Overview
Deoxyhypusine Synthase Disorder (DHPSD) is a rare genetic condition that affects a critical physiological mechanism in which proteins are modified. It is characterized by neurodevelopmental delay and seizures that begin during childhood. Changes (mutations or variations) in the DHPS gene are the root cause of this autosomal recessive genetic disorder.1
Deoxyhypusine synthase (DHS) is a pivotal cellular enzyme responsible for post-translational protein modification2. DHS operates within our cells, regulating the transformation of specific lysine residues in proteins into hypusine. The functionality of various proteins is fundamentally regulated by this enzymatic modification, which is an essential stage in the maturation of proteins.3
The genetic condition DHPSD is introduced as interfering with the normal progression of hypusine modification controlled by DHS.1 This article gives a thorough review of DHPSD, including its causes, signs, symptoms, diagnosis, treatment options, and the impact it has on afflicted individuals and their families.
Causes of DHPSD
Genetic mutations
The main cause of DHPSD is genetic mutations that alter deoxhyousine synthase’s (DHS) normal operation, and it is primarily inherited in an autosomal recessive manner, which means that both parents must carry a mutated copy of the gene for their child to develop the condition. These mutations occur in particular genes linked to DHPSD, which are responsible for the synthesis of the rare amino acid hypusine. Eykaryotypic Translation Initiation Factor-5A (EIF5A) is the only type of protein that contains this amino acid. Many proteins in the body are translated, lengthened or produced with the aid of EIF5A1.
Risk factors
DHPSD is predominantly a genetic condition. However, there may be other risk factors that affect how often it occurs. These include environmental factors, lifestyle factors, or other external influences that could contribute to the severity of the condition.
The complicated aetiology of DHPSD requires a comprehensive understanding of the interaction between genetics and environment because it could throw insights into why people with identical genetic mutations might manifest the condition differently.
Signs and symptoms of DHPSD
- Neurological problems: DHPSD often shows a variety of neurological symptoms, such as developmental delay, intellectual disability, as well as speech and language issues. In some individuals, DHPSD also triggers epilepsy/seizure episodes.4
- Muscular abnormalities: DHPSD often presents the occurrence of muscular abnormalities such as hypotonia, hypertonia and spasticity that impact the patient’s motor skills and mobility.1
- Gastrointestinal issues: Some individuals with DHPSD might experience feeding difficulties and gastrointestinal reflux.1 These problems may result in inadequate nutrition and lower calorie intake, which may have an impact on a child’s growth.
- Chronic infection: Due to immune system dysfunction, individuals with DHPSD may be more prone to recurring infections. Repeated or ongoing infections may increase immunoglobulin consumption, which may eventually result in lower levels of IgA and IgG levels.5
- Immune problems: Plasma cells, a subset of B lymphocytes, a class of white blood cells, are responsible for producing IgA and IgG. Disruption in protein modification caused by DHPSD may hinder the development and function of B cells, impairing their ability to properly produce immunoglobulins.
- Autoimmune: Untreated immune problems in DHPSD may result in autoimmune phenomena in which the body’s own tissues are mistakenly targeted by the immune system. The generation and control of immunoglobulins are both impacted by autoimmune diseases, which can also disrupt normal immune responses.5
It is critical to note that not everyone with DHPSD will have low IgA and
IgG levels or other related immunological problems. The immune problems linked to DHPSD can vary among those affected.4
Diagnosis
Due to its rarity and the requirement for specialized genetic testing, diagnosing DHPSD is a challenging process. Nevertheless, it is essential to make an early and correct diagnosis in order to initiate prompt interventions and supportive care. Several methods and tests used for DHPSD diagnosis include:
- Genetic testing: The primary method for diagnosing DHPSD is genetic testing. Finding specific mutations involves sequencing the DHPSD-related genes, including the EIF5A and DOHH genes. The diagnosis is confirmed by the identification of harmful mutations in these genes.1
- Biochemical analysis: Some DHPSD patients might be subjected to biochemical evaluation, such as checking for hypnotic levels in their blood or urine. Elevated hypusine levels may support confirming the diagnosis.6
- Whole exome sequencing (WES) or whole genome sequencing (WGS): When targeted genetic testing is unsuccessful in providing a diagnosis, WES or WGS may be used to look at a wider spectrum of genetic variations.7 These methods are used to find novel or rare mutations linked to DHPSD.
One of the most critical steps in the diagnostic process is genetic counselling. The genetic basis of DHPSD, the inheritance pattern, and any potential effects on family members are all topics that genetic counsellors discuss with both individuals and families. They aid people in making knowledgeable decisions about genetic testing. In addition, other family members must undertake genetic testing to see if they share the same mutation linked to DHPSD. This can help identify at-risk family members and, if necessary, facilitate early intervention.1
Management and treatment options for DHPSD
Unfortunately, there is no specific cure for DHPSD due to its rarity. DHPSD management requires a multidisciplinary approach that focuses on resolving the symptoms, complications, and overall well-being of affected individuals. This may include physical and occupational therapy, such as
- Physiotherapy: To increase muscle strength, mobility, and motor abilities in individuals with DHPSD, physical and occupational therapy like physiotherapy can help to increase overall independence and functional abilities.1
- Speech therapy: Individuals with DHPSD can benefit from speech and language therapy to address their communication difficulties, speech delays, and swallowing issues. These treatments encourage healthy eating and promote effective communication.8
- Gene therapy: There is ongoing research into prospective gene treatments and precision medicine strategies as our understanding of DHPSD grows. Targeting the underlying genetic abnormalities that cause DHPSD and regaining normal cellular function are the goals of these cutting-edge therapies. However, this is still in the early experimental stages and requires further research, development, and clinical trials.5
- Psychological support: Psychosocial support is essential because of the complexity of DHPSD and its potential effects on both individuals and families. Counsellors, support groups, and mental health specialists can offer emotional support and advice for overcoming the difficulties related to DHPSD.
