- Email: [email protected]
Plausible etiology of brain dysconnectivity in autism – Review and prospectus
Medical Hypotheses xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Plausible etiology of brain dysconnectivity in autism – Review and prospectus Gary Steinman Clinical Adjunct Professor of Biochemistry and Obstetrics/Gynecology, Touro College of Osteopathic Medicine, 230 West 125th St., New York, NY 10017, USA
a r t i c l e
i n f o
Article history: Received 8 April 2015 Accepted 18 June 2015 Available online xxxx
a b s t r a c t This report summarizes recent findings related to the neuropathology of autism. Combining the relevant observations assessed here, a comprehensive, coherent hypothesis explaining the etiology of juvenile autism may be deduced. This proposed mechanism describes a process initiated by insulin-like growth factor deficiency, resulting in brain dysconnectivity as central to the behavioral manifestations of this disease. Ó 2015 Published by Elsevier Ltd.
Introduction In part because autism is found in both members of some monozygotic twin sets, it has been the conventional view that the etiology of this neuropathy stems from an interaction of genetic and environmental factors [1]. In a small minority of cases, there is a coexistence of autism with rare mutations. Recent studies have challenged the view that atypical genetic alterations alone have major relevance to the etiology of the disease [2]. Prior reports described the putative role of insulin-like growth factor (IGF) deficiency in the genesis of juvenile autism [1,3,4]. Among many functions, this factor stimulates oligodendrocytes to produce myelin insulation of neuronal axons in neonates [5,6]. The present study examines the proposed pathway for connectivity defects to arise in the central nervous system (CNS) as a consequence of dysmyelination. Such a glitch might induce flaws in the completion of the synaptic union of axons and dendrites, or axons and target tissues. In addition, the proposal that dysmyelination in CNS neurogenesis in young children [7,8] is central to the creation of abnormal neurologic function such as in autism is further explored here. Three fundamental IGF-associated phenomena that might account for the origin of neural dysfunction in autism are: (1) disorders of synaptic development and function, (2) disorders of nerve impulse transmission related to disrupted axonal myelination, and/or (3) disorders of cell signaling pathways.
E-mail address: [email protected]
Defective connectivity in the autistic brain would appear to be due to one or more consequences of IGF-1 deficiency.
Background The placental biosynthesis of IGF is controlled by growth hormone in the latter developmental stages before birth. Certain antepartum inflammatory processes occurring in the gravida, known to correlate with the subsequent development of autism in the newborn, can act to decrease placental IGF production [9]. In general, IGF promotes protective surveillance of brain cells to prevent neuronal derangement [10]. Gene polymorphisms can down-regulate the production of IGF [11]. Transgenic mice which lack the ability to synthesize IGF have reduced axonal diameters and decreased nerve conduction velocities [12]. A boy with homozygous partial deletion of the IGF-1 gene displayed sensorineural deafness and mental retardation [13]. Autistic children between birth and 4 years of age have lower levels of IGF in their cerebrospinal fluid than unaffected youngsters [14]. These findings in affected persons are consistent with diminished myelination in early neurogenesis. The neuronal growth cone (axon precursor) is guided to sites of need (e.g., muscles) by non-diffusible biochemical factors in the vicinity of the target tissues [15]. To refine the path, both chemoattractive (such as netrins) and chemorepulsive (such as semaphorins) agents are appropriately placed within the receiving tissues [16]. Once the axon reaches a suitable dendritic or organ target, synapse formation ensues [17]. Such trophic interactions begin before birth and continue postnatally.
