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Maple Syrup Urine Disease

Addison, Jenna, Kyra

What is the Disorder?

MSUD is a metabolism disorder passed down through families in which a person cannot break down the amino acids leucine, isoleucine and valine.This is caused by a gene defect.

- poor feeding

- vomiting

- lethargy or lack of energy

- developmental delay

- may lead to seizures, coma or death

- symptoms are most common and severe at birth

- neurological damage

- difficulty being woken up from sleep

- metabolic crisis (major cause of certain symptoms)

- metabolic acidosis

- swelling of the brain

There are several treatment options to assist in lessening the impact on the body. Treatment involves eating a protein free diet, avoiding foods like eggs, meat, fish and nuts. Individuals with MSUD must remain on this diet for their entire life in order to avoid neurological damage. IV is a method used to transfer fluids, sugars and sometimes fats into the patients body. There is also a formula available to cause excess amino acids to be used up within the body, during protein synthesis. Frequent blood tests are necessary to ensure there is no accumulation of amino acids, which would result in neurological damage.

Through consuming a protein free diet, it doesn't add to the protein already built up in the blood, which means there is less amino acids to attempt to break down. Even with following a strict diet, people with MSUD can still experience high levels of leucine during times of physical and emotional stress.

BCKDHA:

  • "Branched chain keto acid dehydrogenase E1, alpha polypeptide"
  • It gives directions to a group of enzymes to enable them to work together
  • Located on chromosome 19

BCKDHB:

  • "Branched chain keto acid dehydrogenase E1, beta polypeptide"
  • Located on chromosome 6

DBT:

  • "Dihydrolipoamide branched chain transaclyase E2"
  • Located on chromosome 1

Maple Syrup Urine Disease can have a serious impact on the central nervous system if left untreated. It affects the myelinated white matter of the brain and can lead to dysmyelination, meaning there is destruction or damage to normal myelination. Individuals with MSUD can also experience cerebral edema, a condition where excess fluid accumulates in the intracellular or extracellular spaces of the brain. It is important to treat this disease as early as possible, as it causes brain cells to rapidly degenerate.

The disease develops from a mutation in the DNA, which causes the absense or deficiency in a particular enzyme, BCKAD, that breaks down the amino acid leucine. The development of the affected individual's DNA would would begin during initial cell production, and the since the liver deaminates amino acids, MSUD indirectly impacts the endocrine system.

Infants should be tested as soon as they can following birth, either on the fifth day of their life, being discharged from the hospital, or after death to discover if it was a possible cause of death.

Genetic or DNA testing is available to see if parents carry the recessive allele. A test is done on a blood sample to look for changes in the pair of specific genes that code for MSUD.

The characteristic odor, and unusually high concentrations of keto and amino acids in the urine typically confirm the suspected possibility of the disease being present.

An enzyme test is available to be done on a blood or skin sample.Test for elevated blood leucine, with a filter blood paper specimen. MSUD is tested by the amounts of leucine, with abnormal amounts being greater than 0.4 mg/mL.

The liver is the largest organ in the body, and develops from the mesodermic germ layer. The livers ability to maintain homeostasis within the body is significantly altered with the mutated enzyme present with MSUD. The liver is therefore unable to deaminate amino acids, causing them to accumulate becoming detrimental to the central nervous system and for protein synthesis.

Endocrine processes cause the amino acids to overflow within the body and appear in waste from the body, causing a maple syrup or burnt sugar scent of the urine. Normally, the endocrine system secretes hormones to promote the secretion of enzymes, however, the enzyme required would be deficient and would not complete the required breakdown of the amino acids from protein sources.

This disease causes an affected individual to be unable to break down amino acids, specifically leucine, valine, and isoleucine. Normally, these amino acids are broken down by a six protein complex, called BCKD (branched-chain alpha-ketoacid dehydrogenase). In someone with MSUD, one of these six proteins in the complex would be deficient, caused by a mutation most commonly within a gene on chromosome 19.

What are the effects?

When and how does it manifest itself?

Depending on the severity of the disorder, the effects will vary.The main effect of the conditions is that it makes the affected persons urine have a sweet smell, like maple syrup. This is a result of decreased or absent enzyme activity. In more serious cases, people may suffer from brain damage or intellectual disability. Both of these effects are brought on by physical stress.

