Abstract
Snyder–Robinson syndrome (SRS) is a form of X-linked mental retardation resulting from mutations in spermine synthase (SMS), which impact neurodevelopment and cognitive outcome. We obtained cerebral, cerebellum, hippocampus, and red nucleus volumes from two males with SRS and 24 age- and gender-matched typically developing controls using volumetric neuroimaging analyses. Total brain volume was enlarged in males with SRS while cerebellum, hippocampus, and red nucleus volumes tended to be reduced compared to controls. Mutations of the X chromosome may modulate the risk for mental retardation through altered early neurodevelopment, disruption in receptor function, and ongoing neural organization and plasticity. Disruption of SMS function may negatively affect regional brain volumes that subserve cognitive and motor abilities. This research provides valuable insight into the effects of polyamine function on brain development.
Keywords: SMS, Spermine synthase, Snyder–Robinson syndrome, MRI, Red nucleus, Cerebellum, Hippocampus, Cerebrum
Introduction
Snyder–Robinson syndrome (SRS) was initially reported as a nonsyndromic X-linked mental retardation (XLMR) condition present in a single family [1]. However, upon reevaluation, the affected males were found to have a thin habitus, kyphoscolioses, and long great toes. Distinctive facial features were observed: asymmetry, prominent lower lip, and a high or cleft palate [2]. Additional clinical features including unsteady gait, seizures, nonspecific movement disorder, and abnormal EEG were noted in a follow-up evaluation [3].
The syndrome was mapped to Xp21.2–p22.2 [2] and subsequent studies identified a splice mutation (c.329+5 G>A) in the spermine synthase (SMS) gene which caused low level of intracellular spermine in lymphocytes and fibroblasts and elevated spermidine/spermine ratios in these cells [3]. Recently, a second family with SRS and a novel mutation in SMS was identified [4]. This family presented with severe epilepsy and cognitive impairment.
SMS encodes an enzyme that is widely expressed in the brain and is responsible for the conversion of spermidine to spermine. Spermine, a polyamine, is known to be involved in cell growth and maintenance [3, 5]. Thus, it is likely that mutations in this gene may result in altered neurodevelopment. Based on this hypothesis, we examined brain morphology in SRS in an effort to provide further understanding of the relationship between SMS, brain development/function, and cognition. We obtained whole and regional brain volumes, including tissue-specific, gray and white matter measurements, from magnetic resonance brain images (MRI) acquired from two males with SRS. We then compared these volumes descriptively with those of age- and gender-matched typically developing controls. Regional volume measurements included cerebellum and red nucleus as abnormalities in these areas have been suggested based on the SRS phenotype [3] and hippocampus as this is a key region involved in the learning and memory functions that tend to be impaired in individuals with MR [6].
Materials and methods
Clinical reports
Patient V-2, [3] age 13.28 years, was born after a 32-week gestation and intrauterine growth retardation. He weighed 1,860 g and was delivered by cesarean section. Development was delayed with sitting at about 1 year, pulling up at 16 months, and walking at 2 years. He had myoclonic seizures from infancy until age 11 years. His forehead was prominent and the face tall and narrow with the left size larger than the right. There was general decrease in muscle mass; deep tendon reflexes were normal. IQ was 36. See Table 1 for further clinical findings.
Table 1.
