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Isovaleric Acidemia

Isovaleryl Coa Dehydrogen Def

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.

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Presentation

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.

Poor Feeding
  • This report concerns an infant who presented at 10 days of age because of lethargy, poor feeding, hypothermia, cholestasis, and thrombocytopenia, leukopenia, and profound pancytopenia. Death occurred at 19 days of age.[ncbi.nlm.nih.gov]
  • Clinical features of IVA include poor feeding, vomiting, lethargy, developmental delay, metabolic acidosis, and a characteristic "sweaty foot" odor. IVA is one of the target disorders for newborn screening by tandem mass spectrometry (MS/MS).[ncbi.nlm.nih.gov]
  • Clinical considerations: Poor feeding, vomiting, lethargy, tachypnea Odor of sweaty feet Dehydration Metabolic ketoacidosis Hyperammonemia Hypoglycemia Referral: If signs are present or infant is ill, check urine ketones and initiate emergency treatment[archildrens.org]
  • The main health problems that people with isovaleric acidemia usually have can include poor feeding, vomiting, seizures, a lack of energy (lethargy), difficulty growing and gaining weight, developmental delay, and an odor of sweaty feet during sickness[thinkgenetic.com]
  • The initial symptoms include poor feeding, vomiting, seizures, and lack of energy (lethargy). These symptoms sometimes progress to more serious medical problems, including seizures, coma, and possibly death.[ghr.nlm.nih.gov]
Odor of Sweaty Feet
  • Generally, the diagnosis cannot be made by clinical or routine clinical chemical investigations, although the odor of "sweaty feet" is a presenting symptom.[ncbi.nlm.nih.gov]
  • Clinical considerations: Poor feeding, vomiting, lethargy, tachypnea Odor of sweaty feet Dehydration Metabolic ketoacidosis Hyperammonemia Hypoglycemia Referral: If signs are present or infant is ill, check urine ketones and initiate emergency treatment[archildrens.org]
  • Definition A metabolic disorder characterized by retarded psychomotor development, a peculiar odor resembling sweaty feet, an aversion to dietary protein, and pernicious vomiting, leading to acidosis and coma.[uniprot.org]
  • The main health problems that people with isovaleric acidemia usually have can include poor feeding, vomiting, seizures, a lack of energy (lethargy), difficulty growing and gaining weight, developmental delay, and an odor of sweaty feet during sickness[thinkgenetic.com]
  • A characteristic sign of isovaleric acidemia is a distinctive odor of sweaty feet during acute illness. This odor is caused by the buildup of a compound called isovaleric acid in affected individuals.[ghr.nlm.nih.gov]
Anemia
  • Laboratory features included hyperglycemia, hyperammonemia, hyperamylasemia, hypocalcemia, neutropenia, thrombocytopenia and subsequent anemia.[ncbi.nlm.nih.gov]
  • P74 ) Endocrine, nutritional and metabolic diseases E70-E88 2019 ICD-10-CM Range E70-E88 Metabolic disorders Type 1 Excludes androgen insensitivity syndrome ( E34.5- ) congenital adrenal hyperplasia ( E25.0 ) Ehlers-Danlos syndrome ( Q79.6 ) hemolytic anemias[icd10data.com]
  • […] the urine, which are not detected in healthy individuals Isovalerylcarnitine in the serum, as well as free carnitine Residual enzyme activity A potential 932C T (A282V) IVD genetic defect in cases with a less severe phenotype Pancytopenia, although anemia[symptoma.com]
  • Initial symptoms may include: A "sweaty feet" odor Vomiting Lethargy progressing to coma Lab findings: Ketoacidosis Elevated ammonia levels in the blood Neutropenia, thrombocytopenia, anemia Follow-up Testing after Positive Screen Quantitative plasma[medicalhomeportal.org]
  • Sickle Cell Anemia Program The Sickle Cell Anemia Program provides information to the public and health professionals about sickle cell anemia and sickle cell trait, and promotes and provides screening, referral, counseling and follow-up services for[health.mo.gov]
Hypothermia
  • This report concerns an infant who presented at 10 days of age because of lethargy, poor feeding, hypothermia, cholestasis, and thrombocytopenia, leukopenia, and profound pancytopenia. Death occurred at 19 days of age.[ncbi.nlm.nih.gov]
  • The former, acute type presents in newborns with poor appetite, vomiting, hypothermia, and dehydration.[symptoma.com]
  • Infants may develop hypothermia and appear to be dehydrated.[e-imd.org]
Weakness
  • 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.[symptoma.com]
  • Between periods of crisis, the child can be healthy, however overall these children may show poor growth, muscle weakness, or learning problems.[forums.thebump.com]
