Cognition and Evolution of Movement Disorders of FOXG1-Related Syndrome

Abstract

FOXG1 -related syndrome is a rare neurodevelopmental encephalopathy characterized by early onset hyperkinetic movement disorders, absent language, autistic features, epilepsy, and severe cognitive impairment. However, detailed evaluation of cognition and evolution of movement disorders over time have not been clearly described before. In this study, we performed whole-exome sequencing in a cohort with unknown severe encephalopathy and movement disorders, with/without autistic behaviors. We identified FOXG1 mutations in three patients. One of them had a novel mutation that has not been described before. The neuropsychological test by Mullen Scales of Early Learning (MSEL) showed severe psychomotor impairments in all patients. There were uneven cognitive abilities in terms of verbal and non-verbal cognitive domains in all of them, with approximately 2 months differences. Gross motor skills and expressive language were more severely affected than the other domains in all the patients. All individuals had early onset hyperkinetic movement disorders. The movement disorders in one of our patients changed from predominantly hyperkinetic in early childhood to more hypokinetic in adolescence with the development of dystonia. To the best of our knowledge, this evolution had never been described before. In conclusion, individuals with FOXG1 -related syndrome may show clinical progression from hyperkinetic to hypokinetic features over time. There were also uneven cognitive abilities in verbal and non-verbal cognitive domains. The FOXG1 mutation should be considered in individuals with a history of hyperkinetic movements, microcephaly, and uneven cognitive abilities with characteristic brain images.

Toward a mechanistic understanding of DNA binding by forkhead transcription factors and its perturbation by pathogenic mutations

“…Mutations of FOX proteins underlie many human diseases. For example, mutation of FOXG1 is linked to FOXG1 syndrome, a serious neurodevelopmental disorder ( 115 , 116 ); FOXA mutations are frequently identified in prostate and breast cancers ( 42 , 117–120 ); FOXC mutations are associated with Axenfeld–Rieger syndrome (ARS) and Lymphoedema distichiasis syndrome (LDS) ( 43 , 121 , 122 ); and the inactivating mutations in FOXP3 result in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) autoimmune syndrome ( 123 , 124 ).…”

Paving Therapeutic Avenues for FOXG1 Syndrome: Untangling Genotypes and Phenotypes from a Molecular Perspective

“…As mentioned before, FOXG1 mutations encompass missense, nonsense, and frameshift mutations as well as microdeletions proximal to or spanning the FOXG1 gene [4], [5], [29], [30], [36]- [38]. Although the mutations distributed throughout the entire gene and could thus localise principally to all known protein domains, a few hotspots were eminently more susceptible to de novo mutations, as has been reported by genotype-phenotype studies [1], [4], [5], [11], [12] (Figure 2). Two of these hotspots located in stretches of cytosine and guanine repeats within the 5'-end of the gene that encodes the N-terminal protein domain, c.256dupC and c.460dupG, respectively [4], [5], [11], [24] (Figure 2).…”

“…Following studies and several clinical screens laid further foundation to specify the FOXG1 syndrome, which is now recognised as a distinct human neurodevelopmental disorder. Despite significant variability in phenotypes and severity observed in individuals depending on the genotype, the core FOXG1 syndrome phenotype consists of severe postnatal microcephaly and mental retardation, deficient language development, poor social interactions and eye contact (indicating a link to ASD), postnatal growth deficiency, problematic sleep patterns, epilepsy, and irritability during infancy [4], [12]. Additionally, data from brain imaging studies uncovered corpus callosum agenesis and reduced white matter, as well as poor and delayed myelination patterns [4], [5], [11].…”

“…Since the first identified case of FOXG1 syndrome [13], more patients with mutations in FOXG1 were diagnosed utilising chromosomal microarray, whole exome sequencing (WES), and gene sequencing methods [1], [4], [5], [7], [11], [12]. As mentioned before, FOXG1 mutations encompass missense, nonsense, and frameshift mutations as well as microdeletions proximal to or spanning the FOXG1 gene [4], [5], [29], [30], [36]- [38].…”

“…Thus far, the identified mutations associated with FOXG1 syndrome include chromosomal microaberrations such as deletions and duplications, as well as frameshift and point mutations [4], [5], [8]- [10]. Depending on the type of mutation, a variability in phenotypic manifestations has been observed [4], [5], [11], [12]. The most severe phenotypes occur in patients with frameshift or nonsense mutations in the N-terminal domain, including the Forkhead domain, while milder phenotypes associate with FOXG1 missense mutations in the Forkhead domain [5].…”