2] Post-transplantation, the
residual activity of BCKAD, can rise to that of mild MSUD levels.
Therefore, transplantation tends to reduce the requirement of dietary
restrictions and episodes of metabolic decompensation. It also does not
reverse previously inflicted brain damage, cognitive dysfunction, and
psychiatric illnesses.[15] However, transplantation doest restrict further
progression of neurological impairment and prevent the development of
cerebral edema.[16][17]
Management in Pregnancy
It is indeed possible for women with MSUD to deliver a healthy child.
The mother must be educated about the potential teratogenic risks of
elevated maternal leucine concentration. In such patients, tight metabolic
control before and throughout gestation is critical. As the placenta and
fetus develop, the maternal need for protein and BCAA exponentially
increases. Therefore, measurements of plasma amino acid
concentrations and fetal growth are imperative to avoid possible
nutritional deficiencies. Maintaining BCAA levels between 100 and 300
micromol/L is said to be compatible with normal infant delivery. At the
time of delivery, referral to a metabolic center must be made. This is
because the post-partum period is deemed dangerous for the mother.
Events such as labor stress, internal blood sequestration, and uterine
involution can act as a source of metabolic decompensation. Therefore,
extra measures must be taken to counteract catabolism during the post-
partum period.
Management of other MSUD Complications
Cerebral Edema
 Administer furosemide (0.5 to 1.0 mg/kg)
 Infusion of mannitol (0.5 to 1.0 g/kg) followed by hypertonic saline (3%-
5%) 
The risk of developing cerebral edema can be reduced by elevating the
head of the bed.[3] Furthermore, it is recommended to use a PICC line in
encephalopathic patients. The use of a PICC line allows the delivery of
nutrition without the need for excess fluid volume.[3]
Cerebral Herniation
 Elevate the head
 Induce hyperventilation with the help of a face mask or endotracheal
tube.
 Infuse mannitol and hypertonic saline.
 Transfer the patient immediately to a pediatric/neonatal intensive care
unit.
Infection
Patients with MSUD are predisposed to candida infections and catheter-
based bacterial or fungal infections. It is vital to monitor patients for
hospital-acquired infections continuously. Failure to treat them can result
in an episode of acute metabolic decompensation.
Acute Pancreatitis
During an acute metabolic decompensation episode, a patient may
develop symptoms such as epigastric pain, mid-back pain, anorexia, and
vomiting. This should raise suspicion of acute pancreatitis and
immediately order serum levels for lipase and amylase. Also, the
physician must suspend enteral feeding and keep the patient NPO.
Treatment is usually supportive, and the patient's nutritional needs can
be managed with the use of special parenteral solutions.
Neuropsychiatric Illnesses
Adult and adolescent patients are at an increased risk of developing
anxiety, depression, and ADHD. These can be treated by prescribing
standard anti-depressants and psychostimulant drugs.
Secondary Complications
Surgical procedures and trauma care should be planned in coordination
with a metabolic specialist.
General Prevention
Patients must be advised never to exceed their daily allowed dose of
branched-chain amino acids.

Differential Diagnosis
It is essential to exclude other clinically distinct entities that can also
manifest as neonatal encephalopathy. These include:
 Hypoglycemia
 Status epilepticus
 Meningitis
 Encephalitis
 Kernicterus
 Birth asphyxia
 Urea cycle defects[3]
 Organic acidopathies such as propionic acidemia and methylmalonic
acidemia[3]
  HMG-CoA lyase deficiency
 Beta-ketothiolase deficiency[3]
 Non-ketotic hyperglycinemia[3]
Sotolone, which is found in fenugreek and lovage, is responsible for the
characteristic maple syrup odor in cerumen and bodily secretions.
[3] Excess ingestion of fenugreek during pregnancy can result in a false
diagnosis of MSUD.[3] In the setting of NICUs, the use of topical benzoin
can also give off a sweet odor.[3]

Prognosis
Good prognosis can be expected in patients who begin therapy before or
immediately after developing symptoms. Plasma leucine concentrations
are known to affect neurocognitive outcomes. Classic MSUD in school-
aged patients has shown high performance than IQ.[18] 61% of adult
MSUD patients live independently and integrate well into society.
[12] However, 56% of patients still require psychological and psychiatric
care.[12] Patients with late-onset MSUD can suffer from slight
developmental delays depending on the residual BCKAD activity.[3] A
delayed diagnosis of more than 7 to 14 days of classic MSUD can result
in irreversible learning disability and cerebral palsy.[3]

