Maple syrup urine disease (MSUD)

Classic MSUD presents in the neonatal period with a characteristic maple-syrup odour of cerumen and urine, ketonuria, irritability, and poor feeding within the first 48 hours of life. Untreated neonates develop lethargy, intermittent apnoea, opisthotonus, and stereotyped ‘fencing’ and ‘bicycling’ movements by age 4-5 days, progressing to coma and central respiratory failure by 7-10 days.

The condition affects the central nervous system, with risk of cerebral oedema during acute leucinosis precipitated by catabolic stress, and produces lifelong neurocognitive and neuropsychiatric morbidity, including reduced full-scale IQ, attention-deficit/hyperactivity disorder, and movement disorders. Intermediate, intermittent, and thiamine-responsive phenotypes present later in infancy or childhood with episodic encephalopathy or developmental regression triggered by intercurrent illness or increased protein load. Clinical presentation and outcomes show wide inter- and intra-familial variability, contributing to a broad spectrum of severity even within classic MSUD.

Affective illnesses, including depression, anxiety, and panic disorder, are frequently reported in cohorts of classic MSUD patients by age 35; reported prevalence varies widely across studies and often reflects small or selected samples.

The estimated incidence of MSUD is approximately 1 in 185,000 live births. Reported incidence from newborn screening programmes varies internationally, ranging from approximately 1 in 220,000 in the United States to 1 in 59,000 in Kuwait. A significantly higher incidence (approximately 1 in 380 live births) has been described in certain Old Order Mennonite populations due to a founder variant.

MSUD results from biallelic germline pathogenic variants in one of three genes encoding subunits of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex: BCKDHA (~45% of cases), BCKDHB (~35%), and DBT (~20%). The BCKD complex catalyses the oxidative decarboxylation of branched-chain alpha-ketoacids, the second step in the degradative pathway of leucine, isoleucine, and valine. Reduced enzyme activity leads to accumulation of branched-chain amino acids and their corresponding alpha-ketoacids in tissues and plasma, producing the metabolic and neurological features of the disease.

MSUD is inherited in an autosomal recessive manner. Each pregnancy of two heterozygous carriers carries a 25% risk of an affected offspring, a 50% risk of an unaffected heterozygous carrier, and a 25% risk of an unaffected non-carrier. Carrier testing of at-risk relatives requires prior identification of the familial pathogenic variants. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The diagnosis of MSUD is established by detection of elevated plasma concentrations of leucine, isoleucine, and valine together with plasma alloisoleucine, the most sensitive and specific biochemical marker (>5 µmol/L in 99.9% of classic and 94% of intermediate MSUD samples). Urinary excretion of branched-chain alpha-ketoacids and ketonuria support the diagnosis. Confirmation requires identification of biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT.

Main differential diagnoses include:

• : neonatal encephalopathy with hyperammonaemia and respiratory alkalosis but no ketosis; OTC, CPS1, and others
• Glycine encephalopathy: neonatal hiccups, myoclonic seizures, elevated CSF glycine, no ketosis; GLDC, AMT, GCSH
• Organic acidaemias: neonatal acidosis with hyperammonaemia, ketosis, and characteristic acylcarnitine profile; PCCA, MMUT, and others.

• Establishing the diagnosis confirms the clinical suspicion at the molecular level, providing prognostic information and a definitive basis for genetic counselling.
• Identification of the underlying pathogenic variants is a prerequisite for individualised surveillance and clinical management; on the basis of the molecular diagnosis, specific monitoring strategies and targeted medical care are planned by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variants have been identified, predictive and carrier testing of at-risk relatives can be performed, supporting informed reproductive and life-planning decisions.

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