Rare disease

Introduction to long-chain acyl-CoA dehydrogenase deficiency (LCAD) Synonym for long-chain acyl-CoA dehydrogenase deficiency (LCAD) General discussion Long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare Genetic disorder of fatty acid metabolism is an autosomal recessive trait. This happens when an enzyme needs to break down some very long-chain fatty acids, or it doesn't work properly. VLCADD is a metabolic disease known as fatty acid oxidation (Fod) disease. In the past, long-chain acyl-CoA dehydrogenase deficiency (LCADD) was applied to one such disease, but it is clear today that all cases that were once thought to be LCADD are actually VLCADD. The breakdown of fatty acids occurs in the mitochondria of each cell. Mitochondria are small, well-defined bodies that are present in the cytoplasm of cells and whose energy is derived from the breakdown of complex substances into simpler substances (mitochondrial oxidation). Classically, two forms of VLCADD have been described: an early, serious form that, if not identified and diagnosed, can lead to extreme weakness of the heart muscle (cardiomyopathy), can be life-threatening, and is a Late-onset, milder form characterized by repeated hypoglycemia (hypoglycemia). In reality, patients may have multiple symptoms, and the disease is best considered a continuum. Since the use of tandem mass spectrometry to expand the newborn screening program, most VLCADD infants in the United States have been detected in the neonatal period. VLCADD children with early onset of signs and symptoms develop symptoms within a few days or weeks after birth. These babies also show signs of hypoglycemia (hypoglycemia), irritability and listlessness (drowsiness). From 2 to 3 months to about two years old, infants with this disease are at risk of heart muscle thickening (hypertrophic cardiomyopathy), arrhythmia, and heart and lung failure. Cardiomyopathy is rare in infancy but can be life-threatening when it occurs. Delayed VLCADD can be characterized by recurrent episodes of lethargy or even coma, hypoglycemia in infancy, and markedly enlarged liver in childhood (hepatomegaly). In late childhood and early adulthood, hypoglycemia becomes uncommon and is replaced by periodic episodes, muscle pain and collapse (rhabdomyolysis). When hypoglycemia associated with VLCADD occurs, there is little or no accumulation of ketone bodies (hypoglycemia) in the blood. (The ketone body is a chemical usually produced by fatty acid metabolism in the liver.) There are very complex chemical substances and unusual acid concentrations in the blood. If VLCADD is suspected, the patient's blood will be examined for these patterns. Affected people may experience acidosis repeatedly in blood and body tissues (metabolic acidosis), sudden stop of breathing (breathing stop), and even cardiac arrest. These symptoms may be related to cardiomyopathy (see below), listlessness, severe sleepiness (sleepiness), and coma. This acute attack can lead to potentially life-threatening complications if not treated promptly and appropriately. (See standard therapy below for details.) VLCADD deficiency may have evidence of fat deposition (fatty infiltration) and abnormal liver enlargement (hepatomegaly), poor muscle tone (low tension), and/or cardiomyopathy. For example, the left lower chamber (ventricle) of the heart may have abnormal thickening (hypertrophy) or stretching or dilatation (expansion) (ie, hypertrophic or dilated cardiomyopathy). Cardiomyopathy can result in decreased contractility of the heart, reduced circulation of blood through the lungs and other parts of the body (heart failure), and a variety of related symptoms that may depend on the nature and severity of the condition, the age of the patient, and other factors. The cause of VLCADD deficiency is inherited by autosomal recessive inheritance. VLCAD gene (ACADVL) gene map site 17p11.2-p11.1. The original report on long-chain acetyl-CoA dehydrogenase deficiency (LCAD) in the literature is incorrect, and all previously published LCAD-deficient cases are VLCAD defects. Chromosomes are found in the nucleus of humans and carry the genetic information of each individual. Human cells usually have 46 chromosomes. The number of human chromosomes is 1 to 22, the sex chromosomes are X chromosomes and Y chromosomes, the males have one X chromosome and one Y chromosome, and the female chromosomes have two X chromosomes. Each chromosome has a short arm designated as "p" and a long arm designated as "q". The chromosome is further subdivided into a number of striped