COLLEGE OF ALLIED HEALTH SCIENCES

BACHELOR OF SCIENCE IN NURSING

BIOLOGY AND CHEMISTRY

MAPLE SYRUP URINE DISEASE

(MSUD)

A Case Study

BY:

(GROUP # 3)

CAPUNO, MICHAEL LAWRENCE

HERMO, JOHN PAUL O.
ISLA, JUNICHI IZAC L.
LIBANG, ARRIANE
I. INTRODUCTION

Maple Syrup Urine Disease (MSUD) is an uncommon hereditary condition first identified
by physician John Menkes in 1954 (Menkes, 1954). The origins of this discovery can be
attributed to the analysis of four siblings, all exhibiting symptoms of infantile brain dysfunction,
along with the identification of unusual substances in their urine samples. Significantly, the
characteristic scent of maple syrup detected in the urine emerged as a defining attribute of
MSUD, serving as an origin of inspiration for its nomenclature.

After further investigation, it was discovered that the abnormal substances in the urine
exhibited a positive association with heightened concentrations of branched-chain amino acids
(BCAAs), namely valine, leucine, and isoleucine (Dancis et al, 1959). Such amino acids play a
crucial role in cognitive function, tissue repair, and musculoskeletal development, typically
undergoing appropriate catabolism inside the human body. Nevertheless, in patients diagnosed
with Maple Syrup Urine Disease (MSUD), there is a disruption in the enzymatic activity
responsible for the metabolism of branched-chain amino acids (BCAAs), impeding this
metabolic process. As a result, the buildup of these hazardous compounds gives rise to a range
of symptoms.

The branched-chain alpha ketoacid dehydrogenase (BCKD) complex is an essential

multi-enzyme complex responsible for the breakdown of branched-chain amino acids (BCAAs).
This complex consists of subunits encoded by particular genes, including BCKDHA, BCKDHB,
DBT, and DLD.

GENE SUBUNIT ENZYME CHROMOSOME

LOCATION

BCKDHA E1-a Branched Chain 19q13

α-Ketoacid
Dehydrogenase

BCKDHB E1-b Branched Chain 6q14

α-Ketoacid
Dehydrogenase

DBT E2 Dihydrolipoamide 1p21

Branched-Chain
Transacylase

DLD E3 Dihydrolipoamide 7q31

Dehydrogenase
 Table 1: MSUD related genes, subunits, enzymes, and chromosome location.

The occurrence of mutations within these genes, including deletions, results in the
manifestation of MSUD due to the impairment of the BCKDH complex's functionality (Nellis &
Danner, 2001; Quental et al., 2008; Bremer, 2016). The mutations mentioned above are
transmitted via an autosomal recessive inheritance pattern when both parents possess a mutant
gene. The observed mode of inheritance is a contributing factor to the relatively low occurrence
rate of MSUD, impacting only 1 in every 185,000 live births (Quental et al, 2010).
Comprehending the genetic underpinnings and intricate metabolic processes of MSUD is crucial
for the timely identification and efficient treatment of this rare condition.

