Difference between revisions of "Maple syrup urine disease 2011"

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(Biochemical disease mechanism)
 
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The maple syrup urine (MSUD) disease is an autosomal recessive disorder which is caused by a disturbance in the amino acid metabolism.
 
The maple syrup urine (MSUD) disease is an autosomal recessive disorder which is caused by a disturbance in the amino acid metabolism.
 
The symptomes of MSUD are mental and physical retardation, feeding problems, vomiting, dehydration, lethargy, hypotonia, seizures, hypoglycaemia, ketoacidosis, opisthotonus, pancreatitis, coma and neurological decline. If the disease remains unrecognized it can also lead to brain damage and in the last resort to death.
 
The symptomes of MSUD are mental and physical retardation, feeding problems, vomiting, dehydration, lethargy, hypotonia, seizures, hypoglycaemia, ketoacidosis, opisthotonus, pancreatitis, coma and neurological decline. If the disease remains unrecognized it can also lead to brain damage and in the last resort to death.
The most characteristical symptome is the sweet smell of the urine, just like maple syrup.
+
The most characteristical symptome is the sweet smell of the urine, just like maple syrup giving the disease its name.
  +
The information provided on this site can also be found in [[Media:MapleSyrupDisease.pdf]]
   
 
== Phenotype ==
 
== Phenotype ==
 
The MSUD occurs because of a defect in the branched-chain alpha-keto acid dehydrogenase complex (BCKDC). This defect leads to a block in oxidative decarboxylation which results in a rising concentration of branched-chain amino acids (BCAA) and their toxic by-products in blood and urine.
 
The MSUD occurs because of a defect in the branched-chain alpha-keto acid dehydrogenase complex (BCKDC). This defect leads to a block in oxidative decarboxylation which results in a rising concentration of branched-chain amino acids (BCAA) and their toxic by-products in blood and urine.
The MSUD can be divided in 5 subtypes:
+
The MSUD can be divided into 5 subtypes:
   
- Classic Severe MSUD
+
'''Classic Severe MSUD'''
   
The classic form of MSUD is the worst one of this disease. The level of the BCAAs are dramatically high in blood, urine and cerebrospinal
+
The classic form of MSUD is the worst one of this disease. The level of the BCAAs is dramatically high in blood, urine and cerebrospinal fluid and the BCKD activity is less than 2% of normal activity level. The children seem normal at birth but after 4 to 7 days after birth the first symptoms like lethargy and little interest in feeding appear. With progress of the disease it comes to weight loss and progressive neurological deterioration and hypo- to hypertonia. If the disease is not treated it leads to coma and death within several months after birth.
fluid and the BCKD activity is less than 2% of normal.
 
The children seams normal at birth but after 4 to 7 days after birth the first symptoms like lethargy and little interest in feeding appear.
 
With progress of the disease it comes to weight loss and progressive neurological deterioration and hypo- to hypertonia. If the disease is
 
not treated it leads to coma and death within several months after birth .
 
   
- Intermediate MSUD
+
'''Intermediate MSUD'''
In the intermediate MSUD the level of BCAAS in blood and urine rises permanent and the neurological impairment becomes worse. The level of
 
BCKD ranges from 3% to 30% of normal. In many cases the acute metabolic decompensation do not occur.
 
   
  +
In the intermediate MSUD the level of BCAAS in blood and urine rises permanently and the neurological impairment becomes worse. The level of BCKD ranges from 3% to 30% of normal. In many cases the acute metabolic decompensation do not occur.
- Intermittent MSUD
 
Patients with the intermittent MSUD develop normal. In normal life situations these people have no symptoms and also a normal level of
 
BCAAS. But in stress situations acute metabolic decompensations arise. The level of activity of BCKD ranges from 5% to 50% of normal.
 
Symptoms can appear between 5 months to 2 years of age when the patients have an infection.
 
