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Last updated: 11/28/2023
Years published: 2019, 2023
NORD gratefully acknowledges Wendy Chung, MD PhD, Clinical and Molecular Geneticist, Kennedy Family Professor of Pediatrics and Medicine, Columbia University Medical Center, and the DHPS Foundation, for the preparation of this report.
Summary
Deoxyhypusine synthase (DHPS) disorder, also known as โneurodevelopmental disorder with seizures and speech and walking impairmentโ is a very rare disorder. It is characterized by global developmental delay, especially speech delay, as well as walking difficulties due to low or highl muscle tone (hypotonia, hypertonia), spasticity or poor coordination. Other features include seizures, mild facial differences and variable short stature.
DHPS is caused by changes (pathogenic variants or mutations) in the DHPS gene and it is inherited in an autosomal recessive pattern.
The signs and symptoms are varied, usually begin in childhood and may include:
โข Neurodevelopmental / cognitive delays
โข Speech and language delays (poor or absent speech)
โข Delayed walking, mild
โข Unsteady gait
โข Balance problems
โข Coordination problems
โข Spasticity
โข Seizures/epilepsy
โข Anomalies in the electroencephalogram (test for electrical activity in the brain)
โข Short stature
โข Failure to thrive (difficulty growing and gaining weight)
โข Facial differences that are mild, variable and may include:
o Low-set ears
o Deep-set eyes
o Prominent skinfolds or creases beneath the lower eyelid
o Different distribution of eyebrow hair growth in the internal region
o Prominent nasal bridge
o High-arched palate
โข Constipation
โข Abnormal curving of the fifth finger
โข Congenital hip dislocation
โข Sacral dimple
โข Muscle tone anomalies such as low muscle tone affecting the trunk of the body (axial hypotonia) and high muscle tone affecting the legs and/or arms (limb hypertonia)
โข High pain threshold
โข Normal brain imaging
โข Behavioral problems such as hand-flapping and pica (desire to eat substances such as chalk or ashes)
โข Immunological problems such as low IgA (1 family) and low IgG (1 family)
โข Problems during the motherโs pregnancy such as high blood pressure (hypertension) or low blood pressure (hypotension)
โข Birth before 37 weeks of pregnancy (premature)
DHPS disorder is caused by changes (pathogenic variants or mutations) in the DHPS gene. The DHPS gene is responsible for production of the deoxyhypusine synthase enzyme that is involved in the synthesis of an unusual amino acid called hypusine. This amino acid is found in only a single protein known as โeukaryotypic translation initiation factor-5Aโ or EIF5A. The EIF5A protein promotes translation, elongation or production of many proteins in the body. The initial step of hypusination, the formation of deoxyhypusine, is catalyzed by deoxyhypusine synthase (DHS) and the DHPS gene variants affect this important cellular process.
DHPS disorder is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
As of November 2022, DHPS disorder has been diagnosed in less than ten individuals.
A diagnosis of DHPS disorder may be suspected based upon characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Children with mild or moderate intellectual disability and speech development problems but no other anomalies may be suspected of having DHPS disorder.
A diagnosis is confirmed through molecular genetic testing for pathogenic variants in the DHPS gene. Whole exome sequencing (WES) is a molecular genetic test that examines the genes in humans that contain instructions for creating proteins (protein-encoding genes). This is called the exome. WES can detect variants in the DHPS gene that are known to cause DHPS disorder or variants in other genes known to cause similar disorders.
Clinical Testing and Workup
Additional tests may be recommended before molecular genetic testing to rule out other conditions or after molecular genetic testing to assess the extent of the disease. These tests may include laboratory tests (such as blood counts, serum electrolytes and tests of kidney, liver and endocrine functions), neurophysiologic testing, neuroimaging and analysis of cerebrospinal fluid (obtained by โspinal tapโ)
The treatment of DHPS disorder is directed toward the specific symptoms that are apparent in each person. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in diagnosing and treating disorders of the brain and central nervous system in children (pediatric neurologists) and adults (neurologists), speech therapists, physical therapists, occupational therapists and other healthcare professionals may need to work together and plan the best management plan.
There are no standardized treatment protocols or guidelines for patients with DHPS disorder. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients.
Following an initial diagnosis, a developmental assessment may be performed and appropriate occupational, physical and speech therapies started. Speech therapy is required and can include one-on-one sessions with a speech therapist, combined sessions where children learn language and social skills as a group, and the use of augmentative and alternative communication (AAC). AAC includes the use of communication devices, both high tech and low-tech ones, that can help children express thoughts, wants, needs and ideas.
Periodic reassessments and adjustment of services should be provided for all affected children. Additional medical, social and/or vocational services including specialized learning programs may be necessary.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Wฤ tor E, Wilk P, Biela A, Rawski M, Zak KM, Steinchen W, Bange G, Glatt S, Grudnik P. Cryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders. Nat Commun. 2023 Mar 27;14(1):1698. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10042821/
DHPS Genecard https://www.genecards.org/cgi-bin/carddisp.pl?gene=DHPS&keywords=dhps Accessed Nov 28, 2023.
DHPS Foundation. Literature Review. https://www.dhpsfoundation.org/dhps/literature-review/ Accessed Nov 28, 2023.
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