Clinical manifestations

Presentation and course

Isovaleric aciduria due to isovaleryl-CoA dehydrogenase deficiency presents with two different clinical phenotypes: (1) an acute neonatal-onset form, which results in profound metabolic acidosis from the first days of life and rapid death (46), and (2) a chronic infantile form with periodic attacks of severe ketoacidosis interspersed with asymptomatic periods (57). Analogous to methylmalonic aciduria and propionic aciduria, the clinical phenotypes of isovaleric acidemia can be considered early (ie, neonatal) disease onset and late (ie, after the newborn period) disease onset groups (58).

Approximately half of the cases present with acute neonatal onset and the other half with chronic intermittent disease (54). Both phenotypes can occur in populations or even within the same family carrying the same mutation (54; 05; 20). In addition, a common mutation is associated with a mild, usually asymptomatic phenotype. Patients carrying this mutation are nevertheless identified by newborn screening. Molecular genetic analysis within this group identifies around 50% of mutant alleles as the single mutation (932C-T; A282V). This mutation is also found in older, healthy siblings but not in previously identified symptomatic patients; thus, this mutation is associated with a usually asymptomatic clinical course (10).

Children are usually born at term after an uneventful pregnancy. If clinical abnormalities develop within the first days of life, patients refuse feeding, start to vomit, and become progressively dehydrated and lethargic. Hypothermia, tremor, twitching, seizures, optic atrophy, and autism spectrum disorder can occur (28; 51; 40). Other possible clinical findings include a foul odor reminiscent of “sweaty feet” (caused by isovaleric acid).

During metabolic crises, patients develop the typical features of an organic acid disorder with acidosis, ketosis, vomiting, progressive alteration of consciousness, and, finally, without appropriate therapy, overwhelming illness, deep coma, and death (54). Acute metabolic decompensation can quickly lead to death triggered by cerebral edema, intracerebral hemorrhage, and/or infection. Neuropathological examination shows cerebellar edema with herniation and spongiform changes in the white matter.

In the chronic intermittent form of isovaleric acidemia, children have recurrent metabolic crises because of high intake of protein or minor infections that induce a catabolic state (54). The metabolic crises are characterized by vomiting, lethargy, coma, acidosis, ketosis, and the odor of “sweaty feet.” Some patients develop a dislike of food with a high protein content, apparently an acquired aversion.

Pancreatitis may be a complication of acute and chronic isovaleric aciduria (39). With age, children become less sensitive to minor infections. Older patients may have normal psychomotor development or a wide range of intellectual disability, depending on the frequency and severity of metabolic decompensations, the age at diagnosis, and timing of therapy initiation.

In contrast to other organic acidopathies, such as propionic acidemia or methylmalonic academia, there is no apparent disease progression or multisystemic organ dysfunction.

The disorder may rarely present with a first acute metabolic decompensation in adulthood (14).

Prognosis and complications

Clinical and neurocognitive outcomes in isovaleric acidemia patients depend on early diagnosis and treatment.

In the first reports, isovaleric acidemia was associated with a poor prognosis; more than half of the patients with acute neonatal onset did not survive the first episode, but with improvement in therapy (ie, by supplementation of glycine and L-carnitine) as well as earlier diagnosis, the outcome has become much more favorable (54). In particular, if treatment can be initiated before a first severe metabolic decompensation, the patient’s prognosis is significantly improved. Individuals who receive treatment before becoming symptomatic usually have normal long-term psychomotor development (35).

In a review of 21 symptomatic isovaleric acidemia patients diagnosed as children or adults between 1976 and 1999, 44% had mild motor disfunction, and only 19% had cognitive deficits (17). IQ was not related to the number of metabolic decompensations but was inversely related to the age at diagnosis. One patient died at 13 days of age. Age at evaluation of the remaining patients ranged from 2.2 years to 25.3 years, with a median of 11.2 years. In contrast to the high neonatal mortality (33%) in 155 published cases, only one patient of the study cohort died due to metabolic decompensation in the neonatal period (5%). Results from the European registry and network for Intoxication-type Metabolic Diseases (E-IMD) confirm that clinical and neurocognitive outcomes depend on early diagnosis and treatment (19).