http://dx.doi.org/10.1016/j.mehy.2015.06.018 0306-9877/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Steinman G. Plausible etiology of brain dysconnectivity in autism – Review and prospectus. Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.06.018
2
G. Steinman / Medical Hypotheses xxx (2015) xxx–xxx
With time, neurons in the neonate display increasing numbers of synapses [18]. The fittest of them survive and the less functional in the remainder are eliminated by apoptosis. The most effective connections are retained peripherally and in the brain. This is promoted by agents such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). According to the Hebb’s postulate, active, functional interplay between a presynaptic axon and a postsynaptic target fortifies the synaptic link [16]. Such strengthening promotes persistence of the joining of neurons with terminal tissues. Conversely, weakly associated unions eventually resolve and disappear (see Fig. 24.1 in Ref. [16]). Postnatal brain development is dependent on enhancement of functional synapse formation. This is promoted by strong, timely impulses sent to the target via the presynaptic axon [16]. Myelinated axons exhibit nerve impulses that are as much as 100 times faster than non-myelinated ones [19]. For proper, efficient, and rapid connectivity to develop between regions of the neonatal brain, early, comprehensive myelination of the participating axons is essential. In contradistinction, autistic brains have been observed to display heterogeneity, with areas of increased or decreased connectivity [20]. This is especially evident in imaging studies of the corpus callosum, where autistic individuals exhibit changes in white matter myelination related to decreased interhemispheric connectivity [21]. Myelination begins around 24–25 weeks post-conception and reaches its peak growth rate by 1 year of age [16]. Symptoms of autism typically appear between 1 and 3 years after birth. In the brains of autistic children, myelination has been shown by imaging and biopsy to be deficient compared to unaffected children [22,23]. Such a diminution would weaken the operation of the axon-target synapse, thereby accounting for the malfunction of areas of the brain involved in behavior. This would include the brain’s prefrontal and temporal areas. ‘‘Pruning’’ of excessive neural synapses by microglia to enhance the functionality of the retained connections has been found to be defective in the CNS of autistic children [18,24]. In unaffected individuals, this normally occurs as a task of high velocity impulse delivery by myelinated presynaptic axons. Such faulty processing may well be the consequence of hypomyelination. Compounding this could be neuronal cell signaling impediments in the IGF-I/P13K/AKT/mTOR pathway [25].
Conclusions Combining the relevant observations reviewed here, a comprehensive, plausible delineation of the fundamental neurogenerative defect underlying the etiology of juvenile autism may be deduced. The pertinent findings include: (1) deficient supply of IGF, causing axonal hypomyelination; (2) weakened axon/dendrite or axon/target synaptogenesis due to diminished impulse velocity or strength when insufficient presynaptic axonal myelination is present; (3) faulty connectivity between regions of an autistic brain; and, (4) attenuated neuronal cell signaling. Hence, the merging of axonal dysmyelination and the resultant synaptic dysfunction could account for defective CNS ‘‘wiring’’ in autism. Connectivity problems in the newborn may also result from cell signaling defects. However, distinguishing the individual roles of substandard myelination, synaptic function, and cell signaling in central dysconnectivity may prove difficult.
; IGF ; ; oligodendrocyte activity ; ; axonal myelination ; ; presynapse nerve impulse velocity ; ; synapse stability ; ; orderly brain connectivity
There is currently no applicable means for repairing already defective myelin insulation in vivo; IGF therapy has been tried to treat adult multiple sclerosis without much success [26]. IGF supplementation might be given to neonates found to be deficient in this growth factor starting at birth, when neurogenesis is very active [27,28]. Breast milk, a natural source of IGF, is one way of doing this [29]; another is subcutaneous injection of IGF-1-containing microspheres [30]. The mechanism reviewed here may be central to the reported success of IGF treatment of autism-like syndromes such as Rett [31,32] and Phelan-McDermid [33]. Overall, autism is characterized by withdrawal from social interactions and delayed speech development as a failure to form interpersonal relationships [34]. As proposed in this report, neonatal IGF deficiency can result in imperfect myelination as detected subjectively by restrained social development and objectively by MRI imaging. On the other hand, some affected children do not display detectable developmental changes until later in their young lives. This suggests that there are two divisions of autistic children, those diagnosed early and others identified later. The difference may be due in part to the effects of IGF deficiency on neurogenesis and nerve function in the newborn. This could be the result of genetic polymorphisms or of insufficient dietary components needed to supply or synthesize IGF. Nutritional deprivation reduces IGF-1 gene expression [35]. Alternatively, diagnosis of ‘‘late onset’’ autism may be related to delayed recognition of behavioral differences by parents [1]. Additional small subsets may occur with coexistent uncommon genetic mutations. The distribution of cases with this disorder is referred to as the autism spectrum [1]. These may actually represent the same disease, differing in degree of neonatal IGF deficiency, and, hence, the extent of neurologic dysfunction. It remains to be determined if the effects on dysconnectivity and dysfunction reviewed here are limited to the central nervous system, especially the behavioral centers of the brain, or include peripheral nerve tracks as well. Autistic children until the age of 4 years display reduced levels of cerebrospinal fluid IGF, which subsequently rises to normal and above-normal levels [14]. This may explain why some affected youngsters have enlarged heads [36]. IGF promotes overall growth in children; those affected with autism are typically not shorter than average following the pubertal growth spurt. The effects of IGF deficiency on neurogenesis may be limited to youngsters in the months or early years immediately following birth. A much needed parameter in the diagnosis of autism is a testable biomarker. If the hypothesis proposed here is supported by further experimental evidence, IGF deficiency could serve that function [37]. Conflict of interest The author of this paper has no conflict of interest in its publication.