II. PATHOPHYSIOLOGY
Maple syrup urine disease (MSUD) is an infrequent hereditary disorder stemming from
flawed genes responsible for encoding the enzyme that acts upon the amino acids valine,
isoleucine, and leucine (Carpenter, 2015). This anomaly primarily results from a reduction in the
activity of the branched-chain alpha-ketoacid dehydrogenase (BCKD) complex, a crucial
component in the breakdown of these specific amino acids. The presence of mutated genes
significantly disrupts the standard action of the BCKD complex, potentially leading to the
accumulation of toxic byproducts in the circulatory system. Without adequately functioning
BCKD enzymes, the body's ability to metabolize and eliminate these amino acids becomes
compromised, giving rise to various neurological symptoms. These symptoms, including
intellectual impairments, developmental delays, and seizures, aligns with the negative end of
the spectrum (Chiong, 2016).
 Figure 1: Schematic diagram of MSUD related compounds
Furthermore, MSUD presents itself in five distinct phenotypes, each characterized by its
unique gene abnormalities, varying symptom severity, and BCKD activity. This leads to the
theory that each MSUD subtype will exhibit its clinical manifestations, emphasizing the intricate
connection between genetic aberrations, enzyme activity, and the spectrum of symptoms
observed in individuals with MSUD.
Classic MSUD
Classic is the most common subtype amongst all the Maple Syrup Urine Disease
variations. The genetic anomaly, primarily mutations in E1α; E1β; E2 gene affects the
branched-chain alpha-ketoacid dehydrogenase (BCKD) complexes, a multi-enzyme dimension
tasked for the breakdown of amino acids such as valine,isoleucine, and leucine (Blackburn et
al., 2017). Specifically, such a type of MSUD is characterized by less than 2% of BCKDH activity
(Fann et.al., 2016). Hence, the symptoms associated with such appears much more earlier in
life, neonatally (Strauss et.al., 2022).
Due to the severe impairment of BCKDH activity, the three amino acids aforementioned
cannot be broken down to their respective intermediates, consequently leading to their
accumulation. This accumulation can translate into negative effects, primarily neurological
ailments—a hallmark of MSUD (Blackburn et.al, 2017).
Seizures are typically the common concern in Classic MSUD affected individuals as
elevated amino acid levels can lead to a phenomenon known as excitotoxicity (Silva et.al,
2022).The primary cause of this is the high levels of excitatory neurotransmitters that causes
excessive stimulation of neurons. Unfortunately, accumulation of amino acids and their
respective byproducts may affect the homeostasis of such neurotransmitters, thus, leading to
abnormal electrical activity to the brain, consequently leading to seizures (Almanai et.al, 2021).
Apart from that, it could also lead to dystonia as it can adversely affect neurological circuits
which may induce abnormal muscle contractions and postures (Hou, 2016).
In the case of metabolic manifestations, Classic MSUD can contribute to the emergence
of ketonuria—a condition characterized by high levels of ketones in the urine (Wynn et.al, 2001).
As a consequence of impaired metabolism of BCAAs, their respective alpha-keto acids
accumulate, leading to its elevated levels. Since such contain ketones, they exhibit a water
soluble characteristic, thus, they can be excreted through the urination.
Moving on to irritability, its connection to Classic MSUD established throughout the elevated
levels of toxic byproducts such as alpha-keto acids as part of the consequence of incomplete
breakdown of amino acids. These toxic substances can exact neurological disturbances which
can further lead to irritability and lethargy (Blackburn et.al, 2017). Moreover, this toxicity can
also lead to vomiting as it could affect the gastrointestinal environment. The presence of these
substances in such an area can activate the vomiting reflex as part of the body’s mechanism to
eliminate harmful substances (Zinnanti et.al., 2008).
At last, a combination of lethargy, vomiting, and other types of physiological discomfort
can inhibit an individual's interest in food, thus contributing to poor feeding (Patil et.al., 2020).
Apart from that, toxic metabolites caused by impaired breakdown of amino acids can affect
appetite-regulating centers in the brain, causing decreased relationship to an adequate nutrition.
Intermittent MSUD

Intermittent MSUD is the second most common type of Maple Syrup Urine Disease,
characterized by a BKDH activity of 5-20% (DT, 2001). This type of MSUD presents symptoms
that are similar but milder compared to the classical form of the disease, allowing affected
individuals to enjoy life more often (Lu et al., 2009). Apart from that, it also shares the same
genetic background, stemming from mutations in the E1α; E1β; E2 gene (Blackburn et al.,
2017). One notable feature of intermittent MSUD is that symptoms appear episodically, in
contrast to the classical form which presents from infancy. The timing of symptom onset is highly
dependent on the percentage of BCKDH activity in the liver. It is important to note that this type
can also manifest some unique symptoms.

Contrary to Classic MSUD, where elevated ketones are often observed in the urine, the
intermittent form of the condition manifests excessive ketones in the blood, a phenomenon
commonly recognized as ketoacidosis (Mescka et al, 2015). This metabolic state arises from the
body's adaptation to alternative energy sources, particularly the utilization of fat. During this
process, ketones are produced as a natural byproduct and subsequently released into the
bloodstream. The shift in energy metabolism, contributing to ketoacidosis in individuals with the
intermittent form of MSUD, underscores one of the unique aspects of this variant.

