History
Classic maple syrup urine disease (MSUD) is the most common type, with symptoms developing in neonates aged 3-7 days, depending on feeding regimen. Breastfeeding may delay onset of symptoms into the second week of life.
Infants with classic maple syrup urine disease appear normal at birth. Symptoms that may develop within the first week of life include fussiness, lethargy, decreased nursing/feeding, emesis, poor weight gain, increasing lethargy, hypotonia and/or hypertonia, a high-pitched cry, seizures, and the characteristic maple syrup smell of the urine. This burnt maple sugar smell is more noticeable in a diaper after the urine has dried. In infants with non-classic maple syrup urine disease (ie, intermediate maple syrup urine disease, intermittent maple syrup urine disease), symptoms tend to be milder and may not be readily apparent early in the course.
Physical
The clinical presentation of an infant/child with maple syrup urine disease varies. Five distinct clinical phenotypes can be distinguished based on age of onset, severity of clinical symptoms, and response to oral thiamine treatment. These types of maple syrup urine disease include classic, intermediate, intermittent, thiamine-responsive, and E3-deficient. [8]
Classic maple syrup urine disease is the most common type. In classic maple syrup urine disease, little or no BCKD enzyme activity (usually < 2% of normal) is present. Infants show symptoms within the first week of life. They generally have poor tolerance for the branched-chain amino acids (BCAAs), so dietary protein must be severely restricted. In the classic type, neurological signs (eg, muscular hypotonia and/or hypertonia, dystonia, seizures, encephalopathy) rapidly develop. Signs of pseudotumor cerebri may be observed, and acute transient ataxia has been reported. Pancreatitis has been occasionally reported. Ketosis and the characteristic urine odor of maple syrup are usually present when the first symptoms develop. Interestingly, this characteristic urine odor has been reported in healthy infants not affected with maple syrup urine disease. The reason for this observation is not understood. [8, 11, 15, 16]
Intermediate maple syrup urine disease is a variant of classic maple syrup urine disease and is less common than classic maple syrup urine disease; approximately 20 patients have been reported with this phenotype. Patients with intermediate maple syrup urine disease have a higher level of BCKD enzyme activity (approximately 3%-8% of normal), and they can usually tolerate a greater amount of leucine. Clinical signs in these patients include neurological impairment, developmental delay of varying degree, and seizures. Presentation may occur at any age, depending on residual BCKD enzyme activity; however, if the patient is ill or fasting, he or she will react in a similar way to a child with classic maple syrup urine disease and will require immediate medical intervention and care.
Intermittent maple syrup urine disease, the second most common type of maple syrup urine disease (after the classic type), is a milder form of the disease owing to the presence of greater enzyme activity (approximately 8%-15% of normal). Patients have normal growth and intelligence. Symptoms may not present until age 12-24 months, usually in response to catabolic stress as due to illness (eg, otitis media) or a surge in protein intake. During these episodes, the characteristic maple syrup odor becomes evident, and metabolic decompensation can occur. Ataxia, lethargy, seizures, and coma may ensue. Patients with intermittent maple syrup urine disease have died during these acute episodes when not appropriately treated.
The descriptive term thiamine-responsive maple syrup urine disease reflects the treatment of this rare type of maple syrup urine disease. Giving large doses of thiamine to the thiamine-responsive child increases BCKD enzyme activity, which, in turn, breaks down the BCAAs. Only one case report described by Scriver et al has been shown to be unambiguously responsive to thiamine. [7] Positive clinical response to supplemental thiamine has been documented in patients and has shown improved metabolic control when moderate dietary restriction of BCAAs is also followed. [7]
E3-deficient maple syrup urine disease (dihydrolipoamide dehydrogenase deficiency [DLDD]) is a very rare type of maple syrup urine disease, with fewer than 10 patients reported in the medical literature (OMIM #246900). The clinical presentation is very similar to that of intermediate maple syrup urine disease, with the exception of early-onset lactic acidosis. These patients have combined deficiencies of the BCKD enzyme complex, pyruvate, and alpha-ketoglutarate dehydrogenases. [8]
Causes
See Pathophysiology.
Complications
Patients with maple syrup urine disease are at risk for metabolic decompensation during periods of increased catabolism. Dietary compliance is necessary to prevent developmental delay and neurological symptoms.