Patients identified by newborn screening who carry a common missense mutation c.932C>T (p.Ala282Val) are usually asymptomatic and most likely do not need treatment. Siblings of these individuals who have the same genotype may remain asymptomatic during episodes of febrile illnesses without any specific treatment (10; 60; 35).

Clinical vignette

A 6-year-old girl was admitted to the hospital with a 3-day history of persistent vomiting but had neither fever nor diarrhea. She was severely dehydrated, drowsy, and hallucinative and had a peculiar fetor like “sweaty feet” but no focal neurologic deficits.

She had previously experienced eight similar episodes associated with prominent metabolic acidosis, which resolved with glucose infusion. She insisted on taking her meals regularly and preferred fruits and vegetables but avoided dairy products and meat. Her somatic and cognitive development had been normal, and she attended primary school with good success. Her family history was unremarkable.

Laboratory investigations revealed severe metabolic acidosis and ketosis. A serum ammonia level was normal. Urine studies showed massive ketonuria and lactaturia as well as highly elevated excretion of both 3-hydroxy isovaleric acid and isovalerylglycine, which established her diagnosis of isovaleric acidemia.

Her severe metabolic acidosis was treated with a single dose of sodium bicarbonate, and she was also treated with high-dose intravenous glucose and carnitine. She recovered completely.

On any ongoing basis, she was treated with a mild protein restriction (which in any case reflected her preferred food pattern), and carnitine supplementation. The family also received an emergency card and a sick-day nutrition plan, which contained high-energy, low-protein food. In case of illness, her carnitine dosage was doubled.

Biological basis

Etiology and pathogenesis

Isovaleric acidemia is an inborn error of leucine metabolism that results from deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (MIM 243500; EC 1.3.99.10), which is caused by a homozygous mutation in the isovaleryl CoA dehydrogenase gene (IVD; OMIM 607036) on chromosome 15q15.1.

Genetics. Isovaleric acidemia is transmitted as an autosomal recessive trait. The gene coding for isovaleryl-CoA dehydrogenase was mapped by southern blot analysis to chromosome 15q14-q15 (29). Subsequent studies have localized the gene to chromosome 15q1. The 172 kDa enzyme is a tetramer of four identical subunits.

The molecular basis was investigated in detail, and various mutations have been described, including missense mutations, an in-frame mutation, and point mutations leading to abnormal splicing and altered mitochondrial import (41; 62; 61; 63; 33; 23; 34). Genetic complementation studies point to involvement of a single genetic locus (08).

Both clinical presentations, acute-neonatal and infantile chronic-episodic, may be found within the same family and, thus, are determined by other genes or nongenetic factors.

The four identical subunits of isovaleryl-CoA dehydrogenase are synthesized on cytosolic polysomes and imported into the mitochondrial matrix where the enzyme is assembled. The finished enzyme is situated in the inner layer of the mitochondrial membrane. It is a flavin enzyme containing ca. 1 mol FAD/subunit. The FAD transports electrons via coenzyme Q to the respiratory chain.

Pathophysiology. Due to the metabolic block, isovaleryl-CoA accumulates, and the pathognomonic metabolite isovalerylglycine is formed by conjugation of isovaleryl-CoA to the amino group of glycine.

The hydrolysis product isovaleric acid is quantitatively less important. The mitochondrial enzyme that had been thought to catalyze this reaction is glycine N-acyltransferase (GLYAT; glycine-N-acylase; EC 2.3.1.13). However, GLYAT and a paralogue, GLATL1, both form N-isovaleryglycine albeit at lower affinities than their preferred substrates (30). Isovalerylglycine is nontoxic and can be secreted via urine. This reaction is an important detoxification pathway, which can be therapeutically augmented.

