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    Home > Active Ingredient News > Endocrine System > Very long chain acyl-CoA dehydrogenase deficiency: signs and symptoms, etiology, epidemiology, diagnosis, and treatment

    Very long chain acyl-CoA dehydrogenase deficiency: signs and symptoms, etiology, epidemiology, diagnosis, and treatment

    • Last Update: 2022-09-06
    • Source: Internet
    • Author: User
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    Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a relatively rare genetic metabolic disease that is an autosomal recessive disorder due to oxidative disorders β long-chain fatty acids in the mitochondria


    First, the general overview

    Very long chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare genetic disorder of fatty acid metabolism that spreads


    The breakdown of fatty acids occurs in the mitochondria of each cell


    Classically, two forms of VLCADD have been described: one is a severe form of early onset that, if not identified and diagnosed, can lead to extreme weakness of the myocardium (cardiomyopathy) and is life-threatening, and a later, milder form characterized by recurrent episodes of hypoglycemia (hypoglycemia


    2.


    Children with early-onset VCADAD develop symptoms


    Hypoglycemia associated with VLCAD occurs


    Affected individuals of any age are at risk of developing a repeated increase in acid levels in the blood and body tissues (metabolic acidosis); Sudden cessation of breathing (respiratory arrest) or even cardiac arrest


    Individuals with VLCADD deficiency may have fat deposition (fat infiltrates) and abnormal enlargement of the liver (hepatomegaly); Poor muscle tone (hypotonia); and/or evidence


    3.


    VLCAD deficiency is inherited in an autosomal recessive manner


    The ACADVL gene is located at 17p13.


    Genetic disorders are determined by a combination of genes for specific traits on the chromosomes of the father and mother


    All individuals carry some abnormal genes


    As mentioned above, VLCADD is a genetic disorder


    4.


    VLCADD was originally described in 1992 and is now thought to have an incidence
    of 1:40,000 infants.
    The introduction of heel bar tandem mass spectrometry for early diagnosis of neonatal VLCAD significantly increases the number of
    infants detected with the disease.

    The incidence rate is 1/100 000 to 1/30 000 between different ethnic groups in foreign countries, and the incidence rate in European and American countries is reported to be about 1/85 000, and there is no epidemiological data
    in China.

    5.
    Differential diagnosis

    Symptoms of the following conditions may be similar
    to those of VLCAD.
    Comparison may be helpful in the differential diagnosis:

    There are several other genes involved in long-chain fatty acid oxidation that overlap
    with the symptoms seen in VLCAD.
    These include long-chain acyl-CoA dehydrogenase or complete mitochondrial trifunction protein deficiency, carnitine palmitoyltransferase 1 and 2 deficiencies, and carnitine-acyl carnitine transpose deficiency
    .
    All of this is inherited
    in an autosomal manner.

    Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is considered the most common fatty acid oxidation disorder
    .
    It is characterized by a lack of an enzyme that acts on medium-chain long fatty acids
    .
    In infancy or early childhood, affected individuals usually begin to experience acute, recurrent episodes
    caused by prolonged fasting.
    Seizures may be characterized by elevated acid levels in the blood and body tissues (metabolic acidosis), hypoketonic hypoglycemia, vomiting, drowsiness, coma, and/or cardiopulmonary arrest
    .
    Other findings may include hepatic fat infiltration, secondary carnitine deficiency, elevated levels of certain organic acids in the urine, and other abnormalities
    .
    MCAD deficiency is inherited
    as autosomal recessive.