Maple Syrup Urine Disease manifests itself within an infant during the first 12-24 hours of it being born. Yet, the disease doesnt reveal itself until upwards of 2 weeks after birth. It can maniest itself in different levels of severity but the most common form is associated with the lowest enzyme activity.

Symptoms

(occuring within 3-4 days after birth)

Liver Transplantation

A possible treatment option for people with MSUD is liver transplantation. This procedure must be thoroughly discussed with physicians and individuals involved, and it also requires life long medicating to prevent the rejection of the donated liver. Although, successful transplants cure individuals of their MSUD symptoms.

Cell Division and Molecular Biology

BCKD is a mitochondrial complex that breaks down certain amino acids.

MSUD is caused by mutations in the BCKDHA, BCKDHB, and DBT genes.

Medication and Treatment Options

Life expectancy

Amino acids begin to build up in the body and these mutations prevent the breakdown of isoleucine, leucine, and valine

The Nervous System

Type of Mutation

Life expectancy is determined by the treatment that is recieved. If successfully treated, individuals with MSUD can live a normal life. However, if it is untreated death can happen during infancy.

MSUD comes from a germline mutation due to the fact it gets inherited through the sperm and the eggs.

More about the Genes

This is classified as a missense mutation as it results in an altered protein because within the body, valine, leucine and isoleucine can not be broken down.

How does the treatment affect the body? Are there any side effects?

Prenatal Screening

Reproduction & Development

Heredity & Genetics

Metabolic Disease Impact

MSUD is a single gene condition, mapped to the 19th chromosome. This disease is inherited in an autosomal recessive pattern meaning both copies of the gene in each cell must have the mutation. Each parent must carry a copy, meaning they are heterozygous, and do not usually show signs or symptoms, because expression would not occur unless an individual was a homozygous recessive genotype.

Pedigree of MSUD

MSUD can be very difficult to manage with the only treatment being dietary restriction. Interestingly, even following a diet absent of protein, certain common illness can bring on spastic episodes where muscles vary from ridgid to floppy. Stress hormones such as adrenaline and cortisol may play a role in the severity of MSUD, as ongoing research may suggest.

DNA & Cell Replication

Punnett Squares

R r

r r

r r r

r r r

Population Genetics

r r r

r r r

0.00540 individuals have MSUD out of 1000 people in Canada

Infants have a higher frequency of this disease because an individual who has MSUD has a low chance of survival unless they follow a very strict diet. As a result, more babies have it than adults and it is diagnosed at an early age.

R R

r r r

Carrier frequency varies, and is notably higher in certain populations of individuals.

Old order Mennonites in Pennsylvania and derivative settlements have a frequency of 1 in 13^3 for MSUD type 1A.

General population, 1 in 321^1 for MSUD type 1A.

Ashkenazi Jewish population have a 1 in 97^4 for MSUD type 1B.

Sources & Citations

Giorgi, A. (n.d.). Maple Syrup Urine Disease. Retrieved May 9, 2015, from

http://www.healthline.com/health/maple-syrup-urine-disease

Haldeman, C. (2012, May 12). Maple Syrup Urine Disease. Retrieved Jun 7, 2015, from

http://www.nlm.nih.gov/medlineplus/ency/article/000373.htm

Roberts, N. (2012) Maple Syrup Urine Disease: New Insights from a Zebrafish Model. Retrieved May 15, 2015, from

http://www.ncbi.nlm.nih.gov/PMC/articles/PMS3380704/

Unknown. Diagnostics for MSUD. (2015). Retrieved May 13 2015, from

http://www.uic.edu/classes/phar/phar332/Clinical_Cases/aametabcasese/MSUD/Diagnostics_of_MSUD.html

Unknown. Maple Syrup Urine Disease. (2015,June 8). Retrieved June 8 2015, from

http://ghr.nlm.nih.gov/condition/maple-syrup-urine-disease

Frequencies

Allelic Frequency:

q^2= 0.00540/1000

q= 0.00232

p=1-q

=0.998

Unknown. Maple Syrup Urine Disease (MSUD). (2015). Retrieved June 8 2015, from

http://learn.genetics.utah.edu/content/disorders/singlegene/msud/

Genotype:

rr (q^2)=5.41 X 10^-6

RR (p^2)=0.995

Rr (2pq)=0.00464

Phenotype:

No disease=0.995

Carrier=0.00464

With disease=5.41 X 10^-6

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