Genetic phenocopies of cerebral palsy: a review
https://doi.org/10.46563/2686-8997-2021-2-1-51-58
Abstract
Cerebral palsy (CP) represents a heterogeneous group of non-progressive disorders of motor development and posture control, leading to activity limitation due to disturbances in a fetal or infant’s developing brain. In CP, motor impairment is often accompanied by disturbances of sensation, cognition, communication, perception, and (or) behavior, and (or) by a seizure disorder. Despite profound knowledge of the CP risk factors, in many patients, the latter cannot be identified, and the neuroimaging features of the brain injury may also be absent. Those patients, at least in part, can include children with undiagnosed genetic phenocopies of the CP.
Literature search was performed using Scopus, Web of Science, PubMed (MEDLINE), and eLibrary databases. In the review, we briefly touch upon the current understanding of CP’s risk factors and pathophysiology. Common neuroimaging findings typical for CP subtypes are presented. We then discuss the role of genetic factors that can lead to the development of CP phenocopies, briefly describing their phenotypic subtypes and some of the specific diseases. Clinical and neuroimaging «red flags» that can prompt a diagnostic search for genetic disorders are reviewed. The role of modern genetic testing techniques, including high-throughput sequencing, in diagnosing CP phenocopies is described. We present a general diagnostic approach to suspected genetic CP phenocopies. Early identification of the pediatric population’s genetic conditions can affect the individual and family prognosis and the patient’s management.
About the Authors
Yury A. Seliverstov
Research Center of Neurology
Russian Federation
Russian Federation
MD., Ph.D., neurologist and researcher in the Research Center of Neurology, Moscow, 125367, Russian Federation.
e-mail: doctor.goody@gmail.com
Artem A. Sharkov
Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University; Genomed Ltd
Russian Federation
Russian Federation
References
1. Bax M., Goldstein M., Rosenbaum P., Leviton A., Paneth N., Dan B., et al. Proposed definition and classification of cerebral palsy, April 2005. Dev. Med. Child Neurol. 2005; 47(8): 571-6. https://doi.org/10.1017/S001216220500112X
2. Wimalasundera N., Stevenson V.L. Cerebral palsy. Pract. Neurol. 2016; 16(3): 184-94. https://doi.org/10.1136/practneurol-2015-001184
3. Carlo W.A., McDonald S.A., Tyson J.E., Stoll B.J., Ehrenkranz R.A., Shankaran S., et al. Cytokines and neurodevelopmental outcomes in extremely low birth weight infants. J. Pediatr. 2011; 159(6): 919-25.e3. https://doi.org/10.1016/j.jpeds.2011.05.042
4. Korzeniewski S.J., Slaughter J., Lenski M., Haak P., Paneth N. The complex aetiology of cerebral palsy. Nat. Rev. Neurol. 2018; 14(9): 528-43. https://doi.org/10.1038/s41582-018-0043-6
5. Novak I., Morgan C., Adde L., Blackman J., Boyd R.N., Brunstrom-Hernandez J., et al. Early, accurate diagnosis and early intervention in cerebral palsy: advances in diagnosis and treatment. JAMA Pediatr. 2017; 171(9): 897-907. https://doi.org/10.1001/jamapediatrics.2017.1689
6. O’Shea T.M. Diagnosis, treatment, and prevention of cerebral palsy. Clin. Obstet. Gynecol. 2008; 51(4): 816-28. https://doi.org/10.1097/GRF.0b013e3181870ba7
