Homocystinuria (Homocystinuria, HCU)

Basic InformationCase's arm length is less than height, with chicken breast, eye degrees 300 degrees, the wrist joint is not loose, the knee is not particularly prominent, speech level is acceptable, the reaction at a slower pace, leaving blood and urine tests and methionine High homocysteine, the results are normal.
Family Trees

(To respect the privacy of cases, case names begin with a pseudonym processing, spectrum and content of the story of his family has been changed)
Theoretical study
High homocysteine ​​(Homocysteine, Hcy) in 1932 was first discovered by the DeVgneaud; 1962 congenital mental retardation in children found homocystinuria (Homocystinuria, HCU), about two years after it was recognized that the high cystamine aciduria cause is because cystathionine-β-synthase (Cystathionine-β-Synthase, CBS) defects, and found that these patients susceptible to thromboembolic disease.
After discovery of methylenetetrahydrofolate reductase in (N5N10-methylene tetrahydrofo1ate reductase, MTHFR) serious flaws, intracellular vitamin B12 metabolism disorders can also cause with homocystinuria similar clinical manifestations.1969 McCully describes homocystinuria patients with vascular disease characteristics, he noted that these patients regardless of metabolic disorders in which step problems, Hcy is the main reason causing these clinical manifestations, and thus presents a high cysteine acid may be associated with arterial sclerosis symptoms related ideas.
1976 Lcken first reported in patients with coronary heart disease have abnormal metabolism of Hcy. The next 15 years, on Hcy and coronary heart disease, the surrounding vascular disease, venous thrombotic disease and cerebrovascular disease report on the relationship between small.
Until 1988, Kang et al found that Hcy metabolism of MTHFR and later, Hcy and coronary heart disease relationship has aroused great concern. Since the 1990s, scientists have carried out around this issue a lot of research, clinical data show that about 80 high homocysteine ​​hyperlipidemia (Hyperhomocysteinemia, HH (e)) is coronary heart disease an independent risk elements of the new, and became the etiology and prevention of coronary heart disease and other aspects of a new hot spot.
Disease Information
Homocystinuria (Homocystinuria, HCU) because patients lack an enzyme called cystathionine synthase (cystathionine-β-synthase, CBS). Taiwan's current newborn screening examination is methionine (methionine), if the screening result is abnormal higher than normal, newborn necessary to the hospital for further checks to see whether there is a high concentration of homocysteine increased.
This disease is an autosomal recessive genetic methionine (methionine) metabolic disorder that causes high homocysteine ​​(homocystine) large accumulation in the blood and urine.
Incidence
Approximately 1/200000 in Europe, Taiwan, the incidence is very low, estimated to be about 1/500000 or less
The most common cause disease because CBS enzyme (cystathionine-β-synthase, CBS) functions cystathionine synthase deficiency: the first is to our body into a high homocysteine ​​methionine then becomes high homocysteine cystathionine. Patients unable to high homocysteine ​​metabolism, so high homocysteine ​​will accumulate in the body, and it gets the blood concentration of methionine also increased. Resulting synthetic homocysteine ​​homocysteine ​​barriers to the process, resulting in a large number of patients from the urine of high homocysteine ​​in the blood and urine values ​​high methionine homocysteine ​​values ​​are high.
Clinical symptoms
This disease causes the body Homocysteine ​​and other toxic amino acid accumulation, resulting in bodily injury, if not treated early, the first is the eye lens prolapse (Ectopic lentis), usually in patients 10 years or so there will be, but also accompanied by other eye symptoms such as: myopia, glaucoma, cataracts or retinal detachment. Bone lesions is another major clinical manifestations, the patient looks lanky, osteoporosis, there may be chicken or concave chest, foot deformation, and vertebral compression fractures and other bone lesions.
Brain injury is a more worrying, mild to moderate mental retardation often see, about 1/5 of the patients will have cramps.
Most notable is the vascular lesions, and sometimes may cause acute vascular thrombosis, resulting in brain or heart ischemia, even cause death, will have the same peripheral vascular changes, in fact, retarded perhaps because vascular lesions caused.Treatment
CBS enzyme (cystathionine-β-synthase, CBS) functions cystathionine synthase deficiency is divided into:
1 for vitamin B6-responsive patients, usually given B6, and folic acid simultaneously (folic acid), to achieve better diet control.
