2.1. HSD10 Disease

More than 10 HSD17B10 gene mutations have been found to cause HSD10 disease, a disorder characterized by intellectual disability, impaired speech and movement, and a weakened heart muscle (cardiomyopathy). This disorder affects males more frequently and severely than females; many affected males do not survive beyond early childhood.

Almost all of the mutations change single amino acids in the HSD10 protein. One mutation, which has been found in multiple unrelated individuals, replaces the amino acid arginine with the amino acid cysteine at position 130 in the protein (written as Arg130Cys or R130C). This mutation results in a nonfunctional protein that is quickly broken down by the cell. Other mutations do not reduce the amount of HSD10 protein in cells, but impair its function in other ways.

A shortage or impaired function of HSD10 disrupts mtRNase P function, which impairs the processing of mitochondrial precursor RNA and the generation of tRNA molecules. A shortage of functional HSD10 also impairs the modification of tRNAs to make them more stable, further reducing the amount of functional tRNA molecules. This reduction in functional tRNAs decreases mitochondrial protein synthesis and the production of energy in the cell. The reduction of energy particularly affects the brain, eyes, and heart, leading to the characteristic features of HSD10 disease.

While the shortage of functional HSD10 protein caused by HSD17B10 gene mutations also reduces the processing of isoleucine and other substances in the body, this mechanism does not appear to be primarily involved in the development of HSD10 disease.

Some individuals have HSD17B10 gene mutations that affect only the breakdown of 2-methyl-3-hydroxybutyryl-CoA, which can be detected with laboratory tests, but do not have the signs and symptoms of HSD10 disease.

2.2. Other Disorders

One specific mutation in the HSD17B10 gene causes a form of X-linked intellectual disability called MRXS10. This disorder is characterized by intellectual disability, uncontrollable movements of the limbs (choreoathetosis), and abnormal behavior. The mutation replaces the DNA building block (nucleotide) cysteine with the nucleotide adenine at position 605 in the HSD17B10 gene (written as 605C>A). Although this mutation does not change the sequence of amino acids that makes up the HSD10 protein, it can disrupt how information in the gene is spliced together to make a blueprint for producing the protein. As a result, there is reduced production of the HSD10 protein. It is unclear how the shortage of HSD10 results in the signs and symptoms of MRXS10.

At least 22 individuals who have intellectual disability without other signs and symptoms have been found to have small duplications of genetic material that include HSD17B10 and nearby genes on the X chromosome. The extra copy of the HSD17B10 gene leads to increased production of the HSD10 protein, which may affect neurosteroid regulation. Extra copies of other genes in this region of the X chromosome may also play a role in causing intellectual disability.