Skip to main content

Advertisement

SpringerLink
Log in

The New Findings in the Genetics and Pathology of Structural Brain Diseases

  • Genetics (A Hamosh, Section Editor)
  • Published:
Current Pediatrics Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Many disorders involving the cerebral hemispheres have been identified and classified; however, in the last five years, significant progress has been made in the identification of genes involved in hindbrain development. Space constraints prohibit an exhaustive review of genetics of brain malformations encountered in the newborn. Rather, this review will address malformations of the corpus callosum, one of the more common malformations, and the hindbrain disorders, a less common entity.

Recent Findings

Neuroimaging of the brain is often one of the first steps in the determination of etiology and prognosis of an encephalopathic condition in the newborn. Structural anomalies of the brain are seen with some frequency in this setting. Due to the complex nature of cortical development, both genetic and non-genetic (environmental, toxins, etc.) factors may lead to a very similar pattern on MRI. In recent years, given the advances in genetic sequencing technologies as well as improvements in neuroimaging field, clarity, and technical advances in imaging sick and small infants, progress has been made to identify the genetic underpinnings of many cortical malformations. This has been particularly the case with regard to posterior fossa abnormalities.

Summary

Congenital malformations of the posterior fossa are relatively rare but are frequently more recognized, given the continuous improvements of neuroimaging. High-resolution genetic testing has led to identification of the etiology for some, but the cause of many still is elusive. Future application of high-resolution genetic testing such as whole exome sequencing will help identify other variants. MRI patterns may not sufficiently differentiate the clinical entities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Gousias IS, Hammers A, Counsell SJ, et al. Magnetic resonance imaging of the newborn brain: automatic segmentation of brain images into 50 anatomical regions. PLoS One. 2013;8(4):e59990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. ∙∙ Shroff MM, Soares-Fernandes JP, Whyte H, et al. MR imaging for diagnostic evaluation of encephalopathy in the newborn. Radiographics. 2010;30(3):763–80. This paper address the normal MR imaging appearances of the physiologic processes of myelination, cell migration, and sulcation, as well as patterns of injury, in the neonatal brain at various stages of gestational development. It also includes a differential diagnosis including metabolic and genetic etiologies.

  3. Christidi F, Karavasilis E, Samiotis K, et al. Fiber tracking: a qualitative and quantitative comparison between four different software tools on the reconstruction of major white matter tracts. Eur J Radiol Open. 2016;18(3):153–61.

    Article  Google Scholar 

  4. Li X, Gao J, Wang M, Wan M, Yang J. Rapid and reliable tract-based spatial statistics pipeline for diffusion imaging in the neonatal brain: applications to the white matter development and lesions. Magn Reson Imaging. 2016. doi:10.1016/j.mri.2016.07.011.

    Google Scholar 

  5. ∙∙ Raybaud C. The corpus callosum, the other great forebrain commissures, and the septum pellucidum: anatomy, development, and malformation. Neuroradiology. 2010;52:447–77. This is a very comprehensive look at the anatomy, development, and radiological appearance of the mid-line structures: septum pellucidum and corpus callosum and demonstrates the continuum of malformations of these structures.

  6. Hatten ME. Central nervous system neuronal migration. Annu Rev Neurosci. 1999;22:511–39.

    Article  CAS  PubMed  Google Scholar 

  7. Mihrshahi R. The corpus callosum as an evolutionary innovation. J Exp Zool (Mol Dev Evol). 2006;306B:8–17.

    Article  Google Scholar 

  8. Silver J. Glia-neuron interactions at the midline of the developing mammalian brain and spinal cord. Perspect Dev Neurobiol. 1993;1:227–36.

    CAS  PubMed  Google Scholar 

  9. Shu T, Richards LJ. Cortical axon guidance by glial wedge during the development of the corpus callosum. J Neurosci. 2001;21:2749–58.

    CAS  PubMed  Google Scholar 

  10. Lent R, Uziel D, Baudrimont M, Fallet C, et al. Cellular and molecular tunnels surrounding the forebrain commissures of human fetus. J Comp Neurol. 2005;483:375–82.

    Article  PubMed  Google Scholar 

  11. Silver J, Lorenz SE, Wahlsten D, et al. Axonal guidance during development of the great cerebral commissures: descriptive and experimental studies, in vivo, on the role of preformed glial pathways. J Comp Neurol. 1982;210:10–29.

