Maple syrup urine disease (MSUD) is an autosomal recessive disorder which can be caused by mutation in at least three genes. These genes encode the components of the branched-chain alpha-keto acid dehydrogenase (BCKAD) complex, which catalyses the catabolism of the branched-chain amino acids (BCAAs), leucine, isoleucine and valine.
Accumulation of these three amino acids and their corresponding ketoacids leads to encephalopathy and progressive neurodegeneration in an affected patient. BCKAD has four subunit components (E1a, E1b, E2 and E3). The three genes associated with MSUD are BCKDHA (E1a subunit gene, MSUD type 1A), BCKDHB (E1b subunit gene, MSUD type 1B) and DBT (E2 subunit gene, MSUD type 2). Molecular genetic testing of all three genes is available.
- Worldwide, MSUD occurs in about 1 case per 185,000 live births.
- Incidence as high as 1 in 380 live births in certain populations - eg, Mennonite settlements in the USA.
- There is considerable genetic heterogeneity due to various mutations that occur in the E1 alpha, E1 beta, E2 and E3 loci of the BCKAD complex.
- Genetic counselling: carrier testing for relatives at increased risk and prenatal diagnosis for pregnancies at increased risk are 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. A bacterial inhibition method, thin layer chromatography and tandem mass spectrometry are all able to detect an increase in leucine, isoleucine and allo-isoleucine.
- Screening for MSUD is now included in the NHS newborn blood spot screening programme.
Five distinct clinical variants can be distinguished, based on age of onset, severity of clinical symptoms and response to thiamine treatment:
- 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.
- 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.
- Individuals with residual 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 5 months and 7 years.
- At risk of the same acute and chronic neurological sequelae as classic MSUD; severe leucinosis, brain swelling and death may occur with sufficient catabolic stress.
- The principle of treatment is the same as for MSUD.
- 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 BCAAs.
- During any physiological stress (eg, infection), they may develop the clinical and biochemical features of classic MSUD, rarely leading to coma and death.
- 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.
- 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.
Any cause of an unwell newborn baby, particularly infection and other metabolic disorders that may present in the first week of life.
MSUD is diagnosed by the presence of clinical features and by decreased levels of BCKAD enzyme activity causing accumulation of BCAAs, allo-isoleucine and branched-chain ketoacids in tissues and plasma.
- Ketonuria can be detected by standard urine test strips; ketonuria in a newborn should always be followed by investigation for metabolic disorders.
- Plasma amino acids: elevation of BCAAs. 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.
- Treatment includes dietary leucine restriction, high-calorie BCAA-free formulas, careful supplementation with isoleucine and valine, and frequent clinical and biochemical monitoring. 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 due to metabolic decompensation is common and requires immediate management in an intensive care unit.
- Liver transplantation has been shown to be effective in treating patients with classic MSUD.
- Transplantation of liver from an unrelated deceased donor restores 9-13% whole-body BCKA oxidation capacity and stabilises MSUD. Reports have shown encouraging short-term outcomes for MSUD patients who received a liver segment from mutation heterozygous living related donors.
- For pregnant women who have MSUD, frequent monitoring of plasma amino acid concentrations and fetal growth is necessary to avoid the opposing risks of leucine teratogenicity and essential amino acid deficiencies.
- 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 MSUD are at increased risk for attention deficit hyperactivity disorder (ADHD), depression and anxiety disorders.
- Non-central nervous system involvement in MSUD can include:
- 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, including zinc, selenium, omega-3 fatty acids, folic acid and selenium.
- Recurrent oesophageal candidiasis.
- Acute pancreatitis.
- Nutritional deficiencies:
- Infants with untreated classic 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 general learning disability 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.
- Combining early diagnosis and aggressive treatment together with close monitoring of leucine levels improves neurological outcome in children with MSUD.
- Dietary management should allow age-appropriate tolerance of leucine, isoleucine, and valine and should maintain stable plasma 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.
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