   
  +
'''Intermittent MSUD'''
- Thiamine-responsive MSUD
 
The progress of the thiamine-responsive MSUD is quite similar to the one of the intermediate MSUD. There is about 5 times more BCAA in the
 
plasma than normal and it is characteristically that alloisoleucine can be detected.
 
This subtype can be handled by a low protein diet which results in a normal BCAA level.
 
   
  +
Patients with the intermittent MSUD develop normal. In normal life situations these people have no symptoms and also a normal level of BCAAS. But in stress situations acute metabolic decompensations arise. The level of activity of BCKD ranges from 5% to 50% of normal. Symptoms can appear between 5 months to 2 years of age when the patients have an infection.
- E3-Deficient MSUD with Lactic Acidosis
 
  +
This subtype of MSUD causes from a defect in the E3 component of the BCKD complex. It is a very form with only 20 reported cases and in
 
  +
'''Thiamine-responsive MSUD'''
the first few month the patient develope quite normal. The symptomes are nearly the same of intermediate MSUD but these patients suffer also
 
  +
lactic acidosis.
 
  +
The progress of the thiamine-responsive MSUD is quite similar to the one of the intermediate MSUD. There is about 5 times more BCAA in the plasma than normal and it is characteristically that alloisoleucine can be detected. This subtype can be treated by a low protein diet which results in a normal BCAA level.
  +
  +
'''E3-Deficient MSUD with Lactic Acidosis'''
  +
  +
This subtype of MSUD is caused by a defect in the E3 component of the BCKD complex. It is an extremely rare form with only 20 reported cases and in the first few month the patient develope quite normal. The symptomes are nearly the same as those of the intermediate MSUD but these patients suffer also from lactic acidosis.
   
   
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=== Cross-references ===
 
=== Cross-references ===
See also description of this disease in
+
A description of this disease can also be found at:
 
* [http://en.wikipedia.org/wiki/Maple_syrup_urine_disease Wikipedia]
 
* [http://en.wikipedia.org/wiki/Maple_syrup_urine_disease Wikipedia]
 
* [http://www.ncbi.nlm.nih.gov/omim/248600 OMIM]
 
* [http://www.ncbi.nlm.nih.gov/omim/248600 OMIM]
Line 50: Line 44:
 
* [http://www.ncbi.nlm.nih.gov/pubmed/20301495 PubMed]
 
* [http://www.ncbi.nlm.nih.gov/pubmed/20301495 PubMed]
 
* [http://themedicalbiochemistrypage.org/msud.html Medical Biochemistry Page]
 
* [http://themedicalbiochemistrypage.org/msud.html Medical Biochemistry Page]
 
   
 
== BCKDHA ==
 
== BCKDHA ==
 
The BCKD complex consists of four proteins:
 
The BCKD complex consists of four proteins:
* BCKDHA (Branched-CHain Keto Acid Dehydrogenase, alpha-subunit)
+
* BCKDHA (Branched-Chain Keto Acid Dehydrogenase, alpha-subunit)
* BCKDHB (Branched-CHain Keto Acid Dehydrogenase, beta-subunit)
+
* BCKDHB (Branched-Chain Keto Acid Dehydrogenase, beta-subunit)
 
* DBT (Dihydrolipoamide Branched-Chain Transacylase)
 
* DBT (Dihydrolipoamide Branched-Chain Transacylase)
 
* DLD (Dihydrolipoamide Dehydrogenase)
 
* DLD (Dihydrolipoamide Dehydrogenase)
Mutations in each of these genes lead to MSUD.
+
Mutations in each of these genes can cause MSUD.
Mutations in the BCKDHA protein are the most common form of MSUD cause.
+
Mutations in the BCKDHA protein are the most common form which lead to MSUD.
   