Clinical findings in V-2 and IV-8 at two different ages
| Pedigree #, [2] | V-2 | IV-8 | ||
|---|---|---|---|---|
| Age (years) | 2 | 13 | 28 | 39 |
| Height, cm (centile) | 82 (5) | 149 (20) | 187 (95) | 188 (>97) |
| Weight, kg (centile) | 9.1 (<3) | 26 (<3) | 54 (<3) | 81.4 (50) |
| Head circumference, cm (centile) | 49 (40) | 53.6 (50) | 59 (90) | 59.5 (95) |
| Facial asymmetry | Mouth (when crying) | + | Orbital and mouth | Face |
| Thin habitus, with muscle hypoplasia | + | + | + | + |
| Kyphoscoliosis | - | - | + | + |
| Narrow chest | + | |||
| Long hands (centile) | − (20) | − (25) | + (>97) | + (85) |
| Hyperextensible fingers | + (mild) | + (mild) | ||
| Long great toes | Hammer toe | + | + | |
| IQ/development | Delayed development | 36 | 60 | 54 |
| Overall status | Preschool | Works as a janitor | Works in sheltered workshop | |
| Other | Testes not descended, myoclonic jerks | Myoclonic seizures | Thoracic vertebra fractures, colectomy for ulcerative colitis | |
| EMG/nerve conduction | Increased insertional activity, fibrillations, and occasional sharp wave in muscles of left foot | |||
| EEG | Abnormal | Normal | Normal | |
| AAS | Normal | Normal | ||
| Ophthalmologic | Myopia and astigmatism | Hyperopia and astigmatism | ||
| EKG | Normal | Normal | ||
| Serum cholesterol | Normal | Normal |
Patient IV-8, [3] age 39.88 years, was born after an uncomplicated pregnancy and delivery. His birth weight was 3,180 g. At 17 months, he was not walking or talking. He was in special education and received speech therapy. He has never had any seizures. At age 20 years, he was found to have osteoporosis. This was detected on X-ray examination following a sledding accident, which resulted in multiple thoracic vertebral compression fractures. He works in a sheltered workshop.
His face was somewhat coarse with a large mouth and full lower lips with facial asymmetry. Palate was normal but with a thick alveolar ridge. He was tall and thin with mildly diminished muscle bulk and kyphoscoliosis. His strength was normal. He had long hands and mildly hyperextensible fingers and long great toes. His speech was thick and slow. He could follow commands and repeat names but had poor performance on simple calculations. His neurologic examination was normal. IQ was 54. See Table 1 for further clinical findings.
MRI acquisition
All MRI scans used in this study were obtained with 1.5 T GE Signa scanners (GE medical systems, Milwaukee, WI) at Stanford and Greenwood. Coronal brain images were acquired with a 3D volumetric radio frequency spoiled gradient echo pulse sequence using the following scan parameters: TR=35 ms, TE=6 ms, flip angle=45°, NEX=1, matrix size=256×192, field of view=24 cm, slice thickness=1.5 mm, 124 contiguous slices.
MRI analysis
MRI scans were obtained from V-2 and IV-8 as well as from 24 age- and gender-matched typically developing controls from our structural neuroimaging database. Participants were excluded from MRI contraindications (e.g., orthodontia). Typically developing controls were excluded for any history of neurological, cognitive, or psychiatric disorders. Institutional Review Boards at both sites approved this study. MRI scans were imported into BrainImage (http://cibsr.stanford.edu/tools) for semiautomated whole brain segmentation and quantification [7, 8] (Supplementary Figure 1). The hippocampus [9] and red nucleus (Supplementary Figure 2) were manually delineated for each participant.
Corrected volumes were computed using the ratio of regional volumes to total brain volume in order to determine differences that were disproportionate to overall brain volume. Brain volume z scores were calculated for participants with SRS, with z±1.6 being considered “significant” [10]. Outlier status was determined using Tukey’s method boxplot [11] in SPSS 16.0 (http://www.spss.com).
Results
Total brain volumes of both patients were somewhat enlarged compared to controls (Fig. 1; Table 2). Total brain volume enlargement appeared to affect gray, white, and cerebral spinal fluid volumes equally (Table 3). Cerebellar volume appeared to be disproportionately as well as absolutely decreased in V-2 (Fig. 1; Table 3). Hippocampal volumes in both patients were disproportionately smaller compared to controls, particularly in IV-8, the adult patient (Fig. 1; Table 3). Absolute brainstem volumes were enlarged in both patients (Table 2) but only V-2’s volume was disproportionately enlarged (Fig. 1; Table 3). Red nucleus volumes in both patients were disproportionately reduced respective to both total brain and brainstem volumes (Fig. 1; Table 3). Tukey’s boxplots indicated that the proportional cerebellum volume and absolute and proportional brainstem volumes of V-2, and the proportional hippocampus and red nucleus volumes (to total brain volume) of IV-8 were outliers (Fig. 2).
Fig. 1.