(2) for vitamin B6 treatment of patients do not respond to the patient a child for use in low methionine milk powder, 1 year old to rely on low-protein diet to control. In the diet, methionine-rich foods, such as meat, fish, eggs, milk intake must be limited, then use milk to supplement low methionine amino acids necessary for the body to maintain normal body growth and physiological functions. You can also intake of protein from beans, and added cysteine ​​(cystine) to improve the severity of complications. In addition to vitamin B6, certain drugs such as folic acid, vitamin B12, and betaine, etc., to reduce the accumulation of body Homocysteine ​​also help.
Disease mutations have been found in human chromosomes on chromosome 21 q22.3 location. Some patients taking high doses of vitamin B6, the blood and urine of high methionine cystine will be reduced. If detected early and with plenty of vitamin B6 therapy and combined vitamin B12, folic acid and betaine supplement, patients can reduce the degree of mental retardation.
In general, if the diet-controlled cases, the prognosis is not very satisfactory. If early detection, early treatment, you can still reach the general level of intelligence, however, the eye disease is difficult to avoid the more stringent controls, the degree of sequelae more light.
Other similar syndrome
Marfan's syndrome
Is an irregular autosomal dominant genetic disease, as systemic connective tissue abnormal mesoderm, eye, cardiovascular and skeletal system abnormalities as the main. Marfan's first reported in 1896. Crystal eye anomaly appears ectopic, especially up and to the temporal side of the shift. Such as the lack of iris pigment layer can be generated after the transillumination test was positive, the pupil muscles loose partial use of drugs such as the pupil is difficult to expand. In addition, the eye anterior chamber may also have abnormalities that may occur, and macular choroidal defects, may also have glaucoma, retinal detachment, nystagmus, strabismus, amblyopia and other complications. See skeletal abnormalities such as: hand, foot and slender limbs, bones, head length and slender face, heart foramen ovale is not closed you can hear a heart murmur, aneurysm and aortic stenosis embolism. Generally more men than women.
HyperMethioninemia (high methionine hyperlipidemia)
Is an important amino acid, it is methyl (methyl groups) and sulfur (sulfur) into the human body, the human tissue structure, carbohydrate metabolism, lipids and amino acids, antioxidants and detoxification processes necessary substances. Methionine is an important amino acid cysteine, glutathione, taurine necessary precursor, via cysteine ​​into insulin and auxiliary transaminase A.
Genetic performance (genetic expression), muscle metabolism, adrenal (catechcolamine) balance constitutes choline (choline) and acetylcholine (acetylcholine), they all must have methylation (via S-adenosylmethionine). Methionine metabolism how much damage it will cause much disorders, including cardiovascular disease, neural tube defects, osteoporosis, and neuropsychiatric disorders.
High homocysteine ​​detection methods used
Homocysteine ​​is an intermediate in methionine metabolism may remethylated into methionine, or broken down into cysteine. If the related enzyme unable to function, homocysteine ​​will accumulate and contribute to LDL cholesterol and vascular endothelial oxidative damage. methionine metabolism requires vitamin B6, B12, folic acid, betaine, and serine, if deficiencies of these nutrients will make the situation worse.
Usually made when collecting urine L-methionine (25mg/kg body weight) functional stimulation experiments can be used to diagnose whether there homocystinuria.
General market high blood homocysteine ​​determination of the methods are the following:
1 enzyme immunoassay (EIA)
Analysis of currently available methods of high homocysteine ​​devaluation enzyme immunoassay. For example in 1998 Frantzen et al proposed the use of an excess of Adenosine with high homocysteine ​​reaction, and then re-use Adenosinekinase will equal Adenosine and ATP into Adenosine-5'-P and ADP, ATP was measured after the reaction by shining the content.
Rozella's, who use L-homocysteine ​​and L-methionine in methionine gamma-lyase catalyzed generate H2S ,2-ketobutyrate and NH3 were measured in the reaction, the principle is either a product by quantitative reverse thrust while high homocysteine ​​samples the content, but the drawback is L-methionine also produce fluorescence signals caused by experimental errors.
