2.1. D-bifunctional Protein Deficiency

More than 60 HSD17B4 gene mutations have been identified in individuals with D-bifunctional protein deficiency, a severe disorder that causes deterioration of nervous system functions (neurodegeneration) beginning in infancy. HSD17B4 gene mutations that cause D-bifunctional protein deficiency can affect one or both of the enzymatic activities of D-bifunctional protein; however, this distinction does not seem to affect the severity or features of the disorder.

Impairment of one or both of the D-bifunctional protein's enzymatic activities prevents it from breaking down fatty acids efficiently. As a result, these fatty acids accumulate in the body. It is unclear how fatty acid accumulation leads to the specific features of D-bifunctional protein deficiency; however, the accumulation may result in abnormal development of the brain and the breakdown of myelin, which is the covering that protects nerves and promotes the efficient transmission of nerve impulses. Destruction of myelin leads to a loss of myelin-containing tissue (white matter) in the brain and spinal cord; loss of white matter is described as leukodystrophy. Abnormal brain development and leukodystrophy likely underlie the neurological abnormalities that occur in D-bifunctional protein deficiency.

2.2. Perrault Syndrome

At least two HSD17B4 gene mutations have been found to cause Perrault syndrome, a condition characterized by hearing loss in affected males and females and ovarian abnormalities in affected females. The HSD17B4 gene mutations involved in this condition reduce the amount of functional D-bifunctional protein that is produced. It is not known what effect these mutations have on fatty acid breakdown in affected individuals or how the mutations lead to the signs and symptoms of Perrault syndrome.