In addition to metabolic differences, the rapid increase in amino acid levels due to
impaired BCKDH activity can be toxic, leading to adverse effects on neurological function.
These effects contribute to ataxia, a condition characterized by uncoordinated and unnecessary
movements (Holmgren, 1980). Furthermore, this metabolic decompensation heightens the risk
of falling into a comatose state, illustrating the broader impact of intermittent MSUD on
neurological well-being.
 The impact of these metabolic disturbances can extend to the immune system.
Recurrent episodes of metabolic imbalances may compromise the immune response, making
individuals more prone to infections. Recurrent otitis media, or middle ear infections, is one of
the diseases caused by immune system impairment related to MSUD (Axler & Holmquist, 2014).
Intermediate MSUD
Intermediate MSUD is closely related to the symptoms exhibited by the classic MSUD,
however, it is characterized with BCKD activity of 3-30%, thus, the symptoms would like to
appear at any age, with an emphasis of later presentation on higher BCKD activity levels
(Strauss, 2020). The primary aberration of this disease occurs as a result of mutations in the
E1α; E1β; E2 subunit of BCKD complex (Blackburn et al., 2017).
E3-deficient MSUD
Both E3-deficient Maple Syrup Urine Disease (MSUD) and Classical MSUD exhibit
symptoms during the newborn period. These symptoms are caused mainly by mutations in the
DLD gene, which impact the functionality of the dihydrolipoyl dehydrogenase enzyme (E3)
within the branched-chain alpha-keto acid dehydrogenase (BCKD) complex (Hong et al., 1996).
The impairment of E3 enzyme activity restricts the efficient functioning of the BCKD complex,
resulting in the buildup of branched-chain amino acids (BCAAs) and their harmful metabolic
byproducts. The present situation gives rise to symptoms resembling those observed in
individuals with intermediate maple syrup urine disease (MSUD). Nevertheless, a notable
characteristic of E3-deficient MSUD is the manifestation of lactic acidosis.
E3-deficient MSUD is characterized by E3 enzyme deficiency, impairing the catabolism
of essential amino acids—valine, isoleucine, and leucine. Without functional E3, the conversion
of keto acid derivatives of these amino acids into critical substrates like acetyl-CoA and
succinyl-CoA for the citric acid cycle is compromised (Giribaldi et al., 2011; Head et al., 2022).
This deficiency undermines efficient energy generation through the citric acid cycle, prompting a
compensatory shift to anaerobic metabolism (Mampilly et al., 2013). Enhanced glycolysis during
anaerobic metabolism produces lactate, contributing to the potential development of lactic
acidosis (Patel et al., 2012). This underscores the interdependence of metabolic pathways and
the consequences of disturbances in amino acid catabolism.
Thiamine-responsive MSUD

Thiamine-responsive Maple Syrup Urine Disease (MSUD) is a distinctive and infrequent

subtype within the spectrum of maple syrup urine illnesses, characterized with 2-40% BCKD
enzyme activity (Strauss, 2020). One distinguishing characteristic of this particular form of
MSUD is its notable ability to positively respond to the administration of Vitamin B1 (Thiamine).
This crucial vitamin plays a major function in the restoration of the impaired activity of the BCKD
enzyme.

Mutations in the DBT gene, which encodes the E2 subunit, predominates, and are
responsible for the manifestation of thiamine-responsive maple syrup urine disease (MSUD).
Thiamine plays a vital role in facilitating the optimal functioning of the BCKD complex, which
experiences impairment in typical MSUD. Thiamine enhances the functionality of the BCKD
complex, hence assisting in the metabolic processes associated with branched-chain amino
acids (Chuang et al., 2004; Imtiaz et al., 2017)
 Individuals with thiamine-responsive maple syrup urine disease (MSUD) display
symptoms that closely resemble those observed in classical MSUD. These symptoms
encompass cognitive abnormalities, challenges with eating, delays in development, and the
distinctive maple syrup odor in urine. Fortunately, the administration of thiamine supplements
provides a method to improve metabolic regulation for persons who are affected by this specific
kind of MSUD.

III. LABORATORY DIAGNOSIS

A genetic metabolic disorder called MSUD prevents the body from effectively breaking
down branched-chain amino acids (BCAAs). Leucine, isoleucine and valine are among the
BCAAs that build up in body tissues and blood as a result of this condition. Certain amino acids
build up in the body because the affected individual cannot properly break them down due to the
genetic abnormalities underlying MSUD. To address MSUD and its consequences, a multimodal
strategy involving laboratory and clinical investigations is needed. Early detection and treatment
are necessary to prevent and lessen the disease's potentially disastrous effects.
A battery of laboratory tests is used to diagnose the Maple Syrup Urine Disease (MSUD)
and provides important insights into the metabolic issues linked to this hereditary disease.
Newborn screening is often the first step to detect elevated levels of branched-chain amino
acids (BCAAs), including valine, isoleucine and leucine, which presumes the inadequacy of the
mitochondrial branched-chain alpha-ketoacid dehydrogenase complex (Chiong et al., 2016).
Enabling the early detection of the disease through the infants by a heel-prick for collecting a
sample of the baby’s blood shortly after birth with subsequent analysis helps to identify if the
amino acids have elevated levels (Maguolo et al, 2022).
The diagnosis of MSUD and its associated ketoacidosis is based on clinical suspicion
and confirmed biochemically by measuring valine, leucine, isoleucine levels and branched-chain
keto acids in the urine (Lee et al., 2008; Ko et al., 2014). Additionally, the elevation of
branched-chain amino acids in biological fluids indicates a deficiency in the branched-chain
ketoacid dehydrogenase complex, which causes MSUD and subsequent ketoacidosis
(Fuenzalida et al., 2021). The increased levels of leucine and isoleucine contributes to the
development of ketoacidosis, as the abnormal metabolism results in the accumulation of
branched-chain keto-acids in the blood—which are highly acidic, inducing a decrease in pH
(acidosis).
Complete blood amino acid analysis is crucial after positive screening results as it yields
quantitative information that emphasizes the abnormal rise in leucine, isoleucine, and valine.
Moreover, MSUD is a genetic disorder, therefore, through the detection of mutations in genes
related to branched-chain ketoacid dehydrogenase (BCKD) complex, specifically: BCKDHA,
BCKDHB, DBT, and DLD, molecular genetic testing may also be used to confirm the existence
of the disease by identifying the mutations of the genes that are associated with such complex
(Tabbouche et al., 2014).
Additional evidence is provided by urine organic acid analysis, which identifies the
accumulation of specific metabolites, most notably alloisoleucine, in the urine. The unique smell
of maple syrup, due to the presence of alloisoleucine, strengthens the case for the MSUD
diagnosis. Alloisoleucine, a stereoisomer of isoleucine, is nowhere present in normal individuals;
therefore, the presence of these compounds is an indicative characteristic of MSUD (Chuang et
al., 2016).
.