    Glutaric aciduria II (GA II) is a metabolic disorder characterized by a lack of either of two enzymes that allow the recirculation of acyl-Coenzyme A dehydrogenase (electron transfer flavin protein or electron transfer flavin protein dehydrogenase) or enzymes
    involved in riboflavin uptake into cells or metabolized into cells.
    Flavin adenine dinucleotide
    .
    Symptoms and findings can be variable, and a decrease in disease severity appears to be associated
    with an increase in age at the onset of symptoms.
    In the neonatal period, associated abnormalities may include metabolic acidosis, hypoglycemia, elevated levels of multiple organic acids in the urine, abnormal odor of "sweaty feet", poor muscle tone (hypotonia), hepatomegaly (hepatomegaly), cardiomyopathy, and coma
    .
    In some of these cases, affected babies may also have facial abnormalities and multiple cysts
    in the kidneys.
    Delayed disease may be associated with fasting-induced episodes characterized by hypoketonemia, metabolic acidosis, drowsiness, coma, secondary carnitine deficiency, and/or other associated abnormalities
    .
    Glutaric aciduria II is inherited
    in an autosomal recessive pattern.

    Reye syndrome is a rare condition that primarily affects children around the age of 4 to 12 years
    .
    In some cases, Reye syndrome is initially suspected to be present in infants or children with fatty acid oxidation disorders, including VLCADD
    .
    The main features of Reye syndrome are the rapid accumulation of fat in the liver and the sudden inflammation and swelling of the brain (acute encephalopathy
    ).
    Associated symptoms and findings may include sudden onset of severe, persistent vomiting; Elevated levels of certain liver enzymes in the blood (hepatic transaminases); Severe disorientation; Uncontrolled electrical disturbance seizures in the brain (seizures); and coma
    .
    The cause of the condition is unknown
    .
    However, there appears to be an association between the onset of Reye syndrome in certain viral diseases, particularly upper respiratory tract infections (e.
    g.
    , influenza B) or in some cases, when children or adolescents use drugs containing aspirin (salicylates
    ).
    , chickenpox (chickenpox
    ).
    Because there may be an association between the use of drugs containing aspirin and the development of Reye's syndrome, it is recommended that infants, children, adolescents, and young adults infected with viruses such as influenza or chickenpox avoid such drugs
    .

    Cardiomyopathic VLCADD needs to be distinguished from
    systemic primary carnitine deficiency, carnitine palmitoyltransferase II( CPT II) deficiency, long-chain 3-hydroxyacyl-CoZY A dehydrogenase / trifunctional protein deficiency, carnitine acyl carnitine transferase deficiency, and severe multiple acyl-CoA dehydrogenase deficiency.

    2.
    The hepatic form of VLCAD deficiency may have clinical features similar to that of a medium-chain acyl-CoA dehydrogenase (MCAD) defect or similar to an electron transfer protein (ETF)/ETF ubiquinone (CoQ) oxidoreductase deficiency, resulting in multiple acyl-CoA dehydrogenase deficiencies, but with different
    biochemical phenotypes.

    3.
    Intermittent rhabdomyolysis can be a feature of McArdle disease, CPT II deficiency, and some primary rhabdomyolysis and myopathy can also be seen
    .
    Differentiation depends on muscle biopsy pathological examination, blood amino acid and esteryl carnitine spectroscopy, urinary organic acid analysis and gene analysis
    .

    6.
    Diagnosis

    VLCAD can be diagnosed based on a comprehensive clinical evaluation; Identification of characteristic findings (e.
    g.
    , hypocotogenesis hypoglycemia, severe skeletal muscle weakness, enlarged heart); Results from a variety of specialized tests, including analysis of various samples such as urine, blood, muscle, liver tissue, skin cells (cultured fibroblasts), and/or white blood cells (white blood cells
    ).
    A comprehensive and complete family history is particularly important
    to determine whether a family has experienced sudden infant death (SID) in the past.
    One estimate is that VLCAD deficiencies accounted for 5%
    of all SIDS deaths before neonatal screening.

    In individuals with the disease, urine organic acid analysis usually shows a decrease or absence of ketone bodies and an increase in certain dicarboxylic acid levels (i.
    e.
    , dicarboxylic aciduria, e.
    g.
    , increased C6-C10, C12-C14 dicarboxylic acid).

    In some cases, blood levels of creatine phosphokinase (CPK) may be elevated, and abnormal myoglobin (myoglobinuria)
    may occur in the urine.

