Luka inherited an X-linked missense mutation that results in a loss-of-function defect in ATP6AP2, an essential assembly factor of the vacuolar H+-ATPase (V-ATPase) complex, also known as the proton pump. This complex plays a crucial role in regulating intracellular pH, enabling protein synthesis, degradation, and elimination across multiple biological pathways. While this mutation has been classified as a subset of Congenital Disorders of Glycosylation (CDG), it also falls within a broader category of V-ATPase-related defects, linking it to lysosomal storage disorders (LSDs) and neurological conditions.

When Luka was diagnosed in December 2021, we were stunned to learn that there were only four known patients in the world with this disease.

A few months later, in collaboration with GeneDx, we identified 15 additional potential ATP6AP2 patients, along with 19 ATP6AP1 patients—ATP6AP1 being a closely related “sister mutation.”

Suddenly, instead of just 1 patient, we had around 30 patients, but we knew this was just the beginning. There are other V-ATPase-related disorders involving assembly factors and subunits of the proton pump that could greatly benefit from being included in our research. These include ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2, and ATP6V0D1—bringing the estimated patient count to around 150 individuals.

To expand our reach, we can establish targeted patient acquisition channels by leveraging:

• Phenotypic screening to identify undiagnosed cases

• Search engine and social media data to enhance patient discovery

• Outreach to specialists who frequently encounter these conditions and can refer potential patients to our study

But this goes even further. There are 16 subsets of CDGs that are impaired by acidification defects, including those affecting Golgi homeostasis. This expands our potential patient population to an estimated 70,000 individuals.

Identifying common phenotypic patterns across adjacent mutations would broaden our target disease population—not just for research but also for therapeutic development.

And defective proton pump function isn’t just linked to CDGs—it also drives Lysosomal Storage Disorders (LSDs). Both categories share a root cause: enzyme dysfunction and/or acidification defects. Now, we're talking about a patient population of at least 150,000 individuals.

By redefining subsets of LSDs and CDGs based on overlapping deficiencies, we can pinpoint “enzyme deficiencies” driven by acidification defects—allowing us to develop a truly targeted therapeutic approach for these conditions.