Please cite this article in press as: Steinman G. Plausible etiology of brain dysconnectivity in autism – Review and prospectus. Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.06.018
G. Steinman / Medical Hypotheses xxx (2015) xxx–xxx
Acknowledgement The author wishes to thank Roberta Zuckerman for her thoughtful critique of the manuscript.
References [1] Steinman G, Mankuta D, Zuckerman R, Gray F, editors. The cause of autism – concepts and misconceptions. New York: Baffin Books Publishing; 2014. pp. 25–30, 119–27, 210–14, 243–50, 273–85. [2] Murdoch JD, Gupta AR, Sanders SJ, et al. No evidence for association of autism with rare heterozygous point mutations in contactin-associate protein-like 1 (CNTNAP2), or in other contactin-associated proteins or contactins. PLoS Genet 2015;11(1):e1004852. http://dx.doi.org/10.1371/journal. pgen.1004852. [3] Steinman G. Predicting autism at birth. Med Hypotheses 2013;81:21–5. [4] Steinman G, Mankuta D. Insulin-like growth factor and the etiology of autism. Med Hypotheses 2013;80:475–80. [5] Ye P, Li L, Richards RG, et al. Myelination is altered in insulin-like growth factor-1 null mutant mice. J Neurosci 2002;22(14):6041–51. [6] Miron VE, Kuhlmann T, Antel JP. Cells of the oligodendroglial lineage, myelination, and remyelination. Biochim Biophys Acta 2011;1812:184–93. [7] O’Kusky JR, Ye P, D’Ercose AJ. Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. J Neurosci 2000;20:8435–42. [8] Morrow E, Walsh C, Rubenstein J. Autism and brain development. Cell 2008;135(3):396–400. [9] Patterson PH. Maternal infection and immune involvement in autism. Trends Mol Med 2001;17(7):389–94. [10] Torres-Aleman I. Serum growth factors and neuroprotective surveillance: focus on IGF-1. Mol Neurobiol 2000;21(3):153–60. [11] Arends N. Polymorphism in the IGF-1 gene: clinical relevance for short children born small for gestational age (SGA). J Clin Endocrinol Metab 2002;87(6):2720. [12] Beck KD, Powell-Braxton L, Widmer HR, et al. IGF-1 gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons. Neuron 1995;14:717–30. [13] Woods KA, Camacho-Hubner C, Savage MO, Clark AJ. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor-I gene. NEJM 1996;335:1363–7. [14] Riikonen R, Makkonen I, Turpeinen U, et al. Cerebrospinal fluid insulin-like growth factors IGF-1 and IGF-2 in infantile autism. Dev Med Child Neurol 2006;48:751–5. [15] Engle EC. Human genetic disorders of axon guidance. Cold Spring Harbor Perspect Biol 2010;2010(2):a001784. [16] Purves D, Augustine GS, Fitzpatrick D, et al., editors. Neuroscience. Sunderland, MA: Sinauer; 2012. pp. 77–106, 517–19, 529–38. [17] Purves D. Body and brain: a trophic theory of neural connections. Cambridge, MA: Harvard Univ. Press; 1988. [18] Tang G, Gudsnuk K, Kuo S-H, et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 2014;83(5):1131–43.
