Maple syrup urine disease

Panel testing recommended at Breda Genetics for this condition:

Maple syrup urine disease (BCKDHA, BCKDHB, DBT, DLD)


Maple syrup urine disease (MSUD) is an autosomal recessive rare genetic disease caused by a defect in the branched-chain alpha-keto acid dehydrogenase enzyme (BCKAD), which represents the key step in the catabolism of branched-chain amino acids. The classic form is characterized by the peculiar maple sirup odor of newborn earwax and urines few days after birth, feeding difficulties, lethargy, focal dystonia, followed by progressive encephalopathy and central respiratory failure in the absence of any treatment. However, the disease exhibits variability in the clinical presentation and in the severity of the symptoms, with five recognized clinical forms, and without a good genotype-phenotype association. The disease is due to bi-allelic mutations in the BCKDHABCKDHBDBT and DLD genes, which encode for functional subunits of BCKAD enzyme.

Detailed clinical description

Branched-chain amino acids are valine, leucine and isoleucine and are part of the nine essential amino acids that the human body is unable to synthesize. The first step of their catabolism takes place mainly in the skeletal muscle because this is the tissue where the BCAA transaminase (BCAT), the enzyme that starts the BCAA degradation, has the greatest activity. It catalyzes the transfer of the BCAAs aminic group to α-ketoglutarate and the modification of the amino acid to the corresponding keto acid. In the second step, intervenes the BCKAD multi-enzyme complex, whose activity is particularly high in the liver. The enzyme, which is located in the inner membrane of mitochondria, catalyzes the decarboxylation of the keto acid.

The disorder is caused by the reduction of BCKAD activity. The enzyme is composed of many components, which include the following functional subunits: E1α, E1β, E2 ed E3. Bi-allelic mutations of genes that code for any one of these 4 subunits lead to a reduction in the enzymatic complex activity and an accumulation of BCAA and keto acids in plasma and tissues.

The five different forms of MSUD so far identified are the classic form, the intermediate form, the intermittent form, the form thiamine-responsive and the E3 form. The classic and the E3 form of the disorder typically manifest in the neonatal period, while other forms can begin at any time of life.

The classic form of the disease is characterized by a BCKAD residual enzymatic activity of less than 2%. In newborns, the first sign of the disease is the maple syrup odor of earwax, often detectable after 12 hours from birth, and in urine during the first week of life. Patients have an increase in the blood concentration of branched-chain amino acid and of allo-isoleucine, combined with an imbalanced ratio of plasma protein concentration. Without treatment, patients can manifest ketonuria, irritability and feeding difficulties as early as two or three days of life. From the fourth or fifth day, the clinical pictures worsen and encephalopathy, lethargy, intermittent apnea, opisthotonus and stereotyped movements appear. Other signs include hypoglycemia and ataxia. Later the clinical picture can evolve to coma and respiratory failure. Death is usually due to cerebral edema.

The intermediate form is characterized by a BCKAD residual enzymatic activity varying between 3% and 30%. The phenotype is similar to the classic form, but with less severe symptoms. Patients usually appear healthy in the neonatal period, even if the maple syrup odor of earwax may be present. During the first year of life they may experience feeding difficulties, growth delay, intellectual disability and are likely to exhibit neurological symptoms typical of the classic form of MSUD.

In the intermittent form, individuals are asymptomatic and have normal growth and neurological development. However, in the context of physical exertion and stress, they can manifest the typical signs of the classic form of MSUD.

The thiamine-responsive form is rare and is associated with mutations in the DBT gene, encoding the E2 subunit. Patients have a clinical picture similar to the intermediate MSUD form and the disease is usually controlled by a diet poor of BCAAs and with a thiamine supplement.

The E3 form, caused by mutations in the DLD gene, breaks away from the other forms. The phenotypic spectrum is wide and can vary from neonatal-onset neurological symptoms to isolated adult-onset liver disease. The most frequent manifestation is the most severe one, with metabolic acidosis, encephalopathy, feeding difficulties, renal failure and early death. Moreover, patients show high levels of lactate, alanine and α-ketoglutarate, which are associated with mitochondrial dysfunction. Individuals with liver disease can show signs and symptoms at any age and experience recurrent hepatopathy episodes that decrease with age and are often triggered by hypercatabolic states.

