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Isovaleric acidaemia
This condition results from a deficiency in an enzyme necessary for breaking down leucine, leading to a build-up of harmful substances. It can present in infants with severe symptoms or later in life with milder forms, requiring careful dietary management.
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Overview
Isovaleric acidaemia (IVA) is an inherited metabolic disorder where the body cannot properly break down the amino acid leucine. Leucine is one of the essential amino acids, meaning it must be obtained through diet. In individuals with IVA, a specific enzyme is missing or not working correctly, which leads to a build-up of toxic compounds in the body [PMID:33008985].
This accumulation of harmful substances can affect various organ systems, particularly the brain. IVA is considered a rare condition, with an estimated prevalence of about 1 in 62,500 live births globally. Early diagnosis and careful management are crucial for improving outcomes.
Symptoms & clinical features
The symptoms of isovaleric acidaemia can vary significantly between individuals. There are typically two main forms: an acute severe form and a chronic intermittent form. The acute form often appears within the first few days or weeks of life.
Infants with the acute form may experience poor feeding, vomiting, lethargy, and a distinctive 'sweaty feet' odour, caused by the build-up of isovaleric acid. If untreated, this can progress to seizures, coma, and life-threatening metabolic crises. The chronic intermittent form may have milder symptoms that appear later in infancy or childhood, often triggered by illness or increased protein intake. These symptoms can include developmental delay, recurrent vomiting, and failure to thrive [PMID:20301389].
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Affected organs
Isovaleric acidaemia primarily affects the brain, leading to neurological complications if left unmanaged. The toxic by-products that accumulate can cause damage to brain cells, potentially resulting in developmental delays or intellectual disability.
Other organs can also be affected during metabolic crises, including the liver, which may show signs of dysfunction. The bone marrow can also be impacted, sometimes leading to low blood cell counts, such as anaemia or thrombocytopenia [PMID:33008985].
Risks & severity
The severity of isovaleric acidaemia varies, from life-threatening in the acute neonatal form to milder, more manageable symptoms in the chronic intermittent form. Without appropriate intervention, severe metabolic crises can lead to significant brain damage, coma, and even death, especially in infants. The distinctive 'sweaty feet' odour is a key clinical indicator of the condition [PMID:20301389].
Individuals with the chronic intermittent form may experience episodes of metabolic decompensation triggered by factors like infections, surgery, or prolonged fasting. Long-term risks can include developmental challenges and intellectual disability, even with treatment, though early and consistent dietary management significantly improves prognosis.
Genetic causes
Isovaleric acidaemia is caused by pathogenic variants in the IVD gene. This gene provides instructions for making an enzyme called isovaleryl-CoA dehydrogenase. This enzyme is vital for the proper breakdown of leucine, one of the essential amino acids found in dietary protein.
When pathogenic variants occur in the IVD gene, the isovaleryl-CoA dehydrogenase enzyme is either absent or does not function correctly. This prevents the normal metabolism of leucine, leading to the accumulation of isovaleric acid and other toxic compounds in the body. These toxic substances then cause the symptoms associated with IVA.
- IVD isovaleryl-CoA dehydrogenaseThe IVD gene provides instructions for producing the isovaleryl-CoA dehydrogenase enzyme, which is critical for processing the amino acid leucine.
Inheritance pattern
Isovaleric acidaemia is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the pathogenic variant - one from each parent - to develop the condition.
Parents who each carry one copy of the pathogenic variant are known as carriers. Carriers typically do not show symptoms of the condition themselves. For each child born to two carrier parents, there is a 25% chance the child will inherit two pathogenic variants and develop IVA, a 50% chance the child will be a carrier like their parents, and a 25% chance the child will inherit two unaffected copies of the gene.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of isovaleric acidaemia often begins with newborn screening, which is offered universally in the UK. This screening identifies potential cases by detecting elevated levels of isovalerylcarnitine in dried blood spot samples. If the newborn screen is positive, further diagnostic tests are performed.
Confirmatory diagnosis involves specialised biochemical tests to measure specific compounds in blood and urine, such as isovalerylglycine. Genetic testing to identify pathogenic variants in the IVD gene provides a definitive diagnosis and can be accessed via the NHS Genomic Medicine Service. The relevant R-code for diagnostic testing is R283 Metabolic disorders.
