Maple syrup urine disease (MSUD) is a rare genetic metabolic disorder called an inborn error of metabolism (IEM). For people with MSUD, the body does not have enough of a properly working enzyme needed to break down certain amino acids (building blocks of protein)1 This enzyme is called the branched chain alpha ketoacid dehydrogenase (BCKD) complex.2
MSUD is caused by mutations in the genes involved in making the BCKD complex, which breaks down the amino acids leucine, isoleucine, and valine (also called branched-chain amino acids, BCAA).3 These amino acids are found in protein-rich foods. The amino acids and their by-products build up in the bodies of people with MSUD and can result in damage to the brain and other organs.1
MSUD is inherited in an autosomal recessive pattern, which means that both parents have one defective copy of the gene, which is passed on to the affected child.4 MSUD occurs in approximately 1 in 185,000 infants, but is more common in Old Order Mennonites, where it has a frequency of 1 in 380.4 It is equally likely to affect males and females.
Types of MSUD
MSUD is sometimes subdivided into 4 types:
Classic MSUD is the most severe and common type4 with symptoms usually appearing in the first week of life in untreated infants. Affected infants have little to no enzyme activity.4
With insufficient enzyme activity, BCAA can accumulate to toxic level (called “metabolic intoxication”), which can damage the brain (called “encephalopathy”). Symptoms may include poor feeding, vomiting, lack of energy, irritability, unusual movements that look like “bicycling” or “fencing”, and a maple syrup (“burnt sugar”) odor that may be detected especially in the earwax and urine.4 Left untreated, it can cause developmental delay, intellectual disability, seizures, coma and death within the first months of life.1,4 Some people with classic MSUD have experienced behavior and mental health issues such as attention deficit hyperactivity disorder (ADHD), impulsivity, anxiety, and depression, even when being treated.4
Intermediate MSUD is very rare, with only about 20 reported cases.1,4 With this form of MSUD, infants have higher levels of enzyme activity than the classic form of MSUD. The disease may appear in infancy or in childhood and is usually diagnosed between 5 months and 7 years of age.4 While milder, it can still lead to developmental delays, seizures, and poor growth. People with intermediate MSUD may experience severe episodes of toxic levels of BCAA (metabolic intoxication or crisis) that can result in damage to the brain (encephalopathy) if physiological stress overwhelms the residual BCKD activity, similar to episodes experienced by people with classic MSUD. This can lead to cognitive challenges and even death.4
Intermittent MSUD is also very rare. People with intermittent MSUD typically have normal early growth and intellectual development.4 The disease is often not detected until the person experiences the stress of fasting, dehydration and/or severe illness (usually this occurs before 2 years of age).4 This may lead to sudden spikes in amino acid levels and severe symptoms such as muscle spasms, poor coordination, coma, brain damage, and death. This is also called “decompensation” or “metabolic crisis”, which can lead to cognitive challenges and even death.4
Thiamine-responsive MSUD usually does not cause symptoms in the newborn period but appears later in infancy. The pattern and timing of symptoms are similar to intermediate MSUD.1,4
Diagnosis of MSUD is based on symptoms and biochemical testing of blood and urine. It is confirmed with molecular genetic testing for mutations in the genes that encode BCKD. Tests may also be done to measure enzyme activity, but this testing is becoming less readily available.4
MSUD can also be detected using newborn screening, which is now being performed in the U.S. and other developed countries. However, newborn screening may not be effective in detecting intermediate and intermittent MSUD, when the person may have sufficient enzyme activity at the time of assessment. If newborn screening is suggestive of MSUD, confirmatory biochemical and molecular genetic testing is performed. Prenatal diagnosis is available for people with a previously diagnosed family member. Genetic counselling can provide valuable information and support for families affected by MSUD.4
There are two main aspects to managing all types of MSUD: chronic treatment with a special diet and acute treatment of a metabolic crisis (where the stress of fasting, dehydration, and/or a serious illness triggers severe symptoms) when it occurs.1 Managing a metabolic crisis can involve treating the underlying stress,4 removing leucine and other by-products from the blood using hemodialysis (a process of purifying a person’s blood when their kidneys are not working appropriately) or hemofiltration (a replacement therapy for people whose kidneys are not working properly), and giving fluids, insulin, sugars and fats through a vein.1 Hemodialysis or hemofiltration should not be undertaken lightly as it can be challenging to manage changes in fluids in the body and other metabolic changes that can occur as a result. Sometimes administration of protein with limited BCAA is helpful given by feeding tube and/or vein.
