一路 BBS

 找回密码
 注册
搜索
查看: 1087|回复: 0
打印 上一主题 下一主题

Mutation in Enzyme CPT2

[复制链接]
跳转到指定楼层
楼主
发表于 7-29-2021 15:39:45 | 只看该作者 回帖奖励 |倒序浏览 |阅读模式
Lisa Sanders, Muscle Memory. At first he thought it was the flu, but he had never felt such weakness and pain. Was there a clue in the ark color of his urine?  New York Times Magazine, July 18, 2021, at page 16.
https://www.nytimes.com/2021/07/ ... PT2-deficiency.html

My comment:
(a) Her column every two weeks have become about very rare diseases, for a few years now. It (column) may satisfy one's curiosity, but is not practical (in daily life).

(b) "The 22-year-old man * * * Every muscle was sore. He felt feverish. * * * his partner had to help him get to the bathroom. Once he was there, the urine he produced was startlingly dark — the color of Coca-Cola. * * * He wasn’t in the emergency department of CHA Cambridge Hospital in Massachusetts for long before the decision to admit him was made. * * * the blood tests done were dangerously abnormal. His kidneys were failing, and it looked as if his liver was damaged, too. His white-blood-cell count was twice the normal level, suggesting a severe infection. * * * The patient told the doctor that he had been working out a few days before he got sick, so the doctor sent a blood sample to look for the presence of creatine kinase (CK), an enzyme that goes up when muscle tissue is injured. Extreme bouts of exercise can cause this kind of injury, and when CK and other muscle components leak into the bloodstream, they [myoglobin also] can cause all kinds of damage — a condition called rhabdomyolysis. A normal level of creatine kinase is in the 100 to 200 range. This patient's CK was [189,000 in blood] * * * Dr Frances Ue was the third-year resident assigned to care for the young man. He hadn't been working out that hard, he told her, after she explained the possible link between his exercise and his current pain. * * * She asked if anything like this had ever happened to him before. Never. Later he recalled an episode of really dark urine when he was sick as a child. But he never had this kind of muscle pain before. * * * The doctors in the emergency room thought exercise-induced rhabdomyolysis was the most likely cause of his symptoms and lab abnormalities, but not the only possibility. They had already sent off tests to look for infections known to affect the liver and kidneys [but test results showed no viral infection] * * * Whatever the cause, she told the anxious young man, his muscles would recover. But his kidneys were in danger. His urine was dark because the oxygen-carrying parts of the muscle known as myoglobin were collecting in the kidneys. Myoglobin is a dark red color; it's why muscle is red. The most important thing the medical team was doing for him right then was giving him [intravenous or iv] fluids to help his kidneys flush out myoglobin and other components released by the damaged muscle. * * * What else? In search of an answer, she turned to the medical literature and found a paper * * * Could he have one of these rare inherited diseases? To answer that question, after the patient recovered enough to leave the hospital, Ue referred him to a neurologist who specializes in neuromuscular diseases. * * * [The patient saw] Dr Courtney McIlduff, a neurologist at Beth Israel Deaconess Medical Center in Boston. Since his week in the hospital, the man reported, he had two more episodes — though neither as severe as the first. Both happened after he took an easy walk. * * * And indeed, he [patient]  had one [inborn errors of metabolism]: He was born without the ability to make an enzyme called carnitine palmitoyltransferase type 2. Patients with CPT2 deficiency are missing the necessary biological equipment to turn some dietary fats into energy. Normally the body runs on a type of sugar made from carbohydrates and stored in the liver [glycogen 肝糖; 'In humans the majority of glycogen is stored in skeletal muscles (∼500 g) and the liver (∼100 g)': from the Web]. When that sugar is used up, the body switches to fat for fuel. Patients with CPT2 deficiency can't do that, or at least not well [the latter is correct in this patient, who was an adult; severe form of CPT2 deficiency appears in infants who soon die]. Without the proper fuel, the muscle cells are injured and release their contents, causing the pain and dark urine. Neither of the man’s parents have this disorder, but they both have one copy of the erroneous gene for this enzyme. It takes two copies to get the disease [cpt2 deficiency is autosomal recessive], and so their son got one copy from each of them.  There is no cure for CPT2 deficiency [short of gene therapy]. It's managed with diet [eat less fat] and lifestyle changes [do less exercise], as well as a supplement that provides fats [excluding long chain fatty acids; take in short-chain ones] that these bodies can break down."
(i) CHA stands for Cambridge Health Alliance (CHA). It boasts of being a teaching hospital to Harvard Medical School (HMS) (same as Beth Israel Deaconess Medical Center in Boston), but in fact a third-rate hospital. "CHA formed in 1996 when two Massachusetts hospitals - Cambridge Hospital and Somerville Hospital [when neither was a teaching hospital of HMS]," per its website.
(ii) "CHA Cambridge Hospital" means the Cambridge Hospital in the CHA.
(iii)
(A) Frances Vivian Ue, MD, MPH

Her bio(graphy) in
About This Blog. In Insights on Residency Training. New England Journal of Medicine (blog)
https://blogs.jwatch.org/general-medicine/index.php/about/
says: "Frances was born and raised in Canada, and she earned an Honors Bachelor of Science from Queen's University [1841- ; public; based in Kingston (at the junction of Lake Ontario and St Lawrence River)] in Ontario. * * * She received a Master's of Public Health from Columbia University * * * She attended Saint Louis University [1919- ; private (founded and run by Jesuits)] School of Medicine and trained in Internal Medicine at Cambridge Health Alliance (CHA) in Massachusetts