bands. For example, chromosome 17p11.2-p11.1 refers to a region between the 11.2 and 11.1 bands on the short arm of chromosome 17. The numbered bands specify the location of thousands of genes present on each chromosome. Genetic diseases are determined by a combination of genes from specific traits on the chromosomes of the father and mother. Recessive genetic disorders occur when an individual inherits a copy of a gene that does not function properly from every parent. If a person accepts a normal gene and a disease's gene, the person will be the carrier of the disease, but usually does not have symptoms. Parents of both carriers will inherit the defective gene, so there will be one affected child per pregnancy, the risk is 25%. At each pregnancy, the risk of having a child who is a carrier like a parent is 50%. For a child, the chance of accepting normal genes from both parents and maintaining a normal genetic trait is 25%. The risks for men and women are the same. All individuals carry some abnormal genes. Parents of close relatives (close relatives) are more likely to carry the same abnormal genes than unrelated parents, thereby increasing the risk of children with recessive genetic disorders. As noted above, VLCADD is a genetic disorder of fatty acid metabolism. Metabolic disorders are caused by structural and functional abnormalities of a particular protein called an enzyme. Enzymes are proteins that accelerate the body's chemical reactions. Enzymes are complex proteins that must be folded in a very precise manner to accelerate specific chemical reactions, allowing metabolism to proceed. The affected population VLCADD was originally described in 1992 and is now considered to have an incidence of 1:40,000 babies. Early diagnosis of neonatal VLCAD using heel rod tandem mass spectrometry significantly increased the number of infants who were found to have the disease. Related diseases The symptoms of the following diseases may be similar to VLCADD. Comparison may be helpful in differential diagnosis: There are several other genes that overlap with the symptoms in VLCADD during long-chain fatty acid oxidation. These defects include long-chain acyl-CoA dehydrogenase or complete mitochondrial trifunctional protein deficiency, carnitine epalmitoyl transferase 1 and 2 deficiency, and carnitine-acylcarnitine transportase deficiency. They are all inherited in an autosomal manner. Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is considered to be the most common fatty acid oxidation disorder. It is characterized by the lack of an enzyme that acts on long-chain fatty acids. In infancy or early childhood, affected people It usually begins to experience acute recurrent episodes caused by long-term fasting. Attacks may be characterized by elevated levels of acid (metabolic acidosis), hypoglycemia, vomiting, lethargy, coma, and/or cardiopulmonary arrest in blood and body tissues. Other findings may include liver fat infiltration, secondary carnitine deficiency, elevated levels of certain organic acids in the urine, and other abnormalities. MCAD deficiency is an autosomal recessive trait. (For more information on this disease, please select "Medium Chain" or "MCAD" as your search term in the rare disease database.) Glutathioneuria II (GluII) is a metabolic disorder characterized by Two enzyme deficiency, acyl-CoA dehydrogenase (electron transfer flavin or electron transfer flavin dehydrogenase), or an enzyme involved in riboflavin entry into cells or metabolized to flavin adenine dinucleotide . Symptoms and outcomes may be variable, and the reduction in disease severity appears to be related to an increase in age at the onset of symptoms. In the neonatal period, related abnormalities may include metabolic acidosis, hypoglycemia, elevated levels of various organic acids in the urine, odor of "sweating feet", poor muscle tone (low tension), enlarged liver (hepatic swelling) Big), cardiomyopathy and coma. In some of these cases, affected infants may also have facial abnormalities and multiple cysts in the kidney. Late onset disease may be associated with fasting-induced episodes characterized by hypoglycemia, metabolic acidosis, lethargy, coma, carnitine deficiency, and/or other related abnormalities. Glutathioneuria II is an autosomal recessive inheritance. (For more information on this disease, please select "glutaric aciduria II" as your search term in the rare disease database.) Reye syndrome is a rare disease that affects children around 4 to 12 years old. . In some cases, Reye syndrome was initially suspected to