3
[19] Roberts TPL, Khan AY, Rey M, et al. MEG detection of delayed auditory evoked responses in autism spectrum disorders: towards an imaging biomarker for autism. Autism Res 2010;3(1):8–18. [20] Hahamy A, Behrmann M, Mlach R. The idiosyncratic brain: distortion of spontaneous connectivity patterns in autism spectrum disorder. Nat Neurosci 2015;18:302–9. [21] Travers BG, Tromp DPM, Adluru A, et al. Atypical development of white matter microstructure of the corpus callosum in males with autism. Mol Autism 2015;6:15. http://dx.doi.org/10.1186/S13229-015-0001-8. [22] Aoki Y, Abe O, Nippashi Y, et al. Comparison of white matter integrity between autism spectrum disorder subjects and typically developing individuals: a meta-analysis of diffusion tensor imaging tractography studies. Mol Autism 2013;4:25. [23] Zikopoulos B, Barbas H. Changes in prefrontal axons may disrupt the network in autism. J Neurosci 2010;30(44):14595–608. [24] Zhan Y, Paolicelli RC, Sforazzini, et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci 2014;17(3):400–6. [25] Chen J, Alberts I, Li X. Dysregulation of the IGF-I/P13K/AKT/mTOR signaling pathway in autism spectrum disorders. Inter J Dev Neurosci 2014;35:35–41. [26] Wilczak N, DeKeyser J, Chesik D. Targeting insulin-like growth factor-1 signaling into the central nervous system for promoting myelin repair. Drug Target Highlight 2008;3:37–44. [27] Riikonen R. Insulin-like growth factor delivery across the blood-brain barrier. Potential use of IGF-1 as a drug in child neurology. Chemotherapy 2006;52(6):279–81. [28] Riikonen R. Insulin-like growth factors: neurobiological regulators in brain growth in autism. In: Zimmerman AW, editor. Autism – current theories and evidence. Totowa, NJ: Humana Press; 2010. p. 233–44. [29] Steinman G, Mankuta D. Breastfeeding as a possible deterrent to autism – a clinical perspective. Med Hypotheses 2013;81:999–1001. [30] Carrascoa C, Torres-Aleman I, Lopez-Lopez C, et al. Microspheres containing insulin-like growth factor I for treatment of chronic neurodegeneration. Biomaterials 2004;25:7007–14. [31] Jou RJ, Mateljevic N, Kaiser MD, et al. Structural neural phenotype of autism: preliminary evidence from a diffusion tensor imaging study using tract-based spatial statistics. AJNR Am J Neuroradiol 2011;32(9):1607–13. [32] Bozdago P, Tavassoli T, Buxbaum JD. Insulin-like growth factor-I rescues synaptic and motor deficits in a mouse model of autism and developmental delay. Mol Autism 2013;4(1):9. http://dx.doi.org/10.1186/2040-2392-4-9. [33] Kolveson A, Bush L, Wang AT, et al. A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome. Mol Autism 2014;5(54):1–9. [34] Rutter M, Schopler E. Autism a reappraisal of concepts and treatment. New York: Plenum Press; 1978. pp. 1–25. [35] Thissen J-P, Beauloye V, Ketelslegers J-M, et al. Regulation of insulin-like growth factor-I by nutrition. In: Houston MS, Holly JMP, Feldman EL, editors. IGF and nutrition in health and disease. Humana Press; 2005. p. 25–52. [36] Zwaigenbaum L, Young GS, Stone WL, et al. Early head growth in infants at risk of autism: a baby siblings research consortium study. J Am Acad Child Adolesc Psychiatry 2014;53(10):1053–62. [37] Steinman G, Mankuta D. Umbilical cord biomarkers in autism determination. Biomarkers Med 2014;8(3):317–9. x.
