Mary and Neveah Taouk were both born with a mutation in the gene known as PGAP1, a recently discovered disorder so rare it has no name. The family know of no other cases in Australia. Specialists have identified perhaps a dozen cases around the world.
What the data actually tells us about PGAP1-CDG (congenital disorder of glycosylation) is that it represents a distinct challenge in medical science. Defects in maturation of the GPI glycan following attachment to proteins cause inherited GPI deficiency, with consequences including neurologic symptoms, particularly developmental delay and intellectual disability, seizures, epileptic encephalopathy, progressive cerebral and cerebellar atrophy, hypotonia, and cortical visual impairment. The sisters experience most of these manifestations.
For the first six months of her life, Mary seemed like a healthy little girl. Charlie and Mira first suspected something was wrong when she started missing developmental milestones. The Taouks wish eight-year-old Mary and four-year-old Neveah could stand and walk without help. They dream their girls might one day learn to communicate with basic gestures. "At least then they could point to where their pain is," Charlie says. "If they were hungry or thirsty or tired, they could let us know and we could help." Seizures regularly rack their girls' bodies in the small hours.
For years, there was no help. Because the condition was ultra-rare with fewer than 10 cases in the world, there was little to no information about it, and that meant there was no help or treatment for them. The Taouk family faced the grim reality that applies to many such disorders: most congenital disorders of glycosylation remain difficult to treat. While the identification and diagnosis of congenital disorders of glycosylation have rapidly progressed, the available treatment options are still quite limited, and mostly, we are only able to manage the disease symptoms rather than to address the underlying cause.
What changed for this family was a chance connection. They were introduced to University of Sydney researcher Dr Wendy Gold, who specialises in ultra-rare disorders and works with experts in gene therapy. With help from their family, Charlie and Mira have donated $315,000 to fund research to develop the world's first gene therapy for the PGAP1 mutation. The donation from the Taouk family will fund two years of research.
Within two years, the researchers hope to develop a PGAP1 gene addition ready for testing, initially in cells outside the body. It will take longer to investigate the feasibility of a therapy for use inside the human body, so the crowdfunded support is crucial. Gene therapy represents the frontier of treatment for CDG, and recent years have brought about remarkable advances in treatment approaches for some CDG. Innovative therapies, targeting both the root cause and resulting manifestations, have transitioned from the research stage to practical application.
The clinical reality is sobering. It is important to note that CDG are congenital, therefore not all the symptoms can be reversed with a therapy. The defects related to processes with a limited prenatal development window such as impaired brain development will not improve upon treatment. In contrast, ongoing metabolic processes, such as bone growth, might benefit from a therapy. This means that even if gene therapy succeeds, some of the girls' developmental delays may be permanent. What it might offer is halting progression of symptoms and improving quality of life.
The research journey ahead is long and uncertain. Success is not guaranteed. Yet for Mary and Neveah, this pathway represents hope where none existed before. Their parents have made a calculated choice to invest in the possibility of a treatment the world has never seen, knowing that the alternative is watching a managed decline they cannot stop.