  • The signs and symptoms include: Metabolic crises Trouble gaining weight Delayed growth Muscle weakness Learning problems Vomiting Poor appetite Seizures Coma Children with chronic intermittent Isovaleric Acidemia do not have constant symptoms.[dovemed.com]
Vomiting
  • Isovaleric acidemia may present with symptoms during the acute stage of severe metabolic acidosis, ketosis, vomiting and altered mental status.[ncbi.nlm.nih.gov]
  • Isovaleric acidemia (IVA) is characterized by periodic vomiting, lethargy, coma, ketoacidosis and a 'sweaty feet' odor.[ncbi.nlm.nih.gov]
  • This enzymatic deficiency leads to severe metabolic derangement, manifested clinically as vomiting, dehydration, and acidosis progressing to seizures, coma, and death.[ncbi.nlm.nih.gov]
  • Recurrent vomiting began at 3 weeks of age. Pyloric stenosis was diagnosed and a pyloromyotomy was done. Transient ketonuria was noted at that time.[jamanetwork.com]
  • Isovaleric acidemia may present in the neonatal period with an acute episode of severe metabolic acidosis, ketosis, and vomiting and may lead to coma and death in the first 2 months of life.[ncbi.nlm.nih.gov]
Nausea
  • The patient’s recent history confirmed a lack of recent nausea, vomiting, diarrhea, signs of dehydration, or decreased level of consciousness.[journals.lww.com]
  • Air Force recruit, in Day 3 of basic training, came to the emergency department with severe nausea, vomiting, and mental status changes. He reported that he had been in good health until the previous day.[thefreelibrary.com]
  • Anorexia and nausea/vomiting during the acute crisis period makes a significant oral intake unlikely.[newenglandconsortium.org]
  • The variability of this disorder is highlighted by the occurrence of a sudden metabolic crisis in a previously well-controlled 18 year old man with IVA who developed acute nausea, vomiting, and mental status changes during basic training camp for the[e-imd.org]
Loss of Appetite
  • Symptoms sometimes appear within the first few days or weeks after birth and may include: developing a distinctive odour of "sweaty feet" poor feeding or loss of appetite weight loss Babies with IVA may also have episodes known as a metabolic crisis.[nhs.uk]
  • In order to prevent problems, call your doctor right away when your child has any of the following: loss of appetite vomiting diarrhea infection or illness fever Children with IVA need to eat more carbohydrates and drink more fluids when they are ill[newbornscreening.info]
Liver Fibrosis
  • One of the cases with the novel c.234 3G C mutation has portoseptal liver fibrosis, the clinical condition that was first reported for IVA.[ncbi.nlm.nih.gov]
Muscle Weakness
  • Between periods of crisis, the child can be healthy, however overall these children may show poor growth, muscle weakness, or learning problems.[forums.thebump.com]
  • The signs and symptoms include: Metabolic crises Trouble gaining weight Delayed growth Muscle weakness Learning problems Vomiting Poor appetite Seizures Coma Children with chronic intermittent Isovaleric Acidemia do not have constant symptoms.[dovemed.com]
Seizure
  • The initial symptoms include poor feeding, vomiting, seizures, and lack of energy (lethargy). These symptoms sometimes progress to more serious medical problems, including seizures, coma, and possibly death.[ghr.nlm.nih.gov]
  • This enzymatic deficiency leads to severe metabolic derangement, manifested clinically as vomiting, dehydration, and acidosis progressing to seizures, coma, and death.[ncbi.nlm.nih.gov]
Lethargy
  • Isovaleric acidemia (IVA) is characterized by periodic vomiting, lethargy, coma, ketoacidosis and a 'sweaty feet' odor.[ncbi.nlm.nih.gov]
  • This report concerns an infant who presented at 10 days of age because of lethargy, poor feeding, hypothermia, cholestasis, and thrombocytopenia, leukopenia, and profound pancytopenia. Death occurred at 19 days of age.[ncbi.nlm.nih.gov]
  • An autosomal recessively inherited organic aciduria characterized by a deficiency in isovaleryl-CoA dehydrogenase, that has wide clinical variability and that can present in infancy with acute manifestations of vomiting, failure to thrive, seizures, lethargy[orpha.net]
  • […] an autosomal recessively inherited organic aciduria characterized by a deficiency in isovaleryl-CoA dehydrogenase, that has wide clinical variability and that can present in infancy with acute manifestations of vomiting, failure to thrive, seizures, lethargy[orpha.net]
  • Clinical features include vomiting, lethargy, metabolic acidosis, and "sweaty feet" odor. The pathognomonic metabolite, isovalerylglycine, is detected on urine organic acid analysis.[ncbi.nlm.nih.gov]

Workup

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 [1].