Please cite this article in press as: Steinman G. Plausible etiology of brain dysconnectivity in autism – Review and prospectus. Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.06.018
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Plausible etiology of brain dysconnectivity in autism – Review and prospectus Gary Steinman Clinical Adjunct Professor of Biochemistry and Obstetrics/Gynecology, Touro College of Osteopathic Medicine, 230 West 125th St., New York, NY 10017, USA
a r t i c l e
i n f o
Article history: Received 8 April 2015 Accepted 18 June 2015 Available online xxxx
a b s t r a c t This report summarizes recent findings related to the neuropathology of autism. Combining the relevant observations assessed here, a comprehensive, coherent hypothesis explaining the etiology of juvenile autism may be deduced. This proposed mechanism describes a process initiated by insulin-like growth factor deficiency, resulting in brain dysconnectivity as central to the behavioral manifestations of this disease. Ó 2015 Published by Elsevier Ltd.
Introduction In part because autism is found in both members of some monozygotic twin sets, it has been the conventional view that the etiology of this neuropathy stems from an interaction of genetic and environmental factors [1]. In a small minority of cases, there is a coexistence of autism with rare mutations. Recent studies have challenged the view that atypical genetic alterations alone have major relevance to the etiology of the disease [2]. Prior reports described the putative role of insulin-like growth factor (IGF) deficiency in the genesis of juvenile autism [1,3,4]. Among many functions, this factor stimulates oligodendrocytes to produce myelin insulation of neuronal axons in neonates [5,6]. The present study examines the proposed pathway for connectivity defects to arise in the central nervous system (CNS) as a consequence of dysmyelination. Such a glitch might induce flaws in the completion of the synaptic union of axons and dendrites, or axons and target tissues. In addition, the proposal that dysmyelination in CNS neurogenesis in young children [7,8] is central to the creation of abnormal neurologic function such as in autism is further explored here. Three fundamental IGF-associated phenomena that might account for the origin of neural dysfunction in autism are: (1) disorders of synaptic development and function, (2) disorders of nerve impulse transmission related to disrupted axonal myelination, and/or (3) disorders of cell signaling pathways.
E-mail address: [email protected]
Defective connectivity in the autistic brain would appear to be due to one or more consequences of IGF-1 deficiency.
Background The placental biosynthesis of IGF is controlled by growth hormone in the latter developmental stages before birth. Certain antepartum inflammatory processes occurring in the gravida, known to correlate with the subsequent development of autism in the newborn, can act to decrease placental IGF production [9]. In general, IGF promotes protective surveillance of brain cells to prevent neuronal derangement [10]. Gene polymorphisms can down-regulate the production of IGF [11]. Transgenic mice which lack the ability to synthesize IGF have reduced axonal diameters and decreased nerve conduction velocities [12]. A boy with homozygous partial deletion of the IGF-1 gene displayed sensorineural deafness and mental retardation [13]. Autistic children between birth and 4 years of age have lower levels of IGF in their cerebrospinal fluid than unaffected youngsters [14]. These findings in affected persons are consistent with diminished myelination in early neurogenesis. The neuronal growth cone (axon precursor) is guided to sites of need (e.g., muscles) by non-diffusible biochemical factors in the vicinity of the target tissues [15]. To refine the path, both chemoattractive (such as netrins) and chemorepulsive (such as semaphorins) agents are appropriately placed within the receiving tissues [16]. Once the axon reaches a suitable dendritic or organ target, synapse formation ensues [17]. Such trophic interactions begin before birth and continue postnatally.
