Objective:

To report a case of recurrent hyperventilation apnea spells in an adolescent female with TCF4+ Pitt Hopkins Syndrome, focusing on the evolving insights into its pathophysiology and the established and investigational treatment strategies. 

Background:

Pitt-Hopkins syndrome (PTHS) is a rare multisystem disorder caused by variants of transcription factor 4 (TCF4) gene, which plays a crucial role in nervous system development. Our patient, a 15 year old female with Pitt-Hopkins syndrome presented with intractable focal epilepsy, disordered respiratory control, severe language delay, intellectual disability and autism spectrum disorder. Shortly after menarche, she experienced worsening hyperventilation-apnea spells (HVAS), occurring every 2-5 minutes for over 24 hours. During these spells, there was no loss of consciousness and she became deeply cyanotic with oxygen saturation as low as 10%, prompting ICU admission. Video-EEG monitoring showed physiologic bifrontal slowing during her spells. After receiving a single dose of IV acetazolamide, her events stopped immediately. Seven months later, her HVAS remain well controlled on daily oral acetazolamide. 

Design/Methods:

NA

Results:

NA

Conclusions:

There are several suspected mechanisms underlying PTHS, each with a promising therapeutic approach. Carbonic anhydrase inhibitors like acetazolamide have demonstrated clinical effectiveness in preventing HVAS, likely through blood acidification and direct action on the chemoreceptors in the retrotrapezoid nucleus (RTN), the primary respiratory drive center. In TCF4 knockout mice, diffuse hypomyelination occurs due to incomplete oligodendrocyte precursor cell (OPC) differentiation. These mice show reduced hyperventilation and improved behavior after administration of promyelinating drugs such as clemastine and sobetirome. Additionally, voltage gated sodium channel NaV1.8 has been shown to be abnormally expressed in the RTN in PTHS mouse models, suggesting that blockade of these channels may offer a therapeutic benefit. Lastly, other novel therapeutic options include vorinostat (chaperone for mRNA folding), trofinetide (IGF-1 analogue), MZ-1866 (recombinant AAV9 vector with TCF4 trasngene), and recurrent stem cell transplants.