 
=== Gene ===
 
=== Gene ===
  +
[[Image:BCKDHAchromosome.jpeg|thumb|right|Figure 1: Location of the BCKDHA gene on chromosome 19.[http://ghr.nlm.nih.gov/gene/BCKDHA]]]
  +
The BCKDHA gene is located between base pair 41,903,693 and base pair 41,930,909 on chromosome 19 (gene map locus: 19q13.1-q13.2). The location of chromosome 19 can be seen in [[:File:BCKDHAchromosome.jpeg | Figure 1]]
  +
The overall length of the gene is 27261 nucleotides. The BCKDHA gene contains 9 exons.
  +
  +
=== Cross References ===
  +
* [http://www.ncbi.nlm.nih.gov/gene/593 NCBI: BCKDHA]
  +
* [http://www.ncbi.nlm.nih.gov/omim/608348 OMIM: BCKDHA]
  +
* [http://ghr.nlm.nih.gov/gene/BCKDHA Genetics Home Reference: BCKDHA ]
  +
 
=== Protein ===
 
=== Protein ===
  +
The BCKDHA gene encodes the alpha subunit of the Branched-Chain Alpha-Keto Acid Dehydrogenase E1. It is expressed in the mitochondrial matrix. Its length is 400 amino acids.
  +
  +
[[Image:1u5b_bio_r_500.jpg|thumb|right|Figure 2: Crystal structure of the branched-chain alpha-keto acid dehydrogenase [http://www.pdb.org/pdb/explore/explore.do?structureId=1U5B]]]
  +
  +
The BCKD complex consists of two alpha subunits and two beta subunits (encoded by the BCKDHB gene). A protein structure for BCKDHA is shown in [[:File:1u5b_bio_r_500.jpg | Figure 2]]
  +
  +
=== Cross References ===
  +
* [http://www.pdb.org/pdb/explore/explore.do?structureId=1U5B PDB: BCKDHA]
  +
* [http://www.uniprot.org/uniprot/P12694 Uniprot: BCKDHA]
   
 
== Biochemical disease mechanism ==
 
== Biochemical disease mechanism ==
MSUD is caused by mutations in the Branched-Chain alpha-keto acid dehydrogenase complex (BCKD). This complex is essential for the break down of branched-chain amino acids (Leucine, Isoleucine and Valine). Leucine, Isoleucine and Valine are part of protein-rich food, such as eggs, milk and meat. Mutations in the BCKD-complex prevent the breakdown of the amino acids, which then accumulate, together with their toxic by-products, in the body.
+
MSUD is caused by mutations in the Branched-Chain Alpha-Keto Acid Dehydrogenase Complex (BCKD). This complex is essential for the break down of branched-chain amino acids (leucine, isoleucine and valine, see [[:File:MSUDdegradation.jpg | Figure 3]]). Leucine, isoleucine and valine are part of protein-rich food, such as eggs, milk and meat. Mutations in the BCKD-complex prevent the breakdown of the amino acids, which then accumulate, together with their toxic by-products, in the body. The KEGG-Pathway> shown in [[:File:Hsa00280.png| Figure 4]] gives a detailed overview of BCKDHA's role in the degradation of branched chain amino acids.
   
[[Image:MSUDaminoacids.jpg|thumb|right|Degradation of Leucine, Isoleucin and Valine(source: NCBI)]]
+
[[Image:MSUDdegradation.jpg|thumb|right|Figure 3: Degradation of leucine, isoleucin and valine(source: [http://www.bio.mtu.edu/faculty/gibson_clip_image005.jpg])]]
[[Image:Hsa00280.png|thumb|Degradation of Leucine, Isoleucin and Valine (source: KEGG)]]
+
[[Image:Hsa00280.png|thumb|Figure 4: Role of BCKDHA in the degradation of leucine, isoleucin and valine (source: KEGG)]]
   
   
 
=== Cross-references ===
 
=== Cross-references ===
* link to KEGG: [http://www.genome.jp/kegg-bin/show_pathway?hsa00280]
+
* [http://www.genome.jp/kegg-bin/show_pathway?hsa00280 KEGG: Branched-Chain amino acid degradation]
* link to MetaCyc: [http://biocyc.org/META/NEW-IMAGE?type=ENZYME&object=CPLX-7047]
+
* [http://biocyc.org/META/NEW-IMAGE?type=ENZYME&object=CPLX-7047 Metacyc]
   
 
== Mutations ==
 
== Mutations ==
 
There are currently listed 39 mutations in the BCKDHA protein.(source: HGMD)
 
There are currently listed 39 mutations in the BCKDHA protein.(source: HGMD)
   
  +
<!--
=== Reference sequence ===
 
 
Which sequence does not cause the disease and is most often found in the population.
 
