What causes DHDDS?
Cause of DHDDS
DHDDS is an ultra-rare genetic condition caused by specific changes to a gene called DHDDS. DHDDS stands for Dehydrodolichyl Diphosphate Synthase which is a protien coding gene. Much is still unknown about the biochemical underpinning of this disease and more research needs to be done to fully understand it.
DHDDS is located in the polyisoprenoid pathway (also called mevalonate pathway) and here contributes to the synthesis of dolichol which displays an essential donor substrate in different glycosylation pathways.
The DHDDS gene mutations with neurological consequences seem to fall on the intersection of Congenital disorders of glycosylation (CDG’s) and inherited storage diseases.
Today, we know of approximately 170 types of CDG. CDG’s are a large group of rare genetic disorders that affect the addition or modification of sugar building blocks called glycans, to proteins and lipids in cells throughout the body. The addition of glycans is critical to the healthy function of cells.
In some ways however the DHDDS gene mutation is unlike CDG’s in that it has so far not shown clear serum glycoprotein hypo glycosylation, and unlike other CDGs involving dolichol metabolism the urinary dolichol D18/D19 ratio is normal. We do not yet understand why this is.
Also, DHDDS gene mutations have some similar features to the inherited lysosomal storage diseases as in some individuals lipidic material and altered lysosomes were found in myelinated fibres and fibroblasts. More research is required to fully understand these findings.
Most of the time DHDDS pathogenic variants appear randomly in a child and are not identified in either parent. This is known as de novo. Occasionally a parent can pass on the DHDDS pathogenic variant to their child if it exists in a few but not all their body’s cells and is present in an egg or sperm. This is known as germline mosaicism. It seems that parents with germline mosaic DHDDS mutations are unaffected as the variant only exists in a few specific cells. Also, in what appears to be rarer cases an affected or unaffected parent can pass on the exact mutation to their child. This is called an inherited mutation.
As well as causing neurological symptoms, changes to this gene are also associated with retinitis pigmentosa type 59. For reasons we do not yet understand retinitis pigmentosa does not seem to be present in individuals with the DHDDS neurological phenotype.