Scatterplot results for MRI volumes. Compared to controls, total brain volume was enlarged while proportional hippocampus and red nucleus volumes are reduced in both individuals with SRS. Proportional cerebellar volume was reduced and proportional brainstem volume was enlarged in the child with SRS. (X axis=age in years, y axis=brain volume in cubic centimeters; TBV=total brain volume)
Table 2.
Brain volumes for V-2, IV-8, and controls (shown in cubic centimeters)
| Volume | V-2 volume (z score) | Child control mean (SD) | IV-8 volume (z score) | Adult control mean (SD) |
|---|---|---|---|---|
| Total brain | 1,670.30 (1.6)a | 1,506.17 (103) | 1,725.90 (1.8)a | 1,412.33 (175.66) |
| Cerebral gray | 804.80 (2.0)a | 697.83 (54.16) | 705.69 (1.1) | 589.24 (105.07) |
| Cerebral white | 545.00 (1.5) | 473.38 (48.22) | 651.85 (1.3) | 478.80 (132.68) |
| Cerebral CSF | 119.60 (−.20) | 123.91 (21.50) | 142.58 (−.32) | 160.83 (57.61) |
| Subcortical gray | 50.60 (1.6)a | 45.04 (3.43) | 50.22 (2.0)a | 39.80 (5.19) |
| Subcortical white | 56.00 (1.9)a | 48.05 (4.25) | 67.90 (2.5)a | 49.50 (7.31) |
| Cerebellum | 124.20 (−1.6)a | 143.43 (12.39) | 150.02 (1.3) | 127.94 (16.83) |
| Hippocampus | 6.42 (−.65) | 7.06 (.98) | 6.81 (−.63) | 7.26 (.72) |
| Brainstem | 51.50 (3.63)a.b | 35.73 (4.3) | 48.90 (2.07)a | 35.57 (6.43) |
| Red nucleus | .32 (−1.3) | .36 (.03) | .25 (−3.0)a | .34 (.03) |
SD standard deviation, CSF cerebral spinal fluid
Z score≥1.6
Tukey’s method outlier
Table 3.
Proportional brain volumes (cubic centimeters)
| Volume | V-2 volume (z score) | Child control mean (SD) | IV-8 volume (z score) | Adult control mean (SD) |
|---|---|---|---|---|
| Cerebral gray/TBV | .48 (.50) | .47 (.02) | .41 (.13) | .40 (.08) |
| Cerebral white/TBV | .33 (.50) | .32 (.02) | .37 (.14) | .36 (.07) |
| Cerebral CSF/TBV | .07 (−1.0) | .08 (.01) | .08 (−1.0) | .10 (.02) |
| Subcortical gray/TBV | .03 (0.0) | .03 (.001) | .029 (.50) | .026 (.006) |
| Subcortical white/TBV | .034 (1.0) | .032 (.002) | .039 (.75) | .036 (.004) |
| Cerebellum/TBV | .074 (−2.3)a,b | .097 (.01) | .09 (0.0) | .09 (.008) |
| Hippocampus/TBV | .003 (−2.5)a | .005 (.0008) | .003 (−5.0)a,b | .005 (.0004) |
| Brainstem/TBV | .031 (2.82)a,b | .024 (.002) | .028 (.69) | .025 (.004) |
| Red nucleus/TBV | .00019 (−1.7)a | .00024 (.00003) | .0001 (−3.5)a,b | .00024 (.00004) |
| Red nucleus/brainstem | .019 (−2.54)a | .028 (.003) | .02 (−1.80)a | .029 (.005) |
SD standard deviation, TBV total brain volume, CSF cerebral spinal fluid
Z score≥1.6
Tukey’s method outlier
Fig. 2.
Tukey boxplot results for regional volumes corrected for total brain volume. Proportional cerebellar and brainstem volumes were significant outliers (circle) in the child with SRS, being reduced and enlarged, respectively, compared to controls. Proportional hippocampal and red nucleus volumes were significant outliers in the adult with SRS, being reduced compared to controls
Discussion
This report is the first morphometric imaging study of neurodevelopment associated with SRS. Though the imaging results should be considered preliminary, these case studies offer a novel opportunity to explore the potential impact of particular X-linked genes on neurodevelopment. Although our sample of controls was relatively small, our volume findings are highly similar to those of other much larger studies of normative brain development [12].