[[Reference_Sequence_BCKDHA|Reference Sequence of BCKDHA]]
 
 
 
=== Neutral mutations ===
 
=== Neutral mutations ===
 
* [[BCKDHA_neutral_mutations|BCKDHA_neutral_mutations]].
 
* [[BCKDHA_neutral_mutations|BCKDHA_neutral_mutations]].
Line 88: Line 95:
 
=== Disease causing mutations ===
 
=== Disease causing mutations ===
 
* [[MSUD_Q80E|Q80E]]
 
* [[MSUD_Q80E|Q80E]]
  +
-->
*
 
  +
*
 
  +
=== Reference sequence ===
  +
  +
This sequence does not cause the disease and is most often found in the population.
  +
  +
[[Reference_Sequence_BCKDHA|Reference Sequence of BCKDHA]]
  +
  +
== TASKS ==
  +
  +
Task 2: [[Sequence_Alignments_BCKDHA|Sequence Alignments]]
  +
  +
Task 3: [[Secondary_Structure_Prediction_BCKDHA|Secondary Structure Prediction]]
  +
  +
Task 4: [[Homology_based_structure_predictions_BCKDHA|Homology based structure predictions]]
  +
  +
Task 5: [[Mapping_SNPs_BCKDHA|Mapping SNPs]]
  +
  +
Task 6: [[Sequence-based mutation analysis_BCKDHA|Sequence-based mutation analysis]]
  +
  +
Task 7: [[Structure-based mutation analysis_BCKDHA|Structure-based mutation analysis]]
  +
  +
Task 8: [[Molecular_Dynamics_Simulations_BCKDHA| Molecular Dynamics Simulations]]
  +
  +
Task 9: [[Normal_Mode_Analysis_BCKDHA | Normal Mode Analysis]]
  +
  +
Task 10: [[Molecular_Dynamics_Analysis_BCKDHA| Molecular Dynamics Analysis]]

Latest revision as of 10:27, 29 March 2012

Summary

The maple syrup urine (MSUD) disease is an autosomal recessive disorder which is caused by a disturbance in the amino acid metabolism. The symptomes of MSUD are mental and physical retardation, feeding problems, vomiting, dehydration, lethargy, hypotonia, seizures, hypoglycaemia, ketoacidosis, opisthotonus, pancreatitis, coma and neurological decline. If the disease remains unrecognized it can also lead to brain damage and in the last resort to death. The most characteristical symptome is the sweet smell of the urine, just like maple syrup giving the disease its name. The information provided on this site can also be found in Media:MapleSyrupDisease.pdf

Phenotype

The MSUD occurs because of a defect in the branched-chain alpha-keto acid dehydrogenase complex (BCKDC). This defect leads to a block in oxidative decarboxylation which results in a rising concentration of branched-chain amino acids (BCAA) and their toxic by-products in blood and urine. The MSUD can be divided into 5 subtypes:

Classic Severe MSUD

The classic form of MSUD is the worst one of this disease. The level of the BCAAs is dramatically high in blood, urine and cerebrospinal fluid and the BCKD activity is less than 2% of normal activity level. The children seem normal at birth but after 4 to 7 days after birth the first symptoms like lethargy and little interest in feeding appear. With progress of the disease it comes to weight loss and progressive neurological deterioration and hypo- to hypertonia. If the disease is not treated it leads to coma and death within several months after birth.

