Abstract
Maple Syrup Urine Disease
(MSUD) is a rare autosomal recessive disorder of Branched Chain Amino Acid (BCAA)
metabolism caused by deficiency of the Branched Chain α
Ketoacid Dehydrogenase (BCKAD) complex. This defect leads to accumulation of
leucine, isoleucine, valine and their toxic metabolites, resulting in severe
neurotoxicity. Classic MSUD, the most severe form, presents in the neonatal
period with rapid neurological deterioration if untreated.
We report a 10-day old
term male infant presenting with lethargy, poor feeding, hypotonia and a
characteristic maple syrup like odour of urine and skin. Investigations
revealed metabolic acidosis, mild hyperammonaemia, hypoglycaemia and cerebral
oedema on neuroimaging, while sepsis was excluded. Plasma amino acid analysis
showed markedly elevated BCAAs and urinary organic acid analysis confirmed
branched chain α ketoacids. Genetic testing later identified biallelic
pathogenic variants affecting the BCKAD complex.
The infant was managed as
a metabolic emergency with high calorie intravenous support, correction of
metabolic abnormalities and temporary protein restriction. A specialized MSUD
formula was introduced after stabilization. Clinical and biochemical
improvement was achieved.
This case highlights the
importance of early recognition and prompt dietary management to prevent
irreversible neurological damage, particularly in settings without newborn
screening.
Keywords:
Neurotoxic, Neonatal encephalopathy, Rare diseases, Metabolic disorders, Infant
Abbreviations:
MSUD:
Maple Syrup Urine Disease; OMIM:
Online Mendelian Inheritance in Man; BCAA:
Branched Chain Amino Acids; BCKAD:
Branched Chain α Ketoacid Dehydrogenase; CoA: Coenzyme A; MS/MS: Tandem Mass Spectrometry; CSF: Cerebrospinal Fluid; CT: Computed Tomography; NICU: Neonatal Intensive Care Unit; IV: Intravenous; ABG: Arterial Blood Gas; kg: Kilogram; mmol/L: Millimoles per Liter; µmol/L: Micromoles
per Liter; pH: Potential of
Hydrogen (measure of acidity/alkalinity); BCKDHA: Branched-Chain Ketoacid Dehydrogenase E1 Subunit Alpha
Gene; BCKDHB: Branched Chain
Ketoacid Dehydrogenase E1 Subunit Beta Gene; DBT: Dihydrolipoamide Branched Chain Transacylase E2 Gene
1.
Introduction
Maple Syrup Urine Disease
(MSUD) is a rare autosomal recessive disorder of Branched‑Chain Amino Acid (BCAA)
metabolism caused by deficiency of the Branched‑Chain α‑Ketoacid
Dehydrogenase (BCKAD) complex1,2.
This enzyme complex is required for the oxidative decarboxylation of the α‑keto derivatives of leucine, isoleucine and valine
into their respective acyl‑CoA intermediates3,4.
Deficiency leads to accumulation of these BCAAs and their corresponding α‑keto acids
in blood, urine and cerebrospinal fluid, resulting in severe neurotoxicity and
metabolic decompensation5,6.
Classic MSUD is the most
severe form, with onset in the first 7 to 10 days of life and rapid progression
to encephalopathy, seizures and, if untreated, death. The disease is so named
because affected infants characteristically develop a sweet, maple syrup like
odour in urine and cerumen, a hallmark clinical clue7,8. With the advent of tandem mass
spectrometry‑based newborn screening, many cases are now detected
presymptomatically, allowing early dietary intervention and markedly improved
outcomes. However, in regions without routine newborn metabolic screening, the
disease often presents as a fulminant metabolic emergency9, as in the following hypothetical case.
This case report
illustrates the clinical presentation, diagnostic work up, acute management and
principles of long‑term care in a term neonate with classic MSUD, emphasizing
the importance of considering inborn errors of metabolism in any infant with
unexplained encephalopathy or unusual body odour.
2.
Clinical Study
A 10th day old male infant was brought to the
emergency department of a tertiary care hospital with a 2nd day history of progressive lethargy, poor feeding
and a high pitched, “fussy” cry. The parents reported that the baby had begun
to “smell unusual,” describing a sweet, burnt‑sugar or maple‑syrup‑like odour
from his urine and skin, particularly around the head and neck. This odour had
become more noticeable over the preceding 24 hours. The infant had been
breastfed since birth and was initially feeding well, but over the last 48
hours his suck became weak, he fed less frequently and he appeared increasingly
“floppy” and difficult to rouse.