2 fluorescence polarization immunoassay (FPIA)
This method has been fluorescent reagent contains flag high homocysteine ​​(F-Ag), and will seize the high homocysteine ​​macromolecular specimen (Ab), and showed a state of dynamic equilibrium (F-Ag: Ab and Ab: Ag). When the sample contains a large number of foreign high homocysteine ​​would seize macromolecular specimen (Ab) will destroy the original when the equilibrium state, and produce large amounts of Ab: Ag. Therefore, by detecting F-Ag: Ab reduction amount (ie the detected fluorescence signal weakening) and the measured solution, high homocysteine ​​levels. Although this method can be automated, but a determination is time-consuming (take up to 2.5 hours).
3 high-performance liquid chromatography (HPLC)
Dias, who's joined in plasma 4-aminosulfonyl-7-fluoro-2 ,1,3-benzoxydiazole fluorescent derivatizing agent, and then use high-performance liquid chromatography separation of the high-cysteine ​​and cystine, time-consuming almost one hour, the current price of BioRad reagent produced by a group of 7 to 7.5 U.S. dollars. England Drew Scientific Company and even more determined with high homocysteine ​​introduction of a front-end derivative of liquid chromatography column dedicated high homocysteine ​​was measured.
4 fluorescence analysis
U.S. Patent No. 6,265,220 using a non-immune type of analysis the high serum homocysteine. Mainly using one containing cis-1 ,4 - dioxo-2 - butenyl group (cis-1 ,4-dioxo-2-butene moiety) or a hydrolyzate derived precursors with high homocysteine ​​or cystamine acid generating fluorescent radioactive substances, and the maximum fluorescence emission wavelength of radiation or high homocysteine ​​due to homocysteine ​​varies. However, the examples include their high cysteine ​​adduct The maximum emission wavelength of 566 nm, and the high cysteine ​​adduct (Homocysteine ​​adduct) the maximum emission wavelength was 577nm, like the speed of the fluorescence emission spectra, in order to distinguish between these two substances rather difficult. In addition, this patent may be made to eliminate the use of antibody cysteine ​​adducts of fluorescence, while retaining only the fluorescence signal of high homocysteine, but this method is not only cumbersome procedures and the use of antibodies will undoubtedly increase this Act Analysis of costs. Reuel's and others made first with p-bromoacetylbenzoic acid and cystine to form a stable adduct without interfering with subsequent homocysteine ​​fluorescent adduct detection, the drawback is that you must go through complex sample pretreatment.


Consultation process and content
1 Initial Counseling
Expressed concern about the case of female cases of long calls is very high, there is a month long 5-6 cm high, this country two, from small six began to grow taller, there are 183 cm high, has long worried about the high base case, then, is not an disease? Counselor asks cases clinical symptoms: high, thin, eye sight is good, with or without history of heart disease, hands and feet length, arm length exceeds the height height; while the case mother replied: Case 183 centimeters long but very thin, not because of his mother. dare to eat too many cases, limiting cases of the daily diet, without heart disease but there is chicken breast, arm's length exceeds the height of the height is not known, nearsighted 300 degrees.
The telephone counseling does not sound like is Marfan Syndrome (Marfan syndrome) cases, but counselors and not the effect, so please his mother. Refer the case to other hospitals for treatment in record: MRI film ---- because cases State one o'clock in the ascending sudden cramps send a medical center in southern checks neurologists discovered the brain CT scan some brain lesions; case since some slow to speak, other behaviors are okay, but after a year No other multi-discovery, and can not confirm the diagnosis. Referral of cases to the north due to a medical center in Pediatric Neurology Department continues to track, did a series of checks and no further confirm the diagnosis, then referral to a genetic specialist tracing and found blood values ​​Homocystine value is 18, more than the normal standard values , began to suspected cases of Homocystinuria (high homocysteine ​​hyperlipidemia) in patients start taking vitamin B6. If the mother willing to seek a second opinion case, then you can bring along the data, with the case went to the genetic clinic physician evaluate your case to see what might be the disease.
