Introduction:
3-Methylglutaconic aciduria type IV is a genetic disorder. It occurs due to a deficiency of an important enzyme named 3-methylglutaconyl-CoA hydratase. This enzyme plays a very important role in leucine metabolism. Leucine is a vital amino acid, in simpler terms, a protein that regulates neural activities, including speaking abilities in an individual. Deficient leucine metabolism results in increased levels of a few acids, namely,
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3-methylglutaconic acid.
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3-methylglutaric acid
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3-hydroxyisovaleric acid.
Increased acid levels can be noted in urine analysis. The term 'aciduria' used in disorder 3 methylglutaconic aciduria type IV accounts for increased acid levels in the urine.
As the leucine metabolism gets disturbed in 3 methylglutaconic aciduria type IV, it is characterized by a range of symptoms, including delayed development of speaking abilities in an individual and severe neural insufficiency. As a result, performing daily activities becomes difficult for individuals suffering from 3 methylglutaconic aciduria type IV.
What Are the Types of 3 Methylglutaconic Aciduria?
Researchers have broadly classified 3 methylglutaconic aciduria into four types:
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3 Methylglutaconic Aciduria Type I: Leucine is metabolized in the body through cycles of events. In this type of 3 methylglutaconic aciduria, the fifth step in leucine catabolism gets affected, and the conversion of 3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) gets hampered. This results in faulty leucine breakdown, which further causes a series of neural insufficiencies.
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3 Methylglutaconic Aciduria Type Il: It results from a genetic mutation in the gene that encodes for tafazzin (it is an essential protein responsible for heart and skeletal muscle activity). This genetic mutation causes severe neutropenia (decreased levels of neutrophils leading to increased susceptibility to infections), retarded growth due to hampered skeletal muscle activities. The other name for this disorder is Barth syndrome.
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3 Methylglutaconic Aciduria Type III: This disorder is also called costeff syndrome. It has an autosomal recessive pattern of inheritance. It is caused due to genetic mutation in the OPA3 gene. This genetic mutation is responsible for optic atrophy (nerve fibers in the optic nerve get degenerated) in individuals suffering from this disorder.
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3 Methylglutaconic Aciduria Type IV: It is also called an unspecified type of 3 methylglutaconic aciduria and is characterized by progressive loss of neurological activities.
Amongst all four types of 2 methylglutaconic acidurias, the highest levels of acids like 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid in the urine are noted in patients suffering from 3 methylglutaconic aciduria type I. Depending on the type of the organic aciduria, if the individual is affected, the symptoms range from mild features like delayed speech development and gastroesophageal reflux to severe symptoms, including frequent seizures and other cerebral abnormalities.
What Is Organic Aciduria?
Organic aciduria describes a group of disorders characterized by increased levels of organic acids in the urine. It is caused due to altered functioning of the protein breakdown procedures. Dysfunctional protein breakdown is related to deficient enzymatic activity involved in the protein breakdown procedure. As a result, the end product of these organic protein breakdown pathways gets reduced, leading to deficiency of particular amino acids and increased acidic byproducts leading to the increased acid content of the urine.
What Are the Signs and Symptoms of 3 Methylglutaconic Aciduria Type IV?
The features of 3 methylglutaconic aciduria can be noted at the time of birth or in the early days of infancy. A few common signs and symptoms noted in infants suffering from 3 methylglutaconic aciduria are as follows:
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The infant refuses to get fed.
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Vomiting: The child faces difficulty digesting food due to increased acidity, resulting in frequent vomiting.
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Dehydration: Increased acidic levels and frequent vomiting leads to water loss from the body causing dehydration in infants.
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Neutropenia: Reduced levels of neutrophils in the blood lead to increased susceptibility to infections and this condition is known as neutropenia. Infections, including fungal, viral, and bacterial, are frequently noted in infants due to decreased immune system activity.
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Hypoglycemia: It explains the reduced glucose levels in infants. Hypoglycemia causes lethargy and disinterest in playing. The infants are often irritated and keep crying, and they are hard to calm.
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In a few infants, seizures are commonly noted. When the child gets seizures, the parent's responsibility is to protect them from getting accidentally hurt.
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In severe, complicated cases, the lethargy noted in the infant can progress to a coma. It is a life-threatening situation; proper medical guidance is required to protect the child at this stage.
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Pancreatitis (pancreas infection leading to inflammation) is another life-threatening infection noted in these individuals.
Critical care is required to prevent these complications from worsening.
How Organic Aciduria Can Be Diagnosed?
Following are a few diagnostic tests that help the doctor detect organic aciduria:
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Blood Sugar Levels: Individuals suffering from organic aciduria generally show reduced glucose levels (hypoglycemia). Medical research papers have depicted that in infants, the glucose level is around 40 mg/dl, 60 mg/dl in children, and approximately 75 mg/dl in children above 16 years of age.
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Tests to Analyze Neutrophil Levels: Neutropenia is a common feature that depicts reduced levels of neutrophils in the blood. Medical research papers state neutrophil levels to be approximately 1500/mm. White blood cell levels can vary in different age groups; slight value changes are also noted in reports from other laboratories; therefore, these points should be noted before coming to a conclusion.
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Liver Function Tests: It is done to check for protein metabolism activities. In cases of organic aciduria, the liver function tests tend to depict abnormal values.
What Are the Management Protocols for 3 Methylglutaconic Aciduria Type IV?
The fundamental motive of the management protocols is to save the individual from life-threatening situations. Symptoms like vomiting and dehydration should be monitored carefully, and electrolyte replacements should be done to treat such medical conditions. Parents should be aware of the child's conditions, and precautionary measures and diet plans should be given to control the acidic levels. In severe complicated conditions like heart enlargement, the surgical approach is the treatment of choice.
Conclusion:
3 methylglutaconic aciduria is a comparatively rare disorder. The symptoms associated with these disorders irritate the child and hamper the child's growth. Hence, the goal of the doctors and parents should be focused on relieving the symptoms of the child. Several research works are being done that aim at improving the treatment approaches. Gene therapy is the latest treatment protocol that is being extensively studied. It is based on targeting faulty genes and enhancing their function to cure the disorder.
