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Snyder-Robinson Syndrome

Synonym: Spermine Synthase Deficiency

, PhD, , PhD, , MD, PhD, and , MD.

Author Information

Initial Posting: .

Summary

Clinical characteristics.

Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome characterized by asthenic build, facial dysmorphism with a prominent lower lip, kyphoscoliosis, osteoporosis, and speech abnormalities. Developmental delay usually presents as failure to meet early developmental milestones and then evolves to moderate to profound global intellectual disability (which appears to remain stable over time) and variable motor disability. Asthenic habitus and low muscle mass usually develop during the first year, even in males who are ambulatory. During the first decade, males with SRS develop osteoporosis, resulting in fractures in the absence of trauma.

Diagnosis/testing.

The diagnosis is suspected in males with characteristic clinical findings and is confirmed with molecular genetic testing when a hemizygous loss-of-function SMS pathogenic variant is identified.

Management.

Treatment of manifestations: Speech, physical, and/or occupational therapy may be helpful. Seizures have shown varying responses to anti-seizure medications; carbamazepine, phenobarbital, and clobazan have been used successfully in some individuals. Calcium supplementation has slightly improved bone mineral density in a few patients.

Surveillance: Because of the osteoporosis, individuals with SRS should be investigated for factures if medically indicated. While receiving calcium supplementation, patients should be monitored regularly for ectopic calcification.

Genetic counseling.

SRS is inherited in an X-linked manner. If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%: Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. No known carriers have had features of SRS. No affected male has reproduced. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are an option if the SMS pathogenic variant has been identified in an affected family member.

Diagnosis

Formal diagnostic criteria have not been established for Snyder-Robinson syndrome (SRS).

Snyder-Robinson syndrome is suspected in males with the following [Arena et al 1996, Cason et al 2003, de Alencastro et al 2008, Becerra-Solano et al 2009, Schwartz et al 2011, Zhang et al 2013]:

  • Intellectual disability (100% [20/20]); classified as moderate to severe generalized psychomotor delay that begins in infancy. IQ ranges from unmeasurable to 60.
  • Hypotonia (100% [20/20]); secondary to poor muscular development
  • Asthenic body build and diminished body bulk (95% [19/20]). Many individuals also have measurably long fingers and toes.
  • Bone abnormalities including osteoporosis (100% [14/14]), fractures and kyphoscoliosis (84%; 16/19), and joint contractures (15% [3/14])
  • Facial dysmorphism including asymmetric face (64% [13/20]) and prominent lower lip (79% [16/20])
  • Ambulation abnormalities (71% [14/19]) ranging from unsteady gait to inability to walk
  • Nasal dysarthric, coarse, or absent speech (100% [19/19])
  • High, narrow, or cleft palate (83% [15/17])
  • Mild short stature (73% [14/19]). Growth rates are normal but the length or height is at least 1 SD below the mean. Height in four of seven (on whom data are available) was less than 2 SD below the mean.
  • Seizures (67%). Usually present by early childhood. Severity and frequency vary.
  • Genital abnormalities (15% [3/20]) including low testicular volume, hypospadias, and undescended testes
  • Renal complications (15% [3/20]). Nephrocalcinosis (unrelated to calcium administration) and renal cysts have been reported in three individuals with SRS.

To confirm/establish the diagnosis of SRS in a proband requires [Schwartz et al 2011] EITHER of the following:

  • Decreased or absent spermine synthase (SMS) enzyme activity in fresh white cells or cultured lymphoblasts
    Note: Increased spermidine to spermine ratio in fresh white cells or cultured lymphoblasts is pathognomonic of SRS. (Absolute levels of spermidine or spermine do not differ significantly between affected individuals and controls.)
  • Identification of a hemizygous loss-of-function pathogenic variant in SMS (See Table 1.)
    • One strategy for molecular diagnosis of a proband suspected of having Snyder-Robinson syndrome is sequence analysis of SMS.
    • Another strategy for molecular diagnosis of a proband suspected of having Snyder-Robinson syndrome is use of a multi-gene panel for X-linked intellectual disability.
      For more information on multi-gene panels click here.

Table 1.