For classic MSUD, which carries higher risk for metabolic intoxication and encephalopathy,5,6 liver transplantation can prevent further brain damage, remove the need for a special diet, and provide protection from metabolic crisis.7 Access to liver transplants may be limited by multiple factors including availability of donors and lack of familiarity with the procedure in metabolic centers.8-10 Liver transplants involve risk of surgery, rejection of the transplanted liver, and the lifelong need to take medications to suppress the immune system.11 Liver transplantation in children also carries its own set of considerations, including the currently unknown impact of life-long immunosuppressant drugs on a child’s growth, development, and psychological well-being.12 However, for a child with classic MSUD, these risks may be outweighed by considerations for the neurological health of the child.7
A metabolic disease specialist coordinates treatment of a person with MSUD. There is currently no pharmacologic treatment option for people with MSUD. The chronic treatment with special diet involves restricting BCAA intake and using medical foods and supplements to maintain the right balance of protein and amino acids. People with thiamine-responsive MSUD may also receive thiamine.4 Managing the diet and supplements requires careful monitoring of amino acid levels in the blood and adjustment for sick days, age, and weight. Adhering to the diet may be difficult.4
Acer, in collaboration with Relief Therapeutics, is advancing ACER-001 (sodium phenylbutyrate) for the treatment of various inborn errors of metabolism, including UCDs and MSUD. ACER-001 was granted orphan drug designation as a potential treatment of MSUD in 2014. Orphan drug designation is intended for the safe and effective treatment, diagnosis, or prevention of rare diseases and disorders that affect fewer than 200,000 people in the U.S.
- Burrage LC, et al. Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Human Molecular Genetics 2014;23:R1-R8.
- Chuang D. Maple syrup urine disease: it has come a long way. J Pediatr. 1998;132:S17-23.
- Danner DJ, et al. Molecular genetic basis for inherited human disorders of branched-chain alpha-keto acid dehydrogenase complex. Ann N Y Acad Sci. 1989;573:369-377.
- Strauss KA, et al. Maple Syrup Urine Disease. In: Pagon RA, Adam MP, Ardinger HH, al. e, eds. GeneReviews® [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK1319/: University of Washington, Seattle; 2006. Accessed March 22, 2017
- Hilliges C, Awiszus D, Wendel U. Intellectual performance of children with maple syrup urine disease. Eur J Pediatr 1993;152:144-147.
- Riviello Jr JJ, et al. Cerebral edema causing death in children with maple syrup urine disease. J Pediatr. 1991;119:42-45.
- Mazariegos GV, et al. Liver Transplantation for Classical Maple Syrup Urine Disease: Long-Term Follow-Up in 37 Patients and Comparative United Network for Organ Sharing Experience. J Pediatr. 2012;160(1):116-121.
- Squires RH, et al. Evaluation of the Pediatric Patient for Liver Transplantation: 2014 Practice Guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Hepatology. 2014:362-398.
- Sirrs SM, et al. . Barriers to Transplantation in Adults with Inborn Errors of Metabolism. JIMD Rep. 2013;8:139-144.
- Camp KM, et al. Phenylketonuria Scientific Review Conference: State of the science and future research needs. Mol Genet Metab. 2014;112(2):87-122.
- Chin HL, et al. Two consecutive partial liver transplants in a patient with Classic Maple Syrup Urine Disease. mol Genet Metab Rep. 2015;4:49-52.
- McDiarmid SV. Liver transplantation. The pediatric challenge. Clin Liver Dis. 2000;4(4):879-927.