7. Cans C. Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers. Dev. Med. Child Neurol. 2000; 42(12): 816-24. https://doi.org/10.1111/j.1469-8749.2000.tb00695.x
8. Rosenbaum P.L., Palisano R.J., Bartlett D.J., Galuppi B.E., Russell D.J. Development of the Gross Motor Function Classification System for cerebral palsy. Dev. Med. Child Neurol. 2008; 50(4): 249-53. https://doi.org/10.1111/j.1469-8749.2008.02045.x
9. Eliasson A.C., Krumlinde-Sundholm L., Rösblad B., Beckung E., Arner M., Öhrvall A.M., et al. The Manual Ability Classification System (MACS) for children with cerebral palsy: scale development and evidence of validity and reliability. Dev. Med. Child Neurol. 2006; 48(7): 549-54. https://doi.org/10.1111/j.1469-8749.2006.tb01313.x
10. Mcintyre S., Taitz D., Keogh J., Goldsmith S., Badawi N., Blair E. A systematic review of risk factors for cerebral palsy in children born at term in developed countries. Dev. Med. Child Neurol. 2013; 55(6): 499-508. https://doi.org/10.1111/dmcn.12017
11. Blair E., Stanley F.J. Intrapartum asphyxia: A rare cause of cerebral palsy. J. Pediatr. 1988; 112(4): 515-9. https://doi.org/10.1016/S0022-3476(88)80161-6
12. Prevalence and characteristics of children with cerebral palsy in Europe. Dev. Med. Child Neurol. 2002; 44(9): 633-40. https://doi.org/10.1111/j.1469-8749.2002.tb00848.x
13. Reid S.M., Dagia C.D., Ditchfield M.R., Carlin J.B., Reddihough D.S. Population-based studies of brain imaging patterns in cerebral palsy. Dev. Med. Child Neurol. 2014; 56(3): 222-32. https://doi.org/10.1111/dmcn.12228
14. Krägeloh-Mann I., Cans C. Cerebral palsy update. Brain Dev. 2009; 31(7): 537-44. https://doi.org/10.1016/j.braindev.2009.03.009
15. Ferriero D.M. The vulnerable newborn brain: imaging patterns of acquired perinatal injury. Neonatology. 2016; 109(4): 345-51. https://doi.org/10.1159/000444896
16. Fahey M.C., Maclennan A.H., Kretzschmar D., Gecz J., Kruer M.C. The genetic basis of cerebral palsy. Dev. Med. Child Neurol. 2017; 59(5): 462-9. https://doi.org/10.1111/dmcn.13363
17. Candy E.J., Hoon A.H., Capute A.J., Nick Bryan R. MRI in motor delay: Important adjunct to classification of cerebral palsy. Pediatr. Neurol. 1993; 9(6): 421-9. https://doi.org/10.1016/0887-8994(93)90020-D
18. Truwit C.L., Barkovich A.J., Koch T.K., Ferriero D.M. Cerebral palsy: MR findings in 40 patients. Am. J. Neuroradiol. 1992; 13(1): 67-78.
19. Rajab A., Yoo S.Y., Abdulgalil A., Kathiri S., Ahmed R., Mochida G.H., et al. An autosomal recessive form of spastic cerebral palsy (CP) with microcephaly and mental retardation. Am. J. Med. Genet. Part A. 2006; 140(14): 1504-10. https://doi.org/10.1002/ajmg.a.31288
20. Takezawa Y., Kikuchi A., Haginoya K., Niihori T., Numata-Uematsu Y., Inui T., et al. Genomic analysis identifies masqueraders of full-term cerebral palsy. Ann. Clin. Transl. Neurol. 2018; 5(5): 538-51. https://doi.org/10.1002/acn3.551
21. Parolin Schnekenberg R., Perkins E.M., Miller J.W., Davies W.I.L., D’Adamo M.C., Pessia M., et al. De novo point mutations in patients diagnosed with ataxic cerebral palsy. Brain. 2015; 138(Pt. 7): 1817-32. https://doi.org/10.1093/brain/awv117
22. McMichael G., Bainbridge M.N., Haan E., Corbett M., Gardner A., Thompson S., et al. Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy. Mol. Psychiatry. 2015; 20(2): 176-82. https://doi.org/10.1038/mp.2014.189
23. Jin S.C., Lewis S.A., Bakhtiari S., Zeng X., Sierant M.C., Shetty S., et al. Mutations disrupting neuritogenesis genes confer risk for cerebral palsy. Nat. Genet. 2020; 52(10): 1046-56. https://doi.org/10.1038/s41588-020-0695-1
24. Zech M., Jech R., Boesch S., Škorvánek M., Weber S., Wagner M., et al. Monogenic variants in dystonia: an exome-wide sequencing study. Lancet Neurol. 2020; 19(11): 908-18. https://doi.org/10.1016/S1474-4422(20)30312-4
25. Zouvelou V., Yubero D., Apostolakopoulou L., Kokkinou E., Bilanakis M., Dalivigka Z., et al. The genetic etiology in cerebral palsy mimics: The results from a Greek tertiary care center. Eur. J. Paediatr. Neurol. 2019; 23(3): 427-37. https://doi.org/10.1016/j.ejpn.2019.02.001
26. Parrini E., Conti V., Dobyns W.B., Guerrini R. Genetic basis of brain malformations. Mol. Syndromol. 2016; 7(4): 220-33. https://doi.org/10.1159/000448639
27. Guerrini R., Dobyns W.B. Malformations of cortical development: clinical features and genetic causes. Lancet Neurol. 2014; 13(7): 710-26. https://doi.org/10.1016/S1474-4422(14)70040-7
28. Rainier S., Sher C., Reish O., Thomas D., Fink J.K. De novo occurrence of novel SPG3A/Atlastin mutation presenting as cerebral palsy. Arch. Neurol. 2006; 63: 445-7. https://doi.org/10.1001/archneur.63.3.445
29. Cailloux F., Gauthier-Barichard F., Mimault C., Isabelle V., Courtois V., Giraud G., et al. Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Eur. J. Hum. Genet. 2000; 8(11): 837-45. https://doi.org/10.1038/sj.ejhg.5200537
30. Chandra S.R., Christopher R., Ramanujam C.N., Harikrishna G.V. Hyperargininemia experiences over last 7 years from a tertiary care center. J. Pediatr. Neurosci. 2019; 14(1): 2-6. https://doi.org/10.4103/jpn.JPN_1_19
31. Komur M., Okuyaz C., Ezgu F., Atici A. A girl with spastic tetraparesis associated with biotinidase deficiency. Eur. J. Paediatr. Neurol. 2011; 15(6): 551-3. https://doi.org/10.1016/j.ejpn.2011.04.012
32. Livne M., Gibson K.M., Amir N., Eshel G., Elpeleg O.N. Holocarboxylase synthetase deficiency: a treatable metabolic disorder masquerading as cerebral palsy. J. Child Neurol. 1994; 9(2): 170-2. https://doi.org/10.1177/088307389400900213
33. Brennenstuhl H., Jung-Klawitter S., Assmann B., Opladen T. Inherited disorders of neurotransmitters: classification and practical approaches for diagnosis and treatment. Neuropediatrics. 2018; 50(1): 2-14. https://doi.org/10.1055/s-0038-1673630
34. Pearson T.S., Pons R., Ghaoui R., Sue C.M. Genetic mimics of cerebral palsy. Mov. Disord. 2019; 34(5): 625-36. https://doi.org/10.1002/mds.27655
35. Peall K.J., Lumsden D., Kneen R., Madhu R., Peake D., Gibbon F., et al. Benign hereditary chorea related to NKX2.1: expansion of the genotypic and phenotypic spectrum. Dev. Med. Child Neurol. 2014; 56(7): 642-8. https://doi.org/10.1111/dmcn.12323
36. Chang F.C.F., Westenberger A., Dale R.C., Smith M., Pall H.S., Perez-Dueñas B., et al. Phenotypic insights into ADCY5-associated disease. Mov. Disord. 2016; 31(7): 1033-40. https://doi.org/10.1002/mds.26598
37. Jinnah H.A., Visser J.E., Harris J.C., Verdu A., Larovere L., Ceballos-Picot I., et al. Delineation of the motor disorder of Lesch-Nyhan disease. Brain. 2006; 129(Pt. 5): 1201-17. https://doi.org/10.1093/brain/awl056