Summary of Molecular Genetic Testing Used in Snyder-Robinson Syndrome

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
Affected MalesHeterozygous Females
SMSSequence analysisSequence variants 4, 5, 620/20 5, 716/16 6, 7
Deletion/duplication analysis 8(Multi)exon and whole-gene deletion/duplication and genomic rearrangements 90/00/0
1.
2.

See Molecular Genetics for information on specific allelic variants.

3.

The ability of the test method used to detect a variant that is present in the indicated gene

4.

Examples of pathogenic variants detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Lack of amplification by PCR prior to sequence analysis can suggest a putative exon, multiexon, or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

6.

Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

7.

Schwartz et al, unpublished data

8.

Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9.

Among more than 11,300 individuals studied, 14 deletions and duplications have been reported to span SMS. Of the copy number variations (CNVs) spanning SMS, only one (which was detected in 2 women) caused clinical pathology: dysmorphic features, intellectual disability, and ocular abnormalities including oculomotor apraxia, heterochromia of the iris, and vision problems. Confounding attribution of these features to hemizygosity for SMS: the CNV deleting SMS also deleted 106 other genes including 35 associated with other disorders; moreover, these women had another deletion spanning SHOX, which is associated with Leri-Weill dyschondrostosis [Firth et al 2009]. Besides the CNV identified in the two women discussed above, two other variants of unknown significance are reported in the database of genomic variants: an intronic deletion observed in 36 unaffected male and female controls [Mills et al 2006], and an exon 7 deletion observed in an unaffected Korean male [Kim et al 2009].

Clinical Characteristics

Clinical Description

Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome with a specific clinical phenotype consisting of asthenic build, facial dysmorphism with a prominent lower lip, kyphoscoliosis, osteoporosis, and speech abnormalities.

Developmental delay and facial dysmorphism manifest within the first year of life. Developmental delay usually presents as failure to meet milestones and then evolves to moderate to profound global intellectual disability. The majority of males with SRS (11 published, 9 unpublished) do not appear to have progressive cognitive decline; rather, they remain cognitively stable throughout their lifetime. Those who develop speech (10/14) develop it late, some as late as age five years. Most individuals with SRS are able to follow simple commands. For two individuals who had no speech, it is unclear if a contributing factor was the absence of social contact [de Alencastro et al 2008]. Delay in motor development, observed in the majority of individuals with SRS, usually presents with delays in normal movements that occur in early childhood and do not resolve.

All reported males with SRS have maintained previously acquired skills; however, two recently identified unreported males have had progressive neurologic decline and loss of previously obtained skills. The measured IQ and cognitive functioning were highest in the original family, possibly due to the presence of residual SMS enzyme activity [Snyder & Robinson 1969, Cason et al 2003].

Asthenic habitus and low muscle mass usually develop during the first year. Although decreased strength is not described in males with SRS, most have progressive loss of muscle mass. Loss of muscle mass occurs even in males who are ambulatory, suggesting that the loss is probably the result of an underlying defect, not lack of use.

During the first decade of life, males with SRS develop osteoporosis. Most experience fractures in the absence of trauma within the first decade, at which point the osteoporosis is discovered; the long bones are most severely affected. Among males reported, the osteoporosis and fracture activity do not progressively worsen with age but remain at the severity found at the time of diagnosis. Bone density measurements were documented in two individuals [Albert, personal observation].

Skewed X-chromosome inactivation has been observed in heterozygous females in at least three families with SRS [Cason et al 2003; de Alencastro et al 2008; Author, personal communication]. It is unclear if skewed X-chromosome inactivation is a protective mechanism. In at least one of the families, presence of the SMS pathogenic variant in a heterozygous female is not associated with skewing of X-chromosome inactivation [Cason et al 2003].

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations have been established for Snyder-Robinson syndrome. Even within a family, the phenotype varies; for example, in one family IQ values ranged from 46 to 77.

Based on the limited data available, the c.166G>A (p.Gly56Ser) and c.443A>G (p.Gln148Arg) pathogenic variants have been associated with more severe manifestations.

