Introduction

An abnormality in amino acid metabolism caused by aberrant activity of the branched-chain alpha-ketoacid dehydrogenase (BCKAD) complex is known as maple syrup urine disease (MSUD). The three necessary branched-chain amino acids (BCAA)—leucine, valine, and isoleucine—are broken down by this complex. The breakdown of BCAA is essential to your body as your muscles “burn” this amino acid complex for energy  Through its impact on the mTOR signaling system, these BCAA are often utilized for enhanced protein synthesis, or more energy generation (i.e., muscle synthesis).¹ The purpose of BCAAs in the brain is to encourage the creation of proteins, neurotransmitters, and energy.²

Branching-chain α-ketoacid dehydrogenase deficiency, or MSUD, is caused by a disruption in the metabolism of BCAA, which accumulates in the brain, other tissues, and plasma. It also results in the urine of the corresponding derivative ketoacids. This disruption is caused by an underlying defect in the BCKAD complex, which is found in the cellular mitochondria, which is like the “powerhouse” of the cell as it is responsible for producing energy to fuel the activities of every cell in your body.

Typically, it shows up in the neonatal stage as feeding difficulties, delayed developmental milestones, failure to thrive, lethargy, irritability, and a smell similar to maple syrup that is initially detected in the urine and then in the cerumen (earwax). Within 7 to 10 days of birth, the most severe, classic type of MSUD can cause irreversible neurological impairment in the form of brain damage, seizures, coma, or central respiratory failure if treatment is not received.³

The various forms of maple syrup urine disease (MSUD)

There are four primary forms of MSUD:

• Classical: The most serious kind of maple syrup urine illness is the most common type. Usually, during the first three days of life, symptoms will appear
• Intermediate: Compared to classic MSUD, this kind of MSUD is less severe. Usually, children between the ages of five months and seven years old exhibit symptoms
• Intermittent: Kids with intermittent MSUD grow normally up until an illness or stressful time triggers symptoms. Compared to people with classic MSUD, people with intermittent MSUD typically tolerate larger doses of the three amino acids
• Thiamine-responsive: Treatment for this kind of MSUD involves a restricted diet and high doses of vitamin B1 (thiamine). Those with thiamine-responsive MSUD show increased tolerance to the three amino acids after receiving therapy⁴

Classic

The most severe and dangerous subtype of the condition is classical MSUD, which is also its most prevalent subtype. Typical clinical characteristics consist of: 

• The activity of the BCKAD enzyme is negligible to absent (0% to 2%)

Within the first ten days after birth, this kind often manifests. 

• After consuming protein, the smell of maple syrup intensifies and is initially detected in one's ears cerumen 12 hours postpartum and in the urine by the end of the first week
• The course of classic MSUD is fast progressing and frequently fatal if treatment is not received
• 48 to 72 hours after birth, if the baby presents with lethargy, vomiting, irritability, and poor feeding, these are the initial nonspecific clinical indications that indicate ketonuria
• Two to three days later, encephalopathy sets in, accompanied by increased lethargy and sporadic apnea
• Muscle tone fluctuation, convulsions, and weight loss are other symptoms. Coma and central respiratory failure may appear 7 to 10 days after birth
• Death from MSUD could occur in less than two months if treatment is not received
• When under physical stress, such as after surgery, during an infection, fasting, or excessive protein consumption, patients with the typical variety of MSUD are most vulnerable to exacerbations of their condition
• Serum leucine titers can be much higher but are typically 2–4 times normal values
• The genes BCKHDA, BCKHDB, and DBT are mutated

Biochemical results 

• Increased alloisoleucine (an isomer of isoleucine that is found in the bodily fluids of individuals affected by MSUD)
• Increased levels of plasma BCAA (leucine, valine, and isoleucine) 
• Elevated branched-chain keto acid levels in urine 
• Lack of ketonuria 
• Positive dinitrophenylhydrazine test results in urine³

Techniques for diagnosis 

By using tandem mass spectrometry for population newborn screening, classical MSUD can be easily diagnosed. If not, encephalopathy, isolated ketosis, and the smell of maple syrup are indicative. With a leucine/valine/isoleucine ratio of roughly 4/2/1, plasma leucine is significantly enhanced. A diagnostic measure is plasma allo-isoleucine >5 umol/L. Branching chain 2-keto acids (BCKAs) in urine are shown to be higher using gas chromatography-mass spectrometry. In addition to identifying causative mutations, molecular genetic testing may also indicate a subtype.

