Deoxyhypusine synthase is involved in the synthesis of an unusual amino acid, hypusine, which is found in only a single protein, eukaryotypic translation initiation factor-5A (EIF5A). EIF5A promotes translation elongation, or production of many proteins. There are no known humans with mutations in EIF5A.
DHPS deficiency or DHPS disorder is an ultra-rare genetic disorder caused by inheriting two faulty copies of the DHPS gene. The DHPS gene encodes for the deoxyhypusine synthase (DHPS) protein, which is an enzyme necessary for creating the aminoacid hypusine.
The disease was described for the first time in 2019, in a medical publication describing the first 5 patients identified with the disease. As of 2024 we are aware of 8 diagnosed cases: 5 in the US, 2 in Canada and one in the UK.
All patients present with neurodevelopmental disorder including speech and walking impairments as well as seizures or abnormal EEG. The oldest known patient is in their 20s, so there is currently little knowledge about the long-term prognosis or life expectancy for people with DHPS deficiency.
To date, all diagnosed patients have one common DHPS mutation or genetic variant, called c.518A>G or p.N173S, that appears to have originated in Ireland. According to genetic databases, this genetic variant is reported in 0.006% of individuals of European descent, or about 60 in 1 million people. Fortunately, the disease requires two bad copies to be inherited, so carriers (having only one bad copy) are asymptomatic.
There is more variability in the second faulty copy of the DHPS gene that the 7 known patients have. While in some cases the patients have the c.1014+1G>A variant, which compromises a splicing site for the gene and results in no DHPS protein being made, other patients have the c.912_917del or Ile306del variant that deletes one letter of their gene and leads to a non-functional DHPS enzyme being produced. The c.1A>G variant, which compromises the starting codon, has also been described once. As for carriers of the N173S variants, people having only one of these variants are believed to be entirely asymptomatic.
Of all of these variants, the only one producing a functional DHPS enzyme is the N173S variant. The mutant protein is estimated to preserve about 20-25% of activity when compared to wild type (regular) DHPS. Therefore, healthy carriers would have 50-60% of DHPS activity, while patients are estimated to have only about 10% of DHPS activity coming from one copy of the N173S gene variant. It is known that in mice, complete loss of DHPS activity is incompatible with embryonic development. There are also no human cases described of complete loss of DHPS due to having 2 non-functional copies of the DHPS. Therefore it appears that some minimal activity is required for survival, and that would be the reason why all patients carry at least one copy of the hypomorph N173S mutation.
If your child has been diagnosed with possible DHPS deficiency, or you have a patient with a genetic report that could indicate DHPS deficiency, we encourage you to reach out to Dr. Wendy Chung as the leading expert in DHPS genetics.