However, in the context of physical exertion and stress, they can manifest the typical signs of the classic form of MSUD. In the intermittent form, individuals are asymptomatic and have normal growth and neurological development. 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. Patients usually appear healthy in the neonatal period, even if the maple syrup odor of earwax may be present. The phenotype is similar to the classic form, but with less severe symptoms. The intermediate form is characterized by a BCKAD residual enzymatic activity varying between 3% and 30%. Later the clinical picture can evolve to coma and respiratory failure. Other signs include hypoglycemia and ataxia. From the fourth or fifth day, the clinical pictures worsen and encephalopathy, lethargy, intermittent apnea, opisthotonus and stereotyped movements appear. Without treatment, patients can manifest ketonuria, irritability and feeding difficulties as early as two or three days 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. 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. The classic form of the disease is characterized by a BCKAD residual enzymatic activity of less than 2%. 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 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.
Maple syrup urine disease code#
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 enzyme is composed of many components, which include the following functional subunits: E1α, E1β, E2 ed E3. The disorder is caused by the reduction of BCKAD activity. The enzyme, which is located in the inner membrane of mitochondria, catalyzes the decarboxylation of the keto acid. In the second step, intervenes the BCKAD multi-enzyme complex, whose activity is particularly high in the liver. It catalyzes the transfer of the BCAAs aminic group to α-ketoglutarate and the modification of the amino acid to the corresponding keto acid. 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. Detailed clinical descriptionīranched-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 disease is due to bi-allelic mutations in the BCKDHA, BCKDHB, DBT and DLD genes, which encode for functional subunits of BCKAD enzyme.
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 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. 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. Maple syrup urine disease (BCKDHA, BCKDHB, DBT, DLD) Summary Panel testing recommended at Breda Genetics for this condition: