Screening for 58 neonatal metabolic disorders in Iran (Part 5 - Fatty Acid Disorders)

Screening for 58 neonatal metabolic disorders in Iran (Part 5 - Fatty Acid Disorders)


In the following, we will discuss one of the most important disorders that is screened during this process, namely fatty acid disorders.


Disorders of fatty acids

- The hereditary pattern of these disorders is the autosomal recessive pattern and is observed in girls and boys equally. For this reason, the prevalence of these diseases is higher in consanguineous marriages.

Approximately one-third of human energy is supplied by fatty acids. Dietary fats are mostly in the form of triglycerides and are absorbed in the small intestine during the metabolic process, free fatty acids [1] and monoacetylglycerols.

Fatty acids are re-produced in the mucosal cells of the striatum and triglycerides. Triglycerides are converted to fatty acids again during lipolysis. Fatty acids in mitochondria are oxidized during the β-oxidation process and lead to energy production.

- This pathway is the main metabolic pathway for energy production in the heart of the liver and skeletal muscle. The importance of these reactions, especially during fasting, is evident because 80% of the energy produced during fasting is due to the metabolism and metabolism of fats.

- The breakdown of fatty acids in mitochondria takes place during a process called β-oxidation of fatty acids (FAO = Fatty Acid Oxidation).

The β-oxidation process of fatty acids involves four steps:
1- Carnitine cycle
2- Beta oxidation: It consists of four consecutive reactions. The first reaction is under the influence of acyl coa dehydrogenase and this enzyme itself includes 4 different types and includes:

- Very Long Chain Acyl Co A Dehydrogenase = VLCAD,

- Long Chain Acyl Co A Dehydrogenase = LCAD,

- Medium Chain Acyl Co A Dehydrogenase = MCAD.

- Short Chain Acyl Co A Dehydrogenase (SCAD).

3- Electronic transmission

4- Production of ketone bodies


- Carnitine (a derivative of amino acids) in:

1- Transfer of fatty acids from cytosol to mitochondria

2- Decomposition of amino acids to acetyl coenzyme A during the beta-oxidation process

3- Finally, energy production is required.

- Carnitine is an amino acid derivative that is required for the transfer of fatty acids from cytosol to mitochondria and subsequently the breakdown of amino acids to acetyl coenzyme A during the beta-oxidation process and ultimately energy production.

Deficiencies in the oxidation of fatty acids in mitochondria are a major group of very important inherited neurotabolic diseases. At least 11% of diseases are related to the fatty acid oxidation disorders identified.

This is due to a lack of an enzyme or transport factor that varies with the age of onset of the disease and the severity of the attacks in each disease.

- Several diseases caused by genetic abnormalities are seen in the transfer of long chain fatty acids across the mitochondrial membrane. These diseases are rooted in a lack of carnitine or a deficiency in the synthesis and transport of acetyl carnitine.

- Because carnitine plays an important role in the metabolism of fatty acids, its reduction plays an important role in fatty acid disorders.

- Carnitine deficiency is seen in both primary and secondary types. Early carnitine deficiency is the result of a defect in the plasma membrane transmitter with a high tendency to carnitine in tissues such as muscle, kidney, heart and fibroblasts (liver has a different carrier). The levels of carnitine in the blood and tissues are greatly reduced due to the inability of the kidneys to reabsorb carnitine.

Severe carnitine deficiency in the heart and skeletal muscle severely impairs the oxidation of long-chain fatty acids.


Clinical signs:

Symptoms appear in three important organs of the body: the liver, heart and muscles:

Hepatic manifestations are usually severe and fatal, and occur during infancy or infancy with low blood sugar in the absence of ketosis, liver dysfunction, seizures, and metabolic acidosis.

Cardiac manifestations are more likely to be hypertrophic and arrhythmic cardiomyopathy during infancy and childhood.

Muscle manifestations are characterized by milder forms of the disease and are more common in adulthood and include muscle involvement and rhabdomyolysis (muscle breakdown). Most of these patients develop heart or liver symptoms in childhood.

The first manifestation of these diseases is often in late infancy.
At older ages, symptoms such as premature fatigue, myalgia, proximal muscle weakness, and rhabdomyolysis attacks may attract attention. Therefore, in adults with these symptoms, fatty acid disorders should be considered for differential diagnosis.

These patients develop muscle weakness during long periods of activity, when the energy expended in the muscles relies on the oxidation of fatty acids.

Myoglobinuria is often seen in these patients due to the breakdown of muscle tissue.
Patients with low or severe enzymatic activity are more likely to have severe forms of the disease and usually have all three of the above symptoms together.

Symptoms often appear episodically, followed by prolonged fasting, exercise stress, or infection (especially viral) that increases the oxidation of fatty acids. If not treated properly, bad prognosis and high mortality are predicted.

   Nutritional Tips

• Carnitine status

Decreased levels of free carnitine may occur in two ways:
Children born to mothers with carnitine deficiency.
Decreased secondary carnitine to metabolic disorders

Both of these conditions make carnitine levels insufficient for conjugation of asyl roots. In such cases, if there is organic acid or fatty acid oxidation defects, the increase in biomarkers is less and the probability of receiving false negative results increases.

