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.