The mechanism of isovaleric acid toxicity remains unclear, though it is likely to be multifactorial. Some findings point to an inhibition of mitochondrial energy metabolism (38; 36). One study demonstrated reduced glutathione levels (an indicator of oxidative stress) in a cohort of 11 patients (50). In bone marrow cell cultures, isovaleric acid is an inhibitor of granulopoietic progenitor cell proliferation, which may explain why neutropenia is frequently seen in isovaleric acidemia during metabolic decompensation (54). In addition, amino-acid depletion may be induced by abnormal amino-acid conjugation combined with protein restriction (37), resulting in impaired protein synthesis, catabolic metabolic decompensation, failure to thrive, and additional nutritional insufficiencies (67; 06; 13).

Epidemiology

Selective screening by analysis of organic acids in urine or tandem mass spectrometry has demonstrated the presence of isovaleric acidemia in different populations around the world (24; 65; 31; 59). In countries where isovaleric acidemia is not part of population newborn screening, the diagnosis can be missed. Reported cases to date do not suggest an ethnic predisposition.

In a systematic review and meta-analysis, 22 population studies of isovaleric acidemia were identified, 17 of which utilized tandem mass spectrometry with a total population screened of 14,304,075, and five of which relied on clinical ascertainment of cases with a total population screened of 5,100,705 (42). The point estimate (and 95% confidence interval) of incidence was 0.36 (0.08 to 1.61) per 100,000 live births worldwide for studies that relied on clinical ascertainment of cases. In contrast, the incidence was 0.79 (0.55-1.13) per 100,000 live births for studies in Western countries and 0.96 (0.63 to 1.45) per 100,000 live births worldwide for studies that relied on tandem mass spectroscopy. In summary, the worldwide incidence of isovaleric acidemia is 1:100,000 live births diagnosed by newborn screening and 1:280,000 among cases diagnosed after the onset of symptoms. Sensitivity was clearly improved using newborn screening approaches with tandem mass spectrometry. (Note: there is a typo in the point estimate for Western countries in the original study, based both on a comparison of the graphed values and the printed numbers and on comparison of the erroneously written value, which is considerably less than the lower bound of the 95% confidence interval.)

Prevention

Isovaleric acidemia can be easily diagnosed in newborn screening programs with electrospray tandem mass spectrometry. If treatment is initiated before the development of severe metabolic decompensation, the patient’s prognosis can be significantly improved. Patients who are diagnosed by newborn screening usually have normal psychomotor development (35). Unfortunately, in the absence of newborn detection, there is often a marked delay in diagnosis, which may have serious adverse consequences for affected children (23).

Prenatal diagnosis is possible in families at risk.

Differential diagnosis

Confusing conditions

The catabolic pathway for leucine comprises six enzymes, all of which are associated with recognized inherited deficiencies: (1) isovaleryl-CoA dehydrogenase, deficient in isovaleric acidemia, and producing increased concentrations of hydroxyisovaleric acid and other metabolites; (2) branched-chain alpha-keto acid dehydrogenase, deficient in maple syrup urine disease; (3) 3-methylcrotonyl-CoA carboxylase, deficient in methylcrotonylglycinuria; (4) dehydrogenase; (5) propionyl-CoA carboxylase, deficient in propionic acidemia; and (6) methylmalonyl CoA mutase, deficient in methylmalonic aciduria.