    Article  CAS  PubMed  Google Scholar 

  12. Myrianthopolous NC. Epidemiology of central nervous system malformations. In: Vinken PJ, Bruyn GW, Myrianthopolous NC, editors. Congenital malformations of the brain and skull. Amsterdam: North-Holland; 1977. p. 139–79.

    Google Scholar 

  13. Jeret JS, Serur D, Wisniewski KE, et al. Frequency of agenesis of the corpus callosum in the developmentally disabled population as determined by computerized tomography. Pediatr Neurosci. 1986;12:101–3.

    Article  CAS  Google Scholar 

  14. Sowell ER, Mattson SN, Thompson PM. e. Mapping callosal morphology and cognitive correlates. Effects of heavy prenatal alcohol exposure. Neurology. 2001;57(2):235–44.

    Article  CAS  PubMed  Google Scholar 

  15. De Meirleir L. Disorders of pyruvate metabolism. Handb Clin Neurol. 2013;113:1667–73.

    Article  PubMed  Google Scholar 

  16. Sajan SA, Fernandez L, Nieh SE, et al. Both rare and de novo copy number variants are prevalent in agenesis of the corpus callosum but not in cerebellar hypoplasia or polymicrogyria. PLoS Genet. 2013;9(10):e1003823.

    Article  PubMed  PubMed Central  Google Scholar 

  17. ∙∙ Barkovich AJ, Millen KJ, Dobyns WB. A developmental classification of malformations of the brainstem. Ann Neurol. 2007;62(6):625–39. This is a very comprehensive article about the radiological and genetic characteristics of the midbrain malformations.

  18. ∙∙ Barkovich AJ, Millen KJ, Dobyns WB. A developmental and genetic classification for midbrain-hindbrain malformations. Brain. 2009;132(Pt 12):3199–230. This is a very comprehensive article about the genetics of the midbrain malformations and demonstrates the radiographic spectrum within the groups.

  19. Abdel Razek AA, Castillo M. Magnetic resonance imaging of malformations of midbrain-hindbrain. J Comput Assist Tomogr. 2016;40(1):14–25.

    Article  PubMed  Google Scholar 

  20. Bosemani T, Poretti A, Huisman TA. Susceptibility-weighted imaging in pediatric neuroimaging. J Magn Reson Imaging. 2014;40(3):530–44.

    Article  PubMed  Google Scholar 

  21. Poretti A, Denecke J, Miller DC, et al. Brainstem disconnection: two additional patients and expansion of the phenotype. Neuropediatrics. 2015;46(2):139–44.

    Article  PubMed  Google Scholar 

  22. Jurkiewicz E, Dobrzańska A, Nowak K, et al. MRI findings in the young infant with brainstem disconnection and extracerebral features. Report of one case and review of the literature. Brain Dev. 2010;32(6):495–8.

    Article  PubMed  Google Scholar 

  23. DuffieldC, Jocson J, Wootton-Gorges SL. Brainstem disconnection. Pediatr Radiol. 2009;39(12):1357–60.

    Article  Google Scholar 

  24. Barth PG, de Vries LS, Nikkels PG, et al. Congenital brainstem disconnection associated with a syrinx of the brainstem. Neuropediatrics. 2008;39(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  25. ∙ Ishak GE, Dempsey JC, Shaw DW, et al. Rhombencephalosynapsis: a hindbrain malformation associated with incomplete separation of midbrain and forebrain, hydrocephalus and a broad spectrum of severity. Brain. 2012;135(Pt 5):1370–86. This is an important reference in that it clarifies the presentations of rhomboencephalosynapsis, which is still underdiagnosed.

  26. Whitehead MT, Choudhri AF, Grimm J, et al. Rhombencephalosynapsis as a cause of aqueductal stenosis: an under-recognized association in hydrocephalic children. Pediatr Radiol. 2014;44(7):849–56.

    Article  PubMed  Google Scholar 

  27. ∙ Poretti A, Boltshauser E. Fetal diagnosis of rhombencephalosynapsis. Neuropediatrics. 2015;46(6):357–8. This is an important demonstration of the fetal diagnosis of atypical presentation of rhomboencephalosynapsis early in gestation.

  28. Demurger F, Pasquier L, Dubourg C, et al. Array-CGH analysis suggests genetic heterogeneity in rhombencephalosynapsis. Mol Syndromol. 2013;4(6):267–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. de Mattos VF, Graziadio C, Machado Rosa RF, et al. Gomez-Lopez-Hernandez syndrome in a child born to consanguineous parents: new evidence for an autosomal-recessive pattern of inheritance? Pediatr Neurol. 2014;50(6):612–5.