Differential diagnosis 

Other inborn metabolic errors such as urea cycle defects, organic acidemias (propionic or isovaleric acidemias, methylmalonic acidemia with homocystinuria, multiple carboxylase deficiency), and beta-ketothiolase deficiency (see these terms) are also considered as differential diagnoses in relation to predominant neurological deterioration. Many inborn errors of metabolism in babies are ruled out by ketosis, which is characterized by the absence of severe metabolic acidosis, hyperammonemia, and hypoglycaemia.⁵

Intermediate urinary disease caused by maple syrup

The much milder variant of MSUD known as "intermediate" usually manifests between the ages of five months and seven years. Typical clinical characteristics consist of:

• BCKAD activity is typically seen in these patients to varying degrees (3% to 30%)
• Symptoms include stunted growth, delayed development, low intellectual achievement, and decreased appetite
• When the patient is under stress from an infection, dehydration, high-protein meals, or fasting, they may experience encephalopathy and ketonuria
• There's a distinct smell of maple syrup in the urine and cerumen
• The genes BCKHDA, BCKHDB, and DBT are mutated
• The biochemical results are quantitatively less severe but identical to those of the classic subtype³

Techniques for diagnosis 

Newborn screening using tandem mass spectrometry can identify intermediate MSUD. Analysis of plasma amino acids is diagnostic otherwise. Whereas valine and isoleucine levels may be normal or elevated, plasma leucine levels are elevated. Patients' plasma BCAA levels are lower than those observed in conventional MSUD (see this term) because they exhibit 3–30% BCKAD activity. Molecular genetic testing can detect a mutation that causes an illness, so validating the diagnosis.

Differential diagnosis 

Other inborn errors of intermediary metabolism, such as argininosuccinic aciduria (and other urea cycle defects), methylmalonic acidemia, propionic acidemia, beta-keto thiolase deficiency, ornithine transcarbamylase deficiency, and neonatal glycine encephalopathy, are differential diagnoses for the presenting symptoms.⁶

Disease caused by intermittent maple syrup urine

One unusual variation of this uncommon illness is intermittent MSUD. Although there's no set age range in which it has to manifest initially, it usually does so in the first year or two of life. Typical clinical characteristics consist of:

• BCKAD residual activity ranges from 5% to 20% of baseline
• When it appears for the first time, it might advance quickly
• Ataxia, encephalopathy, and seizures are possible early signs
• The symptoms that afflicted patients experience can worsen significantly when they are physically stressed
• Three mutated genes: DBT, BCKHDA, and BCKHDB

Biochemical results

• Normal amounts of branched-chain amino acids
• Comparable characteristics to the traditional subtype during periods of illness exacerbation³

Techniques for diagnosis

Newborn screening using tandem mass spectrometry may miss intermittent MSUD. With the exception of periods of physiological stress, when the biochemical profile is comparable to classic MSUD, BCAA levels are often normal or very slightly raised. As it were amid decompensation, branched-chain alpha-keto acids (BCKAs) in the urine can be recognized by ketonuria and gas chromatography-mass spectrometry.

Differential diagnosis

Other inborn errors of intermediary metabolism, such as propionic acidemia (an inherited disorder in which the body is unable to process certain parts of proteins and lipids (fats) properly), beta-ketothiolase deficiency, neonatal glycine encephalopathy, argininosuccinic aciduria (an inherited disorder that causes ammonia to accumulate in the blood),  other urea cycle defects, NAGS deficiency, and ornithine transcarbamylase deficiency, may also be differentially diagnosed based on the symptoms presented.⁷

Thiamine-related urinary disease caused by maple syrup

Patients with thiamine-responsive MSUD respond effectively to high therapeutic doses of thiamine and otherwise have characteristics of other MSUD patients, making them different from the other varieties of MSUD. Typical clinical characteristics consist of:

• BCKAD residual activity ranges from 2% to 40% of baseline
• Among the mutated genes is DBT
• Subtypes of Maple Syrup Urine Disease with Deficits in E3
• Mutations in the gene encoding the E3 (dihydrolipoamide dehydrogenase) component cause E3-deficient subtypes of MSUD

Typical clinical characteristics consist of:

• Usually, patients exhibit concomitant deficits in the pyruvate/alpha-ketoglutarate dehydrogenase complexes and the E3 subunit
• Clinically, lactic acidosis, encephalopathy, feeding issues, liver failure, and early death are common in newborn patients³

Common indications of maple syrup pee disease

Within 48 hours following birth, babies exhibit symptoms of classic MSUD. Older children are more likely to exhibit intermediate and intermittent and thiamine-responsive MSUD symptoms before the age of seven. If therapy is not received, symptoms could worsen and could become fatal. You have to take your child to A&E as soon as they show any signs of MSUD.

• A sweet, syrupy fragrance in your child's sweat, earwax, or urine is one of the tell-tale signs that they have MSUD
• Laziness (they might move gradually or appear frail or exhausted)
• Easily agitated or fussy
• Not consuming food
• If left untreated, symptoms may worsen and lead to a metabolic crisis. Your body experiences a metabolic crisis when your food-processing systems aren't working properly. Amino acids and their harmful byproducts are constructed in your body

The following are signs of a metabolic crisis

• Abnormal muscle contractions include the backward arching of your child's neck, head, or spine from spasms
• Convulsions or seizures (uncontrollably shaking)
• Coma
• A metabolic emergency can be deadly if cleared out untreated
• An infection, an accident, or stress can all act as trigger events for a metabolic crisis, even in children and adults with MSUD diagnoses and under management. Get assistance right away⁴