From the sound of the phone case mother can feel she is a very anxious mother, worried about the case will be like a child gigantism too long becomes heterogeneous, she looked forward to the use of drugs to stop the growth of cases, because my brother is a very good kids, my brother now sophomore his height 178 cm, mothers do not want to grow up to 190 or 200 cases in centimeters, because that is too high, looks like alien, if there is to be able to stop the growth, can be used as long as the doctor said, he is willing to spend money to take the case, but only to stop the growth speed of the case.
The case of female counselors can feel anxiety, but also look forward to the consultant to get a definitive answer, but the counselor can not use the phone to inform of cases of the disease may be, can not agree with another counselor strong parent drug case an expectation, so the case of female counselors want to go to the genetic clinic and counseling services.
(2) consultation and follow-up
Cases accompanied by a parent to come to the case of genetic clinic, physician examination candidates discovered by the arm length is less than height of cases, there are chicken breast, eye degrees 300 degrees, the wrist joint is not loose, the knee is not particularly prominent, speech level acceptable response at a slower pace, leaving blood and urine tests high methionine and cystine, the results are normal.
So counselors alone in the waiting area and talk to the case and found that the case calm personality, but also know why his mother took him to the clinic examination, knowing because he was sick, but still have not found the cause of the morning into the breakfast a little hungry, but not does not matter because Check out the results, wait a minute you can eat breakfast. Observed cases Breakfast: two slices of bread, a banana. Counselor asked: So eat eat it? Case's reply was: my mother said not to eat too much, be in poor health, a little hungry, it does not matter, the body is nice.
The handling of cases and requirements for the mother to do as much as possible, without any resistance, but the case was very anxious mother asked whether the case can be opened to the use of male hormones, because she does not want her children too. Counselors to provide information to inform the cases no longer possible bone has long cases even grow taller may not have too high, because there was no unusual case of HGH checks, but the case of mother insists counselor guarantee intended to Description of cases will not grow to 200 or 210 cm high, on this point the case of female counselors can not promise the requirements and describes the use of male hormones must have a certain condition, NHI will agree to use, at their own expense if the parent case Case injections of male hormones, the case must also have been specialist assessment before deciding whether or not suitable for use.
Throughout the consultation process, consultants can strongly feel the anxiety of female cases, but the height of the case in the current society is not considered particularly high abnormal perception, in order to communicate arguments and his mother was found unacceptable female counselor views, in turn, counselors hear a case mother Why do you feel abnormal cases it is too high? (A) there have been cases of doctors told his mother. Said the case is so high homocysteine ​​in patients can be so high ---- father with the case but the case is not too short mother's height, plus the current environment, good nutrition, so President of cases is not regarded as a higher height in patients with abnormal; (two) case mother stressed that all the grounds are considered acceptable, but the case is deserving student brother, my brother is only 178 cm tall just ah ! Why cases will be higher than the height of his brother, so the case is due to its small six o'clock in the resulting illness, or a certain kind of still can not find the causes.
Because the entire consultation process, the case must be something mother insisted the problem cases, physicians have had to inform the test results according to the actual situation, the current technology can not find, does not mean that the future will not find, it is recommended that the case back to the original patient tracking, or genetic outpatient department regularly checks whether the case will not stop the growth of height growth. Mothers received consultant's recommendations. However, a consultant with other hospitals to communicate, they find cases of mother to all the hospitals and physicians talks, requiring physicians to cases taking male hormones. For this case we need to work together and tracking the case mother be able to bring hope to the clinic regularly track cases, but also hope that all physicians can work together to help mothers through the anxiety of the disease process.
Reference material
1. DEL Wilcken and B, Wilcken, The Natural history of vascular disease in Homocystinuria and the effects of treatment, J. Inherited Metabolic Disorder, 20 (1997) 295 - 3002. S. Harvey Mudd et al, The natural History of Homocystinuria Due to Cystathionine b-Synthase Deficiency, American Journal of Human Genetics, 37:1 - 31, 1985.3. Susan C. Winter et al, Clinical treatment guide to inborn errors of metabolism 1998, Journal of Rare Diseases, Vol 4, No 2, Mar / Apr 1998.