38. Mukhin K.Yu., Kuz’mich G.V., Mironov M.B. Epilepsy with cerebral palsy in children: electro-clinical features and prognosis. Vestnik Rossiyskogo gosudarstvennogo meditsinskogo universiteta. 2011; (5): 37–41. (in Russian)
39. Scheffer I.E., Berkovic S., Capovilla G., Connolly M.B., French J., Guilhoto L., et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017; 58(4): 512-21. https://doi.org/10.1111/epi.13709
40. Mirzaa G.M., Paciorkowski A.R., Marsh E.D., Berry-Kravis E.M., Medne L., Grix A., et al. CDKL5 and ARX mutations in males with early-onset epilepsy. Pediatr. Neurol. 2013; 48(5): 367-77. https://doi.org/10.1016/j.pediatrneurol.2012.12.030
41. Pearson T.S., Akman C., Hinton V.J., Engelstad K., De Vivo D.C. Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS). Curr. Neurol. Neurosci. Rep. 2013; 13(4): 342. https://doi.org/10.1007/s11910-013-0342-7
42. Levy A., Lang A.E. Ataxia-telangiectasia: A review of movement disorders, clinical features, and genotype correlations. Mov. Disord. 2018; 33(8): 1238-47. https://doi.org/10.1002/mds.27319
43. da Graça F.F., de Rezende T.J.R., Vasconcellos L.F.R., Pedroso J.L., Barsottini O.G.P., França M.C. Neuroimaging in hereditary spastic paraplegias: current use and future perspectives. Front. Neurol. 2019; 9: 1117.
44. Al-Hashim A.H., Blaser S., Raybaud C., MacGregor D. Corpus callosum abnormalities: neuroradiological and clinical correlations. Dev. Med. Child Neurol. 2016; 58(5): 475-84. https://doi.org/10.1111/dmcn.12978
45. McIntyre S., Blair E., Goldsmith S., Badawi N., Gibson C., Scott H., et al. Congenital anomalies in cerebral palsy: where to from here? Dev. Med. Child Neurol. 2016; 58(Suppl. 2): 71-5. https://doi.org/10.1111/dmcn.13015
46. Segel R., Ben-Pazi H., Zeligson S., Fatal-Valevski A., Aran A., Gross-Tsur V., et al. Copy number variations in cryptogenic cerebral palsy. Neurology. 2015; 84(16): 1660-8. https://doi.org/10.1212/WNL.0000000000001494
47. Oskoui M., Gazzellone M.J., Thiruvahindrapuram B., Zarrei M., Andersen J., Wei J., et al. Clinically relevant copy number variations detected in cerebral palsy. Nat. Commun. 2015; 6: 7949. https://doi.org/10.1038/ncomms8949
48. Zarrei M., Fehlings D.L., Mawjee K., Switzer L., Thiruvahindrapuram B., Walker S., et al. De novo and rare inherited copy-number variations in the hemiplegic form of cerebral palsy. Genet. Med. 2018; 20(2): 172-80. https://doi.org/10.1038/gim.2017.83
49. McMichael G., Girirajan S., Moreno-De-Luca A., Gecz J., Shard C., Nguyen L.S., et al. Rare copy number variation in cerebral palsy. Eur. J. Hum. Genet. 2014; 22(1): 40-5. https://doi.org/10.1038/ejhg.2013.93
50. Corbett M.A., van Eyk C.L., Webber D.L., Bent S.J., Newman M., Harper K., et al. Pathogenic copy number variants that affect gene expression contribute to genomic burden in cerebral palsy. NPJ Genom. Med. 2018; 3: 33. https://doi.org/10.1038/s41525-018-0073-4
51. Splinter K., Adams D.R., Bacino C.A., Bellen H.J., Bernstein J.A., Cheatle-Jarvela A.M., et al. Effect of genetic diagnosis on patients with previously undiagnosed disease. N. Engl. J. Med. 2018; 379(22): 2131-9. https://doi.org/10.1056/NEJMoa1714458
Review
For citations:
Seliverstov Yu.A., Sharkov A.A. Genetic phenocopies of cerebral palsy: a review. L.O. Badalyan Neurological Journal. 2021;2(1):51-58. (In Russ.) https://doi.org/10.46563/2686-8997-2021-2-1-51-58
Views:
1299
Email this article 
