Last updated:
9/17/2024
Years published: 2016, 2020, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and Charles E. Schwartz, PhD, Senior Research Scientist, Emeritus, Greenwood Genetic Center, for the preparation of this report.
Summary
Snyder-Robinson syndrome (SRS) is a rare disorder of intellectual disability that only affect males. Affected males have a slender build with long limbs, angular profile and prominent muscles or bones (asthenic habitus), low muscle mass, some abnormal facial features (dysmorphism), speech abnormalities, outward curvature and lateral curvature of the spine (kyphoscoliosis) and decreased bone mass leading to fragile bones (osteoporosis). Seizures are also rather common.
The syndrome is caused by changes (variants) in the spermine synthase (SMS) gene. Inheritance is X-linked recessive.
There is no cure or treatment aside from symptom management.
Introduction
Snyder-Robinson syndrome was first described in a single family by Snyder and Robinson in 1969 as a non-syndromic X-linked disorder. Since the first description there are only a few cases described.
The symptoms, progression and severity of SRS are variable among the affected people, even in the same family. The signs and symptoms that have been reported include:
Female carriers may have milder symptoms of SRS.
Snyder-Robinson syndrome is caused by changes (variants) in the SMS gene. Thus far, 26 different variants in the SMS gene have been published or reported.
The SMS gene provides instructions for making an enzyme called spermine synthase. This enzyme helps produce a substance called spermine, which is part of a group of molecules known as polyamines. It does this by transferring a specific chemical group from a compound called decarboxylated S-adenosylmethionine (dcSAM) onto another molecule, spermidine, which is the “precursor” (starting material) for spermine.
Polyamines are important for many functions in our cells. They help cells grow and divide, make new proteins, repair damaged tissues, regulate certain channels in cells, and control when cells need to self-destruct (a normal process called apoptosis). Polyamines are essential for the proper development and function of the brain and other parts of the body.
The variants in the SMS gene result in a deficiency of the spermine synthase enzyme. This means that the enzyme doesn’t work as well as it should, leading to lower levels of spermine. At the same time, spermidine builds up because it isn’t being converted properly. This causes an imbalance, where the ratio of spermidine to spermine becomes higher than normal. Studies have shown that a higher spermidine/spermine ratio is linked to more severe symptoms in people with SRS. The spermine shortage affects normal development, especially in the brain, muscles and bones. However, it’s still unclear how this shortage causes the specific symptoms seen in the syndrome.
This condition is inherited in an X-linked recessive pattern. X-linked genetic disorders are conditions caused by a disease-causing gene variant on the X chromosome and mostly affect males. Females who have a disease-causing gene variant on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the gene variant. Some carrier females may be affected but have milder symptoms. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease-causing gene variant, he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder can reproduce, he will pass the gene variant to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
Snyder-Robinson syndrome is a rare X-linked intellectual disability disorder and as such it is difficult to estimate its prevalence. As SRS has been identified in patients located in the United States, South America and Europe, it is likely not restricted to any ethnic population geographical locale. Less than 100 cases have been reported in the medical literature.
A diagnosis of Snyder-Robinson syndrome can be made based on the clinical presentation and confirmed by genetic testing identifying the variants in the SMS gene. However, since SRS is a rare XLID condition, it is more likely the diagnosis is made after whole exome sequencing (WES) identifies a variant in the SMS gene. Biochemical studies (SMS activity and cellular spermidine/spermine ratios) should be conducted to absolutely insure a proper diagnosis of SRS.
Treatment
There is no treatment which effectively treats Snyder-Robinson syndrome. Initially, as SRS results from a lack of spermine being produced by cells within the body, it was thought spermine supplementation might treat the disorder. However, this approach has proved to be unsuccessful. Thus, treatment is directed towards alleviating some of the symptoms of SRS. Speech, physical, and occupational therapies have been helpful, but results have varied. Calcium supplementation to improve bone mineral density has been tried to counteract osteoporosis. Again, results have varied. Nonetheless, because of osteoporosis and an increased risk for fractures, patients with SRS should be monitored regularly and calcium supplementation should be initiated once decreased bone mineral density is observed.
Treatment of seizures can be attempted with various drugs. However, success with any one drug has been variable and some seizures have been refractory to treatment.