Penetrance

All individuals with Snyder-Robinson syndrome have deficient spermine synthase enzyme activity. However, as its prevalence in the general population has not been determined, penetrance of deficient spermine synthase activity as Snyder-Robinson syndrome cannot be stated.

Sequence variants of SMS have been reported for one seemingly unaffected male [Kim et al 2009]. Spermine synthase activity was not measured, and thus the functional consequences of this variant are unclear.

Additionally, five other nonsynonymous SMS variants were identified in large sequencing cohorts; phenotype, sex, and enzyme function are unavailable for these individuals.

Nomenclature

When Snyder and Robinson first described this syndrome, they labeled it “recessive sex-linked mental retardation in the absence of other recognizable abnormalities” [Snyder & Robinson 1969]. It is now considered an X-linked intellectual disability syndrome with a specific clinical phenotype consisting of asthenic build, facial dysmorphism with a prominent lower lip, kyphoscoliosis, osteoporosis, and speech abnormalities.

Prevalence

The prevalence of SRS is unknown. Of the eleven individuals evaluated and reported in the current literature, all were identified in the Americas: Mexico, Brazil, and the United States. Two additional, as-yet unpublished families are from Belgium and Italy, indicating that the disorder is not unique to the Americas and probably exists in most populations.

Differential Diagnosis

The observation that 30% more males than females have intellectual disability (ID) suggests that pathogenic variants of genes on the X chromosome are among the most frequent causes of ID among males [Stevenson et al 2012]. X-linked intellectual disability (XLID) should be considered in males who are simplex cases (i.e., a single occurrence of ID in a family) as well as in males with a family history of intellectual disability consistent with X-linked inheritance. Consideration of XLID as a cause of ID in simplex cases is relevant since approximately 33% of pathogenic variants causing the more severe forms of XLID arise de novo.

Distinguishing between various forms of syndromic ID by clinical findings alone is often difficult because of overlapping clinical features, and diagnosis frequently requires identification of the molecular cause. Nonetheless, Snyder-Robinson syndrome (SRS) can be distinguished from many forms of syndromic XLID by the combination of hypotonia, facial dysmorphism, asthenic body build, and osteoporosis.

Because osteoporosis is rare in XLID, it can be utilized as a distinguishing feature. XLID syndromes with overlapping findings of SRS and osteoporosis include the following:

  • Duplication of monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and Norrie disease protein (NDP). Individuals with a duplication encompassing these three genes have seizures, moderate to severe intellectual disability, osteoporosis, scoliosis, and speech abnormalities. In contrast to individuals with SRS, they have an excessively friendly mood, normal stature, and normal facial features [Klitten et al 2011].
  • Glycerol kinase deficiency. Individuals with this disorder have developmental delay, osteoporosis, growth retardation, and muscle weakness. In contrast to SRS, this disorder also has adrenal insufficiency [Guggenheim et al 1980].
  • Urban syndrome. Individuals with this disorder have intellectual disability, short stature, and osteoporosis In contrast to SRS, they also have obesity and normal tone [Urban et al 1979].
  • Rett syndrome. Affected individuals frequently have associated seizures, gait abnormalities, osteoporosis, and scoliosis. Unlike persons with SRS, those with Rett syndrome have cardiac abnormalities and no facial dysmorphisms. Females, not males, are typically affected [Prater & Zylstra 2006].

Non-X-linked intellectual disability syndromes with osteoporosis to be considered in the differential diagnosis of SRS include the following:

  • Cerebral palsy (CP). CP is a heterogeneous group of disorders arising from multiple genetic and environmental etiologies. In some individuals the phenotype overlaps that of SRS. Shared features can include seizures, osteoporosis, scoliosis, and developmental delay.
  • Prader-Willi syndrome (PWS). Developmental delay, osteoporosis, and scoliosis are also features of PWS. Unlike individuals with SRS, those with PWS have metabolic syndrome, obesity, and severe behavior problems.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Snyder-Robinson syndrome (SRS), the following evaluations are recommended:

  • Intellectual disability (ID) assessment using standardized neuropsychological tests to determine overall level of cognitive function as well as relative levels of performance and verbal skills. These assessments help guide recommendations for educational resources and special therapies.
  • Neuropsychological assessment (visual, speech, or motor function)
  • Bone density assessment by dual-energy x-ray absorptiometry (DXA) scan to determine the degree of osteoporosis and the need for and response to calcium supplements
  • Assessment of seizures, including EEG if seizures are suspected. The type of seizures may determine the selection of anticonvulsant.
  • Clinical genetics consultation
  • MRI of the brain to assess abnormal calcification (which has been noted in a few individuals and occurs in the absence of calcium supplementation)

Treatment of Manifestations

Speech, physical, and/or occupational therapy may be helpful. Some individuals have performed appropriately in special education programs, learned to follow commands, and held simple jobs [Arena et al 1996]. In contrast, others showed no improvement of psychomotor skills with special education [Becerra-Solano et al 2009].

Calcium supplementation has slightly improved bone mineral density in a few patients [Becerra-Solano et al 2009]. The mechanism of decreased bone mineral density is not well understood. Calcium supplementation should be started once decreased bone mineral density is noted.

Seizures have shown varying responses to anti-seizure medications [Arena et al 1996, de Alencastro et al 2008]. Carbamazepine, phenobarbital, and clobazan have been used successfully to control seizures in some individuals.

Surveillance

Because of the osteoporosis, individuals with SRS are at increased risk for fractures and should be investigated for factures if medically indicated.

While receiving calcium supplementation, patients should be monitored regularly for ectopic calcification with endocrine tests (including calcium, phosphorus, vitamin D, and hormone levels) and radiographs.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Snyder-Robinson syndrome (SRS) is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

  • The father of an affected male will not have the disease nor will he be a carrier of the pathogenic variant.
  • In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism. There are no data regarding frequency or possibility of germline mosaicism in SRS.
  • If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a de novo pathogenic variant (in which case the mother is not a carrier). Of the eight known cases/families with SRS identified to date, one individual’s pathogenic variant is de novo.

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit it will be carriers. No carriers identified so far in these families have had features of SRS.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband. No affected male has reproduced.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, thus helping to determine genetic risk status of the extended family.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the pathogenic variant in the family.

Note: (1) Carriers are females who are heterozygotes for this X-linked disorder; hypothetically, they could develop clinical findings related to the disorder secondary to partial loss of SMS function or skewing of X-chromosome inactivation. To date, no identified heterozygotes have had signs or symptoms attributable to their SMS pathogenic variant. (2) Identification of female heterozygotes requires either (a) prior identification of the pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no pathogenic variant is identified, by deletion/duplication analysis.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SMS pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Medline Plus
  • EuroMRX Consortium Registry
    Radboud University Nijmegen Medical Centre, Department of Human Genetics
    PO Box 9101
    Nijmegen 6500 HB
    Netherlands
    Phone: +31 24 3614017
    Fax: +31 24 3668752
    Email: a.debrouwer@antrg.umcn.nl

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Snyder-Robinson Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
SMSXp22​.11Spermine synthaseSMS @ LOVDSMS

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Snyder-Robinson Syndrome (View All in OMIM)

300105SPERMINE SYNTHASE; SMS
309583MENTAL RETARDATION, X-LINKED, SYNDROMIC, SNYDER-ROBINSON TYPE; MRXSSR

Molecular Genetic Pathogenesis

Arena et al [1996] mapped the disease locus in 1996 and Cason et al 2003 identified a pathogenic variant in SMS in the family reported by Snyder and Robinson [1969].

Gene structure. SMS is 54 kilobase pairs long [Grieff et al 1997]. The gene is transcribed into two mRNA transcripts that encode two protein isoforms. The first (predominant and longest) transcript [NM_004595.4] has 11 exons and encodes a protein with 366 amino acids [Wu et al 2008]. The second, rarer transcript [NM_001258423.1] encodes a 313-amino acid protein, has nine exons, and arises by alternative splicing that removes the second and eleventh exons, which are included in variant 1. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Allelic heterogeneity is present – eight unique SMS pathogenic variants that give rise to SRS have been identified in eight different families.