    Article  PubMed  Google Scholar 

  30. Parisi MA, Dobyns WB. Human malformations of the midbrain and hindbrain: review and proposed classification scheme. Mol Genet Metab. 2003;80(1–2):36–53.

    Article  CAS  PubMed  Google Scholar 

  31. Alexiou GA, Sfakianos G, Prodromou N. Dandy-Walker malformation: analysis of 19 cases. J Child Neurol. 2010;25(2):188–91.

    Article  PubMed  Google Scholar 

  32. Bokhari I, Rehman L, Hassan S, et al. Dandy-Walker malformation: a clinical and surgical outcome analysis. J Coll Physicians Surg Pak. 2015;25(6):431–3.

    PubMed  Google Scholar 

  33. Aldinger KA, Lehmann OJ, Hudgins L, et al. FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation. Nat Genet. 2009;41(9):1037–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Reeder MR, Botto LD, Keppler-Noreuil KM, et al. Risk factors for Dandy-Walker malformation: a population-based assessment. Am J Med Genet A. 2015;9(16):1.

    Google Scholar 

  35. Zhang XB, Gu YQ, Sun XF, et al. Dandy-Walker complex: a clinicopathologic study of 9 cases. Zhonghua Bing Li Xue Za Zhi. 2013;42(12):815–8.

    PubMed  Google Scholar 

  36. Mimaki M, Shiihara T, Watanabe M, et al. Holoprosencephaly with cerebellar vermis hypoplasia in 13q deletion syndrome: critical region for cerebellar dysgenesis within 13q32.2q34. Brain Dev. 2015;37(7):714–8.

    Article  PubMed  Google Scholar 

  37. Alp MY, Çebi AH, Seyhan S, et al. 22.5 MB Deletion of 13q31.1-q34 associated with HPE, DWM, and HSCR: a case report and redefining the smallest deleted regions. Genet Couns. 2016;27(1):43–9.

    CAS  PubMed  Google Scholar 

  38. Peltekova IT, Hurteau-Millar J, Armour CM. Novel interstitial deletion of 10q24.3-25.1 associated with multiple congenital anomalies including lobar holoprosencephaly, cleft lip and palate, and hypoplastic kidneys. Am J Med Genet A. 2014;12(6):24.

    Google Scholar 

  39. Grinberg I, Northrup H, Ardinger H, et al. Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation. Nat Genet. 2004;36(10):1053–5.

    Article  CAS  PubMed  Google Scholar 

  40. Haldipur P, Gillies GS, Janson OK, et al. Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth. Elife. 2014;16(3):03962.

    Google Scholar 

  41. Wakeling EL, Jolly M, Fisk NM, et al. X-linked inheritance of Dandy-Walker variant. Clin Dysmorphol. 2002;11(1):15–8.

    Article  PubMed  Google Scholar 

  42. Parisi MA. Clinical and molecular features of Joubert syndrome and related disorders. Am J Med Genet C. Semin Med Genet. 2009;15(4):326–40.

    Article  Google Scholar 

  43. Badano JL, Mitsuma N, Beales PL, et al. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genom Hum Genet. 2006;7:125–48.

    Article  CAS  Google Scholar 

  44. Briguglio M, Pinelli L, Giordano L, et al. Pontine tegmental cap dysplasia: developmental and cognitive outcome in three adolescent patients. Orphanet J Rare Dis. 2011;6(36):1750–72.

    Google Scholar 

  45. Bachmann-Gagescu R, Dempsey JC, Phelps IG, et al. Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. J Med Genet. 2015;52(8):514–22.

    Article  CAS  PubMed  Google Scholar 

  46. Suzuki T, Miyake N, Tsurusaki Y, et al. Molecular genetic analysis of 30 families with Joubert syndrome. Clin Genet. 2016;19(10):12836.

    Google Scholar 

  47. Ben-Salem S, Al-Shamsi AM, Gleeson JG, et al. Mutation spectrum of Joubert syndrome and related disorders among Arabs. Hum Genome Var. 2014;1:14020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Poretti A, Huisman TA, Scheer I, et al. Joubert syndrome and related disorders: spectrum of neuroimaging findings in 75 patients. AJNR Am J Neuroradiol. 2011;32(8):1459–63.

    Article  CAS  PubMed  Google Scholar 

  49. Poretti A, Meoded A, Rossi A, et al. Diffusion tensor imaging in Joubert syndrome. AJNR Am J Neuroradiol. 2007;28(10):1929–33.