For individuals with this rare genetic condition, collaboration between medical professionals, therapists, and genetics is crucial to providing comprehensive care and maximizing outcomes.
FAQs
What is DHPSD?
Deoxyhyousine Synthase Disorder (DHPSD) is an uncommon genetic disorder characterized by seizures, delayed neurodevelopment, and other symptoms that can affect the quality of life of individuals and family members. It primarily affects children and is caused by genetic changes in particular genes.1
How common is DHPSD?
DHPSD is an exceptionally extremely rare recessive genetic disorder that is inherited in an autosomal recessive pattern. As of November 2022, there are less than ten people who have been diagnosed with DHPSD.1
Who is most at risk of DHPSD?
Both men and women have the same level of risk of DHPSD. With each pregnancy, there is a 25% chance that two carrier parents will also carry the non-working gene and, as a result, have a child that is affected. With each pregnancy, there is a 50% chance that the unborn kid will also be a carrier, like the parents. A child has a 25% chance of inheriting functional genes from both parents1. Hence, individuals most at risk of DHPSD include
- Children born to carrier parents
- Siblings of individuals affected with DHPSD
- Family members with DHPSD history
How is DHPSD inherited?
DHPSD is inherited autosomally recessively; an individual with the condition receives two copies of the defective gene from each carrier parent. Despite having one copy of the defective gene, carrier parents are asymptomatic.1
Are there any ongoing research or treatment options for DHPSD?
Yes. Research is still being done on precision medicine and potential gene treatments for DHPSD. Despite being in the experimental stage, some medicines show promise in addressing the underlying genetic abnormalities.5
Summary
DHPSD is an extremely rare genetic condition characterized by seizures, neurodevelopmental delays, and various associated symptoms. It is inherited autosomally recessively and caused by DHPS gene mutations. By preferentially converting lysine residues into hypusine, which is essential for optimal protein maturation, DHPS plays a key role in post-translational protein modification. DHPSD primarily affects children and presents with neurological disorders, such as seizures, muscle issues, feeding difficulties, and gastrointestinal symptoms, as well as developmental delay. A connection between the illness and immune problems, such as low IgA and IgG levels, has also been identified. Genetic testing is necessary for the diagnosis, and genetic counselling is crucial for assisting affected people and their families. Although there is no cure, supportive care and therapy are used in management. Because DHPSD is extremely uncommon, early detection and a multidisciplinary approach to care are crucial. The risk is higher in children born to carriers, as well as in siblings and other family members with a known family history of the condition. It equally affects both sexes.
References
- Deoxyhypusine Synthase Disorder - Symptoms, Causes, Treatment | NORD [Internet]. rarediseases.org. [cited 2023 Sep 8]. Available from: https://rarediseases.org/rare-diseases/deoxyhypusine-synthase-disorder/
- Padgett, L. R., Robertson, M. A., Connors, C. T., Wu, W., Mirmira, R. G., & Mastracci, T. L. (2021). Deoxyhypusine synthase, an essential enzyme for hypusine biosynthesis, is required for proper exocrine pancreas development. The FASEB Journal, 35(5). https://doi.org/10.1096/fj.201903177R
- Paz, E. A., Garcia-Huidobro, J., & Ignatenko, N. A. (2011). Polyamines in cancer. Advances in Clinical Chemistry, 54, 45-70. https://doi.org/10.1016/B978-0-12-387025-4.00002-9
- Ganapathi, M., Padgett, L. R., Yamada, K., Devinsky, O., Willaert, R., Person, R., Au, Y. B., Tagoe, J., McDonald, M., Karlowicz, D., Wolf, B., Lee, J., Shen, Y., Okur, V., Deng, L., LeDuc, C. A., Wang, J., Hanner, A., Mirmira, R. G., . . . Chung, W. K. (2019). Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder. American Journal of Human Genetics, 104(2), 287-298. https://doi.org/10.1016/j.ajhg.2018.12.017
- Anderson-Baucum, E., Piñeros, A. R., Kulkarni, A., Webb-Robertson, J., Maier, B., Anderson, R. M., Wu, W., Tersey, S. A., Mastracci, T. L., Casimiro, I., Scheuner, D., Metz, T. O., Nakayasu, E. S., Evans-Molina, C., & Mirmira, R. G. (2021). Deoxyhypusine Synthase Promotes a Pro-Inflammatory Macrophage Phenotype. Cell metabolism, 33(9), 1883. https://doi.org/10.1016/j.cmet.2021.08.003
- Chawla, B., Jhingran, A., Singh, S., Tyagi, N., Park, M. H., Srinivasan, N., Roberts, S. C., & Madhubala, R. (2010). Identification and Characterization of a Novel Deoxyhypusine Synthase in Leishmania donovani. The Journal of Biological Chemistry, 285(1), 453-463. https://doi.org/10.1074/jbc.M109.048850
- What are whole exome sequencing and whole genome sequencing?: MedlinePlus Genetics [Internet]. medlineplus.gov. 2021. Available from: https://medlineplus.gov/genetics/understanding/testing/sequencing/
- PhD SI. Speech Therapy | Pompe Disease News [Internet]. pompediseasenews.com. [cited 2023 Sep 8]. Available from: https://pompediseasenews.com/speech-therapy-pompe-disease/
