Disruption of Basal Lamina Components in Neuromotor Synapses of Children with Spastic Quadriplegic Cerebral Palsy

Abstract

Cerebral palsy (CP) is a static encephalopathy occurring when a lesion to the developing brain results in disordered movement and posture. Patients present with sometimes overlapping spastic, athetoid/dyskinetic, and ataxic symptoms. Spastic CP, which is characterized by stiff muscles, weakness, and poor motor control, accounts for ∼80% of cases. The detailed mechanisms leading to disordered movement in spastic CP are not completely understood, but clinical experience and recent studies suggest involvement of peripheral motor synapses. For example, it is recognized that CP patients have altered sensitivities to drugs that target neuromuscular junctions (NMJs), and protein localization studies suggest that NMJ microanatomy is disrupted in CP. Since CP originates during maturation, we hypothesized that NMJ disruption in spastic CP is associated with retention of an immature neuromotor phenotype later in life. Scoliosis patients with spastic CP or idiopathic disease were enrolled in a prospective, partially-blinded study to evaluate NMJ organization and neuromotor maturation. The localization of synaptic acetylcholine esterase (AChE) relative to postsynaptic acetylcholine receptor (AChR), synaptic laminin β2, and presynaptic vesicle protein 2 (SV2) appeared mismatched in the CP samples; whereas, no significant disruption was found between AChR and SV2. These data suggest that pre- and postsynaptic NMJ components in CP children were appropriately distributed even though AChE and laminin β2 within the synaptic basal lamina appeared disrupted. Follow up electron microscopy indicated that NMJs from CP patients appeared generally mature and similar to controls with some differences present, including deeper postsynaptic folds and reduced presynaptic mitochondria. Analysis of maturational markers, including myosin, syntrophin, myogenin, and AChR subunit expression, and telomere lengths, all indicated similar levels of motor maturation in the two groups. Thus, NMJ disruption in CP was found to principally involve components of the synaptic basal lamina and subtle ultra-structural modifications but appeared unrelated to neuromotor maturational status.

Neuromotor synapses in Escobar syndrome

“…Representative patterns of muscle staining from Patient 1 are shown in Figure . Co‐localization of NMJ components was determined by calculating appositional scores using previously described methods [Robinson et al, ]. Compared to spinalis muscle from control patients with idiopathic scoliosis or cerebral palsy (CP), Patient 1 had a significantly higher degree of AChR present outside AChE and significantly less AChE outside AChR ( P < 0.05 by Mann–Whitney; Fig.…”

Adults with Cerebral Palsy have Higher Prevalence of Fracture Compared with Adults Without Cerebral Palsy Independent of Osteoporosis and Cardiometabolic Diseases

“…Cerebral palsy (CP) arises from damage or malformation of the developing brain, and is the most common pediatric‐onset physical disability . The etiology of CP leads to neurological and neuromuscular alterations, which prevent optimal fulfillment of motor function capacity and mechanical loading . Children with CP are therefore predisposed to an inadequate development of muscle and bone during growth, with the underdevelopment of the musculoskeletal system apparent prior to their 2 nd birthday .…”

“…(1)(2)(3)(4)(5) The etiology of CP leads to neurological (6) and neuromuscular (7,8) alterations, which prevent optimal fulfillment of motor function capacity and mechanical loading. (7)(8)(9)(10) Children with CP are therefore predisposed to an inadequate development of muscle and bone during growth, (9)(10)(11)(12)(13) with the underdevelopment of the musculoskeletal system apparent prior to their 2 nd birthday. (14) The result is a structurally weak musculoskeletal system, (9,11,12) which helps to explain the heightened susceptibility for acquiring low-energy fractures among this pediatric population.…”

Nanomedicine in Central Nervous System (CNS) Disorders: A Present and Future Prospective

“…180 Unfortunately, there is no effective cure available for CP due to unknown molecular and biochemical mechanisms involvement. 181 But researchers show the wide interest to use Nanoscience used drug delivery in CP. PAMAM dendrimers and dendrimer-based N-acetyl-Lcysteine administration suppress neuroinflammation & motor dysfunction in CP patients.…”