Maple syrup urine disease
Encyclopedia
Maple syrup urine disease (MSUD), also called branched-chain ketoaciduria, is an autosomal recessive metabolic disorder affecting branched-chain amino acids
. It is one type of organic acidemia
. The condition gets its name from the distinctive sweet odor of affected infants' urine.
(BCKDC), leading to a buildup of the branched-chain amino acids (leucine
, isoleucine
, and valine
) and their toxic by-products in the blood and urine.
The disease is characterized in an infant by the presence of sweet-smelling urine, with an odor similar to that of maple syrup
. Infants with this disease seem healthy at birth but if left untreated suffer severe brain damage
and eventually die.
From early infancy, symptoms of the condition include poor feeding, vomiting
, dehydration
, lethargy, hypotonia
, seizure
s, hypoglycaemia, ketoacidosis
, opisthotonus
, pancreatitis
, coma and neurological decline.
There are several variations of the disease:
and involves both a special diet and frequent testing.
A diet with minimal levels of the amino acids leucine, isoleucine, and valine must be maintained in order to prevent neurological damage. As these three amino acids are required for proper metabolic function in all people, specialized protein preparations containing substitutes and adjusted levels of the amino acids have been synthesized and tested, allowing MSUD patients to meet normal nutritional requirements without causing harm.
Usually, patients are also monitored by a dietitian
. Their diet must be adhered to strictly and permanently. However, with proper management, those afflicted are able to live healthy, normal lives and not suffer the severe neurological damage associated with the disease.
Maple syrup urine disease affects approximately 1 out of 180,000 infants. Due in part to the founder effect
, however, MSUD has a much higher prevalence in children of Amish
, Mennonite
, and Jewish descent.
Mutations in the following genes cause maple syrup urine disease:
These four genes produce proteins that work together as the branched-chain alpha-keto acid dehydrogenase complex
. The complex is essential for breaking down the amino acids leucine
, isoleucine
, and valine
, which are present in many kinds of food (in particular, protein
-rich foods such as milk, meat, and eggs). Mutations in any of these genes reduce or eliminate the function of the enzyme complex, preventing the normal breakdown of isoleucine
, leucine
, and valine
. As a result, these amino acids and their by-products build up in the body. Because high levels of these substances are toxic to the brain
and other organs, this accumulation leads to the serious medical problems associated with maple syrup urine disease.
This condition has an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome
, and two copies of the gene - one from each parent - must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers
of one copy of the defective gene, but are usually not affected by the disorder.
Branched-chain amino acids
A branched-chain amino acid is an amino acid having aliphatic side-chains with a branch...
. It is one type of organic acidemia
Organic acidemia
Organic acidemia, also called organic aciduria, is a term used to classify a group of metabolic disorders which disrupt normal amino acid metabolism, particularly branched-chain amino acids, causing a buildup of acids which are usually not present....
. The condition gets its name from the distinctive sweet odor of affected infants' urine.
Diagnosis and symptoms
MSUD is caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complexBranched-chain alpha-keto acid dehydrogenase complex
The branched-chain α-keto acid dehydrogenase complex is a combination of enzymes responsible for the degradation of the branched-chain amino acids...
(BCKDC), leading to a buildup of the branched-chain amino acids (leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
, isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
, and valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
) and their toxic by-products in the blood and urine.
The disease is characterized in an infant by the presence of sweet-smelling urine, with an odor similar to that of maple syrup
Maple syrup
Maple syrup is a syrup usually made from the xylem sap of sugar maple, red maple, or black maple trees, although it can also be made from other maple species such as the bigleaf maple. In cold climates, these trees store starch in their trunks and roots before the winter; the starch is then...
. Infants with this disease seem healthy at birth but if left untreated suffer severe brain damage
Brain damage
"Brain damage" or "brain injury" is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors...
and eventually die.
From early infancy, symptoms of the condition include poor feeding, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
, lethargy, hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
, seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, hypoglycaemia, ketoacidosis
Ketoacidosis
Ketoacidosis is a metabolic state associated with high concentrations of ketone bodies, formed by the breakdown of fatty acids and the deamination of amino acids. The two common ketones produced in humans are acetoacetic acid and β-hydroxybutyrate....
