Maple syrup urine disease (MSUD) can be caused by mutation in at least 4 genes. These genes encode the components of the branched-chain alpha-keto acid dehydrogenase complex (BCKD), which catalyzes the catabolism of the branched-chain amino acids, leucine, isoleucine, and valine.¹ Accumulation of these 3 amino acids and their corresponding ketoacids leads to encephalopathy and progressive neurodegeneration in an affected patient.²

Epidemiology

• Occurs in about 1 per 300,000 newborns.
• Incidence as high as 1 in 200 births in certain Mennonite settlements in the United States.³
• Autosomal recessive disorder.
• There is considerable genetic heterogeneity due to various mutations that occur in the E1 alpha, E1 beta, E2, and E3 loci of the BCKD complex.⁴

Screening

• MSUD may be detected in the newborn period. A bacterial inhibition method, thin layer chromatography and tandem mass spectrometry are all able to detect an increase in leucine, isoleucine and alloisoleucine.
• These methods may not detect all patients with E3 deficiency or intermittent MSUD.
• Population screening is carried out in some US states. The screening test and availability of results needs to be as soon after birth as possible in order to prevent illness and possible irreversible complications in those affected.
• Prenatal diagnosis can be performed by enzyme testing on cultured amniocytes or chorion villus cells. If mutation is known, DNA testing may be available.

Presentation

Five distinct clinical variants can be distinguished based on age of onset, severity of clinical symptoms, and response to thiamine treatment:

• Classic MSUD:
  • The most common form of MSUD.
  • Symptoms develop in neonates aged 4-7 days (breastfeeding may delay onset of symptoms to the second week of life).
  • Presents with poor feeding, vomiting, poor weight gain and increasing lethargy.
  • Neurological signs (e.g. alternating muscular hypotonia and hypertonia, dystonia, seizures, encephalopathy) develop rapidly.
  • Ketosis and the characteristic odour of maple syrup in the urine are usually present when the first symptoms develop.
• Intermediate MSUD:
  • Only about 20 patients have been reported.
  • Variable degree of neurological impairment, developmental delay and seizures.
  • May present at any age depending on residual enzyme activity.
• Intermittent MSUD:
  • Second most common form of MSUD.
  • Normal growth and intelligence but present during episodes of physical stress (e.g. intercurrent illnesses) with ataxia, lethargy, seizures and coma.
• Thiamine-responsive MSUD:
  • Rare form of MSUD.
  • Show some improvement of metabolic control to thiamine in addition to dietary restriction of branched-chain amino acids.
• E3-deficient MSUD:
  • Additional deficiencies of pyruvate and alpha-ketoglutarate dehydrogenase complexes.
  • Fewer than 10 patients reported.
  • Presentation very similar to intermediate MSUD but with accompanying lactic acidosis.

Differential diagnosis

Any cause of an unwell newborn baby, particularly infection and other metabolic disorders that may present in the first week of life.

Investigations

• Plasma amino acids: elevation of branched-chain amino acids. Detection of alloisoleucine (may not appear until the sixth day of life) is diagnostic.
• Urine organic acids by gas chromatography-mass spectrometry: for the detection of alpha-hydroxyisovalerate, lactate, pyruvate, and alpha-ketoglutarate.
• Enzyme activity can be measured in lymphocytes and/or cultured fibroblasts, though this test is not necessary for diagnosis.

Management

• Main aspect of treatment is dietary restriction of branched-chain amino acids. Dietary therapy must be lifelong (proprietary products are available).
• Episodes of metabolic decompensation: intravenous glucose infusions with added insulin infusions to promote anabolism. Stop intake of branched-chain amino acids, but resume intake as soon as plasma branched-chain amino acids return to normal. Dialysis is occasionally required to remove branched-chain amino acids and ketoacids.
• Surgical: three successful liver transplants in patients with classic MSUD have been reported.⁵

Complications

• Patients are at risk of metabolic decompensation during periods of intercurrent illness, e.g. infection, trauma, surgery.
• Dietary compliance is necessary to prevent developmental delay and neurological symptoms.

Prognosis

• Infants with untreated classic MSUD show significant developmental delay and die within the first months of life. A delay in diagnosis longer than 14 days is invariably associated with mental retardation and cerebral palsy but delay in diagnosis even to the end of the first week of life is likely to cause irreversible damage.⁶
• Children with later-onset (intermediate or intermittent) forms of MSUD may show some form of developmental delay depending on the residual enzyme activity.
• Morbidity can be almost completely prevented by early diagnosis and appropriate treatment both at presentation, and during episodes of potential metabolic decompensation.