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Isovaleric acidemia (IVA)

Abstract

Isovaleric acidemia (IVA) was the first condition to be recognized as an organic acidemia when the odor of sweaty feet that surrounded an infant with episodic encephalopathy was shown to be due to the presence of isovaleric acid. The disorder in leucine degradation is due to deficiency of isovaleryl-CoA dehydrogenase, the mitochondrial enzyme that oxidizes the first irreversible step in this pathway, isovaleryl-CoA to 3-methylcrotonyl-CoA. Early literature on IVA, an autosomal recessive disorder, emphasized two apparent phenotypes. The first was an acute, neonatal presentation with patients becoming symptomatic within the first two weeks of life. Patients appeared initially well, then developed vomiting and lethargy, progressing to coma. The second group presented with relatively non-specific failure to thrive and/or developmental delay (chronic intermittent presentation). In reality it is now apparent that patients can fall anywhere on the spectrum of acute to chronic presentation and that there is probably little predictive value to the initial presentation. Moreover, with the application of MS/MS in newborn screening, potentially asymptomatic patients with one recurring IVD gene mutation and a mild biochemical phenotype are being identified in increasing numbers, representing an additional phenotype of IVA. There are three goals for therapy. The first is prevention of metabolic decompensation by careful clinical observation of the patient. The second goal is long-term reduction of the production of toxic metabolites from general catabolism through dietary manipulation. The third goal of therapy is to prevent the accumulation of toxic metabolites by enhancing alternative metabolic pathways that produce alternative non-toxic compounds that are readily excreted.

Disease name + OMIM number
Isovaleric acidemia (IVA)
MIM 243500

Synonyms (if available)
Isovaleryl-CoA Dehydrogenase (IVD) Deficiency

Epidemiology

The incidence of IVA has a range from 1/62,500 live births in parts of Germany to 1/250,000 in the United States.

Etiology and Pathophysiology

IVA is inherited as an autosomal recessive trait. The gene encoding isovaleryl-CoA dehydrogenase has been cloned and localized to chromosome 15 (15q14-15), and multiple disease-causing mutations have been identified. A significant proportion of the mutant IVD alleles sequenced from infants diagnosed by newborn screening have been found to contain a common recurring missense mutation (932C>T; A282V).

IVA derives its name from the elevated concentrations of isovaleric acid found in patients. The normal concentrations of isovaleric acid in plasma are less than 10 μM. During remission patients may have from normal to 10 times normal concentrations of isovaleric acid (10 to 50 μM), but during severe episodes the levels rise as high as 100 to 500 times normal (600 to 5000 μM). Isovaleric acid has the odor of “sweaty feet“. This odor is generally not noticeable during remission but can be quite pronounced during catabolic episodes. Isovalerylcarnitine and isovalerylglycine are the hallmarks of this disorder in plasma and urine, respectively, and are elevated regardless of a patient’s metabolic condition. Isovalerylglycine appears to be a nontoxic, readily excreted conjugate. The capacity of the glycine N-acylase appears to be adequate to remove the amount of isovaleryl-CoA usually produced by the patients, so little is deacylated to isovaleric acid. However, during acute episodes, when the amount of isovaleryl-CoA is greatly increased by catabolic crisis, the capacity of glycine N-acylase is exceeded, and free isovaleric acid becomes elevated. Quantification of both conjugates has suggested a correlation of the metabolite concentrations with genotype, differentiating between groups of patients with a metabolically severe phenotype associated with heterogeneous IVD gene mutations, and patients with a metabolically mild phenotype associated with the recurring mutation, 932C>T (A282V). A second metabolite of isovaleric acid, 3-hydroxyisovaleric acid may be excreted in abnormal amounts mainly during acute episodes.

A long list of other isovaleryl-CoA derived metabolites has been reported in blood and urine from patients with IVA and can assist in confirmation of the disorder. Isovaleryl conjugates of multiple amino acids have also been detected in urine, as have free 3- and 4-hydroxyisovaleric acids. Isovaleryl-CoA can also be condensed with acetyl-CoA by 3-oxothiolase to form 3-hydroxyisoheptanoic acid. Of these metabolites, which are only significantly elevated in the urine of patients with isovaleric acidemia during acute episodes, only isovalerylglucuronide and isovalerylcarnitine are of importance, and their excretions are usually a small fraction of that of isovalerylglycine. However, in plasma or dried blood spots, elevated isovaleryl (C5-)carnitine is of considerable diagnostic importance.

