Maple Syrup Urine Disease

What is Maple Syrup Urine Disease (MSUD) ?

MSUD is a metabolic disorder caused by the deficiency of branched-chain alpha-keto acid dehydrogenase complex (BCKDC).
BCKDC is required to break down amino acids such as leucine, isoleucine & valine.
Affected infant's urine gives off a sweet odour, which smells similar to that of maple syrup, hence the name MSUD.

It is an inherited, autosomal recessive disorder caused by a mutation in genes. Both parents will have to be unaffected carrier which contains one normal gene and one mutated gene.
The child with both mutated genes will be the affected one with MSUD.
The child with only one mutated genes will be the unaffected carrier.
The child with non mutated  genes will be unaffected at all.

Types of MSUD

Classic MSUD: The most common and severe form of MSUD. Patients with classic MSUD have very little or no enzyme activity (2%<). Affected patients will show symptoms within a few days of birth.

Intermediate MSUD: Rare version of classic MSUD. Patients with intermediae MSUD will have slightly higher enzyme activity compared to those who have classic MSUD (3-8%). The period where symptoms appears varies.

Intermittent MSUD: Milder form of MSUD.  Patients with intermittent MSUD will have the highest enzyme activity compared to intermediate and classic MSUD (8-15%). Symptoms will appear when patient is around 1-2 years old, triggered when child experiences illness or surge in protein level. This type of MSUD does not affect the patient's development physically and intellectually.

Thiamine-responsive MSUD: Rare form of MSUD. Patients with this type can have their conditions improve with large doses of thiamine (Vit B1). However, moderate dietary restrictions are still required. Symptoms appears after infancy.


Symptoms of MSUD

Initial symptoms are:

• Lethargy
• Poor appetite 
• Weight loss
• Distinctive maple sugar odor in earwax, sweat and urine.
• Irregular sleeping pattern 
• High pitched cry

Intermediate and thiamine-response MSUD symptoms:

• Distinctive maple sugar odor in earwax, sweat and urine.
• Developmental delays
• Seizures
• Neurological deficiencies 
• Feeding problems

How does it affect individual?

MSUD will occur due the deficiency of BCKDC, hence amino acids leucine, isoleucine and valine will not be broken down.

The build up of the amino acids will cause:

• Neurological damage in the Central Nervous System (CNS)
• Spastic quadriparesis - paralysis of all limbs with increased muscle tone
• Seizures
• Coma   
• Mortality
• Developmental disabilities
• Metabolic acidosis - produce too much acid in the body
• Hypoglycemia - low blood sugar levels  

Infants with untreated early MSUD have significant developmental delay and die within the first months of life. Children or juveniles with late-onset (ie, intermediate, intermittent) forms of MSUD may have some form of developmental delay, depending on the residual activity of BCKD. All children are at increased risk for metabolic decompensation during periods of increased protein catabolism (eg, intercurrent illness, trauma, surgery). Morbidity can almost entirely be prevented with early diagnosis (in a neonate younger than 10 d), with appropriate treatment at presentation and during episodes of potential metabolic decompensation.

Biochemistry behind the disease

MSUD occurs when there is mutation in 4 genes - BCKDHA, BCKDHB, DBT, and DLD.

These genes create essential protein complexes which are required for the breakdown of certain amino acids (leucine, isoleucine, and valine)

BCKDHA+BCKDHB = E1 component (branched-chain alpha-keto acid decarboxylase)
DBT = E2 component (dihydrolipoyl acyltransferase)
DLD = E3 component (dihydrolipoyl dehydrogenase)

E1+E2+E3= BCKD complex

Accumulation of leucine in particular causes neurological symptoms, whereas elevation of plasma isoleucine is associated with the maple syrup odor. Leucine is rapidly transported across the blood-brain barrier and is metabolized to presumably yield glutamate and glutamine.

Since the way BCKD enzyme complex breakdown leucine, valine and isoleucine are similar (just different reactants and product for individual amino acid), only leucine degradation is shown below

Diagnosis
Types:

1. Plasma amino acid test (determine amount of amino acid in blood)
2. Urine amino acid test (determine amount of amino acid in urine)

Examples:

• Using gas chromatography-mass spectrophotometry to detect amino acids in urine
• Newborn screening using tandem mass spectrophotometry to determine concentration levels of amino acids in blood.

Possible cures

1. Currently, the only possible cure for MSUD is liver transplant.However, there might be a risk of patient rejecting the transplanted organ. Patients that underwent transplantation may be healthy afterwards, but genetically, they still contain the recessive gene which causes MSUD. (Why the liver? Enzymes affected by MSUD are located in the liver.) 
2. Initiate intravenous glucose infusions (5-8 mg/kg/min for infants) as rapidly as possible. Insulin infusions may be added to promote anabolism.

Treatments

1. Patients undergo special diets which includes a man-made infant formula with low levels of amino acids leucine, isoleucine, and valine
2. To reduce amino acids in the body, peritoneal dialysis or hemodialysis can be used

References

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

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

http://thealchemistkitten.wordpress.com/tag/tca-cycle/

http://pathman.smpdb.ca/pathways/SMP00032/pathway?level=2
http://www.smpdb.ca/view/SMP00199
http://www.nytimes.com/health/guides/disease/maple-syrup-urine-disease/overview.html