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Improved Management of Autism Spectrum Disorder (ASD) by Micronutrients
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
In autopsied cerebellar cortex samples of ASD patients, the expression of 9 miRs were altered.43 These miRs target mRNA of neurexin and SHANK3. Abnormalities in these proteins are linked with ASD. In the autopsied brain samples of ASD patients, the expression of miR-142-5p, miR-142-3p, miR-451a, miR-144-3p, and miR-21-5p were upregulated. In addition, the promoter region of the miR-142 was hypomethylated, suggesting that epigenetics is an important factor in dysregulation of microRNA. These miRs target mRNAs destined to be translated into proteins involved in synaptic function. Further analysis revealed that miR-451a and miR-21-5p target mRNA for oxytocin receptor (OXTR). Overexpression of miR-21-5p reduces the levels of OXTR by binding with 3′-UTR OXTR mRNA.44 In autopsied brain samples of ASD patients, the expression of miR-4753-5p and miR-1 in the superior temporal sulcus (STS), and miR-664-3p, miR-4709-3p, miR-4742-3p, and miR-297 in the primary auditory cortex (PAC) was differently expressed compared with controls.45 MicroRNAs in each brain region targeted mRNAs that are involved in making cell cycle protein and canonical signaling pathways, including P13-Akt that are implicated in ASD. MicroRNAs impaired immune pathways only in the STS. Small non-coding RNAs (snoRNAs) and pre-miR were also differentially expressed in ASD patients compare with control subjects.
Biological and genetic factors in DCD
Published in Anna L. Barnett, Elisabeth L. Hill, Understanding Motor Behaviour in Developmental Coordination Disorder, 2019
Melissa K. Licari, Daniela Rigoli, Jan P. Piek
A recent study by Mosca et al. (2016) was the first to specifically concentrate on the genetic origins of DCD. The study examined copy number variations (CNVs) and structural variation of base pairs within DNA in 82 children with DCD, with and without co-occurring ADHD and reading disorder. The study found greater genomic variation, with 26% of the DCD cohort displaying rare de novo CNVs, and 64% inherited CNVs from a parent who also had a neurodevelopmental disorder. The study also found an enrichment of duplications for brain expressed genes, along with an overlap in duplications and deletions in genes previously implicated in other neurological and neurodevelopmental disorders, including FHIT, GAP43, RBFOX1, PTPRN2, SHANK3, 16p11.2 and 22q11.2 seen in ADHD, ASD, epilepsy, schizophrenia and Tourette’s syndrome. While a number of the variations were seen in children with co-occurring disorders, there was also presence of variations in children with isolated cases of DCD, providing significant evidence to support that this disorder has a genetic basis that is heritable.
Argentinian Ambulatory Integral Model to Treat Autism Spectrum Disorders
Published in Elizabeth B. Torres, Caroline Whyatt, Autism, 2017
One of the features we examine during a diagnostic assessment is the presence of lax joints (Shetreat-Klein et al. 2014). The origins of this somewhat common feature in ASD are unknown: Is this a structural abnormality, or is it due to low muscle tone? The prevalence of this difficulty is also unknown, but it is present in children with ASD who also have SHANK3 deletion syndrome (Sarasua et al. 2014).
Evaluation of elements in hair samples of children with developmental language disorder (DLD)
Published in Nutritional Neuroscience, 2023
Ayat Bani Rashaid, Mazin Alqhazo, Dianne F. Newbury, Heba Kanaan, Mohammad El-khateeb, Ahmad Abukashabeh, Feda Al-Tamimi
An Association between zinc deficiency and Shank3 has been investigated in some previous Studies. Shank3 is part of the Shank family proteins localized to the postsynaptic density of excitatory synapses in the cortex and hippocampus [50]. They are the main regulators of postsynaptic function that interrelates with many postsynaptic molecules such as actin cytoskeleton, glutamate receptors, and structural proteins [50,51]. It was found that Shank3 is important for synaptic plasticity and the trans-synaptic connection between the reliability of presynaptic neurotransmitter release and postsynaptic responsiveness [52]. The sterile alpha motif (SAM) domain of shank3 is necessary for postsynaptic localization and fastening zinc, therefore altering zinc levels may control Shank3 function in dendritic spines. This assumption has been supported by finding that zinc is a strong regulator of shank3 function in hippocampus neurons of rats [52]. It was also suggested that Shank3 is a crucial factor of a zinc-sensitive signaling system, regulating the strength of synapses that may be weakened in people with autism spectrum disorders [52–54]. This discussion of the relationship between zinc deficiency and the weakness of synapses in people with ASD could explain the findings of the current study in which language delay is the main symptom of autism spectrum disorder.