Management & lifestyle
Management of isovaleric acidaemia focuses on preventing the build-up of toxic substances and mitigating metabolic crises. This primarily involves a carefully controlled, protein-restricted diet to limit leucine intake. Specialist dietitians work closely with affected individuals and their families to develop an appropriate dietary plan.
Supplements such as L-carnitine and glycine may also be prescribed. These substances help the body excrete the harmful isovaleric acid [PMID:33008985]. During periods of illness or stress, individuals may require urgent medical attention and hospitalisation to manage metabolic crises, which might involve intravenous fluids and glucose. Regular monitoring of metabolic markers is essential, and care is typically coordinated through specialist metabolic centres within the NHS.
UK care pathway
In the UK, individuals suspected of having isovaleric acidaemia, often following a positive newborn screening result, are referred to specialist metabolic centres. These centres provide comprehensive care through multidisciplinary teams, including metabolic consultants, dietitians, and genetic counsellors.
Genetic testing for diagnosis is available through the NHS Genomic Medicine Service (GMS), typically following referral from a clinician. The relevant GMS R-code for diagnostic testing is R283 Metabolic disorders. Genetic counsellors offer support and information about the condition, inheritance patterns, and family planning options.
Frequently asked questions
What is the 'sweaty feet' odour associated with isovaleric acidaemia?
The distinctive 'sweaty feet' odour in individuals with isovaleric acidaemia is caused by the accumulation of isovaleric acid and related compounds in the body. This smell is a key clinical sign, particularly in infants experiencing an acute metabolic crisis.
Is isovaleric acidaemia detectable before birth?
Yes, prenatal diagnosis for isovaleric acidaemia is possible if the pathogenic variants in the parents are known. This can involve genetic testing of foetal cells obtained through amniocentesis or chorionic villus sampling.
What kind of diet is required for someone with isovaleric acidaemia?
Individuals with isovaleric acidaemia require a carefully managed diet that restricts the intake of leucine, an amino acid found in protein-rich foods. This typically involves special low-protein formulas for infants and a controlled diet for older children and adults, designed by a specialist dietitian.
Can isovaleric acidaemia be cured?
Isovaleric acidaemia currently has no cure, but it is a treatable condition. With early diagnosis and consistent management, including dietary restrictions and supplementation, individuals can often live full and healthy lives, preventing severe symptoms and long-term complications.
How does newborn screening help with isovaleric acidaemia?
Newborn screening is crucial for early detection of isovaleric acidaemia. By identifying the condition shortly after birth, before symptoms appear, treatment can begin promptly. This early intervention significantly improves outcomes and helps prevent severe, irreversible damage.
References
- Ogier de Baulny H, Saudubray JM. Branched-chain organic acidurias. Seminars in neonatology : SN. 2002. PMID: 12069539
- Habets DD, Schaper NC, Rogozinski H. Biochemical Monitoring and Management During Pregnancy in Patients with Isovaleric Acidaemia is Helpful to Prevent Metabolic Decompensation. JIMD reports. 2012. PMID: 23430878
- Gokcay G, Baykal T, Gokdemir Y. Breast feeding in organic acidaemias. Journal of inherited metabolic disease. 2006. PMID: 16763892
- Sogut A, Acun C, Aydin K. Isovaleric acidaemia: cranial CT and MRI findings. Pediatric radiology. 2004. PMID: 14534755
- MacDonald A, Depondt E, Evans S. Breast feeding in IMD. Journal of inherited metabolic disease. 2006. PMID: 16763891
- Chalmers RA, de Sousa C, Tracey BM. L-carnitine and glycine therapy in isovaleric acidaemia. Journal of inherited metabolic disease. 1985. PMID: 3930869
- Zaki OK, Priya Doss C G, Ali SA. Genotype-phenotype correlation in patients with isovaleric acidaemia: comparative structural modelling and computational analysis of novel variants. Human molecular genetics. 2017. PMID: 28535199
- Lee PJ, Harrison EL, Jones MG. Improvement in exercise tolerance in isovaleric acidaemia with L-carnitine therapy. Journal of inherited metabolic disease. 1998. PMID: 9584264