The mechanism of the toxicity of isovaleric acid is not known, but it is an inhibitor of succinyl-CoA ligase in the tricarboxylic acid cycle and inhibits liver but not muscle mitochondrial oxygen consumption with glutamic, 2-oxoglutaric, and succinic acids. Isovaleric acid is an inhibitor of granulopoietic progenitor cell proliferation in bone marrow cultures with half-maximal inhibition at 1.6 mM, and this may account for the neutropenia frequently seen in isovaleric acidemia.

Clinical presentation

Nearly all published clinical information on patients with IVA is retrospective, and thus the following discussion of clinical symptoms is limited to the classic presentations of IVA prior to newborn screening, i.e. manifestation in the neonatal period versus later in childhood. Neonatal symptoms are non-specific and include poor feeding, vomiting, decreased level of consciousness, and seizures. Infants may develop hypothermia and appear to be dehydrated. A characteristic smell of “sweaty feet” may be present when the patient is acutely sick though, unlike other organic acidemias, the urine has no odor since the unconjugated isovaleric acid responsible for the odor is not excreted in urine in appreciable quantity. Acidosis with an unexplained anion gap is characteristic, and hyperammonemia, hyper- or hypoglycemia and hypocalcemia may be present. Secondary hyperammonemia is presumed to be due to inhibition of N-acetylglutamate synthase by isovaleryl-CoA and/or intracellular depletion of acetyl-CoA leading to reduced N-acetylglutamate synthesis and impairment of the urea cycle. Pancytopenia, as well as isolated neutropenia and thrombocytopenia, can occur due to bone marrow suppression. Left untreated, patients may progress to coma and death due to cerebral edema or hemorrhage. Overall, the clinical picture can not be distinguished from other organic acidemias nor from β-oxidation defects, urea cycle disorders and other primary causes of hyperammonemia. Patients who survive a neonatal crisis may be clinically indistinguishable from children diagnosed later in life.

Children diagnosed outside the newborn period may present with more chronic, relatively non-specific findings of failure to thrive and/or developmental delay or mental retardation. Minus the “sweaty feet odor” of isovaleric acid, which is not present when a patient is otherwise well, there is little to suggest a specific diagnosis in these children and thus, it must be considered in all patients with this clinical picture. They also are at risk of episodes of acute acidosis and metabolic decompensation, usually due to intercurrent illnesses or other physiological stress including fasting. Acute episodes may be misdiagnosed as diabetic ketoacidosis due to hyperglycemia, acidosis and the apparent presence of blood and urinary ketones. Acute pancreatitis, myeloproliferative syndrome, Fanconi syndrome, and cardiac arrhythmias have been reported; abnormalities of the globus pallidus can be seen.

With the advent of the use of MS/MS to screen newborn blood spots for acylcarnitine concentrations, many patients with IVA have been identified as newborns prior to the development of symptoms. One unexpected finding to arise from newborn screening studies is the identification of individuals with only mild elevations of isovaleryl-CoA related metabolites in plasma and urine, orders of magnitude lower than in the classic forms of IVA, and apparently only partial reduction in IVD activity. Nearly half of the mutant IVD alleles sequenced from infants diagnosed by newborn screening have been found to contain a common recurring missense mutation (932C>T; A282V). All of the affected newborns carrying the common mutation have remained asymptomatic with mild or no dietary protein restriction and carnitine supplementation if necessary over a maximum duration of follow up of up to 5 years of age. Subsequently, asymptomatic siblings of patients identified through newborn screening (ages 3 to 11 years at the time of diagnosis) have been found to be homozygous or compound heterozygous for the same mutation with a similarly mild biochemical phenotype. They have remained without symptoms during episodes of febrile illnesses. Prior to newborn screening, this mutation was identified only in a single patient with mild IVD deficiency originally evaluated for a tic disorder and slight developmental delay. The mutant A282V protein is stable in vitro but is kinetically impaired, exhibiting an increased Km, reduced catalytic efficiency, and diminished thermal stability. Newborn screening patients who carry this common mutation either in a homozygous or compound heterozygous state and their sibs skew the spectrum of IVA. So more than half of IVA patients represent a new mild phenotype and potentially remain asymptomatic. This is an expansion of our view of the natural history of IVA prior to the newborn screening era and leads to significant implications for management and genetic counseling.