There is potential to use a medication called 2-difluoromethylornithine (DFMO) also known as Eflornithine, to help restore balance between the levels of spermidine and spermine in people with Snyder-Robinson syndrome. DFMO is an FDA-approved drug that blocks the production of polyamines, which are the molecules affected in SRS. It is currently used to treat parasitic infections and a condition called hirsutism (excessive hair growth). By inhibiting polyamine production, DFMO might help reduce the buildup of spermidine and restore a more normal balance between spermidine and spermine, potentially improving symptoms in people affected with SRS.
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:
Tollfree: (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/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Leung M, Sanchez-Castillo M, Belnap N, Naymik M, Bonfitto A, Sloan J, Hassett K, Jepsen WM, Sankaramoorthy A, Stewart TM, Foley JR, Rangasamy S, Huentelman MJ, Narayanan V, Ramsey K. Snyder-Robinson syndrome presenting with learning disability, epilepsy, and osteoporosis: a novel SMS gene variant. Rare. 2024;2:100017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11105150/
Gilmour SK. Rebalancing polyamine levels to treat Snyder-Robinson syndrome. EMBO Mol Med. 2023 Nov 8;15(11):e18506. doi: 10.15252/emmm.202318506. Epub 2023 Sep 15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10630864/
Larcher L, Norris JW, Lejeune E, et al. The complete loss of function of the SMS gene results in a severe form of Snyder-Robinson. Eur J Med Genet. 2019 Sep 30:103777. doi: 10.1016/j.ejmg.2019.103777. [Epub ahead of print]
Peng Y, Norris J, Schwartz C, et al. Revealing the effects of missense mutations causing Snyder-Robinson syndrome on the stability and dimerization of spermine synthase. Int. J. Mol. Sci. 2016;17: 77.
Abela L, Simmons L, Steindl K, et al. N8-acetylspermidine as a potential plasma biomarker for Snyder-Robinson syndrome identified by clinical metabolomics. J Inherit Metab Dis. 2016;39:131-137.
Albert JS, Bhattacharyya N, Wolfe LA, et al. Impaired osteoblast and osteoclast function characterize the osteoporosis of Snyder-Robinson syndrome.Orphanet J Rare Dis. 2013;10:27.
Peron A, Spaccini L, Norris J, Bova SM, Selicorni A, Weber G, Wood T, Schwartz CE, and Mastrangelo M. Snyder-Robinson syndrome: a novel nonsense mutation in spermine synthase and expansion of the phenotype. Am. J. Med. Genet. 2013; A 161:2316-2320.
Zhang Z, Norris J, Kalscheuer V, Wood T, Wang L, Schwartz C, Alexov E, and Van Esch H. A Y328C missense mutation in spermine synthase causes a mild form of Snyder-Robinson syndrome. Hum. Mol. Genet.2013;22:3789-3797.
Sowell J, Norris J, Jones K, Schwartz C, and Wood T. Diagnostic screening for spermine synthase deficiency by liquid chromatography tandem mass spectrometry.Clin. Chim. Acta 2011;412: 655-660.
Becerra-Solano LE, Butler J, Castañeda-Cisneros G, et al. A missense mutation, p.V132G, in the X-linked spermine synthase gene (SMS) causes Snyder-Robinson syndrome. Am J Med Genet A. 2009 Mar;149A(3):328-35.
deAlencastro G, McCloskey DE, Kliemann Se, et al. New SMS mutation leads to a striking reduction in spermine synthase protein function and a severe form of Snyder–Robinson X-linked recessive mental retardation syndrome. BMJ 2008;45 (8).
Cason AL, Ikeguchi Y, Skinner C, Wood TC, Lubs HA, Martinez F, Simensen RJ, Stevenson RE, Pegg AE, and Schwartz C. E. X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome. Eur. J. Human Genet. 2003;11: 937-944.
INTERNET
Schwartz CE, Peron A, Kutler MJ. Snyder-Robinson Syndrome. 2013 Jun 27 [Updated 2020 Feb 13]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK144284/ Accessed Sept 17, 2024.
Snyder-Robinson syndrome. Medline Plus. November 1, 2016. https://medlineplus.gov/genetics/condition/snyder-robinson-syndrome/ Accessed Sept 17, 2024.
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