Bifunctional enzyme deficiency

Bifunctional enzyme deficiency, also known as D-bifunctional protein deficiency (DBP deficiency) or peroxisomal bifunctional enzyme deficiency, is a severe autosomal recessive disorder of peroxisomal fatty acid beta-oxidation. The condition is caused by mutations in the HSD17B4 gene, which encodes D-bifunctional protein (DBP), an enzyme essential for the peroxisomal beta-oxidation of very-long-chain fatty acids, branched-chain fatty acids (such as pristanic acid), and bile acid intermediates (DHCA and THCA). Deficiency of this enzyme leads to accumulation of these substrates in body tissues and fluids. The disease predominantly affects the central nervous system and presents in the neonatal period with severe hypotonia, seizures (often intractable), failure to thrive, and characteristic craniofacial dysmorphism resembling Zellweger syndrome. Affected infants typically show profound developmental delay, visual impairment, sensorineural hearing loss, and hepatomegaly. Brain MRI often reveals defects in neuronal migration and progressive white matter abnormalities. The clinical spectrum is divided into several subtypes based on which enzymatic activity is deficient (type I: both hydratase and dehydrogenase; type II: hydratase only; type III: dehydrogenase only; type IV: milder phenotype with later onset). The prognosis for the severe neonatal forms is poor, with most affected children dying within the first two years of life. A milder type IV presentation has been described with later-onset cerebellar ataxia, sensorineural hearing loss, and longer survival into adolescence or adulthood. There is currently no curative treatment for bifunctional enzyme deficiency. Management is supportive and symptomatic, including seizure control, nutritional support, physical therapy, and management of hearing and visual impairment. Dietary restriction of phytanic acid and very-long-chain fatty acids has been attempted but has not demonstrated clear clinical benefit in severe forms.

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