be a fatty acid oxidative disorder in infants or children, including VLCADD. The main feature of Reye syndrome is the rapid accumulation of liver fat, and the brain (acute encephalopathy) is suddenly inflamed and swollen. Related symptoms and outcomes may include sudden and severe persistent vomiting; elevated levels of certain liver enzymes in the blood (liver transaminase); severe disorientation; uncontrolled electrical disturbances in the brain (seizures); and coma. The cause of the disease is unknown. However, the onset of Rey's syndrome is associated with the use of aspirin-containing drugs (salicylate) in children or adolescents with certain viral diseases, especially upper respiratory tract infections (such as influenza B) or in some cases Use chickenpox (chicken pox). Because of the potential link between the use of drugs containing aspirin and the development of Reye syndrome, it is recommended that infants, children, adolescents and young people infected with the virus, such as influenza or varicella, be avoided. (For more information, use "Reye" as your search term in the rare disease database.) Diagnostic VLCADD can be diagnosed based on thorough clinical evaluation; identify characteristic findings (eg hypoglycemia, severe skeletal muscle weakness, heart) Increase); and the results of various specialized tests, including analysis of urine, blood, muscle, liver tissue, skin cells (cultured fibroblasts), and/or white blood cells (white blood cells). A complete family history is especially important in order to determine if a sudden infant death (SID) is in the family's past. One estimate is that VLCAD defects caused up to 5% of small island developing States to die before newborn screening began. In individuals with this disease, urinary organic acid analysis usually shows a decrease or loss of ketone bodies, and some levels of dibasic acids are elevated (ie, dicarboxylic aciduria, such as increased C6-C10, C12-C14 dicarboxylic acids). ). In some cases, elevated levels of creatine phosphokinase (CPK) in the blood and abnormal myoglobin in the urine (myosinuria) occur. Excision (biopsy) and microscopic examination of small sample liver tissue may also show changes in fat infiltration and mitochondria, although this is not necessary in clinical diagnosis. In addition, abnormal enlargement of the heart (cardiac enlargement) associated with cardiomyopathy may be apparent in chest X-ray examination. Prenatal diagnosis can be determined by enzymatic determination of cultured cells or cells obtained from amniotic fluid or villus sampling (CVS). (In amniocentesis, fluid samples around the developing fetus are removed and analyzed, while CVS involves removing tissue samples from a portion of the placenta.) Standard therapy for disease management and treatment is primarily directed at preventing and controlling acute attacks. Precautions include avoiding fasting for more than 10 to 12 hours, maintaining a low-fat, high-carbohydrate diet, and frequent feeding (while keeping fasting to a minimum). Other recommendations may include the use of low fat nutritional supplements, medium chain triglycerides (such as MCT oil), and corn starch (eg, at bedtime). The doctor may also recommend supplementation with carnitine (carnitine) and/or riboflavin. If hospitalized for an acute attack, treatment may require immediate intravenous glucose (10% glucose) and additional support if necessary. Genetic counseling will also benefit affected individuals and their families. In addition, as mentioned above, diagnostic tests for siblings are critical to helping detect and properly manage the disease. Other treatments for this disease are symptomatic and supportive. Investigative Therapy is currently undergoing a clinical trial to treat VLCADD with three heptanolipids, an artificial fat that replaces the MCT oil diet. Studies published to date show that glycemic control is improved in patients treated with triheptanol and the number of rhabdominal episodes is reduced. Cardiomyopathy may also be improved. Bezobet is an experimental drug originally developed to reduce blood cholesterol. Coincidentally, it increases the amount of VLCAD protein in the cells. Limited clinical studies have been published to investigate the use of Bezobet in VLCAD defects, but no active clinical trials have been conducted. Information about current clinical trials can be published on the Internet at www.clinicaltrials.gov. All research funded by the US government, as well as some research supported by the private sector, are posted on this government website.