(B) She looks like East Asian. Japanese surname does not have Ue. However, "ue" is Japanese pronunciation of kanji 上 (as in 井上 I-no-ue, where no is の). Presumably her ancestors shortened the Japanese surname (whatever it was) upon immigration to North America.
(iv) A young woman, Courtney E McIlduff, MD is certified by American Board of Psychiatry & Neurology.
(v)
(A) Myoglobin and hemoglobin confer red color to muscle and red blood cell, respectively, because both molecules are made up of proteins (of different sequences) plus heme whose center is an iron ion (2+, never 3+). When an oxygen molecule is coupled with the iron in a heme, the myoglobin or hemoglobin looks bright red. When the oxygen molecule is detached, the home looks brown -- hence urine of coca cola color.
(B) "Myoglobin serves as a local oxygen reservoir that can temporarily provide oxygen when blood oxygen delivery is insufficient during periods of intense muscular activity. Iron within the heme group must be in the Fe+2 state to bind oxygen."
Chapter 9 Iron Metabolism and Its Disorders. In Kaneko J, Harvey JW and Bruss M (eds), Clinical Biochemistry of Domestic Animals. 6th ed. Elsevier. 2008, starting at page 259 (cited in en.wikipedia.org for myoglobin.
(C) mIn humans, myoglobin is found in skeletal and cardiac muscle, and little to none in smooth muscle.
(D) The quotation in (b) talked about
rhabdomyolysis (n; Ancient Greek rhábdos rod [alluding to skeletal muscle under microscope of alternating dark and light bands] +‎ myo- muscle +‎ -lysis decomposition, breakdown)
https://en.wiktionary.org/wiki/rhabdomyolysis
(vi)
(A) creatine kinase
https://en.wikipedia.org/wiki/Creatine_kinase   
("In tissues and cells that consume ATP rapidly, especially skeletal muscle, but also brain, photoreceptor cells of the retina, hair cells of the inner ear, spermatozoa and smooth muscle, PCr [phosphocreatine] serves as an energy reservoir for the rapid buffering and regeneration of ATP in situ")

CK catalyzes creatine +ATP to phosphocreatine + ADP or the other way around. Basically, phosphocreatine stores energy in the form of the bond between phosphate ion and creatine. When energy is needed suddenly, ATP is used first, then phosphocreatine, followed by the burning of glucose (derived from hydrolysis of glycogen) and subsequently fatty acid.
(B) creatine
https://en.wikipedia.org/wiki/Creatine
("Creatine was first identified in 1832 when Michel Eugène Chevreul [French, male] isolated it from the basified water-extract of skeletal muscle. He later named the crystallized precipitate after the [ancient] Greek word [noun neuter] for meat, κρέας (kreas)" )

creatine's only function is to become phosphocreatine, for the purpose of storing energy (similar to a battery).


(d) Now I will turn to the enzyme and then the disease of its (enzyme's) deficiency resulting from a genetic mutation.
(i) The enzyme is quite familiar in biochemistry.
(A) Qu Q, Zeng F, Liu X, Wang QJ and Deng F, Fatty Acid Oxidation and Carnitine Palmitoyltransferase I: Emerging Therapeutic Targets in Cancer. Cell Death & Disease 7: e2226 (2016).
https://www.nature.com/articles/cddis2016132

View Figure 1 only. Just view; there is no need to understand it. Then immediately read (B) next.
(B) A more recent scholarly eport is lacking. The best one is

Jogl G, Hsiao YS and Liang T, Structure and Function of Carnitine Acyltransferases. Annals of New York Academy of Sciences, 1033: 17 (2004)
http://tonglab.biology.columbia.edu/Research/crat_nyas.pdf
(at pages 18-19: "The central role of carnitine in the energy metabolism of fatty acids is due to the fact that there are no transporters for the CoA esters of fatty acids in the inner mitochondrial membrane. Instead, the CoA esters must first be converted to carnitine
esters (FIG 1A). This reaction is catalyzed by carnitine palmitoyltransferase-I (CPT-I), which is localized in the outer membrane of the mitochondria (FIG 1B). The carnitine esters are transported across the inner membrane and converted back to the CoA esters by CPT-II. The CoA esters then enter the β-oxidation pathway in the mitochondrial matrix")  (footnotes omitted)

I do not know whether you can understand it. If you can not, it is all right.

The key concept is that when humans burns fatty acid as fuel, we take away the two carbons at a time from the end most distant from -COOH, and continue until the whole fatty acid is chopped down to acetic acid (in case of even-numbered fatty acid) or propionic acid (with 3 carbons; in case of odd-numbered fatty acid). The process is beta oxidation of long-chain fatty acid.
(ii) A common mutation (60%) in CPT2 is at the position/ number 113 (counting from amino terminal) of protein that changes from one amino acid serine to another amino acid leucine. What happens with the change that causes the disease? Nobody knows.

I wish to point out that this article in the NYT magazine does not say what kind of mutation the patient had. Nor does this article explain why CPT2 mutation causes the rhabdomyolysis, except a conclusory remark: "Without the proper fuel, the muscle cells are injured and release their contents." This is because nobody in the world knows. I search medical literature intensively and reach this conclusion.  
(iii) carnitine (accent is in the first syllable)
https://en.wikipedia.org/wiki/Carnitine
("carnitine transports long-chain fatty acids into mitochondria to be oxidized for energy production * * * Given its key metabolic roles, carnitine is concentrated in tissues like skeletal and cardiac muscle that metabolize fatty acids as an energy source. * * * carnitine was first extracted from meat extracts in 1905, leading to its name from Latin, caro / carnis [both are noun feminine] * * * Humans synthesize carnitine from" amino acid lysine)
回复

使用道具 举报

您需要登录后才可以回帖 登录 | 注册

本版积分规则

快速回复 返回顶部 返回列表