    Excision (biopsy) and microscopic evaluation of small samples of liver tissue may also reveal fat infiltration and structural changes in mitochondria, although this is not necessary for clinical diagnosis
    .
    In addition, abnormal enlargement of the heart associated with cardiomyopathy (hypertrophy of the heart) may be evident
    on chest x-rays.

    Prenatal diagnosis can be obtained
    by taking enzymatic measurements of cells cultured or from amniotic fluid or during chorionic villus sampling (CVS).
    (By amniocentesis, a sample of fluid around the developing fetus is removed and analyzed, while CVS involves removing tissue samples
    from part of the placenta.
    ) )

    Diagnostic process

    7.
    Treatment

    Disease management and treatment is primarily aimed at preventing and controlling acute exacerbations
    .
    Newborns should not fast for more than 4 hours (including at night)
    during the first 6 months of age.
    This can be gradually increased to 8 hours over the next 6 months of age, and then 8-12 hours
    after age 3.
    Other precautions include maintaining a low-fat, high-carbohydrate diet and feeding regularly (i.
    e.
    , keeping fasting to a minimum for a period of time
    ).
    Other recommendations include the use of low-fat nutritional supplements and medium-chain triglycerides (e.
    g.
    , MCT oil
    ).
    Carnitine supplementation is somewhat controversial, and most metabolic doctors wait until laboratory evidence of carnitine deficiency appears before prescribing
    it.
    Riboflavin, which has sometimes been recommended in the past, does not appear to be beneficial
    .

    The general therapeutic principles of VLCADD are to avoid fasting, to give a high-sugar and low-fat diet, especially to limit the intake of long-chain fatty acids, to supplement medium chain triglycerides (MCTs), to treat symptomatically, and to prevent and treat complications
    .

    1.
    Avoid fasting Frequent feeding can be used as a simple and effective preventive measure to provide the body with enough heat and energy to prevent excessive fat mobilization
    .
    The neonatal period is usually fed every 3 hours; 4 hours apart for infants <6 months; Infants 6 to 12 months of age may be spaced 6 to 8 hours apart at night; Children aged 1 to 7 years are fed 4 hours during the day and can be extended to 10 hours at night; Adults, on the other hand, are generally spaced 8 hours apart (4 to 12 hours).

    Raw corn starch can be given at night or during intense activities to enhance tolerance to fasting, and raw corn starch can sustain the release of glucose, reducing the occurrence of hypoglycemia and the decomposition
    of fat.

    2.
    Reasonable diet and use of MCTs The diet structure should be based on sugars, reduce fat intake, especially long-chain fatty acids, but must ensure the intake of essential fatty acids, while providing enough protein
    .
    Fat intake in general healthy infants accounts for 40% to 50% of total calories, and school-age children account for 30% to 35%.

    Symptomatic patients with VLCADD consume 25% to 30% of total calories, paying particular attention to limiting long-chain fatty acids and supplementing with MCTs
    .
    In children with cardiomyopathy, MCT should account for 90% of total fat intake and 10%
    of long-chain fatty acids.
    Within 1 year of age, 80% of the fat of the most MCT-rich formula should be selected for MCT), such a diet can reverse the pathological changes of the heart muscle in cardiomyopathic patients; Children should limit their intake of long-chain fatty acids to no more than 10% of their total calories after 1 year of age, and MCTs should provide 20%
    of their total calories.
    Children with hepatic and myopathic types up to 1 year of age can choose MCT-rich formula (MCT for 50% fat) or the most MCT-rich formula; After the age of 1 year, it is recommended to choose a diet
    that is beneficial to "heart health".
    50% of the general fat comes from long-chain fatty acids and 50% from MCTs
    .
    The caprylic, capric and other unsweetened xenogenesis of MCTs, although the glycerol in it can be xenogenic as glucose, but the amount produced is small, which cannot meet the needs of patients with repeated episodes
    of hypoglycemia.
    MCT can significantly improve the symptoms of fatty acid oxidation disorder central muscle and skeletal muscle; When patients with VLCADD are in a metabolic disorder, supplementation with MCTs does not prevent liver damage, and even excessive MCT supplementation can exacerbate oxidative stress
    of the mitochondria.