Complications
Failure to diagnose and treat MSUD in a time-sensitive manner can
result in serious consequences. Patients undergoing a treatment plan
can develop an acute illness resulting in a sudden increase in levels of
branched-chain amino acids. This metabolic crisis is usually indicated by
the development of clinical symptoms such as extreme fatigue,
irritability, vomiting, and loss of alertness. If the patient remains
undiagnosed or untreated, the following complications can arise:
 Seizures
 Metabolic acidosis
 Cerebral edema
 Cerebrovascular ischemia
 Intellectual disabilities
 Blindness
 Muscle spasticity
 Irreversible neurological damage
 Osteoporosis
 Acute pancreatitis
 Recurrent esophageal candidiasis due to T-cell suppression from
elevated plasma leucine.
 Essential amino acid deficiency presenting as anemia, hair loss, growth
failure, and acrodermatitis
 

Deterrence and Patient

Education
A thorough understanding of the patient and the public's clinical
condition will ensure adherence to optimal patient care strategies.
Furthermore, it allows physicians and other healthcare team
professionals to provide the best patient outcomes based on evidence-
based medicine. Educational resources should include:
 Educational handouts obtained online from the New England
Consortium of metabolic programs
 The American College of Pediatrics website
  MSUD family support group
 National Library of medicine genetics home reference
 NCBI genes and diseases
 Metabolic Support UK
 European Registry and Network for Intoxication Type Metabolic
Diseases (E-IMD)
 Organic Acidemia Association

Enhancing Healthcare Team

Outcomes
Optimal management of maple syrup urine disease requires an
interprofessional team consisting of an internist, pediatrician, geneticist,
metabolic specialist, pediatric nutritionist, social worker, and pediatric
nurse. The mainstay of therapy is medical, nutritional therapy. The
healthcare team must collaborate to assess caloric needs and execute
dietary treatment strategies such as BCAA restriction, BCAA-free amino
acid supplementation, and valine and isoleucine supplementation. The
pediatric nutritionist must educate the patient never to exceed the daily
intake of amino acids. They should also educate the patient to adhere to
a lifelong restricted diet. The geneticist must counsel the patient or their
parents about their inherited disorder's implications to help them make
informed medical and personal decisions. Outcomes of the patient
depend upon biochemical findings, clinical severity, and molecular
testing. A combination of early diagnosis, aggressive treatment, and
controlling plasma leucine levels help improve neurological outcomes.
[19]
 
(Click Image to Enlarge)