The clinical symptoms and predilection for acute metabolic decompensation in isovaleryl-CoA dehydrogenase deficiency occur also in other organic acid disorders (eg, methylmalonic acidemia and propionic acidemia), fatty acid oxidation disorders, or urea cycle disorders (even the suggestive “odor of sweaty feet” is shared by some other disorders) (28). Classical organic acidemias result from defective mitochondrial catabolism of branched-chain amino acids: isovaleric acidemia, methylmalonic acidemia, and propionic acidemia. Compared to those with methylmalonic acidemia and propionic acidemia, individuals with isovaleric acidemia appear to have a less severe disease course (58). Impaired catabolism of branched-chain amino acids in propionic acidemia, but not in methylmalonic acidemia or isovaleric acidemia, is associated with a metabolic syndrome-like phenotype with abdominal adiposity potentially resulting from ectopic lipid storage (16).

Organic acidopathies can best be differentiated by the specific patterns of nonvolatile urinary organic acids on gas chromatography-mass spectrometry (22).

If vomiting in infancy becomes prominent, hypertrophic pyloric stenosis may be suspected, and patients with isovaleric acidemia have undergone unneeded and potentially risky surgery, especially given their predilection for profound metabolic decompensation (03; 32).

The combination of ketoacidosis, dehydration, and hyperglycemia in patients with isovaleric acidemia has also been misjudged as diabetic ketoacidosis (11).

Diagnostic workup

Neuroimaging. Following a severe metabolic decompensation, cranial MRI of a 19-month-old girl with the chronic-episodic form of the disease showed signal changes in the globi pallidi and the mesencephalic corticospinal tracts, which were hypointense on T1-weighted images and hyperintense on T2 weighted images (53).

Following acute metabolic acidosis, cranial MRI of a 4-month-old girl with the chronic-episodic form of the disease revealed symmetric, bilateral signal-intensity changes in the lentiform nuclei with a symmetric, hyperintense, ring-like appearance bilaterally in the putamen on T1-weighted images (64).

Laboratory studies during decompensation. Metabolic abnormalities during episodes of decompensation may include ketoacidosis, hyperglycemia, hypocalcemia, and hyperammonemia, although the latter is usually mild compared to that in disorders of propionate degradation. Hyperglycemia is most likely due to stress-induced hormonal effects. The combination of ketoacidosis, dehydration, and hyperglycemia has been misjudged as diabetic ketoacidosis (11).

Abnormalities of the hematopoietic system (eg, thrombocytopenia, neutropenia, or pancytopenia) may also occur during metabolic decompensation (54).

Laboratory studies for diagnosis. The best way to distinguish the organic acidemias is through analysis of the urinary nonvolatile organic acid pattern by gas chromatography-mass spectrometry (22; 67). Another complementary and rapid diagnostic technique is the analysis of acylcarnitine profiles by tandem mass spectrometry; the accumulating CoA esters are in equilibrium with their corresponding acylcarnitines, which are easy to analyze in dried blood spots. Mass spectrometry has been adapted to perform newborn screening, leading to early diagnosis and appropriate therapy (09; 35). False-positive results in newborn screening can arise either from antibiotics containing pivalic acid or from pivalic acid derivatives, which are used in the cosmetic industry under the term “neopentanoate” (02; 43; 66).

During metabolic decompensation, the urinary organic acid profile reveals high excretion of isovalerylglycine (2000 to 9000 mmol/mol creatinine), which remains markedly elevated after recompensation (1000 to 3000 mmol/mol creatinine). 3-Hydroxyisovaleric acid is only found elevated during metabolic decompensation.

4-Hydroxyisovaleric, mesaconic acid, methylsuccinic acid, 3-hydroxyisoheptanoic acid, isovalerylglutamic acid, isovalerylglucoronide, isovalerylalanine, and isovalerylsarcosine are minor pathological metabolites detectable in smaller amounts (20 to 300 mmol/mol creatinine) (54).

Other organic acidemias can be differentiated by their specific profiles of urinary organic acids. The acylcarnitine profile in isovaleric aciduria is characterized by high levels of isovalerylcarnitine, depending on the quantity of oral carnitine administration.

The diagnosis of isovaleric acidemia can be confirmed by enzymatic assay or mutation analysis (27).

