Maple Syrup Urine Disease: An Overview

 

Mr. Rinu J George

Associate Professor, [Child Health Nursing] Shri Shankaracharya College of Nursing,

Amdi Nagar, Hudco, Bhilai, CG.

*Corresponding Author E-mail: rinugeorge57@yahoo.com

 

ABSTRACT:

Maple syrup urine disease (MSUD) 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. Maple syrup urine disease can be classified by its pattern of signs and symptoms, or by its genetic cause. The disease is named for the presence of sweet-smelling urine, similar to maple syrup, The treatment of MSUD has two chief components: lifelong therapy to maintain acceptable amino acid levels in the body and immediate medical intervention for metabolic crises.

 

KEYWORDS: Maple syrup urine disease (MSUD), branched-chain amino acids (BCAAs), branched-chain ketoacid dehydrogenase (BCKDC).

 

 


INTRODUCTION:

Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. The condition gets its name from the distinctive sweet odor of affected infants' urine and the color of maple syrup Fig [1]. It is also characterized by poor feeding, vomiting, lack of energy (lethargy), abnormal movements, and delayed development. If untreated, maple syrup urine disease can lead to seizures, coma, and death. [1]

 

Fig [1] Showing Maple syrup urine [13]

 

Maple syrup urine disease (MSUD) is assessed as classic or intermediate. Twelve hours after birth, untreated neonates with classic MSUD have a syrup odor in cerumen; by 12-24 hours, elevated plasma concentrations of branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine) and allo-isoleucine, as well as a generalized disturbance of plasma amino acid concentration ratios; by age two to three days.[2] Maple syrup urine disease (MSUD) is an inherited disorder caused by mutations within the open chain alpha-keto acid dehydrogenase complex. Worldwide incidence of MSUD is 1:225,000 live births. [3] Newborn screening for MSUD should ideally be done within the first 24 to 48 hours after birth. With proper screening, along side guidance, nutritional counseling, medical care follow-up, and ongoing monitoring, newborns with MSUD can typically continue to measure healthful lives. Nurses play a key role in supporting families with a diagnosis of MSUD. [4]

 

CAUSES:

Deficiency of the branched-chain ketoacid dehydrogenase (BCKDC) and associated elevations within the BCAAs and their ketoacids are recognized because the explanation for syrup urine disease (MSUD) for many years. [5]. MSUD is caused by changes (mutations) in three different genes: BCKDHA, BCKDHB and DBT. Mutations in these genes end in absent or decreased activity of human branched-chain alpha-ketoacid dehydrogenase complex (BCKAD) enzymes. These enzymes are responsible for breaking down the branched chain amino acids leucine, isoleucine, and valine that are in protein-rich foods, The BCAAs are the only amino acids that have a split main carbon chain. Accumulation of those amino acids and their toxic byproducts (ketoacids) leads to the intense health problems related to MSUD. The toxicity of those amino acids seems to be restricted to the leucine; indeed, extra valine and isoleucine are often given during treatment. Accumulation of their respective ketoacids results in metabolic acidosis. Researchers are studying other genes related to the same protein complex that may also be associated with maple syrup urine disease. [6][7]

 

TYPES OF MSUD:

MSUD is also known as:

·       BCKDC deficiency

·       branched-chain alpha-keto acid dehydrogenase deficiency

·       branched-chain ketoaciduria

·       branched-chain ketonuria I

 

There are four subtypes of MSUD. All are inherited genetic disorders. They differ by their degree of enzyme activity, severity, and the age when the disease appears.

 

Classic MSUD:

This is the most common and severe form of the condition. A person with this type has little, if any, enzyme activity - about 2 percent or less of normal activity. Symptoms are present in newborns within a few days of birth. Onset is usually triggered when the infant’s body begins to process protein from feedings.

Intermediate MSUD:

This is a rare version of MSUD. Symptoms and age of onset vary greatly. People with this sort of MSUD have a better level of enzyme activity than classic MSUD-about 3 to eight percent of normal activity.