Table 1 Characteristics of the different types of Maple Syrup urine disease

Contributed by Mahdi Alsaleem, MD

References
[1] Edelmann L,Wasserstein MP,Kornreich R,Sansaricq C,Snyderman SE,Diaz GA, Maple syrup urine disease:
Jewish population. American journal of human genetics. 2001 Oct;     [PubMed PMID: 11509994]
[2] Blackburn PR,Gass JM,Vairo FPE,Farnham KM,Atwal HK,Macklin S,Klee EW,Atwal PS, Maple syrup urin
[PubMed PMID: 28919799]
[3] Strauss KA,Puffenberger EG,Morton DH, Maple Syrup Urine Disease 1993;     [PubMed PMID: 20301495]
[4] Quental S,Macedo-Ribeiro S,Matos R,Vilarinho L,Martins E,Teles EL,Rodrigues E,Diogo L,Garcia P,Euséb
analyses of maple syrup urine disease and identification of a founder mutation in a Portuguese Gypsy commu
[5] Suryawan A,Hawes JW,Harris RA,Shimomura Y,Jenkins AE,Hutson SM, A molecular model of human bran
[PubMed PMID: 9665099]
[6] Lynch CJ,Adams SH, Branched-chain amino acids in metabolic signalling and insulin resistance. Nature rev
[7] Morton DH,Strauss KA,Robinson DL,Puffenberger EG,Kelley RI, Diagnosis and treatment of maple syrup d
[8] Scaini G,Morais MO,Galant LS,Vuolo F,Dall'Igna DM,Pasquali MA,Ramos VM,Gelain DP,Moreira JC,Sch
amino acids and lipopolysaccharide causes matrix metalloproteinase activation and blood-brain barrier break
[9] Hallam P,Lilburn M,Lee PJ, A new protein substitute for adolescents and adults with maple syrup urine dise
[10 Frazier DM,Allgeier C,Homer C,Marriage BJ,Ogata B,Rohr F,Splett PL,Stembridge A,Singh RH, Nutrition
] approach. Molecular genetics and metabolism. 2014 Jul;     [PubMed PMID: 24881969]
[11 Hoffmann B,Helbling C,Schadewaldt P,Wendel U, Impact of longitudinal plasma leucine levels on the intell
] PMID: 16326996]
[12 Abi-Wardé MT,Roda C,Arnoux JB,Servais A,Habarou F,Brassier A,Pontoizeau C,Barbier V,Bayart M,Lebo
] F,Dupic L,Theuil B,Ottolenghi C,de Lonlay P, Long-term metabolic follow-up and clinical outcome of 35 pa
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[13 Strauss KA,Wardley B,Robinson D,Hendrickson C,Rider NL,Puffenberger EG,Shellmer D,Moser AB,Morto
] and formula design. Molecular genetics and metabolism. 2010 Apr;     [PubMed PMID: 20061171]
[14 Brunetti-Pierri N,Lanpher B,Erez A,Ananieva EA,Islam M,Marini JC,Sun Q,Yu C,Hegde M,Li J,Wynn RM
] molecular genetics. 2011 Feb 15;     [PubMed PMID: 21098507]
[15 Muelly ER,Moore GJ,Bunce SC,Mack J,Bigler DC,Morton DH,Strauss KA, Biochemical correlates of neuro
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[16 Shellmer DA,DeVito Dabbs A,Dew MA,Noll RB,Feldman H,Strauss KA,Morton DH,Vockley J,Mazariegos
] disease: a case series. Pediatric transplantation. 2011 Feb;     [PubMed PMID: 20946191]
[17 Mazariegos GV,Morton DH,Sindhi R,Soltys K,Nayyar N,Bond G,Shellmer D,Shneider B,Vockley J,Strauss
] patients and comparative United Network for Organ Sharing experience. The Journal of pediatrics. 2012 Jan
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] diagnosis. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neu
Maple syrup urine disease is caused by a defective activity of the
branched-chainα-keto acid dehydrogenase (BCKDH) complex. Due
to the inherited metabolic block, the branched-chain amino acids
leucine, valine and isoleucine and the corresponding branched-chain α-
keto acids accumulate. The BCKDH is a multienzyme complex
composed of a multimeric dihydrolipoamide transacylase (E2) core to
which multiple copies of BCKDH decarboxylase (E1) and
dihydrolipoamide dehydrogenase (E3) as well as two regulatory
enzymes, BCKDH kinase and BCKDH phosphatase, are bound2,3.
The E1 component exists as a heterotetramer composed of two
E1α and two E1α and two E1αβ subunits.The genomic changes
that impair BCKDH activity can occur in any of the catalytic components
of the complex, but both alleles at a single gene locus must harbor
nucleotide changes4-7. Based on the affected loci of the BCKDH
complex, three molecular MSUD genotypes are known thus far:
subtype Ia for mutations affecting the E1α α(BCKDHA ) gene, subtype
Ib for mutations affecting the E1β(BCKDHB) gene and subtype II for
mutations affecting the E2 (DBT) gene.