Several methods have been successfully used for prenatal diagnosis: genetic variant analysis of IVD genes in amniocytes (55), IVD enzyme activity assay in amniotic or chorionic villi sampling (26), and quantification of the characteristic metabolites such as acylcarnitines and organic acids in amniotic fluid (21; 52; 27; 07). Limitations of prenatal diagnosis by mutation analysis include (1) dependence on the availability of complete genetic information from the proband and parents; and (2) some probands carry only one causative mutation, precluding a precise diagnosis by genetic testing alone (07). Prenatal diagnosis by enzymatic analysis requires cell cultivation, which is troublesome and time-consuming. Also, maternal cell contamination may lead to misdiagnosis (18). Use of mass spectrometry in metabolite analysis provides a fast and convenient method for the prenatal diagnosis (07).

Management

Treatment must be supervised by an experienced metabolic center and must continue for life. Special care must be taken to ensure efficient emergency procedures (including travel and holidays) and to always monitor carnitine status and dietary management closely, including careful avoidance of overtreatment or malnutrition (67; 22). Patients should be supplied with an emergency card, letter, or bracelet containing phone numbers and instructions for emergency measures. The team of managing specialists should repeatedly discuss and evaluate the logistics of rational therapeutic measures with both the family and the responsible primary care physician.

Aspirin is contraindicated in patients with isovaleric acidemia because salicylic acid is a competing substrate for glycine-N-acylase, interfering with isovalerylglycine synthesis.

Isovaleric acid is toxic (54); therefore, the primary aim in treating isovaleric acidemia is to both prevent the formation of and lower the levels of accumulating toxic metabolites.

The catabolic pathway is challenged by increased protein intake or increased endogenous protein degradation (54). Therefore, total natural protein intake is restricted according to the patient’s leucine tolerance and is adjusted to age-specific requirements for this essential amino acid. The reduction of leucine intake must be carefully monitored to prevent over-restriction. A diet with inadequate leucine intake can impair protein synthesis and lead to catabolic metabolic decompensation, failure to thrive, and additional nutritional insufficiencies (67; 06; 13). To provide a complementary source of the other amino acids, a leucine-free formula is available (54; 27).

Dietary practice in Europe has been systematically studied and has been found to vary considerably among centers (48). In 2014, a quick-reference, web-based guide was published by E-IMD, but universal treatment recommendations are needed (12).

The other important principle of therapy is to increase the excretion of isovaleric acid as nontoxic glycine and carnitine conjugates (54). Glycine is conjugated to isovaleric acid to form isovalerylglycine by glycine N-acyltransferase (glycine-N-acylase). Normal tissue concentrations of glycine are already lower than the Km concentrations for optimal enzyme functioning and tend to decrease further during metabolic decompensation (54). Therefore, it is important to ensure sufficient glycine levels to allow optimal detoxification. Therapeutic guidelines recommend a dosage of 150 (to at most 250) mg/kg per day of glycine while the patient is stable and under protein restriction (45; 01). The dosage can be augmented during metabolic crises. Glycine supplementation of more than 250 mg/kg/day under stable conditions may reduce isovalerylglycine production (45).

In contrast, in metabolic crises, when isovaleric acid accumulation is increased, glycine supplements to 600 mg/kg/day will increase isovalerylglycine production (45). Isovaleric acidemia is related not only to the extent of impaired isovaleryl-CoA dehydrogenase but also to the ability to detoxify accumulated isovaleryl CoA to isovalerylglycine (45).

Many patients with isovaleric acidemia show low levels of total carnitine in plasma and a high percentage of esterified carnitines in plasma and urine (54; 27). This results from enzymatic production of isovalerylcarnitine by carnitine acetyltransferase and the subsequent loss of isovalerylcarnitine in the urine. Consequently, carnitine stores may become exhausted, resulting in severe secondary metabolic consequences. Therefore, L-carnitine should be supplemented in doses of 40 to 100 mg/kg to ensure high-normal free carnitine levels in plasma.