Diagnostic methods

Diagnosis is made by newborn screening in countries where tandem MS-MS screening is performed. In symptomatic patients, the diagnosis is suggested by the clinical course, and is confirmed by organic acid analysis or by demonstrating a deficiency of isovaleryl-CoA dehydrogenase in tissues. Odor may be mild or absent, however, and thus the clinical picture may be relatively non-specific. Characteristic urine metabolites are isovalerylglycine and 3-hydroxyisovaleric acid, however, a long list of isovaleryl-CoA derived metabolites has been reported in blood and urine from patients with IVA and can assist in confirmation of the disorder. Isovaleric acid itself, which is responsible for the odor, is not detected by most analytic methods. Most of the accumulated isovaleryl-CoA is excreted as the non-toxic glycine and carnitine esters.

Differential diagnosis

Because C5 acylcarnitine represents a mixture of isomers (isovalerylcarnitine, 2-methylbutyrylcarnitine, and pivaloylcarnitine), further diagnostic evaluation is required. Elevations of 2-methylbutyrylcarnitine are seen in patients with 2-methylbutyrylglycinuria caused by a deficiency of short/branched-chain acyl-CoA dehydrogenase (SBCAD), an inborn error of isoleucine catabolism, whereas pivaloylcarnitine is derived from pivalic acid, a component of several antibiotics. Isovaleryl-CoA intermediates can also be seen in deficiencies of the electron transfer flavoprotein and its dehydrogenase (glutaric aciduria type 2).

Antenatal diagnosis and genetic counseling

Prenatal diagnosis can be achieved through enzyme measurement in cultured amniocytes, quantitation of isovalerylglycine in amniotic fluid, and molecular analysis when the mutations in the family are known.

Management and treatment

There are three goals for therapy of IVA. The first is prevention of metabolic decompensation by careful clinical observation of the patient. During times of metabolic stress (including illness and fasting) endogenous leucine from protein catabolism adds significantly to the production of metabolic intermediates. Achieving or maintaining anabolism is the main therapeutic approach to counter this problem. Reducing, but not eliminating, natural protein in the diet for 12-24 hours may help in this regard, but only if additional other calories to promote anabolism can be given. The second goal is long term reduction of the production of toxic metabolites from general catabolism through dietary manipulation. Total protein and caloric intake must be adequate to support normal growth in children and maintain an anabolic state. But this may require the use of an artificial protein source restricted in leucine for a portion of the protein requirement. The third goal of therapy is to prevent the accumulation of toxic metabolites by enhancing alternative metabolic pathways that produce alternative non-toxic compounds that are readily excreted. Carnitine is commonly used for this purpose in many of the organic acidemias. In IVA, glycine also effectively conjugates isovaleryl-CoA but is usually not needed to maintain homeostasis.

The intensity or even necessity of treatment for individuals diagnosed by newborn screening and carrying the common 932C>T (A282V) mutation is unclear. Specifically, the potential for metabolic decompensation under stress conditions remains to be elucidated. It appears reasonable to observe these individuals clinically, particularly when exposed to metabolic stressors such as febrile illnesses or fasting (e.g. when undergoing surgery). Low-dose carnitine supplementation is recommended.

Prognosis

In one summary of 37 symptomatic patients compiled from different publications, 28 presented in the first 2 weeks of life, 7 between 2 weeks and 1 year of age, and the remaining 2 after 1 year of age. Sixteen of the patients were deceased, and of those still alive, 7 were reported to have mild to moderate mental retardation. Most patients with chronic intermittent IVA have normal psychomotor development, but some have developmental delay and mild or even severe mental retardation. Many patients develop a natural aversion to protein-rich foods. 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 United States Air Force.

As opposed to the severe forms of IVA, it is still uncertain whether individuals with the mild type have a disease, a risk of clinical manifestation, or simply express a clinically insignificant biochemical phenotype. While these individuals may have normal leucine homeostasis under physiological conditions, their risk of metabolic decompensation under stress conditions remains to be elucidated.


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