Maple syrup urine disease (MSUD) is an autosomal recessive condition with an incidence of approximately 1 in 150 000 live births with a higher incidence amongst children from consanguineous relationships [1]. It is caused by an enzymatic deficiency with reduction in oxidative decarboxylation of branched-chain amino acids (BCAA) (leucine, isoleucine and valine) resulting in elevated levels and toxic metabolites that cause neurotoxicity [2]. 

The clinical features of MSUD are variable, but the “classic” form is characterised by psychomotor retardation, cerebral degeneration, hypoglycaemia and seizures [3,4]. Adolescents with the condition may have attention deficit hyperactivity disorder, anxiety and developmental delay. The disease takes its name from the characteristic maple syrup odour of the urine from a metabolite of isoleucine [5]. Failure to thrive and feeding difficulties are also common.

Presentation of the classic form occurs in the neonatal period, often with a metabolic ketoacidosis, due to accumulation of leucine and 2-oxo isocaproate in the blood and tissues above critical concentrations during the first week of life [6]. If this is not identified and treated in a short time, the patient can die within a few days or weeks. Milder forms of the disease may present later in childhood.

The treatment of MSUD is two-stage, consisting of therapy to prevent acute decompensation and long-term nutrition therapy. Peritoneal dialysis has successfully reduced BCAA levels in neonates with MSUD [6]. The specific low protein diet limiting BCAA is a lifelong requirement, but compliance is not always optimal and these children must be monitored carefully in order to prevent developmental delay and neurological decompensation. Adequate nutrition can be assured with the use of MSUD-specific medical foods (metabolic formulas) combined with low protein foods.

There are five clinical variants [2]:

Classic MSUD

The most common and severest form typically presents in the the newborn period. There is little or no detectable branched chain α-keto acid dehydrongenase complex activity (<2%) [7]. Patients are prone to decompensation and neurological damage occurs if the condition is not treated.

Intermediate MSUD

Patients may become symptomatic at any age. There are variable features of neurological impairment and developmental delay. Decompensation can occur with catabolic illness, stress, inadequate caloric intake, or high protein consumption.

Intermittent MSUD

This is the second commonest variant where affected individuals appear completely normal and may have normal levels of the BCAA except during periods of extreme catabolic stress [7]. Symptoms usually present between 5 months and 2 years of age. Affected individuals are at risk of decompensation often presenting with ketoacidosis and other typical features of neurotoxicity.

Thiamine-responsive MSUD

Some individuals with mild forms of MSUD have greater metabolic control when using supplemental thiamine. To date there have not been individuals identified who can be successfully managed with thiamine alone without also limiting BCAA.

E3-deficient MSUD 

This is a very rare form with only ten cases reported. Neonates are usually affected, with a lactic acidosis in addition to the typical presenting features. There is also an accumulation of both pyruvate and α-ketoglutarate in addition to the BCAA and their derivatives.

Decompensation

May be triggered by stressful situations such as injury or exercise, intercurrent illness, fasting, surgery, or caused by increased catabolism of endogenous protein.

The clinical manifestations are non-specific but include epigastric pain, vomiting, anorexia, muscle fatigue, and rarely pancreatitis. Neurological features may be similar to those of Wernicke encephalopathy including hyperactivity, lethargy, seizures, dystonia, hallucinations, and ataxia. If the condition is not treated severe ketoacidosis with rapid neurological deterioration and hypoglycaemia can occur, proceeding to death secondary to cerebral oedema and herniation.