Maple syrup urine disease

Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder caused by variants (in BCKDHA, BCKDHB or DBT genes) leading to impaired breakdown of the branched-chain amino acids: leucine, isoleucine and valine. Classic MSUD presents in neonates with poor feeding, vomiting, lethargy, abnormal movements and a characteristic sweet odour of the urine – from this, MSUD gets its name. Milder later-onset forms may appear in infancy or childhood with episodic decompensation and developmental delay.

Characteristics of classic MSUD are:

• it presents soon after birth;
• poor feeding and vomiting;
• increasing drowsiness and lethargy; and
• (where untreated) progressive encephalopathy, which may present as:
  • intermittent apnoea;
  • stereotyped movements, such as ‘fencing’ and ‘bicycling’; and/or
  • coma and central respiratory failure.

Characteristics of milder variant forms of MSUD are:

• it presents later, between the early months and early years of childhood;
• developmental delay;
• feeding problems and poor growth; and
• learning difficulties, particularly in older children.

Periods of severe catabolic stress in individuals diagnosed with MSUD can precipitate acute leucine intoxication leading to:

• vomiting;
• ataxia and altered consciousness in toddlers; and
• hyperactivity, hallucinations and ataxia in children and adults.

MSUD is caused by decreased activity of the branched-chain alpha-ketoacid dehydrogenase complex (BCKAD). BCKAD is comprised of four subunits (E1a (encoded by BCKDHA), E1b (BCKDHB), E2 (DBT) and E3) and is the enzyme responsible for the second step in the catabolic pathway of the branched-chain amino acids: leucine, isoleucine and valine.

Biallelic (homozygous, or compound heterozygous) pathogenic variants in the genes that encode three out of the four subunits of BCKAD can cause MSUD through reduced or loss of function.

Classic MSUD is caused by complete loss-of-function variants in the BCKDHA, BCKDHB or DBT genes, which leads to absent or near absent enzyme activity. Nonsense, frameshift and large deletion variant types have been observed as causative, as well as exon 2 deletion and exon 2–6 duplication events in DBT.

Variant MSUD is caused by missense and some splice-site variants in either the BCKDHA, BCKDHB and/or DBT genes, which leads to partial enzyme activity. Milder cases are homozygous or compound heterozygous for missense and/or splice-site variants. Intermediate cases may be compound heterozygous for a complete loss-of-function variant with an additional missense variant.

Recognised founder variants are listed below.

• BCKDHA, c.1312T>A, p.Tyr438Asn, variant in Swiss Mennonites
• BCKDHB, c.548G>C, p.Arg183Pro, variant in the Ashkenazi Jewish population (classic MSUD)
• BCKDHB, 11kb deletion, variant in Thai populations (classic MSUD)
• DBT, c.1196C>G, p.Ser399Cys, variant in the Malay population

Biochemical testing for the diagnosis of MSUD is typically performed by specialist metabolic laboratories. Testing includes quantitative plasma amino acid analysis and urine organic acid analysis.

Amino acid analysis is used to detect the plasma leucine concentrations, which is characteristically elevated in MSUD patients. Isoleucine and valine are typically also elevated, but may be normal. An elevated plasma allo-isoleucine concentration is diagnostic for MSUD. Integratively, organic acid analysis is used to support the diagnosis by identifying elevated branched-chain keto- and hydroxy-acids in the urine.

MSUD may also be diagnosed by tandem mass-spectrometry analysis of leucine, isoleucine and allo-isoleucine combined in dried blood spots, as part of newborn screening. In England, this analysis is a part of the NHS newborn blood spot screening programme.

This condition may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to metabolic services. Please refer to the local pathway for your region for this condition.

MSUD is an autosomal recessive condition.

• If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
  • 1 in 4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
  • 1 in 2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
  • 1 in 4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

About 1 in 116,000 infants are affected by the condition in the UK.

Families with an affected child should be referred for genetic counselling, as both parents will be carriers and there may be implications for other family members.

Prenatal (amniocentesis or chorionic villus sampling) or preimplantation genetic testing may be possible if the causative pathogenic variants are identified in both parents.

Treatment of neonates with classic MSUD is a medical emergency. The goal of acute management is to promote protein anabolism and avoid catabolism by giving intravenous 10% dextrose/0.45% saline. In severe cases, dialysis may be required to eliminate toxic metabolites.

The management of MSUD is centred upon avoiding the toxic accumulation of branched-chain amino acids (BCAA). This is achieved by the restriction of dietary BCAA and the careful manipulation of calorie intake to avoid catabolism. Patients may also be supplemented with BCAA-free amino acid formula and/or medical meals, to provide non-BCAAs and enable protein synthesis. Treatment is guided by the regular monitoring of plasma amino acid concentrations.

MSUD patients are at risk of developing acute metabolic decompensations. This is commonly precipitated by a stressor such as illness, infection, trauma, surgery or a significant change in diet. Patients are therefore provided with an emergency treatment protocol comprising high-calorie BCAA-free ‘sick-day’ formulas and aggressive dietary leucine restriction.

Long-term dietary treatment of MSUD patients is typically managed by a specialist metabolic team including clinicians, specialist nurses and dietitians.

This condition may be identified before any symptoms appear, for example through the Generation Study. Therefore, management of these individuals may differ from those presenting symptomatically.

For clinicians

• British Inherited Metabolic Diseases Group: Guidelines
• Gov.uk: Maple syrup urine disease (MSUD): detailed information
• Gov.uk: Newborn blood spot screening programme: supporting publications

For patients

• NHS Baby: Newborn blood spot test