Disorders of Leucine Metabolism: Isovaleric Acidaemia (IVA)

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The following information provides a general overview of Disorders of leucine metabolism and is intended for educational purposes only. It should not replace guidance from qualified healthcare professionals. Vitaflo™ International Limited accepts no responsibility for any loss resulting from reliance on the content. For comprehensive and up-to-date recommendations, please refer to national and international clinical guidelines.

What are Disorders of Leucine Metabolism?

Disorders of leucine metabolism are a group of inherited, autosomal, recessive metabolic disorders, characterised by abnormal metabolism of the amino acid leucine. There are a number of disorders, including¹:

isovaleric acidaemia (isovaleryl-coenzyme A (CoA) dehydrogenase deficiency)
isolated 3-methylcrotonyl-CoA carboxylase deficiency
3-methylglutaconic acidurias (3-methylglutaconyl-CoA hydratase deficiency, Barth syndrome and other disorders in which the primary defect has not been demonstrated)
3-hydroxy-3-methylglutaric aciduria (3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency)

The following information on this webpage refers to isovaleric acidaemia (IVA) only (may also be spelt isovaleric ‘acidemia’).

What is Isovaleric Acidaemia (IVA)?

Isovaleric Acidaemia, also referred to as isovaleric aciduria, is the result of a genetic, autosomal, recessive defect which causes a deficiency of the enzyme: isovaleryl‐CoA dehydrogenase, leading to abnormal metabolism of the essential amino acid leucine^2-3.

What is the cause of Isovaleric Acidaemia?

Isovaleric acidaemia (IVA) is caused by a deficiency of the enzyme: isovaleryl‐CoA dehydrogenase (IVD). IVD catalyses the third step in leucine catabolism.

In IVA, the deficiency of this enzyme results in accumulation of isovaleryl Co-A derivatives; isovaleric acid, isovaleryl (C5) carnitine and other metabolites, which are toxic and result in illness⁴.

*Note: you may find our condition-specific resource helpful, intended for use with patients and families to explain the complex science behind the inheritance of Isovaleric Acidaemia, diagnosis and management.

Introduction to Disorders of Leucine Metabolism

Your patients can also read the information on this website.

For further information on resources available, please enquire on: Contact page

What are the symptoms of Isovaleric Acidaemia?

The three main clinical presentations and associated symptoms of untreated Isovaleric acidaemia (IVA) are⁵:

Severe neonatal onset (classical)

Infants may present acutely within the first week of life with:

Poor feeding
Lethargy
Dehydration
Encephalopathy
Metabolic acidosis
Hyperammonaemia
The odour of ‘sweaty feet’

Chronic (intermittent)

Some individuals present later in infancy or childhood, with less specific symptoms of failure to thrive and/or neurological symptoms, as well as cognitive impairment.

Symptoms may also include:

Lethargy with ataxia
Anorexia
Vomiting
Developmental delay
Faltering growth

Attenuated (previously known as ‘mild isovaleric acidaemia’)

Those identified through newborn screening with a ‘metabolically mild’ phenotype typically remain asymptomatic throughout their life.

Testing for Isovaleric Acidaemia: Newborn screening

Early diagnosis and treatment have been shown to significantly improve neurocognitive outcomes in individuals with Isovaleric acidaemia (IVA)⁶.

IVA can be diagnosed at birth via newborn screening (NBS); however, not all countries screen for IVA. NBS for IVA is available in several countries, including the USA, UK, Germany and various other countries in Europe and the Middle East⁴.

Dried blood samples taken from a heel prick are assessed for elevated levels of C5-carnitine, and urine samples are tested for elevated isovalerylglycine.

Diagnostic confirmation of IVA then comes from assessment of the mutation of the IVD gene^3,6. Genetic testing can also provide support in distinguishing between genetic phenotypes, which can inform early treatment, reducing morbidity and mortality in those with classical IVA⁶.

Unscreened patients may present clinically, depending on the disorder genotype, with milder cases tending to present later, typically by the age of 3 years⁷.

How common is Isovaleric Acidaemia?

The incidence of the IVA varies and has been reported as 1 in 67,000 in Germany to 1 in 250,000 in the USA⁴. However, due to the absence of screening in many countries, the worldwide incidence remains unclear⁷.

How is Isovaleric Acidaemia Managed?

The primary aim of management in Isovaleric acidaemia (IVA) is to achieve good metabolic control by limiting the accumulation of toxic metabolites, whilst maintaining normal growth and development³.

This is typically achieved through a leucine-restricted diet, in conjunction with pharmacological interventions such as carnitine and glycine supplementation. These conjugate with isovaleric acid into non-toxic metabolites, which are excreted in the urine, thereby reducing metabolic load and helping to maintain metabolic stability^2-3,8.

The main components of IVA disorder treatment are medical and dietary. These are divided into: acute care (immediate) treatment and long-term care:

Acute Management

During episodes of infection, catabolism significantly increases production of Isovaleric acid (IVA) and puts the individual at risk of metabolic decompensation.

The primary aim of acute clinical management is to stabilise the individual and reverse the catabolic state by giving intravenous glucose and fluids. Intravenous carnitine is often given, and supplementation of glycine is also considered.

These acute clinical management strategies, combined with additional dietary management strategies, form what is typically referred to as an emergency regimen (ER)^3,8-9.

What are ‘Emergency regimens’ and why are they required in Isovaleric Acidaemia?

Infants with IVA are at higher risk of metabolic decompensation due to^3,8:

Illness
Teething
Long periods between feeds
An excess leucine intake

ER are used in IVA to inhibit protein catabolism and promote anabolism, to prevent metabolic decompensation.