, opisthotonus
Opisthotonus
Opisthotonus or opisthotonos, from Greek roots, opistho meaning "behind" and tonos meaning "tension", is a state of a severe hyperextension and spasticity in which an individual's head, neck and spinal column enter into a complete "bridging" or "arching" position...
, pancreatitis
Pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...
, coma and neurological decline.
Classification
Maple syrup urine disease can be classified by its pattern of signs and symptoms, or by its genetic cause. The most common and severe form of the disease is the classic type, which appears soon after birth. Variant forms of the disorder may appear later in infancy or childhood and are typically less severe, but still involve mental and physical problems if left untreated.There are several variations of the disease:
- Classic Severe MSUD
- Intermediate MSUD
- Intermittent MSUD
- Thiamine-responsive MSUD
- E3-Deficient MSUD with Lactic Acidosis
Management
Keeping MSUD under control requires careful monitoring of blood chemistryBlood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
and involves both a special diet and frequent testing.
A diet with minimal levels of the amino acids leucine, isoleucine, and valine must be maintained in order to prevent neurological damage. As these three amino acids are required for proper metabolic function in all people, specialized protein preparations containing substitutes and adjusted levels of the amino acids have been synthesized and tested, allowing MSUD patients to meet normal nutritional requirements without causing harm.
Usually, patients are also monitored by a dietitian
Dietitian
Dietitians supervise the preparation and service of food, develop modified diets, participate in research, and educate individuals and groups on good nutritional habits. The goals of dietitians are to provide medical nutritional intervention, and to obtain, safely prepare, serve and advise on...
. Their diet must be adhered to strictly and permanently. However, with proper management, those afflicted are able to live healthy, normal lives and not suffer the severe neurological damage associated with the disease.
Genetic prevalence
Founder effect
In population genetics, the founder effect is the loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population. It was first fully outlined by Ernst Mayr in 1942, using existing theoretical work by those such as Sewall...
, however, MSUD has a much higher prevalence in children of Amish
Amish
The Amish , sometimes referred to as Amish Mennonites, are a group of Christian church fellowships that form a subgroup of the Mennonite churches...
, Mennonite
Mennonite
The Mennonites are a group of Christian Anabaptist denominations named after the Frisian Menno Simons , who, through his writings, articulated and thereby formalized the teachings of earlier Swiss founders...
, and Jewish descent.
Mutations in the following genes cause maple syrup urine disease:
- BCKDHABCKDHA2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial is an enzyme that in humans is encoded by the BCKDHA gene.-Further reading:...
- BCKDHBBCKDHB2-oxoisovalerate dehydrogenase subunit beta, mitochondrial is an enzyme that in humans is encoded by the BCKDHB gene.- Function :Branched-chain keto acid dehydrogenase is a multienzyme complex associated with the inner membrane of mitochondria, and functions in the catabolism of branched-chain...
- DBTDBT (gene)Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial is an enzyme that in humans is encoded by the DBT gene.-Further reading:...
- DLDDihydrolipoamide dehydrogenaseDihydrolipoamide dehydrogenase , also known as dihydrolipoyl dehydrogenase, mitochondrial, is an enzyme that in humans is encoded by the DLD gene. DLD is a flavoprotein enzyme that degrades lipoamide, and produces dihydrolipoamide....
These four genes produce proteins that work together as the branched-chain alpha-keto acid dehydrogenase complex
Branched-chain alpha-keto acid dehydrogenase complex
The branched-chain α-keto acid dehydrogenase complex is a combination of enzymes responsible for the degradation of the branched-chain amino acids...
. The complex is essential for breaking down the amino acids leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
, isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
, and valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
, which are present in many kinds of food (in particular, protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
-rich foods such as milk, meat, and eggs). Mutations in any of these genes reduce or eliminate the function of the enzyme complex, preventing the normal breakdown of isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
, leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
, and valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
. As a result, these amino acids and their by-products build up in the body. Because high levels of these substances are toxic to the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and other organs, this accumulation leads to the serious medical problems associated with maple syrup urine disease.
This condition has an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
, and two copies of the gene - one from each parent - must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
of one copy of the defective gene, but are usually not affected by the disorder.