The pregnancy was full‑term
and uncomplicated and the delivery was spontaneous vaginal at 39 weeks’
gestation with a birth weight of 3.2 kg. The Apgar scores were 8 and 9 at 1 and
5 minutes, respectively. There was no history of consanguinity, no known
metabolic disease in the family and no newborn metabolic screening result
available at the time of presentation.
On examination, the
infant was moderately dehydrated, with dry oral mucosa, reduced skin turgor and
slightly sunken anterior fontanelles. Vital signs revealed sinus tachycardia
(heart rate 148 beats per minute), tachypnoea (respiratory rate 44 breaths per
minute) and a temperature of 37.2°C. The infant
was semi‑comatose, reacting only faintly to painful stimuli, with minimal
spontaneous movement. He was markedly hypotonic, with poor head control and a
diminished or absent Moro reflex.
A distinctive sweet, maple‑syrup‑like odour was easily detectable in the diapers and on the infant’s skin, particularly around the axillae and neck, confirming the parents’ description. There were no obvious dysmorphic features, rashes, hepatosplenomegaly or focal neurological signs at this stage.
Initial investigations in the emergency department showed:
Metabolic acidosis: Arterial
blood gas pH 7.28, bicarbonate 14 mmol/L, base deficit −12 mmol/L.
Mild hyperammonaemia: Arterial
ammonia 120 µmol/L (normal <60 µmol/L).
Hypoglycaemia: Capillary blood glucose 2.8 mmol/L, necessitating intravenous dextrose infusion.
Mild
liver enzyme elevation and mildly increased bilirubin, but no overt hepatic
failure.
A septic work‑up was
performed to exclude infection‑related encephalopathy. Blood culture, urine
culture and lumbar puncture were carried out. Cerebrospinal fluid analysis was
acellular with normal glucose and protein and cultures remained negative.
Computed Tomography (CT) of the brain showed generalized cerebral oedema with
effacement of sulci and mild ventricular compression, consistent with acute
metabolic encephalopathy.
Given the clinical triad
of early neonatal encephalopathy, poor feeding, lethargy and the characteristic
maple‑syrup odour, Tandem Mass Spectrometry (MS/MS) analysis of plasma amino
acids was urgently ordered.
The
results revealed striking elevations of the branched‑chain amino acids:
Leucine: 1,750 µmol/L (normal newborn reference range: 50–150 µmol/L).
Isoleucine:
420 µmol/L (normal: 30–100 µmol/L).
Valine: 580 µmol/L (normal: 150–350 µmol/L).
Urinary organic acid
analysis showed large amounts of branched‑chain α‑keto
acids, including α‑ketoisocaproic acid (from
leucine) and α‑keto‑β‑methylvaleric
acid (from isoleucine), confirming a functional defect in the BCKAD complex.
These findings, in the context of the clinical presentation and imaging, were
consistent with Classic Maple Syrup Urine Disease.
Genetic testing
subsequently revealed biallelic pathogenic variants in one of the genes
encoding the BCKAD complex (e.g., BCKDHA, BCKDHB or DBT), confirming the autosomal
recessive inheritance pattern. The family was counselled regarding recurrence
risk and the importance of cascade testing for future pregnancies.
3.
Management
The infant was admitted
to the Neonatal Intensive‑Care Unit (NICU) and managed as an acute metabolic
emergency. The primary goals of management were to halt catabolism, reduce the
burden of toxic BCAAs, correct metabolic derangements and prevent further
neurological injury.
Initial
resuscitation and metabolic stabilization
Intravenous high‑calorie dextrose with added
electrolytes and lipid emulsion was initiated to provide abundant energy and
suppress catabolism. This helped reduce the rate of proteolysis and BCAA
production.
Natural protein (including breast milk and standard
formulas) was temporarily withheld to minimize the intake of leucine,
isoleucine and valine.
Intravenous insulin and glucose were used cautiously
to maintain euglycemia and promote anabolism, while avoiding hypoglycemia or
hyperglycemia.