http://dx.doi.org/10.1016/j.mehy.2015.06.018 0306-9877/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Steinman G. Plausible etiology of brain dysconnectivity in autism – Review and prospectus. Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.06.018
2
G. Steinman / Medical Hypotheses xxx (2015) xxx–xxx
With time, neurons in the neonate display increasing numbers of synapses [18]. The fittest of them survive and the less functional in the remainder are eliminated by apoptosis. The most effective connections are retained peripherally and in the brain. This is promoted by agents such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). According to the Hebb’s postulate, active, functional interplay between a presynaptic axon and a postsynaptic target fortifies the synaptic link [16]. Such strengthening promotes persistence of the joining of neurons with terminal tissues. Conversely, weakly associated unions eventually resolve and disappear (see Fig. 24.1 in Ref. [16]). Postnatal brain development is dependent on enhancement of functional synapse formation. This is promoted by strong, timely impulses sent to the target via the presynaptic axon [16]. Myelinated axons exhibit nerve impulses that are as much as 100 times faster than non-myelinated ones [19]. For proper, efficient, and rapid connectivity to develop between regions of the neonatal brain, early, comprehensive myelination of the participating axons is essential. In contradistinction, autistic brains have been observed to display heterogeneity, with areas of increased or decreased connectivity [20]. This is especially evident in imaging studies of the corpus callosum, where autistic individuals exhibit changes in white matter myelination related to decreased interhemispheric connectivity [21]. Myelination begins around 24–25 weeks post-conception and reaches its peak growth rate by 1 year of age [16]. Symptoms of autism typically appear between 1 and 3 years after birth. In the brains of autistic children, myelination has been shown by imaging and biopsy to be deficient compared to unaffected children [22,23]. Such a diminution would weaken the operation of the axon-target synapse, thereby accounting for the malfunction of areas of the brain involved in behavior. This would include the brain’s prefrontal and temporal areas. ‘‘Pruning’’ of excessive neural synapses by microglia to enhance the functionality of the retained connections has been found to be defective in the CNS of autistic children [18,24]. In unaffected individuals, this normally occurs as a task of high velocity impulse delivery by myelinated presynaptic axons. Such faulty processing may well be the consequence of hypomyelination. Compounding this could be neuronal cell signaling impediments in the IGF-I/P13K/AKT/mTOR pathway [25].
Conclusions Combining the relevant observations reviewed here, a comprehensive, plausible delineation of the fundamental neurogenerative defect underlying the etiology of juvenile autism may be deduced. The pertinent findings include: (1) deficient supply of IGF, causing axonal hypomyelination; (2) weakened axon/dendrite or axon/target synaptogenesis due to diminished impulse velocity or strength when insufficient presynaptic axonal myelination is present; (3) faulty connectivity between regions of an autistic brain; and, (4) attenuated neuronal cell signaling. Hence, the merging of axonal dysmyelination and the resultant synaptic dysfunction could account for defective CNS ‘‘wiring’’ in autism. Connectivity problems in the newborn may also result from cell signaling defects. However, distinguishing the individual roles of substandard myelination, synaptic function, and cell signaling in central dysconnectivity may prove difficult.
; IGF ; ; oligodendrocyte activity ; ; axonal myelination ; ; presynapse nerve impulse velocity ; ; synapse stability ; ; orderly brain connectivity
There is currently no applicable means for repairing already defective myelin insulation in vivo; IGF therapy has been tried to treat adult multiple sclerosis without much success [26]. IGF supplementation might be given to neonates found to be deficient in this growth factor starting at birth, when neurogenesis is very active [27,28]. Breast milk, a natural source of IGF, is one way of doing this [29]; another is subcutaneous injection of IGF-1-containing microspheres [30]. The mechanism reviewed here may be central to the reported success of IGF treatment of autism-like syndromes such as Rett [31,32] and Phelan-McDermid [33]. Overall, autism is characterized by withdrawal from social interactions and delayed speech development as a failure to form interpersonal relationships [34]. As proposed in this report, neonatal IGF deficiency can result in imperfect myelination as detected subjectively by restrained social development and objectively by MRI imaging. On the other hand, some affected children do not display detectable developmental changes until later in their young lives. This suggests that there are two divisions of autistic children, those diagnosed early and others identified later. The difference may be due in part to the effects of IGF deficiency on neurogenesis and nerve function in the newborn. This could be the result of genetic polymorphisms or of insufficient dietary components needed to supply or synthesize IGF. Nutritional deprivation reduces IGF-1 gene expression [35]. Alternatively, diagnosis of ‘‘late onset’’ autism may be related to delayed recognition of behavioral differences by parents [1]. Additional small subsets may occur with coexistent uncommon genetic mutations. The distribution of cases with this disorder is referred to as the autism spectrum [1]. These may actually represent the same disease, differing in degree of neonatal IGF deficiency, and, hence, the extent of neurologic dysfunction. It remains to be determined if the effects on dysconnectivity and dysfunction reviewed here are limited to the central nervous system, especially the behavioral centers of the brain, or include peripheral nerve tracks as well. Autistic children until the age of 4 years display reduced levels of cerebrospinal fluid IGF, which subsequently rises to normal and above-normal levels [14]. This may explain why some affected youngsters have enlarged heads [36]. IGF promotes overall growth in children; those affected with autism are typically not shorter than average following the pubertal growth spurt. The effects of IGF deficiency on neurogenesis may be limited to youngsters in the months or early years immediately following birth. A much needed parameter in the diagnosis of autism is a testable biomarker. If the hypothesis proposed here is supported by further experimental evidence, IGF deficiency could serve that function [37]. Conflict of interest The author of this paper has no conflict of interest in its publication.
