DEFINITION
Maple syrup urine disease also called branched-chain ketoaciduria, is an autosomal recessive disorder. This condition is one type of amino acid disorder getting its name from the distinctive sweet odor of affected infants' urine. Maple syrup odor is evident in cerumen soon after birth and in urine by age five to seven days. The compound responsible for the odor is sotolon (sometimes spelled sotolone).
Maple syrup urine disease (MSUD) is caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKAD) composed of BCKDHA, BCKDHB, DBT, and DLD, leading to a build-up to toxic levels in the body of the branched-chain amino acids (leucine, isoleucine, and valine).
GENES
EPIDEMIOLOGY
Maple syrup urine disease occurs in about 1 per 180,000 live births and affects both males and females. MSUDaffects people of all ethnic backgrounds, but higher rates of the disorder occur in populations in which there is a lot of intermarriage, such as the Mennonite (Amish) community in Pennsylvania (U.S.A.). Here, the incidence is estimated of about 1 in 380 newborns.
CLASSIFICATION
There are a number of different forms of MSUD.
The most common and severe type is the classic MSUD, which appears soon after birth. The three genes associated with MSUD are BCKDHA (E1a subunit gene, MSUD type 1A), BCKDHB (E1b subunit gene, MSUD type 1B), and DBT.
The other forms of the disorder may appear later in infancy or childhood and are typically less severe and less common.
These variants of the disease are:
• Intermittent MSUD, that is the second most common form of the disorder
• Intermediate MSUD.
• Thiamine-responsive MSUD
• E3-Deficient MSUD with Lactic Acidosis
SYMPTOMS
Classic MSUD
Symptoms start as soon as a baby is fed protein, usually shortly after birth.
Some of the first symptoms are:
• poor appetite
• weak suck
• weight loss
• high pitched cry
• urine that smells like maple syrup or burnt sugar
Babies with MSUD have episodes of illness called metabolic crisis. Some of the first symptoms of a metabolic crisis are:
• extreme sleepiness
• sluggishness
• irritable mood
• vomiting
If not treated, other symptoms can follow:
• episodes where muscles tone alternates between being rigid and floppy
• swelling of the brain
• seizures
• high levels of acidic substances in the blood, called metabolic acidosis
• coma, sometimes leading to death
Symptoms of a metabolic crisis often happen:
• after going too long without food
• during illness or infection
• during stressful events such as surgery
Even with treatment, some children still develop swelling of the brain or have episodes of metabolic crisis. Children who have repeated metabolic crises may develop permanent brain damage. This can cause lifelong learning problems, mental retardation or spasticity.
Intermittent MSUD
Children with the intermittent form of MSUD have normal growth and intellectual development throughout infancy and early childhood. When they are well, they generally tolerate a normal leucine intake, and plasma amino acid and urine organic acid profiles are normal or show only mild elevations of BCAAs. During infections or other physiologic stress, they can develop the clinical and biochemical features of classic MSUD, in rare cases culminating in coma and death.
Intermediate MSUD
Individuals with residual BCKAD activity (i.e., 3%-30% ex vivo) may appear well during the neonatal period but, nevertheless, have maple syrup odor in cerumen and a consistently abnormal plasma amino acid profile. Individuals with intermediate MSUD can present with feeding problems, poor growth, and developmental delay during infancy, or may present much later in life with nonsyndromic intellectual disability. The majority of persons with intermediate MSUD are diagnosed between ages five months and seven years. They are vulnerable to the same acute and chronic neurologic sequelae as persons with the classic form of the disease. Severe leucinosis, brain swelling, and death can occur if individuals with intermediate MSUD are subjected to sufficient catabolic stress. Basic management principles for such persons do not differ from those with classic MSUD, and the distinction between classic and intermediate types is not absolute.
Thiamine-responsive MSUD
It is not known with certainty if individuals with true thiamine-responsive MSUD exist. In general, such putative individuals have residual ex vivo BCKAD enzyme activity of up to 40% normal and are not ill in the neonatal period, but present later in life with a clinical course similar to intermediate MSUD. To date, no person with "thiamine-responsive" MSUD has been treated solely with thiamine. Rather, they are treated with a combination of thiamine (doses ranging from 10 to 1000 mg per day) and dietary BCAA restriction, making the in vivo contribution of thiamine impossible to discern.
A very rare form of the disorder is E3-deficient MSUD, in which individuals have additional deficient metabolic enzymes.