It is difficult to determine whether treatment with glycine is more effective than treatment with carnitine because all reports lack a common study protocol, do not have adequate sample size, and do not control for the patients’ age, diet, and medication dosage. As a first estimation, excretion of isovaleric acid via glycine is quantitatively more important, together with a moderate restriction of leucine intake (54). Treatment with L-carnitine prevents carnitine deficiency and provides a second detoxification pathway (54). A treatment recommendation from E-IMD recommends L-carnitine in combination with L-glycine in metabolically severe phenotypes (12).

During acute decompensation, isovaleric acidemia must be treated like other organic acidemias. Measures include increased provision of energy via oral, nasogastric, or intravenous routes by 20% to 100% above the recommended daily requirements using carbohydrate (eg, glucose or dextrose 20% orally or glucose intravenously) and fat (intralipid 20%). Soluble insulin should be provided to avoid hyperglycemia and to support intracellular glucose uptake. The intake of natural protein should be stopped for 24 to 48 hours and is then reintroduced gradually as tolerated (22). Additional specific treatment recommendations include augmented doses of glycine and high-dose L-carnitine (54). N-carbamylglutamate (carglumic acid) has been used to overcome neonatal hyperammonemia due to inhibition of N-acetylglutamate synthetase by isovaleryl-CoA, which is analogous to the use of this substance in other organic acidemias (25; 04).

It is unclear whether patients carrying the common mutation (A282V, 932C> T) associated with a biochemically and clinically mild phenotype require any treatment. Close observation during periods of metabolic stress and carnitine supplementation if free carnitine concentrations are very low seems reasonable (60).

Outcomes

Early diagnosis is crucial. If treatment can be initiated before a first severe metabolic decompensation, the patient’s prognosis is significantly improved. Individuals who receive treatment before becoming symptomatic usually have normal long-term psychomotor development (35; 17).

In 24 individuals with classic (early-onset) isovaleric acidemia, newborn screening and early institution of therapy prevented untimely death, except in one individual with lethal neonatal sepsis, but did not completely prevent single or recurrent metabolic decompensations (44). IQ of individuals with isovaleric acidemia was generally in the normal range (albeit on the low side; mean ± SD, 91 ± 10) but was significantly below that of the reference population and was even lower in individuals with severe neonatal decompensations (IQ 79 ± 7) compared to those without crises (IQ 95 ± 8). In contrast, individuals with mild (later onset) isovaleric acidemia had excellent neurocognitive outcomes (IQ 106 ± 16), normal school placement, a benign disease course with no metabolic decompensations, and a normal hospitalization rate. In the later-onset group, metabolic maintenance therapy did not appear to alter the disease course (or benefit the patients). These findings indicate that a one-size-fits-all treatment regimen is not likely to benefit a large proportion of cases with milder phenotypes (44). Consequently, "harmonized stratified therapeutic concepts are urgently needed" (44).

Patients identified by newborn screening who carry the common mutation (A282V, 932C> T) are usually asymptomatic and most likely do not need treatment. Siblings of these individuals who have the same genotype remain asymptomatic during episodes of febrile illnesses without any specific treatment (10; 60; 35).

Special considerations

Pregnancy

In women with isovaleric acidemia, the outcomes for both mother and child seem to be good (58). However, close monitoring of sufficient protein and energy intake is important. Catabolic stress has to be anticipated during labor and involution of the uterus and may require intravenous glucose treatment (58).

Anesthesia

Patients are at risk for metabolic decompensation by catabolism induced by fasting, anesthesia, or a surgical procedure. It is essential to meet increased energy requirements in these situations by intravenous administration of dextrose (22). Augmented doses of glycine and high-dose L-carnitine should be provided. No information is available about particular side effects of drugs normally used to induce anesthesia in patients with isovaleric acidemia.