Spermine and other polyamines are vital for cell proliferation and differentiation [13]. Spermine has neuroprotective effects following brain damage, particularly in the hippocampus and cortex [14, 15]. However, over-accumulation of spermine can induce cell death [16] suggesting a dual role for spermine in cell function and maintenance [5]. Thus, spermine deficiency may result in an imbalance between cell growth and pruning mechanisms, potentially resulting in aberrant neurodevelopment.
The finding of disproportionately reduced cerebellar (corrected for total brain volume) and red nucleus volumes (corrected for both total brain and brainstem volumes) in V-2, the younger patient, suggests that SMS expression has differential effects on the forebrain and hindbrain during early neurodevelopment. The cerebellum and red nucleus are involved in the circuitry subserving motor, speech, and cognitive functions—abilities that tend to be negatively affected by SRS [3]. Both V-2 and IV-8 were noted to have significant developmental motor delays and cognitive deficits (Table 1). Cognitive impairments, including intellectual and executive function, are related to cerebellar abnormalities in fragile X syndrome, a more common form of XLMR [17] as well as a large number of other conditions [18]. Accordingly, the cerebellar and red nucleus abnormalities observed in V-2 may be associated with his cognitive and motor deficits. In the clinical realm, neuroimaging findings suggesting relatively small cerebellar and/or red nucleus volumes in the context of a large cerebrum might also signal the possible diagnosis of SRS in males with cognitive and motor dysfunction and a family history of XLMR.
Cerebellar volume in IV-8 was similar to that of controls potentially suggesting that aberrant cerebellar development is attenuated with age and/or is associated with individual cognitive outcome. Specifically, while both individuals with SRS demonstrated IQ scores in the significantly impaired range, V-2, who demonstrated significantly reduced cerebellar volume, received an IQ score that was over a standard deviation lower than IV-4. However, red nucleus volume was reduced in both patients and, thus, continued cognitive-behavioral disabilities in adults with SRS may be related more to red nucleus morphology. Red nucleus volumes corrected for brainstem volume were reduced more than 1.6 standard deviations in both patients but were not significant Tukey outliers. However, total brainstem was relatively enlarged in both subjects with SRS (a Tukey outlier in IV-4) suggesting that red nucleus is likely reduced irrespective of other brainstem volumes. These hypotheses will require further study, ideally involving longitudinal assessments of individuals with SRS.
Spermine deficiency may be associated with cognitive dysfunction resulting from disrupted receptor processes. Spermine has been shown to block or inhibit inward rectifying potassium (IRK) channels [19], which modulate neuronal activity [20]. Overexpression of certain IRKs may disrupt gamma-amniobutyric acid (GABA) function, affecting the balance between inhibitory and excitatory processes in the hippocampus [21]. Spermine also inhibits N-methyl-d-aspartate and AMPA/Kainate receptors, which mediate the excitatory effect of glutamate [22]. Glutamate and GABA are essential for long-term depression and potentiation-synaptic plasticity mechanisms involved in learning and memory [23].
The gene product implicated in SRS may be directly or indirectly involved in synaptic plasticity-based learning mechanisms [24, 25]. Thus, alteration of signaling pathway function as a result of genetic mutations in the SMS gene may disrupt the mechanisms necessary for the development and maintenance of new synapses. As such, the finding of disproportionately decreased hippocampal volume in the context of overall increased cerebral volume could be related to disrupted synaptic plasticity in SRS. As well, this finding could be related to long-term deficits in hippocampus neuronal excitability resulting from spermine deficiency [26] similar to that seen in individuals with Alzheimer’s disease who interestingly show decreased spermine in certain brain regions [27].
Mutations of the X chromosome may modulate the risk for MR through altered early neurodevelopment in combination with disruption in receptor function and ongoing neural organization and plasticity. Future studies focusing on associations among genetic factors, basic neurobiology, neuroanatomy and cognitive-behavioral outcome in larger numbers of individuals with SRS are required to more fully elucidate potential relationships between structure and function.