ER may vary due to individual clinical needs and local clinical practice. However, they will likely include the following combination of dietary and clinical management strategies³:

Rehydration with intravenous fluid/ glucose polymer
Temporary reduction or suspension of protein intake
Sufficient supply of calories
Supplementation/dose increase of carnitine/and or glycine

Long-Term Management

Long-term management of Isovaleric acidaemia (IVA) is aimed at minimising the accumulation of toxic metabolites whilst maintaining normal growth and development^3,8-9. Pharmacotherapy such as carnitine and glycine supplementation may also help maintain long-term metabolic stability^2,9.

Long-term dietary management includes³:

Sufficient calories to promote anabolism
Protein and leucine intake should be restricted to supply at least safe levels of intake¹⁰
The use of a protein substitute, restricted in leucine, may be required for a portion of the protein requirement
Amino acids and carnitine in plasma should be monitored during treatment. Monitoring and interpretation of urinary isovalerylglycine and plasma isovalerylcarnitine levels should be tailored on an individual basis

Restriction of Protein Intake

High levels of leucine are present in many foods that contain protein, such as meats, fish, eggs, nuts, milk and dairy products, soya and many more.

To help maintain metabolic stability, it is important that protein intake is restricted, which often means avoiding high protein foods.

As leucine is an essential amino acid, a small, measured amount must be included in the diet to prevent leucine deficiency. This is achieved by limiting protein intakes to the WHO safe levels^2-3,10.

Low protein foods

As well as avoiding high protein foods, incorporating low protein foods into the diet is equally essential for the dietary management of Isovaleric acidaemia (IVA). An adequate energy intake is very important in maintaining metabolic control in IVA.

They can be foods naturally low in protein, such as most fruits and some vegetables. It could also be food like fats, oils and many high-sugar foods. Specially manufactured foods, such as bread, milk alternatives, flour mixes, pasta and rice, subject to availability, can also be used².

These types of foods can provide variety, energy, and greater normality to patients’ diets, allowing for versatility in meals and flavours across the week.

bowls of low protein fruit and vegetables

Protein Substitutes

Many patients with Isovaleric acidaemia (IVA) can meet their protein requirements through foods alone^2-3,8.

However, for those who are unable to meet their protein requirements through foods alone, products called protein substitutes are essential. They provide a suitable leucine free protein source and ensure all other essential amino acids and nutrients are supplied to support physiological protein synthesis for growth and development^2-3.

How is Isovaleric Acidaemia managed in infancy?

Dietary management is ideally started as early as possible following diagnosis, to reduce toxic metabolites as quickly as possible.

This will involve balancing intakes of breast milk or standard infant formula (which provide leucine) with a leucine free formula for infants, to achieve good metabolic control, meet all nutritional requirements and optimise growth⁸.

Breastfeeding offers many benefits to mothers and infants, and a family should be supported in making the appropriate choice for their family, if deemed appropriate by the metabolic healthcare team.

References

Wappner RS, Gibson KM. Disorders of leucine metabolism. In: Blau N, Duran M, Gibson KM, Dionisi-Vici C, editors. Physician’s guide to the treatment and follow-up of metabolic diseases. Berlin: Springer; 2006. p. 59–79. https://doi.org/10.1007/3-540-28962-3_8
Pinto A, Daly A, Evans S, Almeida MF, Assoun M, Belanger-Quintana A, et al. Dietary practices in isovaleric acidemia: a European survey. Mol Genet Metab Rep. 2017;12:16–22. https://doi.org/10.1016/j.ymgmr.2017.02.001
EIMD. Isovaleric acidemia guideline. Available from: https://www.e-imd.org/files/medias/files/recommendations/IVA%20guideline_Quick%20reference%20guide_Ensenauer_201408.pdf [cited 2014 Dec 19].
Schlune A, Riederer A, Mayatepek E, Ensenauer R. Aspects of newborn screening in isovaleric acidemia. Int J Neonatal Screen. 2018;4(1):7. https://doi.org/10.3390/ijns4010007
Couce ML, Aldamiz-Echevarría L, Bueno MA, Barros P, Belanger-Quintana A, Blasco J, et al. Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia. J Hum Genet. 2016;62(3):355–60. https://doi.org/10.1038/jhg.2016.144
Mütze U, Henze L, Schröter J, Gleich F, Lindner M, Grünert SC, et al. Isovaleric aciduria identified by newborn screening: strategies to predict disease severity and stratify treatment. J Inherit Metab Dis. 2023;46(6):1063–77. https://doi.org/10.1002/jimd.12653
Megdadi N, Alakil M, Ghanmiyin L, Maaita O, Abulannaz A. Isovaleric acidemia in Jordan. Cureus. 2024;16(1):e52039. https://doi.org/10.7759/cureus.52039
Dixon M, MacDonald A, White F. Disorders of amino acid metabolism, organic acidaemias and urea cycle disorders. In: Shaw V, editor. Clinical paediatric dietetics. 5th ed. Hoboken: Wiley-Blackwell; 2020. p. 513–98.
Chinen Y, Nakamura S, Tamashiro K, Sakamoto O, Tashiro K, Inokuchi T, et al. Isovaleric acidemia: therapeutic response to supplementation with glycine, L-carnitine, or both in combination and a 10-year follow-up case study. Mol Genet Metab Rep. 2017;11:2–5. https://doi.org/10.1016/j.ymgmr.2017.03.002
World Health Organization. Protein and amino acid requirements in human nutrition: report of a joint WHO/FAO/UNU expert consultation. WHO Tech Rep Ser. 2007;(935):1–265.