Carnosinemia
Encyclopedia
Carnosinemia, also called carnosinase deficiency or aminoacyl-histidine dipeptidase deficiency, is a rare autosomal
recessive metabolic disorder caused by a deficiency of carnosinase, a dipeptidase
(a type of enzyme
that splits dipeptide
s into their two amino acid
constituents).
Carnosine
is a dipeptide composed of beta-alanine
and histidine
, and is found in skeletal muscle
and cells of the nervous system
. This disorder results in an excess of carnosine in the urine
, cerebrospinal fluid
(CSF), blood
and nervous tissue
. Neurological disorders associated with a deficiency of carnosinase, and the resulting carnosinemia ("carnosine in the blood") are common.
1. Cellular, or tissue carnosinase. This form of the enzyme is found in every bodily tissue. It is a dimer
, and hydrolyzes
both carnosine and anserine
, preferring dipeptides that have a histidine monomer
in the c-terminus position. Tissue carnosinase is often considered a "non-specific dipeptidase", based in part on its ability to hydrolyze a range of dipeptide substrate
s, including those belonging to prolinase.
2. Serum carnosinase. This is the carnosinase found in the blood plasma
. Deficiency of this form of carnosinase, along with carnosinuria ("carnosine in the urine"), is the usual metabolic indicator of systemic carnosinase deficiency. Serum carnosinase is a glycoprotein
, and splits free carnosine and anserine in the blood. This form of the dipeptidase is not found in human blood until late infancy, slowly rising to adult levels by age 15. Unlike tissue carnosinase, serum carnosinase also hydrolyzes the GABA
metabolite homocarnosine. Homocarnosinosis, a neurological disorder
resulting in an excess of homocarnosine in the brain, though unaffected by tissue carnosinase, is caused by a deficiency of serum carnosinase in its ability to hydrolyze homocarnosine.
A deficiency of tissue and serum carnosinase, with serum being an indicator, is the underlying metabolic cause of carnosinemia.
, developmental delay, mental retardation
, degeneration of axons, sensory neuropathy
, tremor
s, demyelinization
, gray matter
anomalies, myoclonic seizures
, and loss of purkinje fibers
.
The gene
for carnosinase is located on chromosome 18, an autosome
. The carnosine dipeptidase-1 gene (CNDP1
) controls tissue and serum carnosinase. Mutations in CNDP1 are responsible for carnosinase deficiency, resulting in carnosinemia.
Carnosinemia is an autosomal recessive disorder, which means the defective gene is located on an autosome, and two copies of the defective gene - one from each parent - are required to inherit the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
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...
recessive metabolic disorder caused by a deficiency of carnosinase, a dipeptidase
Dipeptidase
Dipeptidases are enzymes secreted by enterocytes into the small intestine. Dipeptidases hydrolyze bound pairs of amino acids, called dipeptides....
(a type of enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that splits dipeptide
Dipeptide
A dipeptide is a molecule consisting of two amino acids joined by a single peptide bond.Dipeptides are produced from polypeptides by the action of the hydrolase enzyme dipeptidyl peptidase. Dietary proteins are digested to dipeptides and amino acids, and the dipeptides are absorbed more rapidly...
s into their two amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
constituents).
Carnosine
Carnosine
Carnosine is a dipeptide of the amino acids beta-alanine and histidine. It is highly concentrated in muscle and brain tissues....
is a dipeptide composed of beta-alanine
Beta-alanine
β-Alanine is a naturally occurring beta amino acid, which are amino acids in which the amino group is at the β-position from the carboxylate group . The IUPAC name for β-alanine would be 3-aminopropanoic acid...
and histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
, and is found in skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
and cells of the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
. This disorder results in an excess of carnosine in the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
, cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
(CSF), blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
and nervous tissue
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
. Neurological disorders associated with a deficiency of carnosinase, and the resulting carnosinemia ("carnosine in the blood") are common.
Enzymology
Carnosinase in humans has two forms:1. Cellular, or tissue carnosinase. This form of the enzyme is found in every bodily tissue. It is a dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
, and hydrolyzes
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
both carnosine and anserine
Anserine
Anserine is a dipeptide found in the skeletal muscle and brain of mammals, and birds.It is an antioxidant and helps reduce fatigue....
, preferring dipeptides that have a histidine monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
in the c-terminus position. Tissue carnosinase is often considered a "non-specific dipeptidase", based in part on its ability to hydrolyze a range of dipeptide substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
s, including those belonging to prolinase.
2. Serum carnosinase. This is the carnosinase found in the blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
. Deficiency of this form of carnosinase, along with carnosinuria ("carnosine in the urine"), is the usual metabolic indicator of systemic carnosinase deficiency. Serum carnosinase is a glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
, and splits free carnosine and anserine in the blood. This form of the dipeptidase is not found in human blood until late infancy, slowly rising to adult levels by age 15. Unlike tissue carnosinase, serum carnosinase also hydrolyzes the GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
metabolite homocarnosine. Homocarnosinosis, a neurological disorder
Neurological disorder
A neurological disorder is a disorder of the body's nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord, or in the nerves leading to or from them, can result in symptoms such as paralysis, muscle weakness, poor coordination, loss of sensation, seizures,...
resulting in an excess of homocarnosine in the brain, though unaffected by tissue carnosinase, is caused by a deficiency of serum carnosinase in its ability to hydrolyze homocarnosine.
A deficiency of tissue and serum carnosinase, with serum being an indicator, is the underlying metabolic cause of carnosinemia.
Symptoms
A variety of neurological symptoms have been associated with carnosinemia. They include: hypotoniaHypotonia
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...
, developmental delay, mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
, degeneration of axons, sensory neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
, tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
s, demyelinization
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
, gray matter
Grey matter
Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil , glial cells and capillaries. Grey matter contains neural cell bodies, in contrast to white matter, which does not and mostly contains myelinated axon tracts...
anomalies, myoclonic seizures
Myoclonus
Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. Brief twitches are perfectly normal. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief...
, and loss of purkinje fibers
Purkinje fibers
For the nervous cells, see Purkinje cellPurkinje fibers are located in the inner ventricular walls of the heart, just beneath the endocardium...
.
Genetics
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
for carnosinase is located on chromosome 18, 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...
. The carnosine dipeptidase-1 gene (CNDP1
CNDP1
Beta-Ala-His dipeptidase is an enzyme that in humans is encoded by the CNDP1 gene.The metabolic disorder Carnosinemia may be caused by mutations in this gene.-Further reading:...
) controls tissue and serum carnosinase. Mutations in CNDP1 are responsible for carnosinase deficiency, resulting in carnosinemia.
Carnosinemia is an autosomal recessive disorder, which means the defective gene is located on an autosome, and two copies of the defective gene - one from each parent - are required to inherit the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
See also
- HyperprolinemiaHyperprolinemiaHyperprolinemia, also referred to as prolinemia or prolinuria, is a condition which occurs when the amino acid proline is not broken down properly by the enzymes proline oxidase or pyrroline-5-carboxylate dehydrogense, causing a build up of proline in the body.-Hyperprolinemia type I:It is...
- HistidinemiaHistidinemiaHistidinemia, also referred to as histidinuria, is a rare autosomal recessive metabolic disorder caused by a deficiency of the enzyme histidase. Histidase is needed for the metabolism of the amino acid histidine.-Diagnosis and symptoms:...
- ProlineProlineProline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
- Inborn errors of metabolism