Please cite this article in press as: Steinman G. Plausible etiology of brain dysconnectivity in autism – Review and prospectus. Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.06.018
G. Steinman / Medical Hypotheses xxx (2015) xxx–xxx
Acknowledgement The author wishes to thank Roberta Zuckerman for her thoughtful critique of the manuscript.
References [1] Steinman G, Mankuta D, Zuckerman R, Gray F, editors. The cause of autism – concepts and misconceptions. New York: Baffin Books Publishing; 2014. pp. 25–30, 119–27, 210–14, 243–50, 273–85. [2] Murdoch JD, Gupta AR, Sanders SJ, et al. No evidence for association of autism with rare heterozygous point mutations in contactin-associate protein-like 1 (CNTNAP2), or in other contactin-associated proteins or contactins. PLoS Genet 2015;11(1):e1004852. http://dx.doi.org/10.1371/journal. pgen.1004852. [3] Steinman G. Predicting autism at birth. Med Hypotheses 2013;81:21–5. [4] Steinman G, Mankuta D. Insulin-like growth factor and the etiology of autism. Med Hypotheses 2013;80:475–80. [5] Ye P, Li L, Richards RG, et al. Myelination is altered in insulin-like growth factor-1 null mutant mice. J Neurosci 2002;22(14):6041–51. [6] Miron VE, Kuhlmann T, Antel JP. Cells of the oligodendroglial lineage, myelination, and remyelination. Biochim Biophys Acta 2011;1812:184–93. [7] O’Kusky JR, Ye P, D’Ercose AJ. Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. J Neurosci 2000;20:8435–42. [8] Morrow E, Walsh C, Rubenstein J. Autism and brain development. Cell 2008;135(3):396–400. [9] Patterson PH. Maternal infection and immune involvement in autism. Trends Mol Med 2001;17(7):389–94. [10] Torres-Aleman I. Serum growth factors and neuroprotective surveillance: focus on IGF-1. Mol Neurobiol 2000;21(3):153–60. [11] Arends N. Polymorphism in the IGF-1 gene: clinical relevance for short children born small for gestational age (SGA). J Clin Endocrinol Metab 2002;87(6):2720. [12] Beck KD, Powell-Braxton L, Widmer HR, et al. IGF-1 gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons. Neuron 1995;14:717–30. [13] Woods KA, Camacho-Hubner C, Savage MO, Clark AJ. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor-I gene. NEJM 1996;335:1363–7. [14] Riikonen R, Makkonen I, Turpeinen U, et al. Cerebrospinal fluid insulin-like growth factors IGF-1 and IGF-2 in infantile autism. Dev Med Child Neurol 2006;48:751–5. [15] Engle EC. Human genetic disorders of axon guidance. Cold Spring Harbor Perspect Biol 2010;2010(2):a001784. [16] Purves D, Augustine GS, Fitzpatrick D, et al., editors. Neuroscience. Sunderland, MA: Sinauer; 2012. pp. 77–106, 517–19, 529–38. [17] Purves D. Body and brain: a trophic theory of neural connections. Cambridge, MA: Harvard Univ. Press; 1988. [18] Tang G, Gudsnuk K, Kuo S-H, et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 2014;83(5):1131–43.
