ACER-001 for Maple Syrup Urine Disease (MSUD)
Maple Syrup Urine Disease (MSUD)
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
- intermediate
- intermittent
- thiamine-responsive4
Classic MSUD is the most severe5 and common type,4 with symptoms usually appearing in the first week of life in untreated infants.5 Affected infants have little to no enzyme activity.5 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).1,4 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
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
Management
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,6,7 liver transplantation can prevent further brain damage, remove the need for a special diet, and provide protection from metabolic crisis.8 Access to liver transplants may be limited by multiple factors including availability of donors and lack of familiarity with the procedure in metabolic centers.10,11 Liver transplants involve risk of surgery, rejection of the transplanted liver, and the lifelong need to take medications to suppress the immune system.12 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.13 However, for a child with classic MSUD, these risks may be outweighed by considerations for the neurological health of the child.8
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 is advancing ACER-001, a pharmacologic treatment option for patients with maple syrup urine disease (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.
» For up-to-date information about ACER-001 for MSUD, subscribe to receive email updates here.
- Burrage LC, Nagamani SCS, Campeau PM, Lee BH. 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, Litwer S, Herring WJ, Elsas LJ. 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, Puffenberger EG, Morton DH. 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.
- Maple Syrup Urine Disease. 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, Rezvani I, DiGeorge AM, Foley CM. Cerebral edema causing death in children with maple syrup urine disease. J Pediatr. 1991;119:42-45.
- Mazariegos GV, Holmes Morton D, Sindhi R, 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, Ng V, Romero R, 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, Faghfoury H, Yoshida EM, Geberhiwot T. Barriers to Transplantation in Adults with Inborn Errors of Metabolism. JIMD Rep. 2013;8:139-144.
- Camp KM, Parisi MA, Acosta PB, et al. Phenylketonuria Scientific Review Conference: State of the science and future research needs. Mol Genet Metab. 2014;112(2):87-122.
- Chin HL, Aw MM, Quak SH, 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.
ACER-001 for Maple Syrup Urine Disease
ACER-001 is a taste-masked, immediate-release formulation of sodium phenylbutyrate (NaPB) developed using a microencapsulation process. Treatment with NaPB is currently being studied as a treatment ofr people with maple syrup urine disease (MSUD). NaPB is approved for people with urea cycle disorders (UCDs) to control their ammonia levels in conjunction with a restricted diet. People with UCDs had been found to have branched-chain amino acid (BCAA) deficiency as a result of NaPB treatment, despite adequate dietary protein intake.2 NaPB was found to increase branched-chain α-keto acid dehydrogenase complex (BCKDC) enzyme activity in healthy people and people with maple syrup urine disease (MSUD).3 This increased BCKDC activity results in a reduction in the plasma levels of BCAA and BCKA in healthy people and those with MSUD,3 suggesting that NaPB may be an effective treatment for people with MSUD, who experience elevated BCAA levels.3,4
The impact of NaPB on reducing blood BCAA levels for people with MSUD is being studied at Baylor College of Medicine in the United States (Clinical Trials #NCT01529060). People with MSUD will be randomly assigned to receive either NaPB or a placebo for two weeks. When the two weeks are completed, all people in the study will receive NaPB for two weeks. For more information about this study, which is currently underway but not recruiting, please visit at ClinicalTrials.gov.
ACER-001 is a formulation of NaPB that has been developed to mask the foul taste of NaPB, which has been reported to be a barrier to adherence.1 As a new formulation, it will be studied to ensure plasma phenylbutyrate levels from treatment with ACER-001 are comparable to other formulations of NaPB. Safety will be assessed based on the number of side effects experienced during treatment, as well as the results of blood and urine tests, and physical examinations. Additional studies will be underway to evaluate the safety and effectiveness of ACER-001 in people with MSUD in the near future.
ACER-001 was granted orphan drug designation as a potential treatment for MSUD in 2014. Orphan drug designation is provided to drugs and biologics that are 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. There is currently no FDA-approved therapy for MSUD, which is sub-optimally managed via a BCAA-restricted diet alone that can be difficult to adhere to and only partially effective.4
» For up-to-date information about ACER-001 for MSUD, subscribe to receive email updates here.
- Shchelochkov OA, Dickinson K, Scharschmidt BF, Lee B, Marino M, Le Mons C. Barriers to drug adherence in the treatment of urea cycle disorders: Assessment of patient, caregiver and provider perspectives. Mol Genet Metab. 2016;8:43-47.
- Scaglia F, Carter S, O’Brien WE, Lee B. Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients. Mol Genet Metab. 2004;81(Suppl 1):S79-S85.
- Brunetti-Pierri N, Lanpher B, Erez A, et al. Phenylbutyrate therapy for maple syrup urine disease. Hum Mol Genet. 2010;19:631-640.
- Burrage LC, Nagamani SCS, Campeau PM, Lee BH. Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Human Molecular Genetics 2014;23:R1-R8.
Patient Resources
The MSUD Family Support Group
The MSUD Family Support Group is a 501(c)(3) charity that brings together healthcare professionals and individuals with maple syrup urine disease (MSUD) and their families. The group helps people with this rare disorder learn how to stay healthy, connect to others and get access to healthcare and support. The group membership is dedicated to providing information and support for those with MSUD and their families, raising awareness of MSUD, and supporting research in the area.
The group also hosts an annual conference, newsletters, a forum to talk to others (members only), and resources that can be ordered.
» Find out more at their website.
The National Organization for Rare Disorders (NORD)
The National Organization for Rare Disorders (NORD), a 501(c)(3) organization, is a patient advocacy organization dedicated to individuals with rare diseases and the organizations that serve them. NORD, along with its more than 250 patient organization members, is committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and patient services.
NORD serves the rare disease community, including patients and their families, patient organizations, researchers, medical professionals, and companies developing orphan products. They also work closely with many government agencies, most notably the National Institutes of Health (NIH) and the Food and Drug Administration (FDA). NORD programs are focused on improving the lives of individuals and families affected by rare diseases.
» Find out more at their website.
The American College of Medical Genetics Clinic Services Search Engine
The American College of Medical Genetics and Genomics (ACMG) maintains a list of genetics clinics with a comprehensive search engine for people in need of a genetics clinic. You can search based on location, specialty, and your own individual needs.
» Find the search engine at the ACMG website.
Physician Resources
- Burrage LC, Nagamani SCS, Campeau PM, Lee BH. 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, Litwer S, Herring WJ, Elsas LJ. 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, Puffenberger EG, Morton DH. 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.
- Maple Syrup Urine Disease. https://www.omim.org/entry/248600 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, Rezvani I, DiGeorge AM, Foley CM. Cerebral edema causing death in children with maple syrup urine disease. J Pediatr. 1991;119:42-45.
- Mazariegos GV, Holmes Morton D, Sindhi R, 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, Ng V, Romero R, 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, Faghfoury H, Yoshida EM, Geberhiwot T. Barriers to Transplantation in Adults with Inborn Errors of Metabolism. JIMD Rep. 2013;8:139-144.
- Chin HL, Aw MM, Quak SH, 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.