Molecular mechanisms that change synapse number
Published in Journal of Neurogenetics, 2018
Alicia Mansilla, Sheila Jordán-Álvarez, Elena Santana, Patricia Jarabo, Sergio Casas-Tintó, Alberto Ferrús
The pineal gland hormone melatonin peaks during the night in diurnal mammals. Its actions may be channelled through its intrinsic antioxidant properties or through its binding to two GPCRs, MT1 and MT2. A set of interactome data for both receptors shows 378 putative partners, some of which are selective for MT1 and are residents in the pre-synapse. The MT1 receptor is found in the hypothalamus, striatum and cortex and it physically interacts with Cav2.2 channels to inhibit Ca2+ entry in an agonist-independent manner (Benleulmi-Chaachoua et al., 2016). Circadian changes in the synapse have been monitored through the metabotropic glutamate receptor5 (mGluR5) in mice along the day. mGluR5 levels increase during the light-on (07:00 to 15:00 hr), or sleep phase for rodents, by approximately 10% (Elmenhorst et al., 2016). Noticeably, altered density of mGluR5 seems to occur in psychiatric disorders and, as indicated by these monitoring data, mGluR5 changes may also be involved in human mood changes. Similar to GluR5, quantitatively minor oscillations of certain protein levels during the day may have noticeable biological effects. This is the case of synaptic Shank3 in hippocampal and striatal brain neurons. Shank3 changes in these regions correlate also with serum melatonin levels and, as expected, with motor activity. The experimental increase of motor exercise leads to a rapid increase of Shank3α expression in thalamus, and cortex, but to a decrease in striatum (Sarowar et al., 2016). This illustrates the hierarchical superposition of brain regions concerning molecular cyclic changes toward coherence of the behavioural output of the organism.
A mini-review: Bridging the gap between autism spectrum disorder and pain comorbidities
Published in Canadian Journal of Pain, 2020
Chad O. Brown, Jarryll Uy, Karun K. Singh
Among the genes in the SFARI database, multiple genes have been identified as being implicated in pain phenotypes. One such gene is SHANK3, a gene mutated in Phelan-McDermid syndrome, where primary symptoms include ASD as well as blunted pain sensitivity.78 Furthermore, in a study evaluating 201 patients with Phelan-McDermid syndrome, it was found that nearly 80% demonstrated insensitivity to pain.79 Mice lacking one or both copies of Shank3 have been shown to have an insensitivity to pain.80 Han et al.80 showed that deletion of Shank3 in peripheral sensory neurons of mice led to a decrease in inflammatory pain sensitivity. It was further shown that the specific deletion of Shank3 in sensory neurons recapitulated pain deficits in Shank3 global knockout mice. This finding suggested that insensitivity to pain seen in patients with SHANK3 mutations may be attributed not solely to dysfunction in the brain but within the PNS. Mutations in the mouse model of ASD harboring deletions in Cntnap2 have been shown to display hypersensitivity to pain.81 Dawes et al.81 demonstrated that sensory neurons of Cntnap2−/− mice had impaired Kv1 channel function that produced unregulated neuronal excitability. They identified the key role of an ASD-associated gene in pain sensitivity and examined potential mechanisms by which it occurs. Additionally, Sener et al.82 examined expression of genes related to aggression and pain sensitivity in whole-blood samples of patients with ASD. They found altered expression of several genes such as SCN9A and OPRM1, which are genes related to pain as well as significantly higher expression of the aggression-related TACR1 gene in patients with ASD.82 This study provided novel insight into potential biomarkers of the consequent behavioral phenotypes of individuals diagnosed with ASD. Understanding of the links between ASD and pain remains poor and thus highlights the need to further identify the underlying causal mechanisms for future therapeutic intervention.