Supplementary Material
Acknowledgments
This research was supported by NIH grant HD 26202. The authors would like to acknowledge Dr. Booil Jo for her assistance with statistical methods.
Footnotes
Electronic supplementary material The online version of this article (doi:10.1007/s10048-009-0184-2) contains supplementary material, which is available to authorized users.
Contributor Information
Shelli R. Kesler, Center for Interdisciplinary Brain Sciences Research, Stanford University School of Medicine, 401 Quarry Road, MC5795, Stanford, CA 94305-5795, USA, skesler@stanford.edu
Charles Schwartz, Greenwood Genetic Center, Greenwood, SC, USA.
Roger E. Stevenson, Greenwood Genetic Center, Greenwood, SC, USA
Allan L. Reiss, Center for Interdisciplinary Brain Sciences Research, Stanford University School of Medicine, 401 Quarry Road, MC5795, Stanford, CA 94305-5795, USA
References
- 1.Snyder RD, Robinson A. Recessive sex-linked mental retardation in the absence of other recognizable abnormalities. Report of a family Clin Pediatr. 1969;8(11):669–674. doi: 10.1177/000992286900801114. [DOI] [PubMed] [Google Scholar]
- 2.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(1):50–58. doi: 10.1002/(SICI)1096-8628(19960712)64:1<50∷AID-AJMG7>3.0.CO;2-V. [DOI] [PubMed] [Google Scholar]
- 3.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(12):937–944. doi: 10.1038/sj.ejhg.5201072. [DOI] [PubMed] [Google Scholar]
- 4.de Alencastro G, McCloskey DE, Kliemann SE, Maranduba CM, Pegg AE, Wang X, Bertola DR, Schwartz CE, Passos-Bueno MR, Sertie 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(8):539–543. doi: 10.1136/jmg.2007.056713. [DOI] [PubMed] [Google Scholar]
- 5.Janne J, Alhonen L, Pietila M, Keinanen TA. Genetic approaches to the cellular functions of polyamines in mammals. Eur J Biochem. 2004;271(5):877–894. doi: 10.1111/j.1432-1033.2004.04009.x. [DOI] [PubMed] [Google Scholar]
- 6.Shalin SC, Egli R, Birnbaum SG, Roth TL, Levenson JM, Sweatt JD. Signal transduction mechanisms in memory disorders. Prog Brain Res. 2006;157:25–41. doi: 10.1016/S0079-6123(06) 57003-7. [DOI] [PubMed] [Google Scholar]
- 7.Kates WR, Warsofsky IS, Patwardhan A, Abrams MT, Liu AM, Naidu S, Kaufmann WE, Reiss AL. Automated Talairach atlas-based parcellation and measurement of cerebral lobes in children. Psychiatry Res. 1999;91(1):11–30. doi: 10.1016/S0925-4927(99) 00011-6. [DOI] [PubMed] [Google Scholar]
- 8.Reiss AL, Hennessey JG, Rubin M, Beach L, Abrams MT, Warsofsky IS, Liu AM, Links JM. Reliability and validity of an algorithm for fuzzy tissue segmentation of MRI. J Comput Assist Tomogr. 1998;22(3):471–479. doi: 10.1097/00004728-199805000-00021. [DOI] [PubMed] [Google Scholar]
- 9.Kates WR, Abrams MT, Kaufmann WE, Breiter SN, Reiss AL. Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile X syndrome. Psychiatry Res. 1997;75(1):31–48. doi: 10.1016/S0925-4927(97) 00019-X. [DOI] [PubMed] [Google Scholar]
- 10.Spiegel M, Schiller J, Srinivasan R. Schaum’s Outline of Probability and Statistics. McGraw-Hill; New York: 2000. [Google Scholar]
- 11.Tukey J. Exploratory data analysis. Addison-Wesley, Reading; 1977. [Google Scholar]
- 12.Ge Y, Grossman RI, Babb JS, Rabin ML, Mannon LJ, Kolson DL. Age-related total gray matter and white matter changes in normal adult brain Part I: volumetric MR imaging analysis. AJNR Am J Neuroradio. 2002;23(8):1327–1333. [PMC free article] [PubMed] [Google Scholar]