DIAGNOSIS
Maple syrup urine disease is suspected based on the physical symptoms, especially the characteristic urine odor.
MSUD is diagnosed by the presence of clinical features and by decreased levels of BCKAD enzyme activity causing accumulation of BCAAs, allo-isoleucine, and branched-chain ketoacids (BCKAs) in tissues and plasma.
Figure Plasma amino values between age 4 and 26 months from a child with classic MSUD show a strong reciprocal relationship between leucine (gray diamonds) and alanine (white circles) (Spearman correlation coefficient= -0.86; p<0.0001).
There will be signs of ketosis and excess acid in blood (acidosis).
Sequence analysis of BCKDHA, BCKDHB, and DBT is clinically available. Individuals with MSUD are always homozygous or compound heterozygous for mutations in the same subunit gene; no individuals with MSUD who are heterozygous for mutations in two different genes have been identified. Most affected individuals are compound heterozygotes for rare sequence variants. No single mutation or gene accounts for a significant proportion of affected alleles, except in genetic isolates.
Genetic counseling is suggested for people who want to have children and who have a family history of maple syrup urine disease. A follow-up blood test for amino acid levels should be done right away to confirm the disease.
PATHOGENESIS
Mutations in the BCKDHA, BCKDHB, DBT, and DLD genes cause maple syrup urine disease. These four genes provide instructions for making proteins that work together as the branched-chain alpha-keto acid dehydrogenase complex. The protein complex is essential for breaking down the amino acids leucine, isoleucine, and valine, which are present in many kinds of food (particularly protein-rich foods such as milk, meat, and eggs).
Mutations in any of these four genes reduce or eliminate the function of the protein complex, preventing the normal breakdown of leucine, isoleucine, and valine. As a result, these amino acids and their byproducts build up in the body. Because high levels of these substances are toxic to the brain and other organs, their accumulation leads to the serious medical problems associated with maple syrup urine disease.
Some types of MSUD are mild or come and go. Even in the mildest form, repeated periods of physical stress can cause mental retardation and high levels of leucine.
Molecular genetic pathogenesis
Maple syrup urine disease is caused by decreased activity of human BCKD, a multi-enzyme complex found in the mitochondria. It catalyzes the oxidative decarboxylation of the branched-chain keto acids (alpha-ketoisocaproate, alpha-keto-beta-methyl valerate, and alpha-ketoisovalerate) in the second step in the degradative pathway of the branched chain amino acids (leucine, isoleucine, and valine). The BCKD is a large complex consisting of three catalytic components:
• The E1 decarboxylase, which is a heterotetramer of alpha and beta subunits (alpha2, beta2)
• The E2 transacylase, which is a homo-24-mer
• The E3 dehydrogenase, which is a homodimer
The three subunits of the BCKD complex (E1, E2, and E3) are encoded by four unlinked genes. The complete functional BCKD complex contains a cubic E2 core surrounded by:
• 12 E1 components
• Six E3 components
• A single kinase
BCKAD colocalizes with branched-chain amino acid transaminases in mitochondria of diverse tissues and is regulated by a kinase-phosphatase pair. In humans, skeletal muscle is the major site for both transamination and oxidation of BCAAs. The liver and kidney each mediate an estimated 10%-15% of whole-body BCAA transamination-oxidation. BCKAD is expressed in brain, where BCAA transamination-oxidation may contribute to cerebral glutamate and GABA production.
BCKDHA
The gene encodes the E1-alpha subunit of the BCKAD complex. It spans nearly 28 kb and comprises nine exons.
More than 60 separate pathogenic sequence variants in the four genes encoding the subunits of the BCKD complex have been identified in individuals with MSUD. No mutations occur in especially high frequency in the overall population. In isolated populations, specific mutations occur at high frequency, including the BCKDHA c.1312T>A mutation in Old Order Mennonites of southeastern Pennsylvania.
BCKDHB
The gene encodes the E1-beta subunit of the BCKD complex. It spans roughly 240 kb and contains 11 exons (a shorter isoform contains 10 exons).
More than 60 separate pathogenic sequence variants in the four genes encoding the subunits of the BCKD complex have been identified in individuals with MSUD. No mutations occur in especially high frequency in the overall population. In isolated populations, specific mutations occur at high frequency, including the BCKDHB c.548G>C mutation in Ashkenazi Jews.
DBT
The gene encodes the E2 subunit of the BCKD complex. It covers approximately 56 kb and contains 11 exons.