New*****

Molecular Biology of Maple Syrup Urine Disease

 The BCKD complex is a multimeric mitochondrial enzyme composed of
three catalytic subunits. The E1 portion of the complex is a thiamine
pyrophosphate (TPP)-dependent decarboxylase with a subunit structure
of α2β2. The E2 portion is a dihydrolipoamide branched-chain
transacylase composed of 24 lipoic acid-containing polypeptides. The
E3 portion is a homodimeric flavoprotein identified as dihydrolipoamide
dehydrogenase, DLD. The E1α gene (symbol: BCKDHA, branched
chain keto acid dehydrogenase E1, alpha polypeptide) is located on
chromosome 19q13.2, spans 55 kb and contains 9 exons that generate
two alternatively spliced mRNAs that encode alpha subunit isoform 1
(445 amino acids) and alpha subunit isoform 2 (444 amino acids). The
E1β gene (symbol: BCKDHB, branched chain keto acid dehydrogenase
E1 subunit beta) is located on chromosome 6q14.1 and is composed of
21 exons that generate three alternatively spliced mRNAs that encode
two different protein isoforms (392 amino acid isoform 1 and 322 amino
acid isoform 2). The E2 gene (symbol: DBT) is located on chromosome
1p21.2, spans 68 kb and contains 14 exons that encode a protein of
482 amino acids. The E3 gene (symbol: DLD) is located on
chromosome 7q31.1, spans 20 kb and contains 14 exons that generate
four alternatively spliced mRNAs, each of which encode a distinct
protein isoform. The DLD gene encodes the same dihydrolipoamide
dehydrogenase subunits found in the PDH and the 2-oxoglutarate (α-
ketoglutarate) dehydrogenase complexes.

The activity of BCKD is regulated by two additional subunits, a kinase

and a phosphatase that reversibly phosphorylate/dephosphorylate,
respectively, the complex. The kinase is encoded by the BCKDK gene
located on chromosome 16p11.2 and is composed of 12 exons that
generate three alternatively spliced mRNAs encoding three distinct
isoforms of the enzyme. The kinase phosphorylates the E1α subunit
rendering the enzyme inactive. The phosphatase that removes the
inhibitory phosphate is encoded by the PPM1K (protein phosphatase,
Mg2+/Mn2+ dependent 1K) gene located on chromosome 4q22.1 and is
composed of 11 exons that encode a protein of 372 amino acids.

The genetic heterogeneity in MSUD patients can be explained by the

complexity in the structure of BCKD. There are four molecular
phenotypes of MSUD based upon the affected locus:

 Type IA is due to mutations in the E1α gene.

 Type IB is due to mutations in the E1β gene.
 Type II is due to mutations in the E2 gene.
 Type III is due to mutations in the E3 gene.

To date a total of 63 mutations have been identified in the four genes of

the catalytic portion of BCKD.

Clinical Classifications of MSUD

Based upon the overall clinical presentation as well as a particular

patients response to thiamine administration, MSUD patients can be
divided into five phenotypic classifications.

Classic MSUD

Classic MSUD is defined by neonatal onset of encephalopathy and is

the most severe form of the disorder. The levels of the BCAAs,
especially leucine, and their α-keto acids, are dramatically elevated in
the blood, urine and cerebrospinal fluid of afflicted infants. The primary
cause of the encephalopathy and neurodegeneration in MSUD infants is
the high levels of the α-keto acid of leucine, α-ketoisocaproic acid, in the
brain. This compound triggers apoptosis in neurons and glial cells by
interfering with mitochondrial energy metabolism. The presence of
alloisoleucine in the fluids is highly diagnostic of MSUD. The level of
BCKD activity in classic MSUD patients is less than 2% of normal.
Affected infants appear normal at birth but symptoms develop rapidly
appearing by 4 to 7 days after birth. The first distinctive signs are
lethargy and little interest in feeding. As the disease progresses infants
will exhibit weight loss and progressive neurological deterioration.
Neurological signs will alternate from hypo- to hypertonia and extension
of the arms resembling decerebrate posturing. At this time the
characteristic burnt sugar or maple syrup odor to the urine is apparent.
If left untreated infants will develop seizures, lapse into a coma and die.
The prognosis for untreated infants is poor with death occurring within
several months of birth due to complications of metabolic crisis and
neurological deterioration.

Intermediate MSUD

Intermediate MSUD is distinguished from classic in that patients do not

experience the severity of classic MSUD in the neonatal period. Infants
will have persistent elevation in BCAAs in body fluids as well as
neurological impairment. The level of BCKD in intermediate MSUD
individuals ranges from 3% to 30% of normal. Many intermediate MSUD
patients do not experience the acute metabolic decompensation present
in classic MSUD.

Intermittent MSUD

In patients with the intermittent form of MSUD the activity of BCKD

ranges from 5% to 50% of normal. These individuals will show normal
early development with normal intelligence. During periods when
patients are asymptomatic their fluid levels of BCAAs will be normal.
These patients are however, at risk for acute metabolic decompensation
during periods of stress. Initial symptoms of the intermittent form of
MSUD usually appear between 5 months and 2 years of age in
association with an infection.

