Isovalericacidemia (IVA) is a rare metabolic disorder that is classified under the category of organic acidemias and is characterized by an inborn deficiency of the isovaleryl-CoA dehydrogenase (IVD) enzyme, which mediates leucine catabolism.
IVA is usually diagnosed in children and manifests with two types - acute and chronic. The former, acute type presents in newborns with poor appetite, vomiting, hypothermia, and dehydration. Prompt treatment is mandatory because the condition may lead to life-threatening neurological sequelae if left untreated, such as lethargy, epileptic phenomena, coma, and death. The young patient emits an odor of "sweaty feet".
On the other hand, the chronic IVA type tends to be dormant until the first few months of life, when it presents with the same symptomatology in addition to restricted growth, muscular weakness and a certain cognitive impairment. In both the acute and chronic type, the episode develops during a period of increased stress, such as an infection or a period of time when the patient has greatly restricted the amount of calory intake for various reasons.
Isovalericacidemia is diagnosed either in newborns or during the first months of life. Laboratory tests yield results that include the following:
Diagnosis of IVA is primarily based on the detection of abnormal concentrations of c5-carnitine in the blood, products of isovaleryl-CoA in the urine and according to compatible results of the molecular analysis .
Treatment of IVA centers around three main targets:
More specifically, dietary modifications are indispensable on a long-term basis, so that the daily protein intake can be reduced. Anabolism in neonates affected by acute IVA can be supported by the administration of a 10% dextrose intravenous solution and toxic by-products can be filtrated through hemodialysis or peritoneal dialysis . During the past recent years, enzyme replacement therapy has been introduced as part of the therapeutic protocol and, as a last resort in cases where conservative methods fail, bone marrow, liver or renal transplantation is also an option . If neurological occurrences complicate the clinical picture of IVA on a long-term basis, the efficacy of treatment still remains under investigation . Individuals that are affected by IVA are expected to survive adulthood and have offspring as well. A vital part of therapy is the identification of individuals who are at a high risk of being affected by isovalericacidemia-related decompensation  .
IVA can affect neurocognitive functions; however, when compared to other organic acidemias/acidurias, it is the type that causes these complications to the least extent  . More specifically, it can lead to neurological and cognitive impairment in approximately 38% of the patients, according to recent studies.
IVA is a genetic condition, classified under the broader category of organic acidemias or organic acidurias, with the two terms being used interchangeably. Its etiology is based on the inborn deficiency of isovaleryl-CoA dehydrogenase, an enzyme that is indispensable for the catabolism of leucine. This deficiency leads to the inability to process leucine and the subsequent buildup of isovaleryl-CoA products, including free isovaleric acid, isovalerylglycine (IVG) and 3-hydroxyisovaleric acid. Recent studies have detected a missense mutation c.932C>T (p.A282V), which is believed to cause a less severe type of IVA, possibly with no symptoms . Screening performed on newborns has lead to the diagnosis of multiple such cases of IVA, leading to a more elevated incidence of IVA amongst newborn individuals than in the adult population .
IVA is a rare disease, estimated to occur with a frequency of 1:250,000 births in the USA and 1:365,000 births in Taiwan, where related epidemiologic studies were conducted . During the recent years, newborn screening aided by tandem mass spectrometry (MS/MS) has lead to a higher frequency of IVD deficiency detection.
The disorder is a result of the deficiency of isovaleryl-CoA dehydrogenase, an enzyme that mediates the third dehydrogenation step of the catabolism of leucine. As a result, the increased concentrations of products such as isovaleric acid, isovaleryl glycine, isovaleryl carnitine and 3-hydroxyisovaleric acid lead to various symptoms through different pathophysiological pathways.
Under normal circumstances, isovaleric acid can be found in the serum in a concentration that does not exceed 10 μM. IVA occurrences lead to concentrations of the acid that may even be as high as 500 the normal value. During such episodes, glycine N-acylase, an enzyme which is responsible for the regulation of the removal of isovaleric acid from the blood in healthy individuals, loses its capability to process such an elevated acidic concentration and isovaleric acid is freely released into the bloodstream. Free isovaleric acid is toxic, even though the exact pathophysiology that underlies its toxicity remains largely undetected. The elevated isovaleric acid concentrations also lead to neutropenia, since it hinders the differentiation process of the granulopoietic progenitor cells; in many cases, pancytopenia is also induced. In every case of isovalericacidemia, isovalerylcarnitine is detected in the blood and isovalerylglycine is found in the urine .