More than 60 separate pathogenic sequence variants in the four genes encoding the subunits of the BCKD complex have been identified in individuals with MSUD. No mutations occur in especially high frequency in the general population. A higher-than-expected percentage of DBTmutations are deletions (both large and small); there is to date no adequate explanation for this. These deletions can make mutationidentification by PCR and sequencing difficult.
Pathophysiology of brain disease in MSDU
Figure
Leucine and aKIC cause a complex neurochemical syndrome that disturbs brain protein accretion, neurotransmitter synthesis, cell volume regulation, neuron growth, and myelin synthesis. The neurotoxicity of leucine stems in part from its ability to interfere with transport of other large neutral amino acids across the blood-brain barrier, reducing the brain's supply of tryptophan, methionine, tyrosine, phenylalanine, histidine, valine, and threonine. Cerebral amino acid deficiency has adverse consequences for brain growth and synthesis of neurotransmitter such as dopamine, serotonin, norephinephrine, and histamine.
Alpha-ketoisocaproic acid and the other BCKAs may exert toxicity by interfering with transamination reactions in muscle and brain. In tissue culture and perfused brain, extracellular aKIC concentrations greater than 60 µmol/L reverse astrocyte transamination reactions, causing a 50% depletion of glutamate and glutamine, and reduced aspartate and pyruvate. Severe deficiencies of cerebral glutamate, GABA, and aspartate have been observed in brains of calves with naturally occurring BCKAD deficiency and in post-mortem brain of a human infant with MSUD. In a murine model of MSUD, leucine and aKIC accumulation in brain tissue is accompanied by depletion of glutamate, GABA, pyruvate, and dopamine, while alpha-ketoglutarate, alanine, and lactate increase.
Cerebral lactate is elevated in humans with acute MSUD encephalopathy and may be related to reversible inhibition of the respiratory chain by elevated cerebral alpha-ketoisocaproic acid. In the mouse model, cerebral ATP and phosphocreatine are low and the ratio of lactate to pyruvate in tissue increases 40-fold, suggesting reduced electron flow through the respiratory chain as reducing equivalents accumulate in mitochondria and cytosol. The cerebral lactic acidosis associated with MSUD encephalopathy resolves without permanent sequelae, and does not have the same prognostic significance as cerebral lactate accumulation caused by ischemia [Strauss, Puffenberger, Morton, unpublished observation]. Thus, although cerebral energy production appears to be impaired in MSUD encephalopathy, it is likely matched to reduced cerebral energy demand.
THERAPY
The treatments for children with MSUD are:
1. Medical Formula
In addition to a low-protein diet, children are often given a special medical formula as a substitute for milk. This formula gives them the nutrients and protein they need while helping keep their BCAA levels in a safe range.
2. Diet low in branched-chain amino acids
The diet is made up of foods that are very low in the BCAAs. This means to avoid foods such as cow’s milk, regular formula, meat, fish, cheese and eggs. Regular flour, dried beans, nuts, and peanut butter also have BCAAs and must be avoided or strictly limited.
There are other medical foods such as special low-protein flours, pastas, and rice that are made especially for people with MSUD. Children with MSUD need to eat more carbohydrates and drink more fluids during any illness.
Lifelong treatment with the MSUD diet is necessary otherwise people are at risk for episodes of metabolic crisis. In this case fluids, sugars, and possibly fats are given through a vein. Peritoneal dialysis or hemodialysis can be used to reduce the level of amino acids.
3. Supplements
Children with a rare form of MSUD, called “thiamine-responsive MSUD”, can often be helped by thiamine supplements. Some children with classic MSUD may also benefit from thiamine.
4. Tracking BCAA levels
It is necessary to have regular blood tests to measure amino acid levels. The diet and formula may need to be adjusted based on blood test results.
5. Liver transplantation
Liver transplant surgery is an optional treatment for people with MSUD. The BCKAD enzyme that causes MSUD is located in the liver. Because of this, some children with MSUD have had liver transplantation surgery (removal of their liver and replacement with a donor liver) to treat their MSUD symptoms.
This major surgical procedure is associated with risks, and individuals who have had a liver transplant must take medication for the rest of their lives to prevent their body from rejecting the donor liver. However, successful liver transplantation cures people of their MSUD symptoms.
If untreated, maple syrup urine disease can lead to coma, death and Neurological damage.
USEFUL LINKS
Maple Syrup Urine Disease
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