    Article  CAS  PubMed  Google Scholar 

  50. Jissendi-Tchofo P, Doherty D, McGillivray G, et al. Pontine tegmental cap dysplasia: MR imaging and diffusion tensor imaging features of impaired axonal navigation. AJNR. 2009;30(1):113–9.

    Article  CAS  PubMed  Google Scholar 

  51. Caan M, Barth PG, Niermeijer JM, et al. Ectopic peripontine arcuate fibres, a novel finding in pontine tegmental cap dysplasia. Eur J Paediatr Neurol. 2014;18(3):434–8.

    Article  PubMed  Google Scholar 

  52. Barth PG, Majoie CB, Caan MW, et al. Pontine tegmental cap dysplasia: a novel brain malformation with a defect in axonal guidance. Brain. 2007;130(Pt 9):2258–66.

    Article  PubMed  Google Scholar 

  53. Singh D, Hsu CC, Kwan GN, et al. Pontine tegmental cap dysplasia: MR evaluation of vestibulocochlear neuropathy. J Neuroimaging. 2015;25(6):1038–43.

    Article  PubMed  Google Scholar 

  54. Nixon JN, Dempsey JC, Doherty D, et al. Temporal bone and cranial nerve findings in pontine tegmental cap dysplasia. Neuroradiology. 2016;58(2):179–87.

    Article  PubMed  Google Scholar 

  55. Clement E, Mercuri E, Godfrey C, et al. Brain involvement in muscular dystrophies with defective dystroglycan glycosylation. Ann Neurol. 2008;64(5):573–82.

    Article  CAS  PubMed  Google Scholar 

  56. Barth PG. Pontocerebellar hypoplasias. An overview of a group of inherited neurodegenerative disorders with fetal onset. Brain Dev. 1993;15(6):411–22.

    Article  CAS  PubMed  Google Scholar 

  57. Tentler D, Leisti J, Schueler M, et al. Deletion including the oligophrenin-1 gene associated with enlarged cerebral ventricles, cerebellar hypoplasia, seizures and ataxia. Eur J Hum Genet. 1999;7(5):541–8.

    Article  CAS  PubMed  Google Scholar 

  58. Vermeulen RJ, Peeters-Scholte C, Van Vugt JJ, et al. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. Neuropediatrics. 2011;42(1):1–3.

    Article  CAS  PubMed  Google Scholar 

  59. Siegel DH, Tefft KA, Kelly T, et al. Stroke in children with posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities (PHACE) syndrome: a systematic review of the literature. Stroke. 2012;43(6):1672–4.

    Article  PubMed  Google Scholar 

  60. Hess CP, Fullerton HJ, Metry DW, et al. Cervical and intracranial arterial anomalies in 70 patients with PHACE syndrome. AJNR. 2010;31(10):1980–6.

    Article  CAS  PubMed  Google Scholar 

  61. Millen KJ, Steshina EY, Iskusnykh IY, et al. Transformation of the cerebellum into more ventral brainstem fates causes cerebellar agenesis in the absence of Ptf1a function. Proc Natl Acad Sci USA. 2014;111(17):14.

    Article  Google Scholar 

  62. Aldinger KA, Mendelsohn NJ, Chung BH, et al. Variable brain phenotype primarily affects the brainstem and cerebellum in patients with osteogenesis imperfecta caused by recessive WNT1 mutations. J Med Genet. 2016;53(6):427–30.

    Article  PubMed  Google Scholar 

  63. Mester J, Eng C. When overgrowth bumps into cancer: the PTEN-opathies. Am J Med Genet C. 2013;2:114–21.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Pittsburgh Children’s Hospital, The University of Pittsburgh, Pittsburgh, PA, USA

    Rawad Obeid

  2. Department of Neurology, Children’s National Medical Center, The George Washington University of the Health Sciences, 111 Michigan Avenue, N.W., Washington, DC, 20010, USA

    Rawad Obeid & Andrea L. Gropman

Authors
  1. Rawad Obeid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea L. Gropman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrea L. Gropman.

Ethics declarations

Disclosure

Amali Mallawaarachchi and Felicity Collins declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical collection on Genetics.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Obeid, R., Gropman, A.L. The New Findings in the Genetics and Pathology of Structural Brain Diseases. Curr Pediatr Rep 4, 164–172 (2016). https://doi.org/10.1007/s40124-016-0112-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40124-016-0112-5

Keywords

Search

Navigation