NORD gratefully acknowledges Charles E. Schwartz, Ph.D, Director of Research, Greenwood Genetic Center, for the preparation of this report.
Snyder-Robinson syndrome (SRS) is a rare x-linked intellectual disability (XLID) disorder in which 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 not uncommon. The syndrome results from an inactivating mutation in the spermine synthase gene resulting in an inability to convert spermidine to spermine.Introduction
Snyder-Robinson syndrome was first described in a single family by Snyder and Robinson in 1969. In 2003 Cason and colleagues determined that SRS resulted from a mutation in the spermine synthase (SMS) gene located at Xp21.3-p22.12. Since then, utilization of biochemical analysis (lack of SMS activity, altered spermidine/spermine ratio) to validate SMS mutations has allowed the identification of an additional ten families with SRS.
The symptoms, progression and severity of SRS does not appear to vary from patient to patient. Affected children have a “gestalt” consisting of facial dysmorphism with a prominent lower lip, an asthenic build, low muscle mass, kyphoscohosis and speech abnormalities. Males with SRS have low muscle tone (hypotonia) at birth. Symptoms appear early, especially the facial features. Developmental milestones are also not met early in life. The developmental delay progresses such that many boys with SRS have some motor disability. Osteoporosis develops which can result in numerous fractures without a causative event. Seizures are not common and severity varies.
All presently known cases of Snyder-Robinson syndrome are caused by mutations in the SMS gene. Thus far, eleven mutations are known although not all have been published. Since the gene resides on the X-chromosome only males are affected. If the mother of a male with SRS carries the mutation, there is a 50% chance another son will have SRS and a daughter will be a carrier. The rate of new mutations appears to be low as only a single case exists in which the mother of the boy with SRS was not a carrier.
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.
A diagnosis of Snyder-Robinson syndrome can be made based on the clinical presentation and confirmed by sequencing of the spermine synthase (SMS) gene. However, since SRS is a rare XLID condition, more likely the diagnosis is made after whole exome sequencing (WES) identifies a mutation in the SMS gene. Additionally, since at present each mutation in SMS is specific to a family, biochemical studies (SMS activity and cellular spermidine/spermine ratios) should be conducted to absolutely insure a proper diagnosis of SRS.
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, 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 the 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. Seizures can be treated with various drugs and success with any one drug will vary.
Presently there are no current clinical trials. However, this may change in the future. Information on current clinical trials can be found at (www.clinicaltrials.gov).
Albert, J. S., Bhattacharyya, N., Wolfe, L. A., Bone, W. P., Maduro, V., Accardi, J., Adams, D. R., Schwartz, C. E., Norris, J., Wood, T., Gafni, R. I., Collins, M. T., Tosi, L. L., Markello, T. C., Gahl, W. A., and Boerkoel, C. F. 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, S. M., Selicorni, A., Weber, G., Wood, T., Schwartz, C. E., 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.
Cason, A. L., Ikeguchi, Y., Skinner, C., Wood, T. C., Lubs, H. A., Martinez, F., Simensen, R. J., Stevenson, R. E., Pegg, A. E., and Schwartz, C. E. X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome. Eur. J. Human Genet. 2003;11: 937-944.
Albert J, Schwartz CE, Boerkoel CF, et al. Snyder-Robinson Syndrome. 2013 Jun 27. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK144284/ Accessed January 11, 2016.
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