- 13.Marton LJ, Pegg AE. Polyamines as targets for therapeutic intervention. Annu Rev Pharmacol Toxicol. 1995;35:55–91. doi: 10.1146/annurev.pa.35.040195.000415. [DOI] [PubMed] [Google Scholar]
- 14.Clarkson AN, Liu H, Pearson L, Kapoor M, Harrison JC, Sammut IA, Jackson DM, Appleton I. Neuroprotective effects of spermine following hypoxic-ischemic-induced brain damage: a mechanistic study. FASEB J. 2004;18(10):1114–1116. doi: 10.1096/fj.03-1203fje. [DOI] [PubMed] [Google Scholar]
- 15.Gilad GM, Gilad VH. Novel polyamine derivatives as neuroprotective agents. J Pharmacol Exp Ther. 1999;291(1):39–43. [PubMed] [Google Scholar]
- 16.Yatin SM, Yatin M, Varadarajan S, Ain KB, Butterfield DA. Role of spermine in amyloid beta-peptide-associated free radical-induced neurotoxicity. J Neurosci Res. 2001;63(5):395–401. doi: 10.1002/1097-4547(20010301) 63:5<395∷AID-JNR1034>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
- 17.Mostofsky SH, Mazzocco MM, Aakalu G, Warsofsky IS, Denckla MB, Reiss AL. Decreased cerebellar posterior vermis size in fragile X syndrome: correlation with neurocognitive performance. Neurology. 1998;50(1):121–130. doi: 10.1212/wnl.50.1.121. [DOI] [PubMed] [Google Scholar]
- 18.Schmahmann JD. Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci. 2004;16(3):367–378. doi: 10.1176/appi.neuropsych.16.3.367. [DOI] [PubMed] [Google Scholar]
- 19.Kurata HT, Marton LJ, Nichols CG. The polyamine binding site in inward rectifier K+channels. J Gen Physiol. 2006;127(5):467–480. doi: 10.1085/jgp. 200509467. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Reimann F, Ashcroft FM. Inwardly rectifying potassium channels. Curr Opin Cell Biol. 1999;11(4):503–508. doi: 10.1016/S0955-0674(99) 80073-8. [DOI] [PubMed] [Google Scholar]
- 21.Best TK, Siarey RJ, Galdzicki Z. Ts65Dn, a mouse model of Down syndrome, exhibits increased GABAB-induced potassium current. J Neurophysiol. 2007;97(1):892–900. doi: 10.1152/jn.00626.2006. [DOI] [PubMed] [Google Scholar]
- 22.Turecek R, Vlcek K, Petrovic M, Horak M, Vlachova V, Vyklicky L. Intracellular spermine decreases open probability of N-methyl-D-aspartate receptor channels. Neuroscience. 2004;125(4):879–887. doi: 10.1016/j.neuroscience.2004.03.003. [DOI] [PubMed] [Google Scholar]
- 23.Harney SC, Rowan M, Anwyl R. Long-term depression of NMDA receptor-mediated synaptic transmission is dependent on activation of metabotropic glutamate receptors and is altered to long-term potentiation by low intracellular calcium buffering. J Neurosci. 2006;26(4):1128–1132. doi: 10.1523/JNEUROSCI.2753-05.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Ingi T, Worley PF, Lanahan AA. Regulation of SSAT expression by synaptic activity. Eur J Neurosci. 2001;13(7):1459–1463. doi: 10.1046/j.0953-816x.2001.01529.x. [DOI] [PubMed] [Google Scholar]
- 25.Shin J, Shen F, Huguenard JR. Polyamines modulate AMPA receptor-dependent synaptic responses in immature layer v pyramidal neurons. J Neurophysiol. 2005;93(5):2634–2643. doi: 10.1152/jn.01054.2004. [DOI] [PubMed] [Google Scholar]
- 26.Williams K. Interactions of polyamines with ion channels. Biochem J. 1997;325(Pt 2):289–297. doi: 10.1042/bj3250289. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Morrison LD, Kish SJ. Brain polyamine levels are altered in Alzheimer’s disease. Neurosci Lett. 1995;197(1):5–8. doi: 10.1016/0304-3940(95) 11881-V. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.