 

Intermittent MSUD:

This form doesn’t interfere with normal physical and intellectual growth and development. Symptoms usually don’t appear until a toddler is between 1 and a couple of years aged. It’s a milder form of classic MSUD. Individuals have significant enzyme activity-about 8 to fifteen percent of normal activity. The initial reaction of the disease often occurs when the kid experiences stress, illness, or an unusual increase in protein.

 

Even though thiamine can be beneficial, dietary restrictions also are necessary. [8]

 

PATHOPHYSIOLOGY:

MSUD is a metabolic disorder caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKAD), leading to a buildup of the branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products (ketoacids) in the blood and urine.The buildup of these BCAAS will lead to the maple syrup odor that is associated with MSUD. The BCKAD complex begins by breaking down leucine, isoleucine, and valine through the utilization of branch-chain aminotransferase into their relevant α-ketoacids. The second step involves the conversion of α-ketoacids into acetoacetate, acetyl-CoA, and succunyl-CoA through oxidative decarboxylation of α-ketoacids. The BCKAD complex consists of 4 subunits designated E1α, E1β, E2, and E3. The E3 subunit is also a component of pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex. MSUD can result from mutations in any of the genes that code for these enzyme subunits, E1α, E1β, E2, and E3. Mutations of those enzyme subunits will cause the BCKAD complex unable to interrupt down leucine, isoleucine, and valine. The levels of these branched chain amino acids will become elevated and lead to the symptoms associated with MSUD. Glutamate levels are maintained within the brain by BCAA metabolism functions and if not properly maintained can cause neurological problems that are seen in MSUD individuals. High levels of leucine has also been shown to affect water homeostasis within subcortical gray matter leading to cerebral edema, which occurs is MSUD patients if left untreated. [9]

 

CLINICAL CHARACTERISTICS:

Some initial symptoms characteristic of classic MSUD are:

·       A distinctive maple sugar odor in earwax, sweat, and urine

·       Irregular sleep patterns

·       Alternating episodes of hypertonia (muscle rigidity) and hypotonia (muscle limpness)

·       High-pitched cry

·       Lethargy

·       Poor appetite

·       Weight loss

·       Weak sucking ability

 

Signs of intermediate and thiamine-response MSUD include:

developmental delays

·         Feeding problems

·         Poor growth

·         Seizures

·         Neurological deficiencies

·         A distinctive maple sugar odor in earwax, sweat, and urine [8]

 

DIAGNOSIS:

Newborn screening for syrup urine disease involves analyzing the blood of 1–2 day-old newborns through tandem mass spectrometry. Once the newborn is 2–3 days old the blood concentration of branched-chain amino acids like leucine is bigger than 1000µmol/L and alternative screening methods are used. Instead, the newborn's urine is analyzed for levels of branched-chain alpha-hydroxyacids and alpha-ketoacids. The blood concentration of leucine and isoleucine is measured relative to other amino acids to work out if the newborn features a high level of branched-chain amino acids. [14]

 

STANDARD THERAPIES:

Treatment:

The treatment of classic, intermediate, intermittent, and thiamine-responsive MSUD has two chief components: lifelong therapy to take care of acceptable aminoalkanoic acid levels within the body and immediate medical intervention for metabolic crises. Affected children must be regularly monitored to ensure that their amino acid levels remain within acceptable normal ranges. Individuals with MSUD must remain on a protein-restrictive diet that limits the quantity of branched-chain amino acids they absorb. Protein-restriction must start as soon as possible after birth to market proper growth and development. It is particularly important to limit the amount of leucine in the diet. The three amino acids are added to the diet separately in small amounts in order that affected individuals can grow and develop normally. The amount of leucine, isoleucine and valine which will be tolerated by a toddler varies based upon residual enzyme activity [10]

 

Some physicians recommend an attempt of thiamine therapy to work out whether an affected individual is thiamine-responsive. However, no individual with MSUD has been treated solely with thiamine. Even if affected individuals strictly follow a specialized diet, a risk of metabolic crisis still exists. Episodes of metabolic crisis require immediate medical intervention to lower the amount of branched-chain amino acids, especially leucine, within the plasma. Various techniques have been used to reduce plasma leucine levels including dialysis or a process in which plasma is removed from the body and passed through a filter before being returned to the body (hemofiltration). [11]