Blood and Urine Test % with Normal BCKD % with Abnormal BCKD
Activity Activity

Ketoacidosis In general, the normal range >1 mmol/L

of ketoacids is between 0 and
0.5 mmol/L

Leucine 57 - 286 μmol/L Elevated levels (Above upper

range limit)

Isoleucine 25 - 102 μmol/L Elevated levels (Above upper

range limit)

Valine 49 - 202 μmol/L Elevated levels (Above upper

range limit)

Plasma Alloisoleucine Not detected or <5 μmol/L, >5 μmol/L

which is considered within the
normal range

Lactic Acid 4.5 to 19.8 mg/dL (0.5 to 2.2 4 mmol/L or higher

mmol/L)

Ketones in urine <0.6 mmol/L 0.6 to 1.5 mmol/L potentially

Table 2: MSUD related values reflected on blood and urine profile

IV. TREATMENT/MANAGEMENT

The integrated care of Maple Syrup Urine Disease (MSUD) requires a holistic strategy
that focuses on treating cerebral encephalopathy, associated metabolic decompensations and
neurocognitive deficits. Numerous intervention methodologies, including dietary therapy, liver
transplantation, and close monitoring of plasma BCAA levels, have been addressed.

The dietary management aims to reduce toxic metabolites quickly by restricting dietary
BCAA to amounts that allow individuals to achieve and maintain plasma BCAA amino acid
concentrations within the targeted treatment ranges, reduce catabolism, promote anabolism,
monitor nutritional status, and alter intake to promote normal growth, development, and health
maintenance (Gündüz et al., 2018). Such is achieved by limiting protein-intake, especially
protein sources rich in BCAA’s. This kind of restriction prevents further accumulation of affected
amino acids, thereby mitigating the occurrence of neurological disturbances.

Apart from that, liver transplantation has been established as an accepted treatment
modality in the management of MSUD, offering an alternative treatment with good outcomes for
patients (Patel et al., 2015). Patients with classic form MSUD, which is defined by a clinical
phenotype of extreme leucine intolerance, have successfully undergone liver transplantation,
resulting in the removal of dietary protein restriction and stability, but not the reversal of
underlying neurocognitive impairments. (Squires et al., 2014; Strauss et al., 2006). Furthermore,
successful liver transplantation, in the setting of close cooperation between transplantation
centers and metabolic centers, is an alternative treatment option that may potentially improve
cognitive performance in MSUD patients (O'Reilly et al., 2020). A patient that underwent a liver
transplant still contains MSUD genes and has a 25% chance of passing the genes down to its
offspring. In MSUD patients, liver transplantation provides an adequate enzyme supply,
reducing the buildup of branched-chain amino acids (BCAAs) and allowing patients to live a
normal life without the requirement for a stringent protein-restricted diet. (Herden et al., 2019).

To effectively monitor and provide emergency care for metabolic crises in Maple Syrup
Urine Disease (MSUD), it is crucial to have continuous plasma amino acid monitoring and the
capability to prepare MSUD hyperalimentation solution on demand (Mazariegos et al., 2012).
Furthermore, it is important to note that while dietary therapy and liver transplantation can
improve survival rates and decrease the frequency of metabolic crises, they cannot prevent all
central nervous system (CNS) manifestations of the disease (Xu et al., 2020).

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