Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Nov;178:233-240.e10.
doi: 10.1016/j.jpeds.2016.08.032. Epub 2016 Sep 15.

Phenotype Differentiation of FOXG1 and MECP2 Disorders: A New Method for Characterization of Developmental Encephalopathies

Affiliations
Free PMC article

Phenotype Differentiation of FOXG1 and MECP2 Disorders: A New Method for Characterization of Developmental Encephalopathies

Mandy Ma et al. J Pediatr. .
Free PMC article

Abstract

Objective: To differentiate developmental encephalopathies by creating a novel quantitative phenotyping tool.

Study design: We created the Developmental Encephalopathy Inventory (DEI) to differentiate disorders with complex multisystem neurodevelopmental symptoms. We then used the DEI to study the phenotype features of 20 subjects with FOXG1 disorder and 11 subjects with MECP2 disorder.

Results: The DEI identified core domains of fine motor and expressive language that were severely impaired in both disorders. Individuals with FOXG1 disorder were overall more severely impaired. Subjects with FOXG1 disorder were less able to walk, had worse fine motor skills, more disability in receptive language and reciprocity, and had more disordered sleep than did subjects with MECP2 disorder (P <.05). Covariance, cluster, and principal component analysis confirmed a relationship between impaired awareness, reciprocity, and language in both disorders. In addition, abnormal ambulation was a first principal component for FOXG1 but not for MECP2 disorder, suggesting that impaired ambulation is a strong differentiating factor clinically between the 2 disorders.

Conclusions: We have developed a novel quantitative developmental assessment tool for developmental encephalopathies and propose this tool as a method to identify and illustrate core common and differential domains of disability in these complex disorders. These findings demonstrate clear phenotype differences between FOXG1 and MECP2 disorders.

Keywords: FOXG1; MECP2; autism; developmental encephalopathy; intellectual disability; natural history; quantitative phenotyping.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Histogram illustrating distribution of ages at the time of study of subjects with FOXG1 and MECP2. The mean age of subjects with FOXG1 was 8.9 years, and the median age was 6.7 years. The mean age of subjects with MECP2 disorder was 14.75 years, and the median age was 9.0 years. There were slightly more subjects with MECP2 disorder in the 25- to 35-year category.
Figure 2
Figure 2
Distributions of Developmental Encephalopathy Inventory (DEI) scores for subjects with FOXG1 and MECP2 disorders. Twelve neurobehavioral domains were assayed in this study. For both disorders, G, expressive language, was consistently severely affected in all subjects.
Figure 3
Figure 3
Comparison of mean DEI scores for subjects with FOXG1 and MECP2 in the 12 neurobehavioral domains assayed in this study. Significant differences were found in A, ambulation; H, receptive language; J, reciprocity; and L, sleep with FOXG1 subjects more severe in all realms. The only domain where subjects with MECP2 were significantly more severe was that of D, breathing. *P < .05.
Figure 4
Figure 4
Covariance of DEI scores in 12 neurobehavioral domains with age at the time of study. For all domains, subjects with FOXG1 disorder showed no significant covariance with age, suggesting that maximal disability did not increase over the lifespan. Among subjects with MECP2 disorder, there was significant positive covariance between age and awareness of self and environment and significant negative covariance between age and mood disorders.
Figure 5
Figure 5
Covariance between DEI domains among subjects with FOXG1 disorder. There were significant relationships between A, awareness and expressive language, B, awareness and receptive language, C, receptive and expressive language, D, reciprocity and expressive language, and E, sleep and expressive language. F, Significant negative variance was found between autonomic nervous system disorders and awareness. ANS, autonomic nervous system.
Figure 6
Figure 6
Covariance between DEI domains among subjects with MECP2 disorder. There were significant relationships between A, awareness and reciprocity; B, awareness and sensory; and C, reciprocity and sensory. D, Significant negative variance was found between ANS and receptive language; E, breathing and receptive language; and F, expressive language and mood.
Figure 7
Figure 7
Dendrograms showing clusters of significant impairment among subjects with FOXG1 and MECP2 disorders. A, Subjects with FOXG1 shared in common disordered ambulation, fine motor skills, and expressive language. A secondary cluster of abnormal receptive language and reciprocity was also found. B, Subjects with MECP2 similarly shared disordered fine motor skills and expressive language, as well as an additional cluster of impaired ambulation and breathing. Principal component analysis factormaps for subjects with FOXG1 and MECP2. C, For FOXG1 ambulation, reciprocity, awareness, and receptive language were most important for the first principal component. All were negatively correlated with DEI score for autonomic nervous system dysfunction. For the second principal component, the realms expressive language, breathing, and sleep are the most important, and these variables are not correlated to ambulation, reciprocity, awareness, and receptive language. D, For subjects with MECP2, sleep and receptive language were most important for the first principal component, and these were negatively correlated with ambulation, fine motor dysfunction, and autonomic nervous system dysfunction. For the second principal component the realms expressive language, reciprocity, and awareness were most important, and these were negatively correlated with breathing. Circos plot illustrating core dysfunctions shared and variant between E, FOXG1 and F, MECP2 disorders. Severe abnormalities in expressive language, ambulation, and fine motor function are seen in both disorders; however, sleep dysregulation and breathing dysfunction emerged as variant between the 2 conditions. DEI scores >2.0 (frequently impaired or worse) were plotted.
Figure 7
Figure 7
Dendrograms showing clusters of significant impairment among subjects with FOXG1 and MECP2 disorders. A, Subjects with FOXG1 shared in common disordered ambulation, fine motor skills, and expressive language. A secondary cluster of abnormal receptive language and reciprocity was also found. B, Subjects with MECP2 similarly shared disordered fine motor skills and expressive language, as well as an additional cluster of impaired ambulation and breathing. Principal component analysis factormaps for subjects with FOXG1 and MECP2. C, For FOXG1 ambulation, reciprocity, awareness, and receptive language were most important for the first principal component. All were negatively correlated with DEI score for autonomic nervous system dysfunction. For the second principal component, the realms expressive language, breathing, and sleep are the most important, and these variables are not correlated to ambulation, reciprocity, awareness, and receptive language. D, For subjects with MECP2, sleep and receptive language were most important for the first principal component, and these were negatively correlated with ambulation, fine motor dysfunction, and autonomic nervous system dysfunction. For the second principal component the realms expressive language, reciprocity, and awareness were most important, and these were negatively correlated with breathing. Circos plot illustrating core dysfunctions shared and variant between E, FOXG1 and F, MECP2 disorders. Severe abnormalities in expressive language, ambulation, and fine motor function are seen in both disorders; however, sleep dysregulation and breathing dysfunction emerged as variant between the 2 conditions. DEI scores >2.0 (frequently impaired or worse) were plotted.
Figure 8
Figure 8
Diagnostic criteria for autism spectrum disorder (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) map to domains within the DEI. Deficits in social communication and social interaction map to the domains of awareness of self and environment and language (primarily expressive). Restricted, repetitive patterns of behavior, interests, or activities map to the domains movements and sensory function.