Thiamine-responsive MSUD

There is a similar course of progress in the symptoms of thiamine-

responsive MSUD patients to that seen in intermediate MSUD patients.
Plasma BCAA levels are around 5 times normal and alloisoleucine is
characteristically detectable in these patients. Administration of thiamine
and consumption of a low protein diet results in a reduction of BCAA
levels to normal. Withdrawal of thiamine treatment results in a rapid
rebound in the elevation of plasma BCAA concentration. These
responses to thiamine are the reason for this classification of MSUD.
There is a wide range of heterogeneity in thiamine-responsive MSUD
patients and thiamine treatment alone is insufficient to result in lower
levels of BCAAs.

Dihydrolipoyl dehydrogenase (E3)-deficient MSUD

As the name of this classification implies, this form of MSUD is due to a

deficiency in the E3 component of the BCKD complex. This form of
MSUD is very rare with only 20 reported cases. The symptoms of the
E3-deficient form are similar to those of intermediate MSUD, but there is
an accompanying severe lactic acidosis. Infants with the E3-deficient
form of MSUD are relatively normal for the first few months of life.
Persistent lactic acidosis will be seen to develop between 2 and 6
months of age.

Treatment of Maple Syrup Urine Disease

 The treatment of classic, intermediate, intermittent, and thiamine-
responsive MSUD involves lifelong therapy to maintain an diet with
sufficient calories and protein for growth but does not contribute to
enhanced branched-chain amino acid (BCAA) catabolism. In addition,
there must be immediate medical intervention for metabolic
decompensation. Various techniques have been used to reduce plasma
leucine levels including hemodialysis or hemofiltration, the latter being a
process where the blood is removed, filtered, and then returned to the
body.

Management of an MSUD patient’s diet remains a constant balancing

act between giving enough protein and BCAA to provide for normal
growth and development while simultaneously ensuring that the
patient’s metabolism remains in a therapeutic. Because α-
ketoisocaproic acid (the α-ketoacid of leucine) is particularly toxic to the
brain it is particularly important to limit the amount of leucine in the diet.
MSUD children must be regularly monitored to ensure that their diet is
adequate and that amino acid levels remain within acceptable normal
ranges.

Because there is a form of MSUD referred to as thiamine-responsive

MSUD, it is often recommended that all MSUD patients be given a trial
of thiamine therapy to determine whether or not they have the thiamine-
responsive form. However, no individual with MSUD can be successfully
treated with thiamine alone.

Liver transplantation has been shown to be successful in curing classic

MSUD patients of their disease. Following the transplant these patients
remain symptom-free and are able to consume a normal diet. The
limitation to transplantation is the availability of a donor liver and the
high cost of this procedure.

1. Naylor EW. Newborn screening in maple syrup urine disease

(branched-chain ketoaciduria). In: Neonatal screening for inborn errors
of metabolism, Bickel H, Guthrie R, Hammersen G (Eds), Springer
Verlag, Berlin 1980. p.19.
2. Chuang DT, Shih VE. Maple syrup urine disease (branched-chain
ketoaciduria). In: The metabolic and molecular bases of inherited
disease, 8th ed, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds),
McGraw-Hill, New York 2001. p.1971.
3. Quental S, Vilarinho L, Martins E, et al. Incidence of maple syrup urine
disease in Portugal. Mol Genet Metab 2010; 100:385.
4. Morton DH, Strauss KA, Robinson DL, et al. Diagnosis and treatment of
maple syrup disease: a study of 36 patients. Pediatrics 2002; 109:999.
5. Chuang DT. Maple syrup urine disease: it has come a long way. J
Pediatr 1998; 132:S17.
6. Korein J, Sansaricq C, Kalmijn M, et al. Maple syrup urine disease:
clinical, EEG, and plasma amino acid correlations with a theoretical
mechanism of acute neurotoxicity. Int J Neurosci 1994; 79:21.
7. Zhang B, Zhao Y, Harris RA, Crabb DW. Molecular defects in the E1
alpha subunit of the branched-chain alpha-ketoacid dehydrogenase
complex that cause maple syrup urine disease. Mol Biol Med 1991;
8:39.
8. Patel MS, Harris RA. Mammalian alpha-keto acid dehydrogenase
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