The most common and severe form of this disease is the classic type, which appears soon after birth, and as long as it remains untreated, gives rise to progressive and unremitting symptoms.

Variant forms of the disorder may become apparent only later in infancy or childhood, with typically less severe symptoms that may only appear during times of fasting, stress, or illness, but still involve mental and physical problems if left untreated.

Although MSUD can be stabilized, there are still threats of metabolic decompensation and loss of bone mass that can lead to osteoporosis, pancreatitis, and intracranial hypertension.

[9] Symptoms of lethargy and characterized odor of maple syrup will occur when the individual experiences stress, does not eat or develops an infection.

Some signs that may seen from E3-deficient MSUD include feeding difficulties, developmental delay, acidosis, encephalopathy, liver failure, and early death.

[10] Untreated in older individuals, and during times of metabolic crisis, symptoms of the condition include uncharacteristically inappropriate, extreme or erratic behavior and moods, hallucinations, lack of appetite, weight loss,[10] anemia, diarrhea, vomiting, dehydration, lethargy,[10] oscillating hypertonia and hypotonia,[10] ataxia,[10] seizures,[10] hypoglycaemia, ketoacidosis, opisthotonus, pancreatitis,[3] rapid neurological decline, and coma.

[citation needed] Signs and symptoms of MSUD vart between patients and are greatly related to the amount of residual enzyme activity.

Mutation in any of these genes reduces or eliminates the function of the enzyme complex, preventing the normal breakdown of isoleucine, leucine, and valine.

Because high levels of these substances are toxic to the brain and other organs, this accumulation leads to the serious medical problems associated with maple syrup urine disease.

[citation needed] Amino acid transport deficiency and neurotransmitter synthesis impairment are significant concerns in individuals with maple syrup urine disease.

However, increased plasma levels and higher affinity of leucine may saturate LAT1, thereby competitively preventing the transportation of other amino acids, resulting in lower concentrations within the brain.

Methionine, a precursor for S-adenosylmethionine, is essential for one-carbon metabolism in the brain, while other LAT1-transported amino acids are involved in the synthesis of neurotransmitters, including histamine, serotonin, dopamine, and norepinephrine.

[citation needed] Another aspect of MSUD pathology involves the impact of elevated BCAA and BCKA on sodium-potassium ATPase activity, leading to electrolyte imbalances that contribute to cerebral edema and seizures.

Recent review articles have expanded on the neurotoxicity associated with MSUD, highlighting its contribution to changes in cellular bioenergetics (via disruption of the citric acid cycle in mitochondria), oxidative stress, and pro-inflammatory states.

Four to five days after birth, other signs can present, such as stereotyped movements like "fencing" and "bicycling" along with worsening encephalopathy including lethargy, irregular apnea, and opisthotonus.

Regular metabolic consultations, including blood draws for full nutritional analysis, are recommended; especially during puberty and periods of rapid growth.

MSUD management also involves a specially tailored metabolic formula, a modified diet, and lifestyle precautions such as avoiding fatigue and infections, as well as consuming regular, sufficient calories in proportion to physical stress and exertion.

Those with MSUD must be hospitalized for intravenous infusion of sugars and nasogastric drip-feeding of formula, in the event of metabolic decompensation, or lack of appetite, diarrhea or vomiting.

[citation needed] ILE and VAL plasma concentrations should ideally be between 200-400 mmol/L to maintain metabolic balance and avoid BCAA deficits.

Hemodialysis can be started as soon as a diagnosis is made when it is combined with dietary feeds that maintain recommended calorie and amino acid intake.

[27] A diet with carefully controlled levels of the amino acids leucine, isoleucine, and valine must be maintained at all times to reduce toxic metabolites to prevent neurological damage.

[citation needed] When Leucine plasma levels elevate due to not following the strict MSUD diets, infection, or physiological stress this may induce acute metabolic decompensation.

During decompensation, the individual must be still receiving the proper amount of calories, insulin, free amino acids, isoleucine, and valine to help promote protein synthesis.

Liver transplantation is a treatment option that can completely and permanently normalize metabolic function, enabling discontinuation of nutritional supplements and strict monitoring of biochemistry and caloric intake, relaxation of MSUD-related lifestyle precautions, and an unrestricted diet.

As a major surgery, the transplant procedure itself also carries standard risks, although the odds of its success are greatly elevated when the only indication for it is an inborn error of metabolism.

To prevent detrimental abnormalities in the development of the embryo or fetus, dietary adjustments should be made and plasma amino acid concentrations of the mother should be observed carefully and frequently.

Early detection, protein-restricted diet low in branched-chain amino acids, close monitoring of blood chemistry, and aggressive treatment during a metabolic crisis can lead to a good prognosis with little or no abnormal developments.

The severity of the cognitive delay is related to the time the condition remained undiagnosed and the effectiveness of dietary control including during metabolic crises.

Younger children with late-onset MSUD may experience developmental delay also, depending on the enzyme activity of BKCD (branched-chain alpha-keto acid dehydrogenase).

Early diagnosis can prevent morbidity in most cases as long as correct treatment is administered at presentation and periods of possible metabolic decompensation.