Three SRS-causing SMS pathogenic variants have been published to date: c.329+5G>A, c.166G>A, and c.395T>G (Table 2). Mutation of the splice donor site of intron 4, c.329+5G>A, is predicted to produce a protein missing 22 amino acids from exon 4 and the addition of 22 novel amino acids prior to premature truncation [Cason et al 2003].

Another five SRS-causing SMS pathogenic variants have been identified but not yet published. The prevalence of the eight pathogenic variants in various ethnic groups has not been determined.

Table 2.

SMS Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein Change
(Alias 1)
Reference Sequences
c.329+5G>A 2(188fsTer111)NM_004595​.4
NP_004586​.2
c.395T>Gp.Val132Gly
c.166G>Ap.Gly56Ser
c.443A>Gp.Gln148Arg

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

Additional variants are listed in Table 3 (pdf).

Normal gene product. The predominant SMS transcript encodes an enzyme [NP_004586.2] that is an essential element in the polyamine biosynthesis pathway that mediates conversion of spermidine to spermine. Polyamines are small positively charged molecules that are essential for proper cell growth, DNA transcription, and ion channel function [Jänne et al 1975, Williams 1997].

The pathogenic missense variants in Table 2 alter highly conserved amino acids [de Alencastro et al 2008, Becerra-Solano et al 2009, Schwartz et al 2011].

The protein has three domains: N-terminal (amino acids 1-117), central (amino acids 138-172), and C-terminal (catalytic, amino acids 173-366).

Mutagenesis studies of SMS have identified several amino acids key for its function.

  • A pathogenic variant of residue Asp276 (which is needed for proper transfer of the aminopropyl group and activation of SMS) decreased the Kcat/Km more than 200,000 fold.
  • Pathogenic variants of residue Glu353 (which mediates binding of spermindine) and Asp 201(which interacts with the aminopropyl group) decreased the Kcat/Km more than 800 fold and more than 100,000 fold, respectively [Wu et al 2008].

Abnormal gene product. Loss of spermine synthase enzymatic activity causes SRS. Decreased SMS enzyme activity confirms the pathogenicity of an SMS sequence variant. Evidence supporting SMS pathogenic loss-of-function variants as the cause of SRS includes the following:

References

Literature Cited

  • Arena JF, Schwartz C, Ouzts L, Stevenson R, Miller M, Garza J, Nance M, Lubs H. X-linked mental retardation with thin habitus, osteoporosis, and kyphoscoliosis: linkage to Xp21.3-p22.12. Am J Med Genet. 1996;64:50–8. [PubMed: 8826448]
  • Becerra-Solano LE, Butler J, Castaneda-Cisneros G, McCloskey DE, Wang X, Pegg AE, Schwartz CE, Sánchez-Corona J, García-Ortiz JE. A missense mutation, p.V132G, in the X-linked spermine synthase gene (SMS) causes Snyder-Robinson syndrome. Am J Med Genet A. 2009;149A:328–35. [PMC free article: PMC2653108] [PubMed: 19206178]
  • Cason AL, Ikeguchi Y, Skinner C, Wood TC, Holden KR, Lubs HA, Martinez F, Simensen RJ, Stevenson RE, Pegg AE, Schwartz CE. X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome. Eur J Hum Genet. 2003;11:937–44. [PubMed: 14508504]
  • de Alencastro G, McCloskey DE, Kliemann SE, Maranduba CM, Pegg AE, Wang X, Bertola DR, Schwartz CE, Passos-Bueno MR, Sertié 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. J Med Genet. 2008;45:539–43. [PubMed: 18550699]
  • Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, Van Vooren S, Moreau Y, Pettett RM, Carter NP. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009;84:524–33. [PMC free article: PMC2667985] [PubMed: 19344873]
  • Grieff M, Whyte MP, Thakker RV, Mazzarella R. Sequence analysis of 139 kb in Xp22.1 containing spermine synthase and the 5' region of PEX. Genomics. 1997;44:227–31. [PubMed: 9299240]
  • Guggenheim MA, McCabe ER, Roig M, Goodman SI, Lum GM, Bullen WW, Ringel SP. Glycerol kinase deficiency with neuromuscular, skeletal, and adrenal abnormalities. Ann Neurol. 1980;7:441–9. [PubMed: 6249182]
  • Jänne O, Bardin CW, Jacob ST. DNA-dependent RNA polymerases I and II from kidney. Effect of polyamines on the in vitro transcription of DNA and chromatin. Biochemistry. 1975;14:3589–97. [PubMed: 1164498]
  • Kim JI, Ju YS, Park H, Kim S, Lee S, Yi JH, Mudge J, Miller NA, Hong D, Bell CJ, Kim HS, Chung IS, Lee WC, Lee JS, Seo SH, Yun JY, Woo HN, Lee H, Suh D, Lee S, Kim HJ, Yavartanoo M, Kwak M, Zheng Y, Lee MK, Park H, Kim JY, Gokcumen O, Mills RE, Zaranek AW, Thakuria J, Wu X, Kim RW, Huntley JJ, Luo S, Schroth GP, Wu TD, Kim H, Yang KS, Park WY, Kim H, Church GM, Lee C, Kingsmore SF, Seo JS. A highly annotated whole-genome sequence of a Korean individual. Nature. 2009;460:1011–5. [PMC free article: PMC2860965] [PubMed: 19587683]
  • Klitten LL, Moller RS, Ravn K, Hjalgrim H, Tommerup N. Duplication of MAOA, MAOB, and NDP in a patient with mental retardation and epilepsy. Eur J Hum Genet. 2011;19:1–2. [PMC free article: PMC3039513] [PubMed: 20808325]
  • Mills RE, Luttig CT, Larkins CE, Beauchamp A, Tsui C, Pittard WS, Devine SE. An initial map of insertion and deletion (INDEL) variation in the human genome. Genome Res. 2006;16:1182–90. [PMC free article: PMC1557762] [PubMed: 16902084]
  • Prater CD, Zylstra RG. Medical care of adults with mental retardation. Am Fam Physician. 2006;73:2175–83. [PubMed: 16836033]
  • Schwartz CE, Wang X, Stevenson RE, Pegg AE. Spermine synthase deficiency resulting in X-linked intellectual disability (Snyder–Robinson syndrome). In: Pegg AE, Casero RA Jr, eds. Polyamines: Methods and Protocols. Methods in Molecular Biology, Vol 720. New York, NY: Springer Science + Business Media; 2011:437-45. [PubMed: 21318891]
  • Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A. A conditional knockout resource for the genome-wide study of mouse gene function. Nature. 2011;474:337–42. [PMC free article: PMC3572410] [PubMed: 21677750]
  • Snyder RD, Robinson A. Recessive sex-linked mental retardation in the absence of other recognizable abnormalities. Report of a family. Clin Pediatr (Phila) 1969;8:669–74. [PubMed: 5823961]
  • Stevenson RE, Schwartz CE, Rogers RC. Atlas of X-Linked Intellectual Disability Syndromes. 2 ed. New York, NY: Oxford University Press; 2012.
  • Urban MD, Rogers JG, Meyer WJ 3rd. Familial syndrome of mental retardation, short stature, contractures of the hands, and genital anomalies. J Pediatr. 1979;94:52–5. [PubMed: 758422]
  • Williams K. Interactions of polyamines with ion channels. Biochem J. 1997;325:289–97. [PMC free article: PMC1218558] [PubMed: 9230104]
  • Wu H, Min J, Zeng H, McCloskey DE, Ikeguchi Y, Loppnau P, Michael AJ, Pegg AE, Plotnikov AN. Crystal structure of human spermine synthase: implications of substrate binding and catalytic mechanism. J Biol Chem. 2008;283:16135–46. [PMC free article: PMC3259631] [PubMed: 18367445]
  • Zhang Z, Norris J, Kalscheuer V, Wood T, Wang L, Schwartz C, Alexov E, Van Esch H. A Y328C missense mutation in spermine synthase causes a mild form of Snyder-Robinson syndrome. Hum Mol Genet. 2013;22:3789–97. [PMC free article: PMC3749864] [PubMed: 23696453]

Chapter Notes

Revision History

  • 27 June 2013 (me) Review posted live
  • 28 January 2013 (ja) Original submission
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