Similar articles

See all similar articles

Cited by 5 articles

  • Transcription and Beyond: Delineating FOXG1 Function in Cortical Development and Disorders.
    Hou PS, hAilín DÓ, Vogel T, Hanashima C. Hou PS, et al. Front Cell Neurosci. 2020 Feb 25;14:35. doi: 10.3389/fncel.2020.00035. eCollection 2020. Front Cell Neurosci. 2020. PMID: 32158381 Free PMC article. Review.
  • FOXG1-Related Syndrome: From Clinical to Molecular Genetics and Pathogenic Mechanisms.
    Wong LC, Singh S, Wang HP, Hsu CJ, Hu SC, Lee WT. Wong LC, et al. Int J Mol Sci. 2019 Aug 26;20(17):4176. doi: 10.3390/ijms20174176. Int J Mol Sci. 2019. PMID: 31454984 Free PMC article. Review.
  • Severity Assessment in CDKL5 Deficiency Disorder.
    Demarest S, Pestana-Knight EM, Olson HE, Downs J, Marsh ED, Kaufmann WE, Partridge CA, Leonard H, Gwadry-Sridhar F, Frame KE, Cross JH, Chin RFM, Parikh S, Panzer A, Weisenberg J, Utley K, Jaksha A, Amin S, Khwaja O, Devinsky O, Neul JL, Percy AK, Benke TA. Demarest S, et al. Pediatr Neurol. 2019 Aug;97:38-42. doi: 10.1016/j.pediatrneurol.2019.03.017. Epub 2019 Mar 27. Pediatr Neurol. 2019. PMID: 31147226
  • Data Science for Child Health.
    Bennett TD, Callahan TJ, Feinstein JA, Ghosh D, Lakhani SA, Spaeder MC, Szefler SJ, Kahn MG. Bennett TD, et al. J Pediatr. 2019 May;208:12-22. doi: 10.1016/j.jpeds.2018.12.041. Epub 2019 Jan 25. J Pediatr. 2019. PMID: 30686480 Free PMC article. Review. No abstract available.
  • Delineating FOXG1 syndrome: From congenital microcephaly to hyperkinetic encephalopathy.
    Vegas N, Cavallin M, Maillard C, Boddaert N, Toulouse J, Schaefer E, Lerman-Sagie T, Lev D, Magalie B, Moutton S, Haan E, Isidor B, Heron D, Milh M, Rondeau S, Michot C, Valence S, Wagner S, Hully M, Mignot C, Masurel A, Datta A, Odent S, Nizon M, Lazaro L, Vincent M, Cogné B, Guerrot AM, Arpin S, Pedespan JM, Caubel I, Pontier B, Troude B, Rivier F, Philippe C, Bienvenu T, Spitz MA, Bery A, Bahi-Buisson N. Vegas N, et al. Neurol Genet. 2018 Nov 7;4(6):e281. doi: 10.1212/NXG.0000000000000281. eCollection 2018 Dec. Neurol Genet. 2018. PMID: 30533527 Free PMC article.
Feedback