Homocystinuria
Encyclopedia
Homocystinuria, also known as cystathionine beta synthase deficiency or CBS deficiency, is an inherited disorder of the metabolism
of the amino acid
methionine
, often involving cystathionine beta synthase
. It is an inherited autosomal recessive trait, which means a child needs to inherit the defective gene from both parents to be affected (or from parents where one is a carrier and one is affected with the disease).
, muscle
s, CNS
, and cardiovascular system. Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of homocysteine
in the serum
and an increased excretion of homocysteine in the urine
. Infants appear to be normal and early symptoms, if any are present, are vague.
).
). Slightly less than 50% respond to this treatment and need to intake supplemental vitamin B6 for the rest of their lives. Those who do not respond require a low methionine
diet, and most will need treatment with trimethylglycine
. A normal dose of folic acid
supplement and occasionally adding cysteine
to the diet can be helpful.
Betaine (N,N,N-trimethylglycine) is used to reduce concentrations of homocysteine by promoting the conversion of homocysteine back to methionine. The re-formed methionine is then gradually removed by incorporation into body protein.
The methionine that is not converted into protein is converted to S-adenosyl-methionine which goes on to form homocysteine again.
Betaine is, therefore, only effective if the quantity of methionine to be removed is small. Hence treatment consists of a diet low in methionine and betaine.
In classical homocystinuria (CBS) the plasma methionine usually increases above the normal range of 30 micromoles/L and the concentrations should be monitored as potentially toxic levels (more than 400 micromole/l) may be reached.
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of the 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...
methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
, often involving cystathionine beta synthase
Cystathionine beta synthase
Cystathionine-β-synthase, also known as CBS, is an enzyme that in humans is encoded by the CBS gene. It catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine:...
. It is an inherited autosomal recessive trait, which means a child needs to inherit the defective gene from both parents to be affected (or from parents where one is a carrier and one is affected with the disease).
Presentation
This defect leads to a multisystemic disorder of the connective tissueConnective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...
, muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
s, CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, and cardiovascular system. Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...
in the serum
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...
and an increased excretion of homocysteine 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...
. Infants appear to be normal and early symptoms, if any are present, are vague.
Possible Signs and symptoms
- A family history of homocystinuria
- FlushFlushing (physiology)For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
across the cheeks - Musculoskeletal
- Tall, thin build (resembling Marfanoid habitusMarfanoidMarfanoid is a term used to describe a constellation of findings including long limbs, arachnodactyly and hyperlaxity.Associated conditions include:* Marfan syndrome...
) - Long limbs (dolichostenomeliaDolichostenomeliaDolichostenomelia is a human condition or habitus in which the limbs are unusually long. The name is derived from Ancient Greek...
) - High-arched feet (pes cavusPes cavusHigh arch is a human foot type in which the sole of the foot is distinctly hollow when bearing weight. That is, there is a fixed plantar flexion of the foot...
) - Knock-knees (genu valgumGenu valgumGenu valgum, commonly called "knock-knee", is a condition where the knees angle in and touch one another when the legs are straightened. Women have a wider pelvis than men and a relatively shorter length of the thigh bone, and as a result, have a greater static genu valgum than men...
) - Pectus excavatumPectus excavatumPectus excavatum is the most common congenital deformity of the anterior wall of the chest, in which several ribs and the sternum grow abnormally. This produces a caved-in or sunken appearance of the chest...
and Pectus carinatumPectus carinatumPectus carinatum, , also called pigeon chest, is a deformity of the chest characterized by a protrusion of the sternum and ribs. It is the opposite of pectus excavatum.-Causes:...
- Tall, thin build (resembling Marfanoid habitus
- Mental retardationMental retardationMental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
- Seizures
- Psychiatric disease
- Eye anomalies:
- ectopia lentisEctopia lentisEctopia lentis is a displacement or malposition of the eye's crystalline lens from its normal location. A partial dislocation of a lens is termed lens subluxation or subluxated lens; a complete dislocation of a lens is termed lens luxation or luxated lens.-Ectopia lentis in dogs and cats:Although...
(downward dislocation) or subluxationSubluxationA subluxation may have different meanings, depending on the medical specialty involved. It implies the presence of an incomplete or partial dislocation of a joint or organ. The World Health Organization defines both the medical subluxation and the chiropractic subluxation...
of lensLens (anatomy)The crystalline lens is a transparent, biconvex structure in the eye that, along with the cornea, helps to refract light to be focused on the retina. The lens, by changing shape, functions to change the focal distance of the eye so that it can focus on objects at various distances, thus allowing a... - MyopiaMyopiaMyopia , "shortsightedness" ) is a refractive defect of the eye in which collimated light produces image focus in front of the retina under conditions of accommodation. In simpler terms, myopia is a condition of the eye where the light that comes in does not directly focus on the retina but in...
(Nearsightedness) - GlaucomaGlaucomaGlaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
- Optic atrophy
- ectopia lentis
- Vascular diseaseVascular diseaseVascular disease is a form of cardiovascular disease primarily affecting the blood vessels.Some conditions, such as angina and myocardial ischemia, can be considered both vascular diseases and heart diseases .Cigarette smoking is the major risk factor....
- extensive atheromaAtheromaIn pathology, an atheroma is an accumulation and swelling in artery walls that is made up of macrophage cells, or debris, that contain lipids , calcium and a variable amount of fibrous connective tissue...
formation at young age which affects many arteries but not the coronary arteries - Intra vascular thrombosisThrombosisThrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
- extensive atheroma
Mortality/morbidity
The life expectancy of patients with homocystinuria is reduced only if untreated. It is known that before the age of 30, almost one fourth of patients die as a result of thrombotic complications (e.g. heart attackMyocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
).
Treatment
No specific cure has been discovered for homocystinuria; however, many people are treated using high doses of vitamin B6 (also known as pyridoxinePyridoxine
Pyridoxine is one of the compounds that can be called vitamin B6, along with pyridoxal and pyridoxamine. It differs from pyridoxamine by the substituent at the '4' position. It is often used as 'pyridoxine hydrochloride'.-Chemistry:...
). Slightly less than 50% respond to this treatment and need to intake supplemental vitamin B6 for the rest of their lives. Those who do not respond require a low methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
diet, and most will need treatment with trimethylglycine
Trimethylglycine
Trimethylglycine is an organic compound that occurs in plants as either glycine betaine or a choline-containing glycine betaine compound. Trimethylglycine was the first betaine discovered by science; originally it was simply called betaine because, in the 19th century, it was discovered in sugar...
. A normal dose of folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
supplement and occasionally adding cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
to the diet can be helpful.
Betaine (N,N,N-trimethylglycine) is used to reduce concentrations of homocysteine by promoting the conversion of homocysteine back to methionine. The re-formed methionine is then gradually removed by incorporation into body protein.
The methionine that is not converted into protein is converted to S-adenosyl-methionine which goes on to form homocysteine again.
Betaine is, therefore, only effective if the quantity of methionine to be removed is small. Hence treatment consists of a diet low in methionine and betaine.
In classical homocystinuria (CBS) the plasma methionine usually increases above the normal range of 30 micromoles/L and the concentrations should be monitored as potentially toxic levels (more than 400 micromole/l) may be reached.