 

The aim of aggressive therapy for metabolic crises is to undertake and reduce, then reverse, the increased protein catabolism that's the basis explanation for such episodes. This means that any method to increase calories, to reduce protein catabolism [for energy needs] may be helpful. This includes a high glucose intake with intravenous glucose, if necessary, supplemented by a “glucose-insulin drip” since insulin is understood to reinforce endogenous protein synthesis. Intravenous fat is another important source of calories. In addition, it's essential to supply all the opposite amino acids in amounts sufficient to allow new protein synthesis. This is done by the judicious use of intra GI drips or more usually, parenteral nutrition IV using solutions that lack leucine. Many hospitals may use total parenteral nutrition solutions that lack branched-chain aminoalkanoic acid. In addition, insulin may be used to stimulate a metabolic process known as anabolism. During anabolism, various cellular components (including proteins) are combined (synthesized) to formed energy-rich compounds.

 

Other treatment is symptomatic and supportive. Early intervention is vital in ensuring that children with MSUD reach their highest potential. Genetic counseling is recommended for affected individuals and their families.[10]

 

GENETIC COUNSELING:

MSUD is inherited in an autosomal recessive manner. At conception, each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member. [12]

 

REFERENCE:

1.        Maple syrup urine disease, genetics home reference, us national library of medicine, available at https://ghr.nlm.nih.gov/ condition/maple-syrup-urine-disease#sourcesforpage, assessed on 18/04/2020

2.        Strauss KA, Puffenberger EG, Morton DH. Maple Syrup Urine Disease. 2006 Jan 30 [Updated 2013 May 9]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK1319/

3.        Carleton SM, Peck DS, Grasela J, Dietiker KL, Phillips CL, DNA carrier testing and newborn screening for maple syrup urine disease in Old Order Mennonite communities, Genet Test Mol Biomarkers. 2010 Apr;14(2):205-8. doi: 10.1089/gtmb.2009. 0107.

4.        Harris-Haman P, Brown L, Massey S, Ramamoorthy S, Implications of Maple Syrup Urine Disease in Newborns, Nurs Womens Health. 2017 Jun - Jul;21(3):196-206. doi: 10.1016/j.nwh.2017.04.009.

5.        Burrage LC, Nagamani SC, Campeau PM, Lee BH. Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Hum Mol Genet. 2014;23(R1):R1–R8. doi:10.1093/hmg/ddu123

6.        Danner DJ. Maple Syrup Urine Disease. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:468-9.

7.        Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:1971-96.

8.        Maple Syrup Urine Disease (MSUD), healthline, available at https://www.healthline.com/health/maple-syrup-urine-disease, assessed on 18//04/2020

9.        In Burtis, Carl A.; Ashwood, Edward R.; Bruns, David E. (eds.). Tietz Textbook of Clinical Chemistry and Molecular Diagnostics (5th ed.). Elsevier Health Sciences. p. 2062. ISBN 978-1-4160-6164-9.

10.     Maple Syrup Urine Disease, Rare Disease Database, NORD national organization of rare diseases, available at https://rarediseases.org/rare-diseases/maple-syrup-urine-disease/ assessed on 18/04/2020

11.     Simon E, Flaschker N, Schadewaldt P, Langenbeck U, Wendel U. Variant maple syrup urine disease (MSUD) – the entire spectrum. J Inherit Metab Dis. 2006; 29:716-24

12.      Strauss KA, Puffenberger EG, Morton DH. Maple Syrup Urine Disease. 2006 Jan 30 [updated 2013 May 9]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from http://www. ncbi.nlm.nih.gov/books/NBK1319

13.     Maple syrup urine diseases, liberal dictionary, available at https://www.liberaldictionary.com/maple-syrup-urine-disease/ assessed on 18/04/2020

14.     Strauss KA, Puffenberger EG, Morton DH. Maple Syrup Urine Disease. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993.

 

 

 

Received on 23.04.2020          Modified on 09.05.2020

Accepted on 21.05.2020       ©A&V Publications All right reserved

Int.  J. of Advances in Nur. Management. 2020; 8(3):253-256.

DOI: 10.5958/2454-2652.2020.00055.4