Haploinsufficiency of PRRT2 Leading to Familial Hemiplegic Migraine in Chromosome 16p11.2 Deletion Syndrome

Abstract

Microdeletion in the 16p11.2 loci lead to a distinct neurodevelopmental disorder with intellectual disability and autism spectrum disorder in addition to dysmorphia, macrocephaly, and increased body mass index. One of the deleted genes in this region is PRRT2 which codes for proline-rich transmembrane protein 2. Heterozygous variants in PRRT2 cause four distinct neurological disorders including benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia (PKD), PKD with infantile convulsions, and familial hemiplegic migraine (FHM). A 13-year-old male with a known history of 16p11.2 deletion and resultant cognitive delay presented with sudden onset of headache, left-sided weakness, facial droop, and aphasia concerning for acute ischemic stroke. Magnetic resonance imaging of the brain was performed urgently which did not reveal any acute processes and his presentation met criteria for hemiplegic migraine. There have been reports of PKD and BFIE in this microdeletion syndrome; however, our proband is the first case that presented with FHM related to haploinsufficiency of PRRT2. This report highlights the importance of counseling patient families regarding acute paroxysmal presentations in this syndrome.

Keywords

chromosome 16p11.2 deletion - PRRT2 - familial hemiplegic migraine

Publication History

Received: 24 February 2022

Accepted: 24 May 2022

Accepted Manuscript online:
26 May 2022

Article published online:
17 July 2022

• References

• 1 Hanson E, Nasir RH, Fong A. et al; 16p11.2 Study Group Clinicians. Cognitive and behavioral characterization of 16p11.2 deletion syndrome. J Dev Behav Pediatr 2010; 31 (08) 649-657
• 2 Rein B, Yan Z. 16p11.2 copy number variations and neurodevelopmental disorders. Trends Neurosci 2020; 43 (11) 886-901
• 3 Ebrahimi-Fakhari D, Moufawad El Achkar C, Klein C. PRRT2-Associated Paroxysmal Movement Disorders. January 11, 2018. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A. ed. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993. –2021
• 4 Vgontzas A, Burch R. Episodic migraine with and without aura: key differences and implications for pathophysiology, management, and assessing risks. Curr Pain Headache Rep 2018; 22 (12) 78
• 5 Gillentine MA, Lupo PJ, Stankiewicz P, Schaaf CP. An estimation of the prevalence of genomic disorders using chromosomal microarray data. J Hum Genet 2018; 63 (07) 795-801
• 6 Walters RG, Jacquemont S, Valsesia A. et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 2010; 463 (7281): 671-675
• 7 Taylor CM, Smith R, Lehman C. et al. 16p11.2 Recurrent Deletion. September 22, 2009 [updated October 28, 2021]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A. ed. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993. –2021
• 8 Chung WK, Roberts TP, Sherr EH, Snyder LG, Spiro JE. 16p11.2 deletion syndrome. Curr Opin Genet Dev 2021; 68: 49-56
• 9 Qureshi AY, Mueller S, Snyder AZ. et al; Simons VIP Consortium. Opposing brain differences in 16p11.2 deletion and duplication carriers. J Neurosci 2014; 34 (34) 11199-11211
• 10 Fruscione F, Valente P, Sterlini B. et al. PRRT2 controls neuronal excitability by negatively modulating Na+ channel 1.2/1.6 activity. Brain 2018; 141 (04) 1000-1016
• 11 Ebrahimi-Fakhari D, Saffari A, Westenberger A, Klein C. The evolving spectrum of PRRT2-associated paroxysmal diseases. Brain 2015; 138 (Pt 12): 3476-3495
• 12 Lipton J, Rivkin MJ. 16p11.2-related paroxysmal kinesigenic dyskinesia and dopa-responsive parkinsonism in a child. Neurology 2009; 73 (06) 479-480
• 13 Dale RC, Grattan-Smith P, Fung VS, Peters GB. Infantile convulsions and paroxysmal kinesigenic dyskinesia with 16p11.2 microdeletion. Neurology 2011; 77 (14) 1401-1402
• 14 Termsarasab P, Yang AC, Reiner J, Mei H, Scott SA, Frucht SJ. Paroxysmal kinesigenic dyskinesia caused by 16p11.2 microdeletion. Tremor Other Hyperkinet Mov (N Y) 2014; 4: 274
• 15 Vlaskamp DRM, Callenbach PMC, Rump P. et al. PRRT2-related phenotypes in patients with a 16p11.2 deletion. Eur J Med Genet 2019; 62 (04) 265-269