<span class="center-menu">← <small>PREVIOUS: [[3. Etiology and Contributing Factors]]</small> | <small>NEXT: [[3.2. Viral Infections and Autoimmune mechanisms]]</small> →</span> -------- ##### Summary >[!Summary] >**Familal Patterns** >- family history of similar complaints: 25%[[#^1]][[#^2]] ; 12.5%[[#^3]][[#^03]] >- patients without an antecedent viral infection are more likely to have a family history of similar complaints[[#^5]] > >**Genetical Factors** >- genetic abnormality has been identified with hyperadrenergic POTS: single point mutation causing loss of function in norepinephrine transporter (NET) - resultant diminished norepinephrine clearance leads to hyperadrenergic state in response to sympathetic nerve activation[[#^4]] >- a search for single-nucleotide polymorphisms in the SLC6A2 gene encoding the norepinephrine transporter (NET) failed to demonstrate pathogenic variants in patients with POTS, but the expression of NET on the cell membrane is dependent on phosphorylation and glycosylation, indicating that other genes or epigenetic modification may contribute to hyperadrenergic POTS[[#^6]] -------- >_“25% have a family history of similar complaints”_ <small>([[Benarroch-2012]], [p. 1](zotero://open-pdf/library/items/WEZLT9QC?page=1&annotation=AIHGKDDN))</small>^1 >*“Twenty-seven patients (25%) had a family history of orthostatic intolerance.” *<small>([[Sandroni-1999]], [p. 2](zotero://open-pdf/library/items/X25GXI7E?page=2&annotation=VDFFR2EU))</small>^2 >*“12.5% had a family history of orthostatic intolerance” *<small>([[Thieben-2007]], [p. 3](zotero://open-pdf/library/items/5WXWEQWX?page=3&annotation=BS9PU3GQ))</small>^3 >*“The increased prevalence of POTS among family members suggests a genetic predisposition. With 1 notable exception of a particular mutation causing POTS in members of a single family,37 no evidence supports a monogenic cause of POTS.”* <small>([[Raj-2022]], [p. 3](zotero://open-pdf/library/items/YN8BG2FZ?page=3&annotation=YDIJTU97))</small> #new >![[Thieben-2007-3-x308-y75.png#invert_B| 500]] ><small>([[Thieben-2007]], [p. 3](zotero://open-pdf/library/items/5WXWEQWX?page=3&annotation=GTHC9YR2))</small>^3 >*“patients without an antecedent viral infection were more likely to have a family history of similar complaints” *<small>([[Sandroni-1999]], [p. 5](zotero://open-pdf/library/items/X25GXI7E?page=5&annotation=R38Z6X2I))</small>^5 ##### [[5.1. Hyperadrenergic POTS | Hyperadrenergic POTS]] >*“A specific genetic abnormality has been identified in a kindred with hyperadrenergic POTS [11]. These individuals have a single point mutation causing loss of function in the *<small>([p. 3](zotero://open-pdf/library/items/CCJLQKRB?page=3&annotation=EQHDZFR3))</small> *norepinephrine transporter (NET). The resultant diminished norepinephrine clearance leads to a hyperadrenergic state in response sympathetic nerve activation.” *<small>([[Raj-2013]], [p. 4](zotero://open-pdf/library/items/CCJLQKRB?page=4&annotation=LR9PWBE2))</small>^4 >*“A search for single-nucleotide polymorphisms in the SLC6A2 gene encoding the norepinephrine transporter (NET) failed to demonstrate pathogenic variants in patients with POTS,45 but the expression of NET on the cell membrane is dependent on phosphorylation and glycosylation, indicating that other genes or epigenetic modification may contribute to hyperadrenergic POTS.”* <small>([[Wells-2017]], [p. 6](zotero://open-pdf/library/items/HLELIN7I?page=6&annotation=T8JV5LZ2))</small>^6