IVA cannot be prevented since it is a genetic disorder. Severe complication and metabolic crises, however, can be prevented by careful monitoring of the patient during periods of increased metabolic stress, such as an infection or poor nutrition. A paramount preventive measure is a dietary regime that includes sufficient calories but is low in leucine and proteins in general.
Isovalericacidemia (IVA) is a genetic condition that follows the autosomal recessive pattern of inheritance. Its primary characteristic is the isovaleryl-CoA dehydrogenase (IVD) deficiency, an enzyme that mediates one of the steps of the catabolism of the leucine amino acid. Specifically, the third step of the catabolism of leucine involves the conversion of isovaleryl-CoA to 3-methylcrotonyl CoA; the lack of IVD leads to an impaired catabolism and, thus, various toxic products are released in the circulation, including free isovaleric acid and isovaleryl carnitine.
The condition presents either acutely, with vomiting, poor feeding, epileptic occurrences and lethargy in neonates or in a periodic pattern in older children, which evinces all of the aforementioned symptoms as well as a hindered growth, muscular weakness, and cognitive impairment. IVA can lead to a state of coma and death due to neurological complications, if the diagnosis is delayed or appropriate treatment is not administered. In both the acute and chronic type of IVA, the presence of a "sweaty feet" odor is the characteristic feature and is caused by the isovaleric acid.
A definitive diagnosis is made after a complete laboratory panel is performed, which will typically display pancytopenia, ketonuria, hyperammonemia and the presence of isovaleric acid and its toxic metabolites both in the serum and in the urine .
In its acute phase, IVA is treated with the administration of fluids, such as a 10% dextrose solution, peritoneal dialysis, and hemodialysis, according to the particular needs and severity. Treatment also consists of dietary restriction of protein intake and enzyme replacement therapy. If an early diagnosis and appropriate treatment are achieved, the prognosis is excellent.
Isovalericacidemia (IVA) is a genetic metabolic disorder. This means that it is passed down from parents to offspring and affects the way a specific part of the proteins is broken down in the organism. The amino acid that cannot properly be metabolized in IVA is leucine and, as a result, various toxic substances are released into the bloodstream. Since one of the predominant toxic products is free isovaleric acid, the condition has been defined as isovalericacidemia. Another term is isovaleric aciduria, which is used interchangeably.
IVA is caused by a mutation in the gene that is responsible for the proper production of an enzyme called isovaleryl-CoA dehydrogenase (IVD). The disorder is inherited in an autosomal recessive manner, which means that the defective gene from one parent needs to be paired with another defective gene from the other parent, in order for the condition to arise. Otherwise, if a single defective gene from one of the parents is present, IVA does not develop. If both parents possess a single defective gene, they are carriers of the disease and they have 25% possibility of giving birth to a child that will be affected by the disease.
The condition presents with two types: acute IVA and chronic IVA. Acute IVA is usually diagnosed during the first days of a neonate's life and causes symptoms such as poor feeding, vomiting, and a sleepy tendency. If it is not diagnosed in time and properly treated, it can be life-threatening, as it can cause neurological complications like seizures, coma, and death. The second disease type is the chronic IVA, which is diagnosed later and presents with periodic episodes of IVA. The symptoms are the same; additional signs are a hindered growth, muscular weakness, cognitive problems. The state of coma and death can be reached in both cases. Another characteristic sign of isovaleric acidosis is the smell that the patients emit, which is similar to that of sweaty feet.
Laboratory testing is necessary to diagnose IVA. Except for genetic testing, either as prenatal care or after birth, that can detect the genetic mutation if there is a family history of the disease, various other findings are typical in IVA. First of all, metabolic acidosis is detected in the blood, which also contains products such as free isovaleric acid that are normally not present there. Urine also contains abnormal products, such as ketones and isovaleryl glycine. Pancytopenia is also a possible finding: this means that the patient's blood contains less than the normal concentration of red blood cells, white blood cells and platelets. Isovalericacidemia is treated with a reduction of the proteins the patient consumes in their diet, enzyme replacement and, ultimately a liver or bone marrow transplant if all other methods fail.