    3.
    Levocarnitine There has been controversy
    over levonitin supplementation for fatty acid β oxidative disorders.
    In VLCADD, due to the obstruction of the β oxidation pathway of very long-chain fatty acids, there is excessive accumulation of long-chain fatty acids in the mitochondria, which need to be combined with free carnitine to form an acyl carnitine transport out of the mitochondria, which will cause the lack of free carnitine in the blood, so carnitine supplementation can maintain stable
    free carnitine levels in the blood.
    Generally given 50 to 100 mg/(kg·d).

    Levocarnitine in combination with dietary therapy can significantly alleviate cardiac dysfunction
    in patients with VLCADD.
    Short-term application can promote ketone production and reduce the occurrence of fasting hypoglycemia, but too much promotes the production and accumulation of long-chain acyl carnitine, which has a toxic effect
    on the body.
    Primassin et al.
    found that supplementation with carnitine did not prevent the reduction of free carnitine in muscles by establishing a mouse model of VLCADD, especially after exercise, but caused a large accumulation of acyl carnitine in skeletal muscle and toxic effects
    .

    4.
    If hospitalized for an acute episode, treatment may require prompt intravenous glucose (10% glucose) and additional support measures
    if necessary.

    5.
    Other treatments For patients with recurrent episodes of hypoglycemia, intravenous glucose can be injected to correct symptoms of
    hypoglycemia.
    It has been found that the activator bezafibrate of the peroxisome proliferation activator receptor α can improve the fatty acid oxidation capacity of VLCADD cells, and increase the expression of VLCAD mRNA and protein in the cells of VLCADD patients, improve the enzyme activity of mutant proteins by upregulating gene expression, and benzabept can also reduce the production
    of long-chain acyl carnitine with toxic effects 。 It has been reported in the literature that the muscle relaxant dantrolenesodium has a good effect on adult patients with VLCADD with myalgia spasms, myotonic rigidity, rhabdomyolysis, and the main mechanism is that dantrolline sodium salt can bind to the main Ca2+ release channel of the skeletal muscle plasma reticulum Ryandonine receptor, limit the release of Ca2+ from the sarcoplasmic reticulum/myoplasmic reticulum, and prevent the continuous increase of intracellular Ca2+ and the abnormal mitochondrial function caused by the elevation of Ca2+; It can also act on the neuromuscular junction to interrupt the excitatory-contraction coupling for therapeutic purposes
    .

    6.
    Genetic counselling should be provided to the families of all affected individuals
    .
    In addition, as mentioned above, diagnostic tests for siblings are essential
    to help detect and properly manage the condition.
    Other treatments for this disorder are symptomatic and supportive
    .

    VIII.
    Treatment in research

    A clinical trial is currently underway on the treatment of VLCADD with glyceryl triheptanoate, a man-made fat that replaces dietary MCT oil
    .
    Studies published to date have shown that in patients treated with triglyceride, glucose control was improved and episodes of rhabdomyopathy were reduced
    .
    Cardiomyopathy also improved
    .
    At the time of writing, it is being reviewed for fda approval
    .

    Benzalfibrate is an experimental drug
    originally developed to lower blood cholesterol.
    Coincidentally, it was shown to increase the amount of
    VLCAD protein in cells.
    Limited clinical studies have been published to study the use of benzabrate in VLCAD deficiency, but there are no ongoing clinical trials
    .
    Reneo Pharmaceuticals (REN-01, known as PPAR delta), a more effective drug that increases the oxidative effect of fatty acids, is in clinical trials
    .

    9.
    Rare disease information registration

    If you are willing to seek constantly updated information, it is recommended that you register the patient's information here, even if you are not fully diagnosed, you can register, click to enter:

    Patient Information Registry System for Rare Diseases

    Resources:

    Schiff M, Mohsen AW, Karunanidhi A, McCracken E, Yeasted R, Vockley J.
    Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency.
    Mol Genet Metab.
    2013; 109(1):21-7.