Biochemical tests can lead to the exact diagnosis, by quantitative analysis of plasma amino acids. Patients have high levels of plasma leucine, combined with low levels of other essential and non-essential amino acids. Usually, also the concentration of valine and isoleucine are increased, but in some cases they can be normal or even decreased.
Quite specific for MSUD is the detection of plasma levels of allo-isoleucine (>5 µmol/L), a metabolite found in all the forms of MSUD. Typical is also the urine excretion of branched-chain hydroxy acids and α-keto acids, in patients with more than 48-72 hours of life. To detect these metabolites, a quantitative analysis can be performed throughout gas-chromatography/ mass spectrometry or through test with dinitrophenylhydrazine. The use of tandem mass spectrometry in newborn screening has simplified plasma amino acid profiling, making a timely and more effective medical intervention possible for patients with MSUD.


MSUD is a rare disorder vast majority of the population, with a frequency of 1/185.000 live birth. As a result of a founder effect, some Mennonite populations from Pennsylvania, Kentucky, New York, Wisconsin, Michigan, Iowa and Missouri have a carrier frequency of 1/10 and a frequency of the disorder of 1/380 live birth.

Molecular genetics

BCKDHA gene codes for E1α subunit and is associated with type Ia Maple syrup urine disease, which accounts for 45% of all MSUD cases*. Mutations are mainly missense and small deletions/insertions and there are not recurrent mutations in the general population. However, in some Mennonite populations of Pennsylvania the mutation c.1312T>A (p.Tyr438Asn) is recurrent.

BCKDHB gene codes for E1β subunit and is associated with type Ib Maple syrup urine disease, which accounts for about 35% of all MSUD cases*. Mutations are mainly missense, small deletions/insertions and splicing, and there are not recurrent mutations in the general population. However, in the Ashkenazi population the mutation c.548G>C (p.Arg183Pro) is recurrent.

DBT gene codes for E2 subunit and is associated with type 2 Maple syrup urine disease, which accounts for about 20% of all MSUD cases*. There are not recurrent mutations in the general population, however a higher than expected frequency was found for small and large deletions in this gene.

Mutations in the DLD gene, which codes for E3 subunit, cause dihydrolipoamide dehydrogenase deficiency, also known as Maple syrup urine disease type 3.  This disorder is quite different from other forms of MSUD.

* the total number of patients considered in the calculation is given by the sum of the cases of mutations in the BCKDHA, BCKDHB and DBT genes. Cases of MSUD resulting from mutations in the DLD gene are not included in the calculation.

Differential diagnosis

In newborns with encephalopathy, asphyxia, hypoglycemia, status epilepticus, kernicterus, meningitis and encephalitis must be excluded.

The few metabolic deficits that have neonatal encephalopathy as a symptom include hyperchetosis syndrome, urea cycle defects, glycine encephalopathy, propionic or methylmalonic acidemia. However, only maple syrup disease is the only one that has earwax smell or a positive test with dinitrophenylhydrazineurine in the urine.

Usually, plasma amino acid analysis is sufficient to rapidly diagnose the disease. The molecule responsible for the typical maple sirup odor can be found also in some foods such as fenugreek and lovage. It has been reported that maternal indigestion of fenugreek during pregnancy can cause a false suspect of maple syrup disease.

Genetic testing strategy

The most suitable choice for genetic confirmation in patient with typical signs and/or positive biochemical tests for maple syrup disease is the sequencing of an NGS multigene panel including BCKDHABCKDHBDBT and DLD.

Panel testing recommended at Breda Genetics for this condition:

Maple syrup urine disease (BCKDHA, BCKDHB, DBT, DLD)


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Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. Holeček M. Nutr Metab (Lond). 2018 May 3;15:33. PMID: 29755574

Maple syrup urine disease: mechanisms and management. Blackburn PR, Gass JM, Vairo FPE, Farnham KM, Atwal HK, Macklin S, Klee EW, Atwal PS. Appl Clin Genet. 2017 Sep 6;10:57-66. PMID: 28919799

Neurological damage in MSUD: the role of oxidative stress. Sitta A, Ribas GS, Mescka CP, Barschak AG, Wajner M, Vargas CR. Cell Mol Neurobiol. 2014 Mar;34(2):157-65. PMID: 24220995

Domino liver transplantation in maple syrup urine disease: a case report and review of the literature. Badell IR, Hanish SI, Hughes CB, Hewitt WR, Chung RT, Spivey JR, Knechtle SJ. Transplant Proc. 2013 Mar;45(2):806-9. PMID: 23267808

Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Burrage LC, Nagamani SC, Campeau PM, Lee BH. Hum Mol Genet. 2014 Sep 15;23(R1):R1-8. PMID: 24651065

Orphanet: ORPHA268145

OMIM: 248600

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