Ketonuria
  • Hyperglycemia, ketonemia, ketonuria and metabolic acidosis are the main clinical features of diabetic ketoacidosis (DKA) and these same symptoms can also be seen in acute attacks of metabolic diseases.[ncbi.nlm.nih.gov]
  • At admission, he had vomiting associated with dehydration, acidosis, ketonuria, coma and a pungent, rather unpleasant odor.[ncbi.nlm.nih.gov]
  • Transient ketonuria was noted at that time. His subsequent course was marked by intermittent episodes of vomiting brought on by infections or excessive protein ingestion. A "funny odor" Full Text[jamanetwork.com]
  • Billing ICD Codes: 796.6 Abnormal findings on neonatal screening 276.2 Acidosis Acidosis 270.3 Disturbances of branched-chain amino-acid metabolism, Disturbances of metabolism of leucine, isoleucine, and valine, Hypervalinemia Intermittent branched-chain ketonuria[genedx.com]
  • 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.[symptoma.com]

Treatment

Treatment of IVA centers around three main targets:

  • Prevention of metabolic acidosis by consistent monitoring of the patients and the promotion of anabolism
  • Reduction of the toxic by-products, released by the catabolic process
  • Enhancement of alternative metabolic pathways, in order to hinder the buildup of toxic products

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 [8]. 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 [9]. If neurological occurrences complicate the clinical picture of IVA on a long-term basis, the efficacy of treatment still remains under investigation [10]. 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 [11] [12].

Prognosis

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 [6] [7]. More specifically, it can lead to neurological and cognitive impairment in approximately 38% of the patients, according to recent studies.

Etiology

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 [2]. 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 [3].

Epidemiology

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 [4]. During the recent years, newborn screening aided by tandem mass spectrometry (MS/MS) has lead to a higher frequency of IVD deficiency detection.

Sex distribution
Age distribution

Pathophysiology

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 [5].

Prevention

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.

Summary

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 [1].

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.

Patient Information

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.

References

Article

  1. Saunders WB, Rezvani I, Rosenblatt DS. Valine, leucine, isoleucine and related organic acidemias. In: Kliegman RM, Behrman RE, Jenson HB, editors. Textbook of pediatrics.18th ed. Philadelphia: Elsevier; 2007:538–542.
  2. Ensenauer R, Vockley J, Willard JM, et al. A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening. Am J Hum Genet. 2004; 75: 1136-1142.
  3. Dionisi-Vici C, Deodato F, Röschinger W, et al. 'Classical' organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis. 2006; 29: 383-389.
  4. Lin WD, Wang CH, Lee CC, et al. Genetic mutation profile of isovaleric acidemia patients in Taiwan. Mol. Genet. Metab. 2007;90:134–139.
  5. Vockley J, Ensenauer R. Isovaleric acidemia: New aspects of genetic and phenotypic heterogeneity. Am J Med Genet C Semin Med Genet. 2006;142C:95–103.
  6. Hörster F, Garbade SF, Zwickler T, et al. Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters. J Inherit Metab Dis. 2009;32:630–639.
  7. Surtees RA, Matthews EE, Leonard JV. Neurologic outcome of propionic acidemia. Pediatr Neurol. 1992;8:333–337.
  8. Champion MB; An approach to diagnosis of inherited metabolic disease; Arch Dis Child Educ Pract Ed. 2010;95:40-46.
  9. Capelli I, Battaglino G, Baraldi O, et al. Kidney Transplantation and inborn errors of metabolism. G Ital Nefrol. 2015;32(2).
  10. Martin-Hernandez E, Lee PJ, Micciche A, et al. Long-term needs of adult patients with organic acidaemias: outcome and prognostic factors. J Inherit Metab Dis. 2009;32:523–533.
  11. Vockley J, Ensenauer R. Isovaleric acidemia: new aspects of genetic and phenotypic heterogeneity. Am J Med Genet C Semin Med Genet. 2006;142C:95–103.
  12. Simon E, Flaschker N, Schadewaldt P, et al. Variant maple syrup urine disease (MSUD)-the entire spectrum. J Inherit Metab Dis. 2006;29:716–724.

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Last updated: 2019-07-11 21:17