General description

Isovaleric acidemia is a rare autosomal recessive inborn error of metabolism with significant clinical implications. sovaleric acidemia is an autosomal recessive disorder caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD). The IVD gene is located on chromosome 15q14-15 and consists of 12 exons spanning 15 kb of genomic DNA. More than 70 heterogeneous mutations in the IVD gene have been identified in patients with IVA. This enzyme deficiency disrupts the metabolic pathway of leucine, specifically preventing the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA. Consequently, isovaleric acid and its derivatives accumulate in blood, urine, and tissues to toxic levels.

The clinical presentation of IVA demonstrates considerable variability, ranging from asymptomatic to severe life-threatening manifestations. Two major clinical scenarios are typically described: an acute neonatal form and a chronic intermittent form, though in reality, the disease exists on a continuum.

A pathognomonic feature of IVA is the characteristic "sweaty feet" odor, resulting from the accumulation of isovaleric acid in body fluids. This distinctive odor is particularly noticeable during acute metabolic decompensation and may be detected in patient sweat or cerumen.

In the acute neonatal form, symptoms typically manifest within days after birth. Initial presentations include poor feeding, vomiting, lethargy, and progressive encephalopathy. Physical examination may reveal hypotonia and hypothermia. Laboratory findings demonstrate severe metabolic acidosis, ketonuria, hyperammonemia, and hypoglycemia.

Patients with the chronic intermittent form typically develop symptoms during childhood, with metabolic decompensations triggered by infections, increased protein intake, or fasting. These individuals may exhibit developmental delay, intellectual disability, seizures, and movement disorders such as tremor, dysmetria, and extrapyramidal movements.

References

1. Reddy, Nihaal, et al. "Neuroimaging findings of organic acidemias and aminoacidopathies." Radiographics 38.3 (2018): 912-931.
2. Sogut, Ayhan, et al. "Isovaleric acidaemia: cranial CT and MRI findings." Pediatric radiology 34 (2004): 160-162.