3
[19] Roberts TPL, Khan AY, Rey M, et al. MEG detection of delayed auditory evoked responses in autism spectrum disorders: towards an imaging biomarker for autism. Autism Res 2010;3(1):8–18. [20] Hahamy A, Behrmann M, Mlach R. The idiosyncratic brain: distortion of spontaneous connectivity patterns in autism spectrum disorder. Nat Neurosci 2015;18:302–9. [21] Travers BG, Tromp DPM, Adluru A, et al. Atypical development of white matter microstructure of the corpus callosum in males with autism. Mol Autism 2015;6:15. http://dx.doi.org/10.1186/S13229-015-0001-8. [22] Aoki Y, Abe O, Nippashi Y, et al. Comparison of white matter integrity between autism spectrum disorder subjects and typically developing individuals: a meta-analysis of diffusion tensor imaging tractography studies. Mol Autism 2013;4:25. [23] Zikopoulos B, Barbas H. Changes in prefrontal axons may disrupt the network in autism. J Neurosci 2010;30(44):14595–608. [24] Zhan Y, Paolicelli RC, Sforazzini, et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci 2014;17(3):400–6. [25] Chen J, Alberts I, Li X. Dysregulation of the IGF-I/P13K/AKT/mTOR signaling pathway in autism spectrum disorders. Inter J Dev Neurosci 2014;35:35–41. [26] Wilczak N, DeKeyser J, Chesik D. Targeting insulin-like growth factor-1 signaling into the central nervous system for promoting myelin repair. Drug Target Highlight 2008;3:37–44. [27] Riikonen R. Insulin-like growth factor delivery across the blood-brain barrier. Potential use of IGF-1 as a drug in child neurology. Chemotherapy 2006;52(6):279–81. [28] Riikonen R. Insulin-like growth factors: neurobiological regulators in brain growth in autism. In: Zimmerman AW, editor. Autism – current theories and evidence. Totowa, NJ: Humana Press; 2010. p. 233–44. [29] Steinman G, Mankuta D. Breastfeeding as a possible deterrent to autism – a clinical perspective. Med Hypotheses 2013;81:999–1001. [30] Carrascoa C, Torres-Aleman I, Lopez-Lopez C, et al. Microspheres containing insulin-like growth factor I for treatment of chronic neurodegeneration. Biomaterials 2004;25:7007–14. [31] Jou RJ, Mateljevic N, Kaiser MD, et al. Structural neural phenotype of autism: preliminary evidence from a diffusion tensor imaging study using tract-based spatial statistics. AJNR Am J Neuroradiol 2011;32(9):1607–13. [32] Bozdago P, Tavassoli T, Buxbaum JD. Insulin-like growth factor-I rescues synaptic and motor deficits in a mouse model of autism and developmental delay. Mol Autism 2013;4(1):9. http://dx.doi.org/10.1186/2040-2392-4-9. [33] Kolveson A, Bush L, Wang AT, et al. A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome. Mol Autism 2014;5(54):1–9. [34] Rutter M, Schopler E. Autism a reappraisal of concepts and treatment. New York: Plenum Press; 1978. pp. 1–25. [35] Thissen J-P, Beauloye V, Ketelslegers J-M, et al. Regulation of insulin-like growth factor-I by nutrition. In: Houston MS, Holly JMP, Feldman EL, editors. IGF and nutrition in health and disease. Humana Press; 2005. p. 25–52. [36] Zwaigenbaum L, Young GS, Stone WL, et al. Early head growth in infants at risk of autism: a baby siblings research consortium study. J Am Acad Child Adolesc Psychiatry 2014;53(10):1053–62. [37] Steinman G, Mankuta D. Umbilical cord biomarkers in autism determination. Biomarkers Med 2014;8(3):317–9. x.
Please cite this article in press as: Steinman G. Plausible etiology of brain dysconnectivity in autism – Review and prospectus. Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.06.018