Intermediate MSUD

In the intermediate MSUD the level of BCAAS in blood and urine rises permanently and the neurological impairment becomes worse. The level of BCKD ranges from 3% to 30% of normal. In many cases the acute metabolic decompensation do not occur.

Intermittent MSUD

Patients with the intermittent MSUD develop normal. In normal life situations these people have no symptoms and also a normal level of BCAAS. But in stress situations acute metabolic decompensations arise. The level of activity of BCKD ranges from 5% to 50% of normal. Symptoms can appear between 5 months to 2 years of age when the patients have an infection.

Thiamine-responsive MSUD

The progress of the thiamine-responsive MSUD is quite similar to the one of the intermediate MSUD. There is about 5 times more BCAA in the plasma than normal and it is characteristically that alloisoleucine can be detected. This subtype can be treated by a low protein diet which results in a normal BCAA level.

E3-Deficient MSUD with Lactic Acidosis

This subtype of MSUD is caused by a defect in the E3 component of the BCKD complex. It is an extremely rare form with only 20 reported cases and in the first few month the patient develope quite normal. The symptomes are nearly the same as those of the intermediate MSUD but these patients suffer also from lactic acidosis.



Cross-references

A description of this disease can also be found at:

BCKDHA

The BCKD complex consists of four proteins:

  • BCKDHA (Branched-Chain Keto Acid Dehydrogenase, alpha-subunit)
  • BCKDHB (Branched-Chain Keto Acid Dehydrogenase, beta-subunit)
  • DBT (Dihydrolipoamide Branched-Chain Transacylase)
  • DLD (Dihydrolipoamide Dehydrogenase)

Mutations in each of these genes can cause MSUD. Mutations in the BCKDHA protein are the most common form which lead to MSUD.

Gene

Figure 1: Location of the BCKDHA gene on chromosome 19.[1]

The BCKDHA gene is located between base pair 41,903,693 and base pair 41,930,909 on chromosome 19 (gene map locus: 19q13.1-q13.2). The location of chromosome 19 can be seen in Figure 1 The overall length of the gene is 27261 nucleotides. The BCKDHA gene contains 9 exons.

Cross References

Protein

The BCKDHA gene encodes the alpha subunit of the Branched-Chain Alpha-Keto Acid Dehydrogenase E1. It is expressed in the mitochondrial matrix. Its length is 400 amino acids.

Figure 2: Crystal structure of the branched-chain alpha-keto acid dehydrogenase [2]

The BCKD complex consists of two alpha subunits and two beta subunits (encoded by the BCKDHB gene). A protein structure for BCKDHA is shown in Figure 2

Cross References

Biochemical disease mechanism

MSUD is caused by mutations in the Branched-Chain Alpha-Keto Acid Dehydrogenase Complex (BCKD). This complex is essential for the break down of branched-chain amino acids (leucine, isoleucine and valine, see Figure 3). Leucine, isoleucine and valine are part of protein-rich food, such as eggs, milk and meat. Mutations in the BCKD-complex prevent the breakdown of the amino acids, which then accumulate, together with their toxic by-products, in the body. The KEGG-Pathway> shown in Figure 4 gives a detailed overview of BCKDHA's role in the degradation of branched chain amino acids.

Figure 3: Degradation of leucine, isoleucin and valine(source: [3])
Figure 4: Role of BCKDHA in the degradation of leucine, isoleucin and valine (source: KEGG)


Cross-references

Mutations

There are currently listed 39 mutations in the BCKDHA protein.(source: HGMD)


Reference sequence

This sequence does not cause the disease and is most often found in the population.

Reference Sequence of BCKDHA

TASKS

Task 2: Sequence Alignments

Task 3: Secondary Structure Prediction

Task 4: Homology based structure predictions

Task 5: Mapping SNPs

Task 6: Sequence-based mutation analysis

Task 7: Structure-based mutation analysis

Task 8: Molecular Dynamics Simulations

Task 9: Normal Mode Analysis

Task 10: Molecular Dynamics Analysis