Sodium bicarbonate was administered to correct significant metabolic acidosis and close monitoring of electrolytes and fluid balance was maintained.
3.1. Initiation of MSUD specific diet
Once the infant
stabilized hemodynamically and feeding was tolerated, a specialized MSUD
formula, low in leucine, isoleucine and valine but supplemented with other
essential amino acids was introduced via nasogastric tube. The quantity of
natural protein (expressed breast milk) was carefully titrated to meet growth
requirements while keeping plasma leucine and isoleucine levels within
prescribed target ranges.
Serial plasma amino acid
analyses were performed to guide dietary adjustments. Over the next 48 hours,
leucine and isoleucine levels began to decline, the maple syrup odour gradually
diminished and the infant’s level of consciousness improved. He started to feed
more actively and his tone and responsiveness normalized.
Monitoring and supportive care
Metabolic monitoring included repeated measurements of
plasma amino acids, ammonia, blood gases, electrolytes and glucose.
Neurological status was monitored continuously and the
infant was observed for signs of seizures or recurrent encephalopathy.
Brain imaging was not repeated in the acute phase, but
the initial CT findings were compatible with reversible cerebral oedema in the
context of metabolic decompensation.
Long‑term management plans were discussed with the parents and the regional metabolic team. The infant was transitioned to a lifelong, protein‑restricted diet based on MSUD specific medical foods, with strict avoidance of prolonged fasting and illness‑related protocols (e.g., increased caloric intake and temporary reduction of natural protein during febrile episodes). Regular follow up at the metabolic clinic was arranged to monitor growth, nutritional status, developmental milestones and plasma amino acid levels.
4.
Discussion
Classic Maple Syrup Urine
Disease (MSUD) is a severe inborn error of metabolism that typically presents
in the first week of life with nonspecific but rapidly progressive symptoms.
The hallmark clinical clue is the characteristic maple syrup or burnt sugar odour
in urine and cerumen, arising from the accumulation of branched chain α‑keto
acids10,11. In this hypothetical
case, the presence of such odour, combined with early encephalopathy, metabolic
acidosis and hyperammonaemia, strongly directed the differential diagnosis
toward MSUD.
The biochemical defect
lies in the BCKAD complex, which catalyses the oxidative decarboxylation of α‑keto derivatives of leucine, isoleucine and valine.
Complete or near‑complete loss of enzyme activity in classic MSUD results in
marked elevations of these BCAAs and their corresponding keto acids, which are
neurotoxic and cause mitochondrial dysfunction, oxidative stress and disruption
of neurotransmitter metabolism. This leads to cerebral oedema, seizures and, if
untreated, irreversible brain damage or death12.
The clinical spectrum of
MSUD includes classic, intermediate, intermittent and thiamine‑responsive
forms, with classic being the most severe and earliest onset phenotype. Classic
MSUD is characterized by onset in the neonatal period, rapid neurological
deterioration and marked biochemical abnormalities unless promptly treated.
Intermediate and milder forms may present later in infancy or childhood with
episodic neurological symptoms triggered by catabolic stress, whereas thiamine responsive
variants may show partial clinical improvement with high dose thiamine
supplementation9,13.
Early diagnosis is
critical. Tandem mass spectrometry of newborn blood spots allows detection of
elevated leucine and isoleucine before clinical onset, enabling presymptomatic
dietary intervention and preventing the first metabolic crisis14. However, in the absence of newborn
screening, the disease often presents as a fulminant metabolic emergency, as in
this case. Awareness of the characteristic odour and the possibility of an
inborn error of metabolism is essential for timely referral and appropriate
investigations.
Long term outcomes depend
on the severity of the initial episode, the timing of diagnosis and adherence
to a strict dietary regimen. Lifelong protein restriction, use of MSUD specific
medical foods and careful metabolic monitoring can prevent recurrent crises and
support normal growth and development. However, prior metabolic decompensations
may still be associated with residual cognitive impairment, motor deficits or behavioural
problems15.
Gene therapy and enzyme replacement strategies are under investigation, but at present, dietary management remains the cornerstone of treatment16. This case underscores the importance of early recognition, rapid metabolic stabilization and multidisciplinary follow‑up in improving both survival and quality of life for infants with classic Maple Syrup Urine Disease.
5. References