In such cases, and if blood carnitine levels are low, tests should be repeated after administration of 100 mg / Kg of carnitine. Dietary therapy with carnitine increases the plasma levels of carnitine and its non-specific entry into the cell, which is beneficial for these patients.

In contrast, in children treated with carnitine, high carnitine should not be attributed to metabolic disorders.        

Accumulation of long-chain toxic acetyl carnitine, especially in long-chain fatty acid oxidation defects, may cause severe lactic acidosis in infancy, heart muscle damage, and liver damage similar to those in respiratory chain defects.

For example, MCAD or Medium Chain Acyl CoA dehydrogenase Deficiency, which is the most common disorder in the group of fatty acid disorders and with a prevalence of 1: 10000 to 1: 14000. These patients have problems when they are hungry for a long time or undergo an infectious process (due to the body's need to produce more energy). The first manifestations of the disease occur in these people between the ages of three months and two years.


MCAD accounts for 1 to 3% of Sudden infant death syndrome, which is the most severe form. If this disease is diagnosed in time, its effective treatment can have a good clinical consequence for these patients.

Common clinical symptoms of carnitine include: mild recurrent muscle cramps to severe weakness and death.

Lack of ketosis is due to the cessation of oxidation of fatty acids in the liver, which also reduces gluconeogenesis.

Decreased oxidation of fatty acids in the muscle leads to increased glucose uptake and consequently severe hypoglycemia, and the person suffers from hypoxotic coma, which can be accompanied by symptoms of liver failure and increased blood ammonia.

Renal excretion of high levels of acetyl carnitine can also lead to a secondary reduction in carnitine.

In addition to liver transaminases, creatine kinase and uric acid are often high in these diseases.

In infants or children with hypoglycemia, high levels of uric acid and creatine kinase (none of which are routinely checked in the pediatric clinic) have been shown to be a warning sign of fatty acid oxidation defects.


Specifications of embryos with fatty acid disorders

Many fetuses with fatty acid disorders are:
Intrauterine growth disorder (IUGR),

- Failure,

- Preeclampsia,

Acute Fatty Liver of Pregnancy

- and HELLP syndrome.


Neonatal screening:

During the screening of metabolic diseases in infants 2 to 7 days of age, MS / MS markers related to acyl carnitines were measured using the MS / MS test.

Among the markers measured during this screening are the profile of acetyl carnitine, which is considered as the primary marker for screening for fatty acid disorders.
If the result of the above tests is abnormal in Westernization, the MS / MS test should be repeated 1 to 2 days later with re-blood sampling. Obviously, if there is an enzymatic problem, the amount of these markers in the second sample will change more.

Secondary markers: After confirming the increase in primary markers during the above two sampling stages, the changes of the secondary markers during the two sampling stages are also calculated.

If these changes are observed in secondary markers, the individual's response is considered "outside the normal range" and is reported as a "suspicious" test for amino acid disorders, and confirmatory or diagnostic tests are recommended to confirm the diagnosis.



Diagnosis:

Perform profiles of organic acids in the urine in the form of increasing carboxylic acids and acyl glycines.
Measurement of enzyme levels in fibroblasts
Investigation of carnitine uptake in fibroblasts
Genetic testing: Today, there are specific genetic tests (DNA tests) that can be used to determine if a fetus is carrying a defective gene.


treatment:

The main purpose of treatment in these diseases is the following:

Try to prevent the accumulation of toxic metabolites as well as compensate for the metabolic substance that is deficient
Withdrawal of toxins accumulated in the body by methods such as fluid administration (to compensate for the lack of breastfeeding, increase fluid flow and ensure effective excretion of toxic metabolites)
Vitamin therapy (as therapeutic cofactors in cases of deficiency and deficiency of related groups and increased metabolism)


- These patients will be easily controlled and have a normal life by slightly modifying their diet.

- Treatment is mainly by avoiding a long fast to keep blood sugar levels normal (between 2 and 6 hours, a person should eat a light, low-fat, high-glucose diet).

In some cases, administration of carnitine (especially in metabolic crises and secondary carnitine deficiency due to urinary excretion). Prescribing carnitine in MCAD causes more excretion of medium-chain esters.

- Depending on the type of disease, it is important to control the type and size of fat consumed.

Intestinal or enteral or intravenous glucose administration is necessary (to correct hypoglycemia and provide energy) to reduce the need to use fats.

- Intravenous or enteral feeding of cornstarch powder at night as a source of glucose supply.

- As the child gets older, the frequency of attacks decreases with increasing body mass (due to increased resistance to hunger due to increased body mass).

Diet in disorders associated with carnitine deficiency can contain medium-chain triacylglycerols, because these fatty acids enter mitochondria through a mechanism independent of carnitine.

Attention:

In general, 12% of disorders are completely cured. More than 55% of treatment disorders are beneficial and lead to a nearly normal life. In 33% of cases, treatment has the least effect.

  

RelatedNews Screening for 58 neonatal metabolic disorders in Iran (Part 5 - Fatty Acid Disorders)

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