Maple syrup urine disease (MSUD, branched-chain ketoaciduria), is an autosomal recessive metabolic disorder affecting branched-chain amino acids. It is one type of organic acidemia. The condition gets its name from the distinctive sweet odor of affected infants' urine, particularly prior to diagnosis, and during times of acute illness.
The disease is named for the presence of sweet-smelling urine, with an odor similar to that of maple syrup, when the person goes into metabolic crisis. The smell is also present and sometimes stronger in the ear wax of an affected individual at these times. Infants with this disease seem healthy at birth but quickly deteriorate, often with severe brain damage, which may be permanent. Without prompt treatment they will die from brain swelling.
Untreated, and during times of metabolic crisis, symptoms of the condition include anorexia, vomiting, dehydration, lethargy, hypotonia, seizures, hypoglycaemia, ketoacidosis, opisthotonus, pancreatitis, rapid neurological decline, coma and cerebral oedema.
Mutations in the following genes cause maple syrup urine disease:
- BCKDHA (Online 'Mendelian Inheritance in Man' (OMIM) 608348)
- BCKDHB (Online 'Mendelian Inheritance in Man' (OMIM) 248611)
- DBT (Online 'Mendelian Inheritance in Man' (OMIM) 248610)
- DLD (Online 'Mendelian Inheritance in Man' (OMIM) 238331)
These four genes produce proteins that work together as the branched-chain alpha-keto acid dehydrogenase complex. The complex is essential for breaking down the amino acids leucine, isoleucine, and valine. These are present in some quantity in almost all kinds of food, but in particular, protein-rich foods such as dairy products, meat, soy, gluten, eggs, nuts, whole grains, seeds, avocadoes, algae, edible seaweed, beans and pulses. Mutations in any of these genes reduces or eliminates the function of the enzyme complex, preventing the normal breakdown of isoleucine, leucine, and valine. As a result, these amino acids and their by-products build up in the body. Because high levels of these substances are toxic to the brain and other organs, this accumulation leads to the serious medical problems associated with maple syrup urine disease.
This condition has an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome, and two copies of the gene – one from each parent – must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder.
Genetic counseling is suggested for prospective parents with a family history of maple syrup urine disease. Some states, such as Pennsylvania, screen all newborns for signs of MSUD. If a screening test shows that your baby may have MSUD, a follow-up blood test for amino acid levels should be done right away to confirm the disease.
Prior to the easy availability of plasma amino acid measurement, diagnosis was commonly made based on suggestive symptoms and odor. Affected individuals are now often identified with characteristic elevations on plasma amino acids which do not have the characteristic odor. The compound responsible for the odor is sotolon (sometimes spelled sotolone).
Maple syrup urine disease can be classified by its pattern of signs and symptoms, or by its genetic cause. The most common and severe form of the disease is the classic type, which appears soon after birth, and as long as it remains untreated, gives rise to progressive and unremitting symptoms. Variant forms of the disorder may appear later in infancy or childhood, with typically less severe symptoms that may only appear during times of fasting, stress or illness, but still involve mental and physical problems if left untreated.
There are several variations of the disease:
- Classic Severe MSUD
- Intermediate MSUD
- Intermittent MSUD
- Thiamine-responsive MSUD
- E3-Deficient MSUD with Lactic Acidosis
This disease can be life threatening if untreated. Even with dietary treatment, stressful situations and illness can still cause high levels of certain amino acids. Death may occur during these episodes. With strict dietary treatment, children have grown into healthy adulthood.
Keeping MSUD under control requires careful monitoring of blood chemistry, both at home and in a hospital setting. DNPH or specialised dipsticks are used to test the patient's urine for ketones (a sign of metabolic decompensation), when metabolic stress is likely or suspected. Fingerstick tests are performed regularly and sent to a laboratory to determine blood levels of leucine, isoleucine and valine. Regular metabolic consultations, including blood-draws for full nutritional analysis, are recommended; especially during puberty and periods of rapid growth. MSUD management also involves a specially tailored metabolic formula, a modified diet, and lifestyle precautions such as avoiding fatigue and infections, as well as consuming regular, sufficient calories in proportion to physical stress and exertion. Without sufficient calories, catabolism of muscle protein will result in metabolic crisis. Those with MSUD must be hospitalised for intravenous infusion of sugars and nasogastric drip-feeding of formula, in the event of metabolic decompensation, or anorexia, diarrhea or vomiting. Food avoidance, rejection of formula and picky eating are all common problems with MSUD. Some patients may need to receive all or part of their daily nutrition through a feeding tube.
A diet with carefully controlled levels of the amino acids leucine, isoleucine, and valine must be maintained at all times in order to prevent neurological damage. Since these three amino acids occur in all natural protein, and most natural foods contain some protein, any food intake must be closely monitored, and day-to-day protein intake calculated on a cumulative basis, to ensure individual tolerance levels are not exceeded at any time. As the MSUD diet is so protein-restricted, and adequate protein is a requirement for all humans, tailored metabolic formula containing all the other essential amino acids, as well as any vitamins, minerals, omega 3 fats and trace elements (which may be lacking due to the limited range of permissible foods), are an essential aspect of MSUD management. These complement the MSUD patient's natural food intake to meet normal nutritional requirements without causing harm. If adequate calories cannot be obtained from natural food without exceeding protein tolerance, specialised low protein products such as starch-based baking mixtures, imitation rice and pasta may be prescribed, often alongside a protein-free carbohydrate powder added to food and/or drink, and increased at times of metabolic stress. Some patients with MSUD may also improve with administration of high doses of thiamine, a cofactor of the enzyme that causes the condition.
Usually MSUD patients are monitored by a dietitian. Liver transplantation is another treatment option that can completely and permanently normalise metabolic function, enabling discontinuation of nutritional supplements and strict monitoring of biochemistry and caloric intake, relaxation of MSUD-related lifestyle precautions, and an unrestricted diet. This procedure is most successful when performed at a young age, and weaning from immunosuppressants may even be possible in the longrun. However, the surgery is a major undertaking requiring extensive hospitalisation and rigorous adherence to a tapering regime of medications. Following transplant, the risk of periodic rejection will always exist, as will the need for some degree of lifelong monitoring in this respect. Despite normalising clinical presentation, liver transplantation is not considered a cure for MSUD. The patient will still carry two copies of the mutated BKAD gene in each of their own cells, which will consequently still be unable to produce the missing enzyme. They will also still pass one mutated copy of the gene on to each of their biological children. As a major surgery the transplant procedure itself also carries standard risks, although the odds of its success are greatly elevated when the only indication for it is an inborn error of metabolism. In absence of a liver transplant, the MSUD diet must be adhered to strictly and permanently. However, in both treatment scenarios, with proper management, those afflicted are able to live healthy, normal lives without suffering the severe neurological damage associated with the disease.