In-depth analysis reveals complex molecular aetiology in a cohort of idiopathic cerebral palsy

Abstract

Cerebral palsy is the most prevalent physical disability in children; however, its inherent molecular mechanisms remain unclear. In the present study, we performed in-depth clinical and molecular analysis on 120 idiopathic cerebral palsy families, and identified underlying detrimental genetic variants in 45% of these patients. In addition to germline variants, we found disease-related postzygotic mutations in approximately 6.7% of cerebral palsy patients. We found that patients with more severe motor impairments or a comorbidity of intellectual disability had a significantly higher chance of harboring disease-related variants. By a compilation of 114 known cerebral-palsy-related genes, we identified characteristic features in terms of inheritance and function, from which we proposed a dichotomous classification system according to the expression patterns of these genes and associated cognitive impairments. In two patients with both cerebral palsy and intellectual disability, we revealed that the defective TYW1, a tRNA hypermodification enzyme, caused primary microcephaly and problems in motion and cognition by hindering neuronal proliferation and migration. Furthermore, we developed an algorithm and demonstrated in mouse brains that this malfunctioning hypermodification specifically perturbed the translation of a subset of proteins involved in cell cycling. This finding provided a novel and interesting mechanism for congenital microcephaly. In another cerebral palsy patient with normal intelligence, we identified a mitochondrial enzyme GPAM, the hypomorphic form of which led to hypomyelination of the corticospinal tract in both human and mouse models. In addition, we confirmed that the aberrant Gpam in mice perturbed the lipid metabolism in astrocytes, resulting in suppressed astrocytic proliferation and a shortage of lipid contents supplied for oligodendrocytic myelination. Taken together, our findings elucidate novel aspects of the etiology of cerebral palsy and provide insights for future therapeutic strategies.

The Effect of Constraint-Induced Movement Therapy Combined With Repetitive Transcranial Magnetic Stimulation on Hand Function in Preschool Children With Unilateral Cerebral Palsy: A Randomized Controlled Preliminary Study

“…Cerebral palsy is the most common physical disability in childhood, occurring in 2.5–3.5 per 1,000 live births and with complicated etiology (Bax et al, 2005 ; Li et al, 2021 ). Unilateral cerebral palsy (UCP), which mainly affects the function of children's lateral extremity, accounts for 44% of the cases (Stavsky et al, 2017 ).…”

Safety and effects of transcranial direct current stimulation on hand function in preschool children with hemiplegic cerebral palsy: A pilot study

“…Cerebral palsy is characterized as movement and posture disorders with complicated etiology and stable prevalence of 2-3.5 cases per 1,000 live births (Colver et al, 2014;Li et al, 2022). Hemiplegic cerebral palsy (HCP) is the most common type of cerebral palsy, accounting for 44% (Zelnik et al, 2016).…”

Plasma Metabolomic Changes in Children with Cerebral Palsy Exposed to Botulinum Neurotoxin

“…Cerebral palsy (CP) describes a group of static and nonprogressive brain lesions characterized by disorders of movement and posture resulting in activity limitations, which is the most common physical disability in children . Incidence of CP is about 2.0 to 3.5 per 1000 live births, and spastic CP is the most common type; the etiology of cerebral palsy is complicated . Spasticity, in combination with increased muscle tightness, reduced motor control, and abnormal posture, contributes to limitations in ambulation, functional ability, balance, physical fitness, and participation.…”