Maple syrup urine disease 2011

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.