Epidemiology

• Worldwide, maple syrup urine disease (MSUD) occurs in about 1 case per 185,000 live births.^[1]
• Incidence as high as 1 in 180 births in certain populations, eg Mennonite settlements in the USA.^[2]
• There is considerable genetic heterogeneity due to various mutations that occur in the E1 alpha, E1 beta, E2, and E3 loci of the branched-chain alpha-keto acid dehydrogenase (BCKAD) complex.^[1]

Screening

• Genetic counselling: carrier testing for relatives at increased risk and prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutations have been identified in an affected family member. Prenatal diagnosis can be performed by enzyme testing on cultured amniocytes or chorion villus cells.
• At approximately 24 hours of life, newborn siblings of an affected individual, who have not been tested prenatally, can be tested by plasma amino acid analysis.^[3] A bacterial inhibition method, thin layer chromatography and tandem mass spectrometry are all able to detect an increase in leucine, isoleucine and allo-isoleucine.
• Population screening is not available in the UK but is carried out in some countries, eg Australia and New Zealand, and in some US states. The screening test and availability of results need to be as soon after birth as possible in order to prevent illness and possible irreversible complications in those affected.

Presentation

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

• Classic maple syrup urine disease (MSUD):
  • The most common form of MSUD.
    Maple syrup odour in cerumen is the first clinical sign of MSUD and is present 12-24 hours after birth.^[3]
  • Symptoms otherwise develop in neonates aged 2-3 days (breast-feeding may delay onset of symptoms to the second week of life).
  • Presents with poor feeding, vomiting, poor weight gain and increasing lethargy.
  • Neurological signs (eg 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:^[3]
  • Individuals with residual branched-chain alpha-keto acid dehydrogenase (BCKAD) activity may appear well during the neonatal period but have maple syrup odour in cerumen and a consistently abnormal plasma amino acid profile. May present with feeding problems, poor growth, and developmental delay during infancy, or may present much later in life with learning difficulties.
  • Usually diagnosed between ages five months and seven years.
  • At risk of the same acute and chronic neurological sequelae as classic MSUD, and severe leucinosis, brain swelling, and death may occur with sufficient catabolic stress.
  • The principle of treatment is the same as for MSUD.
• Intermittent MSUD^[3]:
  • Affected children have normal growth and intellectual development throughout infancy and early childhood.
  • Tolerate a normal leucine intake when well. Plasma amino acid and urine organic acid profiles are normal or show only mild elevations of branched-chain amino acids (BCAAs).
  • During any physiological stress (eg infection), they may develop the clinical and biochemical features of classic MSUD, rarely leading to coma and death.
• Thiamine-responsive MSUD:^[3]
  • Have residual BCKAD enzyme activity and are not ill in the neonatal period. Present later in life with a clinical course similar to intermediate MSUD.
  • No patient has so far been treated only with thiamine. A combination of thiamine and dietary BCAA restriction has been required.
• E3-deficient MSUD:
  • Additional deficiencies of pyruvate and alpha-ketoglutarate dehydrogenase complexes.
  • Fewer than 10 patients reported.
  • Presentation is 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

Maple syrup urine disease (MSUD) is diagnosed by the presence of clinical features and by decreased levels of branched-chain alpha-keto acid dehydrogenase (BCKAD) enzyme activity causing accumulation of branched-chain amino acids (BCAAs), allo-isoleucine, and branched-chain ketoacids in tissues and plasma.^[3]

• Ketonuria can be detected by standard urine test strips; ketonuria in a newborn should always be followed by investigation for metabolic disorders.^[3]
• Plasma amino acids: elevation of branched-chain amino acids. Detection of allo-isoleucine (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, although this test is not necessary for diagnosis.

Management^[3]

• Treatment includes dietary leucine restriction, high-calorie branched-chain amino acid (BCAA)-free formulas, careful supplementation with isoleucine and valine, and frequent clinical and biochemical monitoring.^[3] Dietary therapy must be lifelong (proprietary products are available).
• Episodes of metabolic decompensation: treat the appropriate stress (eg infection), ensuring sufficient calories (may include intravenous glucose infusions), added insulin infusions to promote anabolism, and free amino acids, isoleucine, and valine to achieve sustained net protein synthesis in tissues. Stop intake of BCAAs, but resume intake as soon as plasma BCAAs return to normal.
• Some centres use haemodialysis or haemofiltration to remove extracellular BCAAs.
• Cerebral oedema is a common complication of metabolic decompensation and requires immediate management in an intensive care unit.
• Surgical: liver transplantation has been shown to be effective in treating patients with classic MSUD.^[2]
• For pregnant women who have MSUD, frequent monitoring of plasma amino acid concentrations and fetal growth are necessary to avoid the opposing risks of leucine teratogenicity and essential amino acid deficiencies.^[3]

Complications

• Patients are at risk of metabolic decompensation during periods of intercurrent illness, eg infection, trauma, surgery.
• Dietary compliance is necessary to prevent developmental delay and neurological symptoms.
• Adolescents and adults with maple syrup urine disease (MSUD) are at increased risk for attention deficit hyperactivity disorder (ADHD), depression, and anxiety disorders.^[3]
• Non-central nervous system involvement in MSUD can include:^[3]
  • Nutritional deficiencies:
    • Chronic deficiency of leucine, isoleucine, or valine which may cause anaemia, acrodermatitis, hair loss, growth failure, arrested head growth, anorexia and lethargy.
    • Commercially available MSUD synthetic formulae may provide insufficient intake of some nutrients, eg zinc, selenium, and omega-3 fatty acids, folic acid and selenium.
  • Osteoporosis.
  • Recurrent oesophageal candidiasis.
  • Acute pancreatitis.

Prognosis

• Infants with untreated classic maple syrup urine disease (MSUD) show significant developmental delay and die within the first months of life. A delay in diagnosis for 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.
• 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.

Prevention^[3]

• Dietary management should allow age-appropriate tolerance of leucine, isoleucine, and valine, and maintain stable plasma branched-chain amino acid (BCAA) concentrations and BCAA concentration ratios.
• Use of a "sick-day" formula recipe (no leucine and enriched with calories, isoleucine, valine, and non-BCAAs), combined with rapid and frequent amino acid monitoring, allows many catabolic illnesses to be managed without admission to hospital.