    Shigematsu Y, Hirano S, Hata I, et al.
    Selective screening for fatty acid oxidation disorders by tandem mass spectrometry: difficulties in practical discrimination.
    J Chromatograph B Analyt Technol Biomed Life Sci.
    2003; 792:63-72.

    Kluge S, Kuhnelt P, Block A, et al.
    A young woman with persistent hypoglycemia, rhabdomyolysis, and coma: recognizing fatty acid oxidation defects in adults.
    Crit Care Med.
    2003; 31:1273-76.

    Spiekerkoetter U, Tenenbaum T, Heusch A, et al.
    Cardiomyopathy and Pericardial Effusion Point to a Fatty Acid b-Oxidation Defect after exclusion of an Underlying Infection.
    Pediatr Cardiol.
    2003; 24:295-97.

    Solis JO, Singh RH.
    Management of fatty acid oxidation disorders: a survey of current treatment strategies.
    J Am Diet Assoc.
    2002; 102:1800-03.

    Wilcox RL, Nelson CC, Stenzel P, et al.
    Postmortem screening for fatty acid oxidation disorders by analysis of Guthrie cards by tandem mass spectrometry in sudden unexpected death in infancy.
    J Pediatr.
    2002; 141:833-36.

    Boles RG.
    Very long-chain acyl CoA dehydrogenase deficiency in an infant presenting with massive hepatomegaly.
    J Inherit Metab Dis.
    2002; 25:315-16.

    Gregersen N, Andresen BS, Corydon MJ, et al.
    Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship.
    Hum Mutat.
    2001; 18:169-89.

    Marsden D, Nyhan WL, Barshop BA.
    Creatine kinase and uric acid: early warning for metabolic imbalance resulting from disorders of fatty acid oxidation.
    Eur J Pediatr.
    2001; 160:599-602.

    Wood JC, Magera MJ, Rinaldo P, et al.
    Diagnosis of very long-chain acyl-CoA dehydrogenase deficiency from an infant’s newborn screening card.
    Pediatrics.
    2001; 108:E19.

    Touma EH, Rashed MS, Vianey-Saban C, et al.
    A severe genotype with favorable outcome in very long-chain acyl-CoA dehydrogenase deficiency .
    Arch Dis Child.
    2001; 84:58-60.

    Zytkovicz TH, Fitzgerald EF, Marsden D, et al.
    Tandem mass spectroscopic analysis for amino, organic and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program.
    Clin Chem.
    2001; 47:1945-55.

    Gregersen N.
    Andresen BS, Bross P.
    Prevalent mutations in fatty acid oxidation disorders: diagnostic considerations.
    Eur J Pediatr.
    2000; 159 Suppl 3:S213-18.

    Gregersen N, Bross P, Jorgensen MM, et al.
    Defective folding and rapid degradation of mutant proteins is a common disease mechanism in genetic disorders.
    J Inherit Metab Dis.
    2000; 23:441-47.

    Roe CR, Wiltse HE, Sweetman L, et al.
    Death caused by perioperative fasting and sedation in a child with unrecognized very long-chain acyl-CoA dehydrogenase deficiency.
    J Pediatr.
    2000; 136:397-99.

    Scholte HR, Van Coster RN, de Jonge PC, et al.
    Myopathy in very long-chain acyl-CoA dehydrogenase deficiency: clinical and biochemical differences with fatal cardiac phenotype.
    Neuromuscul Disord.
    1999; 9:313-19.

    Baby’s First Test: Very-long-chain acyl-CoA dehydrogenase deficiency.
    2015.
    Available at:  Accessed October 21, 2019.

    Vianey-Saban C.
    Acyl-CoA dehydrogenase, very long chain, deficiency of.
    Orphanet.
    Last update: February 2014.
    Available at:  Accessed October 21, 2019.

    McKusick VA, ed.
    Online Mendelian Inheritance in Man (OMIM).
    The Johns Hopkins University.
    Entry Number: 201475; Last Update: 10/19/2017.
    Available at:  Accessed October 21, 2019.

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