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.
